US 5,733,924 AGrant
DC 107 Derivatives and Treatment Methods
Issue Date:1998-03-31
•14 Claims
Abstract
DC107 derivatives represented by the formula (I): ##STR1## or pharmacologically acceptable slats thereof, wherein R.sup.1 is hydrogen, lower alkoxyalkyl, aralkyloxyalkyl, lower alkoxyalkoxyalkyl, lower alkoxyalkoxyalkoxyalkyl, aralkyl, tetrahydropyranyl, COR.sup.4 or the like; R.sup.2 represents hydrogen or COR.sup.5 ; R.sup.3 represents lower alkyl, lower alkenyl, aralkyl which may be substituted with substituted or unsubstituted aryl, lower alkoxyalkyl, aralkyloxyalkyl, substituted or unsubstituted aryloxyalkyl, lower alkoxycarbonylalkyl, lower alkanoyloxyalkyl, alicyclic alkanoyloxyalkyl or the like, or bonds to Y to represent a single bond; Y bonds to R.sup.3 to represent a single bond, or bonds to Z to represent a single bond; Z represents hydrogen or bonds to Y to represent a single bond; W represents oxygen or NR.sup.6, with the proviso that the compound wherein R.sup.1, R.sup.2 and Z each represents hydrogen, R.sup.3 bonds to Y to represent a single bond, and W represents oxygen (DC107) is excluded.!
Metadata
Assignee
- Kyowa Hakko Kogyo Co., Ltd.
Inventors
- Yutaka Kanda
- Yutaka Saitoh
- Hiromitsu Saito
- Tadashi Ashizawa
- Kazuyo Sugiyama
- Katsushige Gomi
- Shingo Kakita
- Yuichi Takahashi
- Chikara Murakata
Application Information
Application Number:US 7769385
Filing Date:1997-04-17
Priority Date:1995-06-16
Art Unit:189
Classifications
IPC:
A61K 3700
Field of Search:
540549514450;451;467;471;472;473;476;477;4821;9;101;23;183;430;431;461;471;473;478;480
Patent Drawings
This patent does not have any drawings.
Description
TECHNICAL FIELD
This invention relates to novel DC107 derivatives having an antibacterial activity and an antitumor activity.
BACKGROUND ART
DC107 (leinamycin) is a compound produced by a microorganism belonging to the genus Streptomyces and disclosed in Japanese Published Unexamined Patent Application No. 112988/89. DC107 exhibits an antibacterial activity against various bacteria and also an antitumor activity and has a chemical structure represented by the formula (I) described below wherein R.sup.1, R.sup.2 and Z each represents a hydrogen atom, R.sup.3 bonds to Y to represent a single bond, and W represents an oxygen atom.
DISCLOSURE OF THE INVENTION
The present invention relates to the DC107 derivatives represented by the formula (I): ##STR2## or pharmacologically acceptable salts thereof, wherein R.sup.1 represents hydrogen, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, a lower alkoxyalkoxyalkoxyalkyl group, an aralkyl group, a tetrahydropyranyl group, ##STR3## {wherein Q.sup.1 represents CH.sub.2, O, S, SO, SO.sub.2 or N--Q.sup.3 (wherein Q.sup.3 represents a substituted or unsubstituted aryl group or a lower alkoxycarbonyl group), and Q.sup.2 represents a lower alkyl group}, COR.sup.4 wherein R.sup.4 represents an alkyl group, an alicyclic alkyl group, an aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a lower alkoxy group, an alicyclic alkoxy group, a 9-fluorenylmethoxy, an aralkyloxy group, a substituted or unsubstituted aryloxy group, (CH.sub.2).sub.m R.sup.4A <wherein m represents an integer of from 1 to 6, R.sup.4A represents hydroxy, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyloxy group, NR.sup.4B COR.sup.4C {wherein R.sup.4B represents hydrogen or a lower alkyl group, and R.sup.4C represents hydrogen, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group, a 9-fluorenylmethoxy group, (CH.sub.2).sub.n NHCOR.sup.4D (wherein n represents an integer of from 1 to 6, R.sup.4D represents an alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group or a 9-fluorenylmethyloxy group) or CHR.sup.4E NHCOR.sup.4F (wherein R.sup.4E represents a lower alkyl group or a hydroxy lower alkyl group, and R.sup.4F has the same meaning as R.sup.4D)}> or CHR.sup.4G NHCOR.sup.4H (wherein R.sup.4G has the same meaning as R.sup.4E, and R.sup.4H has the same meaning as R.sup.4C)!; R.sup.2 represents hydrogen or COR.sup.5 (wherein R.sup.5 represents a lower alkyl group, an aralkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group); R.sup.3 represents a lower alkyl group, a lower alkenyl group, a substituted or unsubstituted aralkyl group in which aryl may be substituted, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a substituted or unsubstituted aryloxyalkyl group, a lower alkoxycarbonylalkyl group, a lower alkanoyloxyalkyl group, an alicyclic alkanoyloxyalkyl group or ##STR4## or R.sup.3 bonds to Y to represent a single bond; Y bonds to R.sup.3 to represent a single bond or bonds to Z to represent a single bond; Z represents hydrogen or bonds to Y to represent a single bond; W represents oxygen or NR.sup.6 (wherein R.sup.6 represents a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, an aralkyloxy group, a substituted or unsubstituted arylsulfonylamino group or a lower alkoxycarbonylamino group), with the proviso that the compound wherein R.sup.1, R.sup.2 and Z each represents hydrogen, R.sup.3 bonds to Y to represent a single bond, and W represents oxygen (DC107) is excluded.
In the present invention, the compounds represented by the formula (I) above are hereinafter referred to as compound (I). Other formula numbers are also applied to the corresponding compounds in the same manner.
In the definition of each of the groups in the formula (I), the alkyl group includes a straight chain or branched chain alkyl group having from 1 to 20 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl and the like. The alkyl group contained in the lower alkoxyalkyl group, the aralkyloxyalkyl group, the lower alkoxyalkoxyalkyl group, the lower alkoxyalkoxyalkoxyalkyl group, the lower alkoxycarbonylalkyl group, the substituted or unsubstituted aryloxyalkyl group, the lower alkanoyloxyalkyl group and the alicyclic alkanoyloxyalkyl group has the same meaning as the above-described alkyl group. The alicyclic alkyl group includes those having from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The alicyclic alkyl group contained in the alicyclic alkoxy group and the alicyclic alkanoyloxyalkyl group has the same meaning as the above-described alicyclic alkyl group.
The lower alkyl group represents the above-described alkyl group in which the group has from 1 to 8 carbon atoms. The lower alkyl group contained in the lower alkoxy group, the lower alkoxyalkyl group, the lower alkoxyalkoxyalkyl group, the lower alkoxyalkoxyalkoxyalkyl group, the lower alkoxycarbonyl group, the hydroxy lower alkyl group, the lower alkoxycarbonylalkyl group, the lower alkanoyloxyalkyl group and the lower alkoxycarbonylamino group has the same meaning as the above-described lower alkyl group.
The lower alkenyl group and the lower alkenyl moiety in the lower alkenyloxy group include a straight chain or branched group having from 3 to 6 carbon atoms, for example, allyl, crotyl, prenyl and the like.
The aralkyl group and the aralkyl moiety in the aralkyloxy group and the aralkyloxyalkyl group include those having from 7 to 15 carbon atoms, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
The aryl group and the aryl moiety in the aryloxy group, the aryloxyalkyl group and the arylsulfonylamino group include phenyl, naphthyl and the like.
The heterocyclic group represents a 3-membered to 8-membered aliphatic or aromatic group which is composed of cyclic compound containing at least one hetero atom selected from oxygen, sulfur, nitrogen and the like, or a condensed cyclic compound group in which said cyclic compound group is condensed with the same or a different cyclic compound or a benzene ring, and preferred examples include a 5-membered or 6-membered nitrogen-containing aromatic heterocyclic group such as imidazolyl, pyridyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl and the like, or a 5-membered or 6-membered nitrogen-containing alicyclic heterocyclic group such as pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperidino, piperadinyl, morpholino, thiomorpholino, homopiperidinyl, homopiperadinyl, tetrahydropyridinyl and the like.
Substituents on the aryl group, the aryloxy group, the aralkyl group, the aralkyloxy group, the aryloxyalkyl group, the arylsulfonylamino group and the heterocyclic group are the same or different and include, for example, from 1 to 3 substituents selected from halogen, nitro, lower alkyl, hydroxyl, lower alkoxy, lower aroyloxy, lower alkoxycarbonyl, N,N-di-lower alkylcarbamoyloxy, N-acetylhexahydroisonicotinyloxy and the like. In the substituents, the halogen includes fluorine, chlorine, bromine and iodine, and the lower alkyl and the lower alkyl moiety contained in the lower alkoxy, the lower aroyloxy, the lower alkoxycarbonyl and the di-lower alkylcarbamoyloxy have the same meanings as the above-described lower alkyl.
The pharmacologically acceptable salts of the compounds (I) include, for example, acid addition salts such as hydrochloride, hydrobromide, sulfate, formate, acetate, benzoate, maleate, fumarate, succinate, tartarate, citrate, oxalate, methanesulfonate, p-toluenesulfonate, aspartate, glutamate and the like.
Processes for preparing the compounds (I) are described hereinafter.
Preparation Process 1
Of the compounds (I), the compound (I) wherein R.sup.1 is a group other than hydrogen, R.sup.2 and Z each is hydrogen, R.sup.3 bonds to Y to represent a single bond, and W is oxygen is referred to as compound (Ia), the compound (I) wherein R.sup.1 and R.sup.2 are groups other than hydrogen, Z is hydrogen, R.sup.3 bonds to Y to represent a single bond, and W is oxygen is referred to as compound (Ib), the compound (I) wherein R.sup.1 and R.sup.2 each is hydrogen, Y bonds to Z to represent a single bond, and W is oxygen is referred to as compound (Ic), the compound (I) wherein R.sup.2 is hydrogen, R.sup.1 is a group other than hydrogen, Y bonds to Z to represent a single bond, and W is oxygen is referred to as compound (Id), and the compound (I) wherein R.sup.1 and R.sup.2 each is a group other than hydrogen, Y bonds to Z to represent a single bond, and W is oxygen is referred to as compound (Ie). These compounds (I) wherein W is oxygen can be prepared, for example, from DC107 as a starting material via the following synthetic route: ##STR5## {wherein R.sup.1a represents a group defined as the above-described R.sup.1 excluding hydrogen, R.sup.2a represents COR.sup.5 (wherein R.sup.5 has the same meaning as defined above), R.sup.3a represents a lower alkyl group, a lower alkenyl group, a substituted or unsubstituted aralkyl group in which aryl may be substituted, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a substituted or unsubstituted aryloxyalkyl group, a lower alkoxycarbonylalkyl group, a lower alkanoyloxyalkyl group, an alicyclic alkanoyloxyalkyl group or ##STR6##
Compounds (Ia), (Ib), (Ic), (Id) and (Ie) can be prepared by, for example, the following steps based on the above-described synthetic route, depending upon the type of R.sup.1a, R.sup.2a and R.sup.3a.
Step 1 ##STR7## (wherein R.sup.3a and R.sup.4 have the same meanings as defined above.)
Of the compounds (Ia) or (Id), the compound (Ia1) or (Id1) wherein R.sup.1 represents COR.sup.4 (wherein R.sup.4 has the same meaning as defined above) can be obtained by reacting DC107, which is disclosed in Japanese Published Unexamined Patent Application No. 112988/89 or compound (Ic) with the compound (II) represented by the following formula:
(wherein R.sup.4 has the same meaning as defined above) or the compound (III) represented by the following formula:
(wherein R.sup.4 has the same meaning as defined above and X represents chlorine, bromine or iodine) in a solvent which is inert to the reaction and in the presence of a base. In the above reaction, when DC107 is used, the compound (Ia1) is produced and, when the compound (Ic) is used, the compound (Id1) is produced. The compound (II) or the compound (III) is generally used in an amount of one equivalent or more, preferably from 1 to 100 equivalents, to DC107 or the compound (Ic).
The solvent used in the reaction may be any solvent which is inert to the reaction, and examples thereof include chloroform, dichloromethane, ether, tetrahydrofuran, acetone, dimethylformamide and acetonitrile which can be used singly or as a mixture thereof. As the base, for example, pyridine, triethylamine or diisopropylethylamine may be used singly or as a mixture thereof, and the reaction can be promoted by further adding dimethylaminopyridine, etc. to the reaction system in an amount of from 0.1 to 2 equivalents. The base is generally used in an amount of one equivalent or more, preferably from 1 to 200 equivalents, to DC107 or the compound (Ic). The reaction is generally completed within from 5 minutes to 24 hours at a reaction temperature in the range of from -20.degree. to 50.degree. C.
Step 2 ##STR8## (wherein R.sup.3a has the same meaning as defined above, and R.sup.7 represents a group defined as the above-described R.sup.4 excluding a lower alkoxy group, an alicyclic alkoxy group, a 9-fluorenylmethoxy group, an aralkyloxy group and a substituted or unsubstituted aryloxy group.)
Of the compounds (Ia) or (Id), the compound (Ia2) or (Id2) wherein R.sup.1a represents COR.sup.7 (wherein R.sup.7 has the same meaning as defined above) can also be prepared by reacting DC107 or the compound (Ic) with the compound (IV) represented by the following formula:
(wherein R.sup.7 has the same meaning as defined above) in an inert solvent in the presence of a condensing agent. The solvent used in the reaction may be any of the above-described inert solvents, but chloroform and dichloromethane are preferred. The condensing agent may be any of those generally used for the condensation of a carboxylic acid and an alcohol, for example, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like, and dimethylaminopyridine and the like can be further added to the reaction system in an amount of from 0.1 to 10 equivalents. The compound (IV) and the condensing agent are generally used in an amount of from 1 to 100 equivalents to DC107 or the compound (Ic). The reaction is generally completed within from 10 minutes to 24 hours at a reaction temperature of from 0.degree. to 30.degree. C.
Step 3 ##STR9## (wherein R.sup.3a has the same meaning as defined above, and R.sup.8 represents a nitrogen-containing alicyclic heterocyclic group.)
Of the compounds (Ia) or (Id), the compound (Ia4) or (Id4) wherein R.sup.1a represents COR.sup.8 (wherein R.sup.8 has the same meaning as defined above) can be prepared by reacting the compound (Ia3) or the compound (Id3) wherein R.sup.1a is p-nitrophenyloxycarbonyl with a nitrogen-containing alicyclic heterocyclic group in an inert solvent. The solvent used for the reaction may be any of the above-described inert solvents, but chloroform and dichloromethane are preferably used. The nitrogen-containing alicyclic heterocyclic group is generally used in an amount of from 1 to 10 equivalents. The reaction is generally completed within from 10 minutes to 24 hours at a reaction temperature of from 0.degree. to 30.degree. C.
Step 4-1 ##STR10## (wherein R.sup.1a, R.sup.3a and R.sup.5 have the same meanings as defined above.)
The compound (Ib1) or the compound (Ie1) can be prepared by reacting the compound (Ia) or (Id) with the compound (V) represented by the following formula:
(wherein R.sup.5 has the same meaning as defined above) or the compound (VI) represented by the following formula:
(wherein R.sup.5 and X have the same meanings as defined above) in a solvent which is inert to the reaction in the presence of a base. When the compound (Ia) is used, the compound (Ib1) is produced and, when the compound (Id) is used, the compound (Ie1) is produced.
The solvent for use in the reaction may be any solvent which is inert to the reaction, and examples thereof include chloroform, dichloromethane, ether, tetrahydrofuran, acetone, dimethylformamide, acetonitrile and the like which can be used singly or as a mixture thereof. As the base, for example, pyridine, triethylamine, diisopropylethylamine and the like may be used singly or as a mixture thereof, and dimethylaminopyridine and the like may further be added to the reaction system in an amount of from 0.1 to 10 equivalents.
The compound (V) or the compound (VI) is generally used in an amount of one equivalent or more, preferably from 1 to 100 equivalents, to the compound (Ia) or the compound (Id), and the base is generally used in an amount of one equivalent or more, preferably from 1 to 500 equivalents, to the compound (Ia) or the compound (Id). The reaction is generally completed within from 5 minutes to 20 hours at a reaction temperature in the range of from -20.degree. to 50.degree. C.
Step 4-2 ##STR11## (wherein R.sup.3a and R.sup.5 have the same meanings as defined above.)
In a similar manner as Step 4-1, when DC107 or the compound (Ic) is used as a starting material in Step 4-2, the compound (Ib2) or (Ie2) having the same substituent in R.sup.2a as R.sup.1a (R.sup.1a .dbd.R.sup.2a .dbd.COR.sup.5) can also be obtained, together with the compound (Ia5) or the compound (Id5). In this case, the production ratio of (Ia5) and (Ib2), or (Id5) and (Ie2) varies depending upon the reaction conditions such as the type of the compound (V) or the compound (VI), the amount thereof, and the solvent used.
Step 5 ##STR12## (wherein R.sup.1a and R.sup.3a have the same meanings as defined above.)
The compound (Ic) and the compound (Id) can be prepared by reacting DC107 or the compound (Ia) with the compound (VII) represented by the following formula:
(wherein R.sup.3a and X have the same meanings as defined above) in a solvent which is inert to the reaction in the presence of a base.
The solvent used in the reaction may be any solvent which is inert to the reaction, and examples thereof include chloroform, dichloromethane, ether, tetrahydrofuran, acetone, dimethylformamide, acetonitrile and the like which can be used singly or as a mixture thereof. As the base, for example, amines such as pyridine, imidazole, triethylamine, diisopropyl ethylamine and the like, and a carbonate or bicarbonate of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and the like may be used, and dimethylaminopyridine and the like may be used as a catalyst. Further, the reaction can be promoted by adding potassium iodide, sodium iodide, tetrabutylammonium iodide and the like to the reaction system in an amount of from 1 to 100 equivalents.
The compound (VII) is generally used in an amount of one equivalent or more, preferably from 1 to 100 equivalents, to DC107 or the compound (Ia). The base is generally used in an amount of one equivalent or more, preferably from 1 to 200 equivalents, to DC107 or the compound (Ia). The reaction is generally completed within from 10 minutes to 24 hours at a reaction temperature in the range of from 0.degree. to 50.degree. C.
Step 6-1 ##STR13## (wherein R.sup.3a has the same meaning as defined above, and R.sup.9 represents lower alkoxyalkyl, aralkyloxyalkyl, lower alkoxyalkoxyalkyl or lower alkoxyalkoxyalkoxyalkyl.)
Of the compounds (Id), the compound (Id6) wherein R.sup.1a is lower alkoxyalkyl, aralkyloxyalkyl, lower alkoxyalkoxyalkyl or lower alkoxyalkoxyalkoxyalkyl can be prepared by reacting the compound (Ic) with the compound (VIII) represented by the following formula:
(wherein R.sup.9 and X have the same meanings as defined above.) The reaction is conducted in a solvent which is inert to the reaction, such as chloroform, dichloromethane, dimethylformamide, acetonitrile, ether, tetrahydrofuran and the like, in the presence of a tertiary amine such as triethylamine, diisopropylethylamine, N-methylpiperidine and the like. The compound (VIII) is generally used in an amount of from 1 to 100 equivalents, and the tertiary amine is generally used in an amount of from 1 to 200 equivalents. The reaction is generally completed within from 1 to 24 hours at a reaction temperature of from 0.degree. to 50.degree. C.
Step 6-2 ##STR14## (wherein R.sup.9 has the same meaning as defined above.)
In a similar manner as Step 6-1, when DC107 is used as a starting material in Step 6-2, the compound (Ia6) or the compound (Ic1) wherein one of R.sup.1a and R.sup.3a represents lower alkoxyalkyl, aralkyloxyalkyl or lower alkoxyalkoxyalkyl, and the compound (Id7) wherein both R.sup.1a and R.sup.3a represent lower alkoxyalkyl, aralkyloxyalkyl, lower alkoxyalkoxyalkyl or lower alkoxyalkoxyalkoxyalkyl may be obtained. The production ratio of the compounds (Ia6), (Ic1) and (Id7) varies depending upon the reaction conditions used such as the type of base, the equivalent, the solvent, the reaction temperature, and the like.
Step 7 ##STR15## wherein R.sup.3a has the same meaning as defined above, and R.sup.10 represents tetrahydropyranyl, lower alkoxyalkyl, aralkyl or ##STR16## (wherein Q.sup.1 and Q.sup.2 have the same meanings as defined above)!.
The compound (Ia7) or the compound (Id8) can be prepared by reacting DC107 or the compound (Ic) with 3,4-dihydro-2H-pyran in the case where R.sup.10 represents tetrahydropyranyl, with aralkyl 2,2,2-trichloroacetimidate in the case where R.sup.10 is aralkyl, or with lower alkoxyalkyl in the case where R.sup.10 is lower alkoxyalkyl, with ##STR17## (wherein Q.sup.1 and Q.sup.2 have the same meanings as defined above) in the case where R.sup.10 is ##STR18## (wherein Q.sup.1 and Q.sup.2 have the same meanings as defined above) each in an amount of from 1 to 300 equivalents to DC107 or the compound (Ic), in a solvent which is inert to the reaction in the presence of an acid.
The solvent used in the reaction can be any solvent which is inert to the reaction such as chloroform, dichloromethane, ether, tetrahydrofuran, acetone, dimethylformamide, acetonitrile and the like which can be used singly or as a mixture thereof. Examples of the acid used in the reaction include organic acids such as p-toluenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, trifluoroacetic acid, trifluoromethanesulfonic acid and the like, inorganic acids such as hydrochloric acid, sulfuric acid and the like, and Lewis acids such as titanium tetrachloride and a complex of boron trifluoride and diethyl etherate. The acid is generally used in an amount of from 0.1 to 5 equivalents to DC107 or the compound (Ic). The reaction is generally completed within from 5 minutes to 24 hours at a reaction temperature of from -30.degree. to 30.degree. C.
Preparation Process 2
Of the compounds (I), the compounds (I) wherein R.sup.1 is hydrogen, R.sup.2 represents COR.sup.5 (wherein R.sup.5 has the same meaning as defined above), and W is oxygen are referred to as compound (If) or compound (Ig). The compound (If) or the compound (Ig) can be prepared by, for example, the following step.
Step 8 ##STR19## (wherein R.sup.3a and R.sup.5 have the same meanings as defined above.)
The compound (If) or the compound (Ig) can be prepared by treating the compound (Ib3) or the compound (Ie3) with an organic acid such as p-toluenesulfonic acid, camphorsulfonic acid and the like or an inorganic acid such as hydrochloric acid, sulfuric acid and the like in an amount of from 0.1 to 100 equivalents in a solvent such as methanol, ethanol and the like. The reaction is generally completed within from 5 minutes to 24 hours at a reaction temperature of from -30.degree. to 30.degree. C.
Preparation Process 3
Of the compounds (I), the compounds (I) wherein W represents oxygen or NR.sup.6 (wherein R.sup.6 has the same meaning as defined above) are referred to as compound (Ih) and compound (Ii), respectively. The compound (Ii) can be prepared from the compound (Ih) by, for example, the following step.
Step 9 ##STR20## (wherein R.sup.1, R.sup.2, R.sup.3, Y, Z and R.sup.6 have the same meanings as defined above.)
The compound (Ii) can be prepared by reacting the compound (Ih) with the compound (IX) represented by the following formula:
(wherein R.sup.6 has the same meaning as defined above) or a hydrochloride thereof, in a solvent which is inert to the reaction.
The solvent which can be used for the reaction include methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, acetonitrile and the like which can be used singly or as a mixture thereof. Also, the reaction can be promoted by adding pyridine or an acid to the reaction system. The acid is preferably an organic acid such as p-toluenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate and the like, but an inorganic acid such as hydrochloric acid, sulfuric acid and the like may also be used.
The compound (IX) is generally used in an amount of from 1 to 50 equivalents to the compound (I), and pyridine or an acid may be used in an amount of from 1 to 100 equivalents. The reaction is generally completed within from 5 minutes to 24 hours at a reaction temperature of from 0.degree. to 30.degree. C.
The object compounds in the above-described preparation processes can be isolated and purified by purification procedures ordinary used in the organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like.
Further, the compounds (I) may exist in the form of adducts with water and various solvents, and it is to be understood that these adducts are also included within the scope of the compounds according to the present invention.
Specific examples of the compound (I) obtained by the above-described preparation processes are shown in Table 1 below.
The antibacterial activity and the antitumor activity of typical compounds (I) are hereinafter described with reference to test examples.
Test Example 1
Antibacterial Activity
The antibacterial activity as determined by the agar dilution method using a medium prepared by dissolving 3 g of Bacto-Tryptone (a product of Difco Laboratories), 3 g of a meat extract, 1 g of an yeast extract, 1 g of glucose and 16 g of agar in one liter of water (pH 7). The antibacterial activities of typical compounds in terms of the minimum growth inhibitory concentration (MIC) are shown in Table 2 below.
Test Example 2
Antitumor Activity of Test Compounds Against P388 Leukemia
Ascites were collected from the abdominal cavity of P388 ascites tumor-bearing cancer mice (DBA/2) on the 7th day after transplantation. A number of P388 cells in the ascites was counted, and a tumor cell floating liquid of 5.times.10.sup.6 cells/ml was prepared using a physiological saline solution. Then, 0.2 ml of the solution containing 1.times.10.sup.6 cells was transplanted into the abdominal cavity of CDF.sub.1 mice having a body weight of from 20 to 25 g.
The test compound was dissolved in a physiological saline solution containing polyoxyethylene sorbitan monooleate, and 0.2 ml of the solution was administered intraperitoneally to CDF.sub.1 mice (five mice per group) on the 24 hours after the tumor transplantation, and thereafter a number of survival days of mice was observed for a period of 30 days.
The effect of the test compound was determined in terms of the ratio of average survival days of the group administered with the test compound to average survival days of the control group (non-medicated group) (i.e., an increased life span, ILS%). The results obtained are shown in Table 3 below.
The compound according to the present invention is useful as an antibacterial agent and an antitumor agent and can be used as it is or in various dosage forms. For example, when the compound (I) is used as an injectable preparation, it can be used after dissolving in a diluting agent which is ordinary used in the art, for example, a physiological saline solution, a glucose injectable solution, a lactose injectable solution, a mannitol injectable solution or the like, or it may be used as a freeze-dried injectable preparation based on the Japanese Pharmacopeia, or a powdery injectable preparation mixed with sodium chloride. Also, an auxiliary agent such as polyethylene glycol, HCO-60 (a surface active agent; a product of Nikko Chemical Co., Ltd.) and the like or a carrier such as ethanol and/or liposome, cyclodextrin and the like may be added to the injectable preparation. These injectable preparations are generally administered intravenously, but may be administered intraarterially, intraperitoneally or intrathoracically.
The compound (I) can be used as an oral preparation by mixing and formulating the compound (I) into a dosage form such as tablets, granules, powders, syrup and the like with appropriate excipients, disintegrating agents, binders, lubricating agents and the like in a usual manner.
The dosage level varies depending upon the administration method, the type of the compound (I) as well as the age and the severity of conditions, and the method for administration can also be varied by the severity of conditions and the dosage level, but the compound (I) can be generally administered parenterally as an injectable preparation or orally. For example, it can be administered at a dose in the range of from 0.06 to 6 mg/kg once a week or once at an interval of three weeks.
The present invention is further illustrated by the following Examples.
BEST MODE FOR CARRYING OUT THE INVENTION
In the following examples, the physical and chemical properties of each of the compounds were determined by the following apparatus:
In the physical data of the compounds in the following examples, "HRFABMAS" means a high resolution MS measurement by the FAB method; "Anal" means an elemental analysis; "calcd" means a theoretical value based on the molecular formula; and "found" means a measured value. In the examples, "Cbz" means carbobenzyloxy, "Boc" means tert-butoxycarbonyl, and "Fmoc" means 9-fluorenylmethylcarbonyl.
Also, in the following examples, the term "usual post-treatment" as used therein means the following treatment was conducted after the reaction.
First, that treatment includes, after completion of the reaction in each step, adding, if necessary, water, an acid, a buffering solution or the like to the reaction solution, and extracting the mixture with a water-insoluble solvent such as ethyl acetate, ether, chloroform, dichloromethane and the like. Next, the resulting extract is washed with water, an aqueous sodium chloride solution or the like, dried over anhydrous sodium sulfate or the like, and the solvent is distilled off under reduced pressure.
EXAMPLE 1
Synthesis of Compound 1
DC107 (52 mg, 0.102 mmol) was dissolved in dichloromethane (2.0 ml) and pyridine (0.1 ml, 1.2 mmol), and then acetic anhydride (0.05 ml, 0.53 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) were added thereto, followed by stirring at 25.degree. C. for 1.5 hours. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with ether/hexane=10/1) to obtain Compound 1 (46 mg, 82% yield).
IR (KBr) 3400, 2950, 1720, 1660, 1615, 1540, 1450, 1450, 1370, 1230, 1100, 1030, 1000, 950, 900, 805 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.80 (dd, J=16.5, 11.6 Hz, 1H), 7.28 (s, 1H), 6.67 (br d, J=6.6 Hz, 1H), 6.65 (d, J=11.6 Hz, 1H), 6.36 (dd, J=11.6, 11.6 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.79 (br s, 2H), 5.36 (dq, J=6.6, 6.6 Hz, 1H), 4.45 (br s, 1H), 3.06 (br s, 2H), 2.35 (dt, J=12.8, 3.9 Hz, 1H), 2.06 (dt, J=12.8, 5.2 Hz, 1H), 2.00 (s, 3H), 1.88 (dt, J=12.8, 5.2 Hz, 1H), 1.78 (s, 3H), 1.77 (d, J=6.6 Hz, 3H), 1.75 (m, 1H), 1.72 (s, 3H)
SIMS m/z 553 (M+H).sup.+
HRFABMS calcd for C.sub.24 H.sub.29 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 553.1137, found 553.1160
EXAMPLE 2
Synthesis of Compound 2
According to the procedure as described in Example 1, Compound 2 (34 mg, 76% yield) was obtained from DC107 (40.7 mg, 0.080 mmol), chloroform (4.0 ml), pyridine (0.162 ml, 2.0 mmol), propionic anhydride (0.051 ml, 0.40 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.024 mmol).
IR (KBr) 3420, 3350, 2926, 1718, 1653, 1615, 1540, 1448, 1373, 1271, 1185, 1082, 1003, 947, 893, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.83 (dd, J=16.6, 11.3 Hz, 1H), 7.28 (s, 1H), 6.68 (br d, J=6.4 Hz, 1H), 6.64 (d, J=11.3 Hz, 1H), 6.35 (dd, J=11.3, 11.3 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.81 (br d, J=9.8 Hz, 1H), 5.78 (d, J=9.8 Hz, 1H), 5.36 (dq, J=6.4, 6.4 Hz, 1H), 4.50 (br s, 1H), 3.08 (d, J=15.3 Hz, 1H), 3.03 (d, J=15.3 Hz, 1H), 2.34 (dt, J=12.8, 4.0 Hz, 1H), 2.27 (dq, J=7.6, 1.5 Hz, 2H), 2.07 (ddd, J=13.4, 12.8, 5.5 Hz, 1H), 1.88 (ddd, J=14.3, 12.8, 5.5 Hz, 1H), 1.79 (ddd, J=14.3, 13.4, 4.0 Hz, 1H), 1.79 (s, 3H), 1.77 (d, J=6.4 Hz, 3H), 1.73 (s, 3H), 1.04 (t, J=7.6 Hz, 3H)
FABMS m/z 567 (M+H).sup.+.
HRFABMS calcd for C.sub.25 H.sub.31 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 567.1293, found 567.1313
EXAMPLE 3
Synthesis of Compound 3
According to the procedure as described in Example 1, Compound 3 (23 mg, 51% yield) was obtained from DC107 (40.0 mg, 0.078 mmol), dichloromethane (1.0 ml), pyridine (0.82 ml, 10.1 mmol), pivaloyl chloride (0.63 ml, 5.15 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol).
IR (KBr) 3400, 2936, 1718, 1654, 1617, 1540, 1460, 1364, 1149, 1100, 1000, 950 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.83 (dd, J=16.6, 11.3 Hz, 1H), 7.28 (s, 1H), 6.80 (br d, J=6.6 Hz, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.33 (dd, J=11.6, 11.3 Hz, 1H), 5.97 (d, J=16.6 Hz, 1H), 5.88 (br d, J=9.5 Hz, 1H), 5.66 (d, J=9.5 Hz, 1H), 5.36 (dq, J=6.6, 6.6 Hz, 1H), 4.61 (br s, 1H), 3.12 (d, J=15.0 Hz, 1H), 3.00 (d, J=15.0 Hz, 1H), 2.40-2.33 (m, 1H), 2.13-2.06 (m, 1H), 1.93-1.62 (m, 2H), 1.82 (s, 3H), 1.80 (d, J=6.6 Hz, 3H), 1.74 (d, J=1.2 Hz, 3H), 1.08 (s, 9H)
FABMS m/z 595 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.35 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 595.1606, found 595.1603
EXAMPLE 4
Synthesis of Compound 4
According to the procedure as described in Example 1, Compound 4 (23 mg, 51% yield) was obtained from DC107 (40.2 mg, 0.079 mmol), dichloromethane (4.0 ml), pyridine (0.034 ml, 0.42 mmol) and lauroyl chloride (0.048 ml, 0.21 mmol).
IR (KBr) 3450, 3330, 2926, 2856, 1714, 1646, 1615, 1521, 1447, 1368, 1190, 1100, 1000, 947,890, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.81 (dd, J=16.8, 11.3 Hz, 1H), 7.27 (s, 1H), 6.73 (br d, J=6.3 Hz, 1H), 11.3 (d, J=11.3 Hz, 1H), 6.02 (d, J=16.8 Hz, 1H), 5.80 (br d, J=9.9 Hz, 1H), 5.76 (d, J=9.9 Hz, 1H), 5.36 (dq, J=6.7, 6.3 Hz, 1H), 4.52 (br s, 1H), 3.09 (d, J=15.1 Hz, 1H), 3.03 (d, J=15.1 Hz, 1H), 2.38-2.32 (m, 1H), 2.22 (t, J=7.3 Hz, 2H), 2.06 (dt, J=12.8, 5.2 Hz, 1H), 1.93-1.10 (m, 20H), 1.80 (s, 3H), 1.77 (d, J=6.7 Hz, 3H), 1.72 (s, 3H), 0.88 (t, J=6.7 Hz, 3H)
FABMS m/z 693 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.49 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 693.2702, found 93.2675
EXAMPLE 5
Synthesis of Compound 5
According to the procedure as described in Example 1, Compound 5 (55 mg, 72% yield) was obtained from DC107 (52 mg, 0.102 mmol), dichloromethane (2.5 ml), pyridine (0.050 ml, 0.62 mmol) and palmitoyl chloride (100 mg, 0.36 mmol).
IR (KBr) 3420, 3330, 2928, 2856, 1713, 1647, 1614, 1529, 1453, 1371, 1263, 1200, 1101, 1000, 948, 892, 808, 720 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.97 (dd, J=16.9, 11.5 Hz, 1H), 7.27 (s, 1H), 6.72 (br d, J=6.3 Hz, 1H), 6.63 (d, J=11.3 Hz, 1H), 6.34 (dd, J=11.5, 11.3 Hz, 1H), 6.00 (d, J=16.9 Hz, 1H), 5.81 (br d, J=10.0 Hz, 1H), 5.74 (d, J=10.0 Hz, 1H), 5.35 (dq, J=6.6, 6.3 Hz, 1H), 4.59 (br s, 1H), 3.09 (d, J=15.2 Hz, 1H), 3.01 (d, J=15.2 Hz, 1H), 2.34 (ddd, J=13.0, 12.2, 4.4 Hz, 1H), 2.21 (t, J=7.5 Hz, 2H), 2.07 (ddd, J=13.0, 12.2, 5.6 Hz, 1H), 1.94--1.75 (m, 2H), 1.80 (s, 3H), 1.77 (d, J=6.6 Hz, 3H), 1.73 (d, j=1.0 Hz, 3H), 1.54-1.05 (m, 26H), 0.88 (t, J=6.8 Hz, 3H)
FABMS m/z 749 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.57 N.sub.2 O.sub.6 S.sub.3 (M+H).sup.+ 749.3328, found 749.3331
EXAMPLE 6
Synthesis of Compound 6
According to the procedure as described in Example 1, Compound 6 (50 mg, 81% yield) was obtained from DC107 (51 mg, 0.099), dichloromethane (5.0 ml), pyridine (0.16 ml, 1.99 mmol) and cyclohexanecarbonyl chloride (0.134 ml, 1.0 mmol).
IR (KBr) 3450, 3350, 2932, 2858, 1730, 1652, 1612, 1530, 1447, 1369, 1247, 1193, 1166, 1130, 1100, 1001, 940, 892 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.81 (dd, J=16.7, 11.5 Hz, 1H), 7.28 (s, 1H), 6.75 (br d, J=6.3 Hz, 1H), 6.64 (d, J=11.5 Hz, 1H), 6.35 (dd, J=11.5, 11.5 Hz, 1H), 6.00 (dd, J=16.7, 0.6 Hz, 1H), 5.83 (br d, J=9.4 Hz, 1H), 5.69 (d, J=9.4 Hz, 1H), 5.36 (dq, J=6.6, 6.3 Hz, 1H), 4.37 (br s, 1H), 3.11 (d, J=15.2 Hz, 1H), 3.02 (d, J=15.2 Hz, 1H), 2.35 (ddd, J=13.0, 12.2, 4.7 Hz, 1H), 2.21 (tt, J=11.2, 3.6 Hz, 1H),2.08 (ddd, J=13.0, 12.2, 5.4 Hz, 1H), 1.94-1.50 (m, 6H), 1.82 (s, 3H), 1.78 (d, J=6.6 Hz, 3H), 1.73 (d, J=1.2 Hz, 3H), 1.39-1.11 (m, 6H)
FABMS m/z 621 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.37 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 621.1763, found 621.1742
EXAMPLE 7
Synthesis of Compound 7
According to the procedure as described in Example 1, Compound 7 (17 mg, 84% yield) was obtained from DC107 (17 mg, 0.033 mmol), dichloromethane (0.8 ml), pyridine (0.10 ml, 1.2 mmol), benzoyl chloride (0.040 ml, 0.34 mmol) and 4-dimethylaminopyridine (5.0 mg, 0.041 mmol),
IR (KBr) 3400, 2934, 1718, 1653, 1620, 1520, 1457, 1380, 1320, 1266, 1100, 1069, 799, 712 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.01 (dd, J=16.8, 11.6 Hz, 1H), 7.87 (dd, J=8.5, 1.2 Hz, 2H), 7.48 (dt, J=7.6, 1.2 Hz, 1H), 7.30 (s, 1H), 7.27 (dd, J=8.5, 7.6 Hz, 2H), 6.78 (br d, J=6.4 Hz, 1H), 6.67 (d, J=11.9 Hz, 1H), 6.37 (dd, J=11.6, 11.3 Hz, 1H), 6.08 (dd, J=9.8, 1.1 Hz, 1H), 6.07 (d, J=16.8 Hz, 1H), 5.95 (br d, J=9.8 Hz, 1H), 5.32 (dq, J=6.7, 6.4 Hz, 1H), 4.54 (br s, 1H), 3.09 (d, J=14.9 Hz, 1H), 3.03 (d, J=14.9 Hz, 1H), 2.39 (dt, J=13.1, 4.0 Hz, 1H), 2.11 (dt, J=13.1, 5.2 Hz, 1H), 1.92-1.81 (m, 2H), 1.82 (d, J=1.1 Hz, 3H), 1.79 (s, 3H), 1.60 (d, J=6.4 Hz, 3H)
SIMS m/z 615 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.31 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 615.1293, found 615.1307
EXAMPLE 8
Synthesis of Compound 8
According to the procedure as described in Example 1, Compound 8 (21 mg, 56% yield) was obtained from DC107 (30 mg, 0.060 mmol), dichloromethane (3.0 ml), pyridine (0.14 ml, 1.78 mmol) and p-fluorobenzoyl chloride (0.105 ml, 0.89 mmol).
IR (KBr) 3420, 2930, 1721, 1653, 1604, 1520, 1506, 1448, 1411, 1370, 1266, 1155, 1104, 1091, 992, 950, 894, 854, 799, 764 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.90 (dd, J=16.6, 11.6 Hz, 1H), 7.95-7.88 (m, 2H), 7.31 (s, 1H), 6.97-6.91 (m, 2H), 6.66 (d, J=11.3 Hz, 1H), 6.66 (br d, J=6.4 Hz, 1H), 6.39 (dd, J=11.6, 11.3 Hz, 1H), 6.10 (d, J=9.6 Hz, 1H), 6.09 (d, J=16.6 Hz, 1H), 5.92(br d, J=9.6 Hz, 1H), 5.36 (dq, J=6.7, 6.4 Hz, 1H), 4.31 (br s, 1H), 3.07 (br s, 2H), 2.39 (dt, J=13.0, 4.0 Hz, 1H), 2.13 (dt, J=13.0, 5.2 Hz, 1H), 1.95-1.75 (m, 2H), 1.82 (d, J=0.9 Hz, 3H), 1.79 (s, 3H), 1.62 (d, J=6.7 Hz, 3H)
FABMS m/z 633 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.30 FN.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 633.1199, found 633.1203
EXAMPLE 9
Synthesis of Compound 9
According to the procedure as described in Example 1, Compound 9 (40 mg, 75% yield) was obtained from DC107 (40 mg, 0.079 mmol), dichloromethane (4.0 ml), pyridine (0.16 ml, 2.0 mmol) and 2-quinoxaloyl chloride (46 mg, 0.24 mmol).
IR (KBr) 3420, 2932, 1716, 1659, 1613, 1546, 1493, 1446, 1367, 1341, 1269, 1231, 1156, 1104, 980, 895, 799, 774 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.41 (s, 1H), 8.96 (dd, J=16.9, 11.2 Hz, 1H), 8.14 (dd, J=8.3, 1.3 Hz, 1H), 7.92 (dd, J=8.3, 1.3 Hz, 1H), 7.86 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.78 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.31 (s, 1H), 6.68 (d, J=11.2 Hz, 1H), 6.64 (br d, J=6.4 Hz, 1H), 6.39 (dd, J=11.2, 11.2 Hz, 1H), 6.26 (d, J=9.7 Hz, 1H), 6.13 (d, J=16.6 Hz, 1H), 6.00 (br d, J=9.7 Hz, 1H), 5.36 (dq, J=6.6, 6.4 Hz, 1H), 4.28 (br s, 1H), 3.11 (d, J=15.3 Hz, 1H), 3.05 (d, J=15.3 Hz, 1H), 2.44 (dt, J=12.9, 4.2 Hz, 1H), 2.14 (dt, J=13.7, 5.0 Hz, 1H), 1.98-1.72 (m, 2H), 1.86 (d, J=1.2 Hz, 3H), 1.77 (s, 3H), 1.66 (d, J=6.6 Hz, 3H)
FABMS m/z 667 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.31 N.sub.4 O.sub.7 S.sub.3 (M+H).sup.+ 667.1355, found 667.1360
EXAMPLE 10
Synthesis of Compound 10
According to the procedure as described in Example 1, Compound 10 (48 mg, 85% yield) was obtained from DC107 (50 mg, 0.098 mmol), dichloromethane (5.0 ml), pyridine (0.16 ml, 1.96 mmol) and ethyl chloroformate (0.094 ml, 0.98 mmol).
IR (KBr) 3400, 2930, 1735, 1660, 1615, 1540, 1450, 1374, 1256, 1202, 1095, 998, 784 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.76 (dd, J=16.6, 11.4 Hz, 1H), 7.27 (s, 1H), 6.66 (br d, J=6.5 Hz, 1H), 6.66 (d, J=11.4 Hz, 1H), 6.37 (dd, J=11.4, 11.4 Hz, 1H), 6.07 (d, J=16.6 Hz, 1H), 5.78 (br d, J=10.0 Hz, 1H), 5.73 (d, J=10.0 Hz, 1H), 5.36 (dq, J=6.5, 6.5 Hz, 1H), 4.41 (br s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.04 (s, 2H), 2.34 (dt, J=12.7, 4.0 Hz, 1H), 2.06 (ddd, J=13.0, 12.7, 5.3 Hz, 1H), 1.89 (ddd, J=12.7, 12.4, 5.3 Hz, 1H), 1.77 (s, 3H), 1.76 (ddd, J=13.0, 12.4, 4.0 Hz, 1H), 1.75 (d, J=1.2 Hz, 3H), 1.74 (d, J=6.5 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H)
FABMS m/z 583 (M+H).sup.+
HRFABMS calcd for C.sub.25 H.sub.31 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 583.1242, found 583.1259
EXAMPLE 11
Synthesis of Compound 11
According to the procedure as described in Example 1, Compound 11 (50 mg, 84% yield) was obtained from DC107 (50 mg, 0.098mmol), dichloromethane (5.0 ml), pyridine (0.080 ml, 0.98 mmol) and isobutyl chloroformate (0.089 ml, 0.69 mmol).
IR (KBr) 3400, 3340, 2966, 1740, 1660, 1615, 1530, 1448, 1378, 1252, 1202, 1099, 996, 968, 946. 894, 808,785 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.82 (dd, J=16.2, 11.3 Hz, 1H), 7.26 (s, 1H), 6.71 (br d, J=6.6 Hz, 1H), 6.65 (d, J=11.5 Hz, 1H), 6.37 (dd, J=11.5, 11.3 Hz, 1H), 6.06 (d, J=16.2 Hz, 1H), 5.78 (br d, J=9.7 Hz, 1H), 5.68 (d, J=9.7 Hz, 1H), 5.35 (dq, J=6.6, 6.4 Hz, 1H), 4.52 (br s, 1H), 3.89 (dd, J=10.5, 6.6 Hz, 1H), 3.82 (dd, J=10.5, 6.6 Hz, 1H), 3.09 (d, J=15.3 Hz, 1H), 3.03 (d, J=15.3 Hz, 1H), 2.35 (dt, J=12.7, 3.7 Hz, 1H), 2.07 (dt, J=12.7, 5.2 Hz, 1H), 2.03-1.70 (m, 2H), 1.86 (dq, J=6.8, 6.6 Hz, 1H), 1.79 (s, 3H), 1.75 (d, J=6.4 Hz, 3H), 1.75 (d, J=1.0 Hz, 3H), 0.83 (d, J=6.8 Hz, 3H), 0.88 (t, J=6.8 Hz, 3H)
FABMS m/z 611 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.35 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 611.1555, found 611.1568
EXAMPLE 12
Synthesis of Compound 12
According to the procedure as described in Example 1, Compound 12 (40 mg, 81% yield) was obtained from DC107 (40 mg, 0.079mmol), dichloromethane (4.0 ml), pyridine (0.064 ml, 0.79 mmol) and phenyl chloroformate (0.030 ml, 0.24 mmol).
IR (KBr) 3400, 2924, 1761, 1720, 1660, 1612, 1522, 1490, 1448, 1369, 1251, 1206, 1101, 1022, 949, 894, 767 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.83 (dd, J=16.5, 11.3 Hz, 1H), 7.32 (ddd, J=8.5, 7.3, 1.2 Hz, 2H), 7.29 (s, 1H), 7.20 (dt, J=7.3, 1.2 Hz, 1H), 7.08 (dt, J=8.5, 1.2 Hz, 2H), 6.69 (br d, J=6.7 Hz, 1H), 6.68 (d, J=11.3 Hz, 1H), 6.40 (dd, J=11.3, 11.3 Hz, 1H), 6.11 (d, J=16.5 Hz, 1H), 5.85 (d, J=10.2 Hz, 1H), 5.83 (d, J=10.2 Hz, 1H), 5.38 (dq, J=6.7, 6.7 Hz, 1H), 4.43 (br s, 1H), 3.09 (d, J=12.5 Hz, 1H), 3.05 (d, J=12.5 Hz, 1H), 2.38 (ddd, J=13.1, 12.8, 4.0 Hz, 1H), 2.09 (dt, J=13.1, 4.9 Hz, 1H), 1.91 (ddd, J=12.8, 12.5, 4.9 Hz, 1H), 1.80 (ddd, J=13.1, 12.5, 4.0 Hz, 1H), 1.77 (d, J=6.7 Hz, 3H), 1.76 (s, 3H), 1.76 (s, 3H)
FABMS m/z 631 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.31 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 631.1242, found 631.1258
EXAMPLE 13
Synthesis of Compound 13
According to the procedure as described in Example 1, Compound 13 (64 mg, 96% yield) was obtained from DC107 (51 mg, 0.99 mmol), dichloromethane (5.0 ml), pyridine (0.080 ml, 0.98 mmol) and p-nitrophenyl chloroformate (59.8 mg, 0.30 mmol).
IR (KBr) 3370, 2936, 1764, 1718, 1654, 1616, 1570, 1526, 1491, 1458, 1348, 1250, 1216, 1106, 164, 949, 897, 861, 799, 751 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.73 (dd, J=16.6, 11.2 Hz, 1H), 8.23 (ddd, J=9.0, 3.2, 2.2 Hz, 2H), 7.32 (ddd, J=9.0, 3.2, 2.2 Hz, 2H), 7.30 (s, 1H), 6.68 (d, J=11.3 Hz, 1H), 6.52 (br d, J=6.6 Hz, 1H), 6.38 (dd, J=11.3, 11.2 Hz, 1H), 6.12 (d, J=16.6 Hz, 1H), 5.89 (d, J=9.8 Hz, 1H), 5.85 (br d, J=9.8 Hz, 1H), 5.42 (dq, J=6.8, 6.6 Hz, 1H), 4.11 (br s, 1H), 3.17(d, J=15.6 Hz, 1H), 2.99 (d, J=15.6 Hz, 1H), 2.40 (dt, J=13.0, 4.1 Hz, 1H), 2.11 (dt, J=13.0, 4.5 Hz, 1H), 1.92 (dt, J=14.4, 4.5 Hz, 1H), 1.72-1.70 (m, 1H), 1.76 (d, J=6.8 Hz, 3H), 1.76 (d, J=0.7 Hz, 3H), 1.72 (s, 3H)
FABMS m/z 676 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.30 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 676.1093, found 676.1093
EXAMPLE 14
Synthesis of Compound 14
According to the procedure as described in Example 1, Compound 14 (29 mg, 74% yield) was obtained from DC107 (31 mg, 0.060 mmol), dichloromethane (3.0 ml), pyridine (0.66 ml, 8.17 mmol) and benzyl chloroformate (1.18 ml, a 30% toluene solution, 2.47 mmol).
IR (KBr) 3330, 2934, 1744, 1720, 1655, 1614, 1530, 1455, 1382, 1255, 1099, 1000, 949, 895, 799, 783, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.84 (dd, J=16.3, 11.2 Hz, 1H), 7.35-7.22 (m, 5H), 7.30 (s, 1H), 6.64 (d, J=11.2 Hz, 1H), 6.62 (br d, J=6.6 Hz, 1H), 6.34 (dd, J=11.2, 11.2 Hz, 1H), 6.05 (d, J=16.3 Hz, 1H), 5.79 (br d, J=9.6 Hz, 1H), 5.72 (d, J=9.6 Hz, 1H), 5.32 (dq, J=6.6, 6.6 Hz, 1H), 5.10 (s, 2H), 4.50 (br s, 1H), 3.08 (d, J=15.2 Hz, 1H), 3.01 (d, J=15.2 Hz, 1H), 2.33 (dt, J=12.7, 3.9 Hz, 1H), 2.08 (dt, J=12.7, 5.6 Hz, 1H), 1.93-1.72 (m, 2H), 1.79 (s, 3H), 1.74 (d, J=1.0 Hz, 3H), 1.69 (d, J=6.6 Hz, 3H)
FABMS m/z 645 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.33 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 645.1399, found 645.1415
EXAMPLE 15
Synthesis of Compound 15
According to the procedure as described in Example 1, Compound 15 (18.5 mg, 43% yield) was obtained from DC107 (30 mg, 0.059 mmol), dichloromethane (2.5 ml), pyridine (0.029 ml, 0.35 mmol) and 9-fluorenylmethyl chloroformate (45 mg, 0.17 mmol).
IR (KBr) 3410, 2930, 1746, 1718, 1654, 1612, 1520, 1449, 1383, 1323, 1260, 1102, 949, 805, 758, 740 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.01 (dd, J=16.6, 11.3 Hz, 1H), 7.72-7.09 (m, 8H), 7.30 (s, 1H), 6.65 (d, J=11.3 Hz, 1H), 6.62 (br d, J=6.6 Hz, 1H), 6.35 (dd, J=11.3, 11.3 Hz, 1H), 6.06 (d, J=16.6 Hz, 1H), 5.84 (br d, J=9.6 Hz, 1H), 5.69 (d, J=9.6 Hz, 1H), 5.32 (dq, J=6.6, 6.6 Hz, 1H), 4.64 (br s, 1H), 4.46 (dd, J=10.5, 7.0 Hz, 1H), 4.24 (dd, J=10.5, 7.4 Hz, 1H), 4.14 (dd, J=7.4, 7.0 Hz, 1H), 3.14 (d, J=15.3 Hz, 1H), 2.99 (d, J=15.3 Hz, 1H), 2.35 (ddd, J=13.0, 12.0, 4.0 Hz, 1H), 2.11 (ddd, J=13.5, 13.0, 6.1 Hz, 1H), 1.95-1.60 (m, 2H), 1.83 (s, 3H), 1.78 (br s, 3H), 1.72 (d, J=6.6 Hz, 3H)
FABMS m/z 733 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 733.1712, found 733.1734
EXAMPLE 16
Synthesis of Compound 16
Compound 13 (4.3 mg, 0.0063 mmol) was dissolved in chloroform (0.5 ml), and piperidine (0.0025 ml, 0.025 mmol) was added thereto, followed by stirring at 25.degree. C. for 30 minutes. The reaction mixture was purified by thin layer chromatography (developed with ether/methanol=97/3) to obtain Compound 16 (1.0 mg, 26% yield).
IR (KBr) 3430, 2938, 2860, 1700, 1671, 1617, 1540, 1433, 1371, 1258, 1233, 1151, 1100, 1023, 949, 894, 854, 799, 760 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.73 (dd, J=16.4, 11.6 Hz, 1H), 7.28 (s, 1H), 6.84 (br s, 1H), 6.63 (d, J=11.1 Hz, 1H), 6.38 (dd, J=11.6, 11.1 Hz, 1H), 6.04 (d, J=16.4 Hz, 1H), 5.79 (br d, J=9.5 Hz, 1H), 5.73 (d, J=9.5 Hz, 1H), 5.37 (dq, J=6.7, 6.4 Hz, 1H), 4.52 (br s, 1H), 3.55-3.10 (m, 4H), 3.11 (d, J=15.1 Hz, 1H), 3.03 (d, j=15.1 Hz, 1H), 2.34 (ddd, J=13.1, 11.9, 5.2 Hz, 1H), 2.06 (ddd, J=12.8, 11.9, 5.2 Hz, 1H), 1.93-1.80 (m, 2H), 1.81 (s, 3H), 1.80-1.38 (m, 6H), 1.75 (d, J=6.7 Hz, 3H), 1.74 (s, 3H)
FABMS m/z 622 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.36 N.sub.3 O.sub.7 S.sub.3 (M+H).sup.+ 622.1715, found 622.1730
EXAMPLE 17
Synthesis of Compound 17
According to the procedure as described in Example 16, Compound 17 (1.5 mg, 9% yield) was obtained from Compound 13 (18 mg, 0.027 mmol), chloroform (1.5 ml) and pyrrolidine (0.0045 ml, 0.054 mmol).
IR (KBr) 3420, 2938, 1703, 1670, 1612, 1521, 1424, 1375, 1260, 1200, 1181, 1098, 1000, 861, 762 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 100 MHz) .delta. ppm; 8.80 (dd, J=16.5, 11.5 Hz, 1H), 7.28 (s, 1H), 6.88 (br d, J=6.2 Hz, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.30 (dd, J=11.5, 11.5 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5.80 (br s, 2H), 5.36 (dq, J=6.2, 6.5 Hz, 1H), 3.5-3.0 (m, 6H), 2.5-1.4 (m, 8H), 1.78 (s, 3H), 1.75 (s, 3H), 1.72 (d, J=6.5 Hz, 3H)
FABMS m/z 608 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.34 N.sub.3 O.sub.7 S.sub.3 (M+H).sup.+ 608.1559, found 608.1586
EXAMPLE 18
Synthesis of Compound 18
DC107 (71 mg, 0.14 mmol) was dissolved in dichloromethane (9.0 ml), and then 3,4-dihydro-2H-pyran (0.164 ml, 1.81 mmol) and camphorsulfonic acid (77 mg, 0.33 mmol) were added thereto, followed by stirring at 0.degree. C. for 4 hours. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with chloroform/methanol=99/1) to obtain Compound 18 (49 mg, 58% yield). From .sup.1 H NMR data, Compound 18 was found to be a mixture of diastereomers at about 5:4 due to the asymmetric carbon of the tetrahydropyranyl group.
IR (KBr) 3400, 3320, 2930, 2850, 1715, 1651, 1612, 1538, 1450, 1373, 1260, 1098, 1025, 970, 890, 867, 808 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; major isomer: 9.25 (dd, J=16.5, 11.6 Hz, 1H), 7.25 (s, 1H), 6.88 (br d, J=6.4 Hz, 1H), 6.63 (d, J=11.6 Hz, 1H), 6.36 (dd, J=11.6, 11.6 Hz, 1H), 6.01 (d, J=16.5 Hz, 1H), 5.94 (d, J=9.7 Hz, 1H), 5.30 (dq, J=6.7, 6.4 Hz, 1H), 5.08 (dd, J=9.7, 1.2 Hz, 1H), 5.00 (br s, 1H), 4.58 (t, J=4.6 Hz, 1H), 3.78-3.74 (m, 1H), 3.50-3.45 (m, 1H), 3.25 (d, J=15.0 Hz, 1H), 2.90 (d, J=15.0 Hz, 1H), 2.35-2.28 (m, 1H), 2.12-2.06 (m, 1H), 1.95-1.44 (m, 8H), 1.88 (s, 3H), 1.79 (d, J=6.7 Hz, 3H), 1.72 (d, J=1.2 Hz, 3H); minor isomer: 9.04 (dd, J=16.5, 11.6 Hz, 1H), 7.25 (s, 1H), 6.86 (br d, J=6.4 Hz, 1H), 6.63 (d, J=11.6 Hz, 1H), 6.39 (dd, J=11.6, 11.6 Hz, 1H), 6.05 (d, J=16.5 Hz, 1H), 5.87 (d, J=9.8 Hz, 1H), 5.27 (dq, J=6.4, 6.4 Hz, 1H), 4.93 (br s, 1H), 4.91 (dd, J=9.8, 1.2 Hz, 1H), 4.63 (br s, 1H), 3.72-3.67 (m, 1H), 3.45-3.39 (m, 1H), 3.22 (d, J=14.6 Hz, 1H), 2.88 (d, J=14.6 Hz, 1H), 2.35-2.28 (m, 1H), 2.14-2.06 (m, 1H), 1.90-1.40 (m, 8H), 1.90 (s, 3H), 1.72 (d, J=6.4 Hz, 3H), 1.72 (s, 3H)
FABMS m/z 595 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.35 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 595.1606, found 595.1606
EXAMPLE 19
Synthesis of Compound 19
DC107 (10 mg, 0.020 mmol) was dissolved in dichloromethane (1.0 ml), and then ethyl vinyl ether (0.224 ml, 2.35 mmol) and pyridinium p-toluenesulfonate (5.3 mg, 0.021 mmol) were added thereto, followed by stirring at 25.degree. C. for 1 hour. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by separation thin layer chromatography (developed with chloroform/methanol=99/1) to obtain Compound 19 (5.0 mg, 43% yield). From .sup.1 H NMR data, Compound 19 was found to be a mixture of diastereomers at about 3:2 due to the asymmetric carbon of the 1-ethoxyethyl group.
IR (KBr) 3420, 3350, 2990, 1721, 1645, 1613, 1540, 1460, 1367, 1096, 957, 810 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; major isomer: 9.18 (dd, J=16.6, 11.5 Hz, 1H), 7.25 (s, 1H), 6.84 (br d, J=6.4 Hz, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.37 (d, J=11.5 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.90 (br d, J=9.5 Hz, 1H), 5.26 (dq, J=6.4, 6.4 Hz, 1H), 5.10 (br s, 1H), 4.83 (dd, J=9.5, 1.2 Hz, 1H), 4.69 (q, J=5.4 Hz, 1H), 3.52-3.25 (m, 2H), 3.24 (d, J=14.6 H, 1H), 2.86 (d, J=14.6 Hz, 1H), 2.35-1.80 (m, 4H), 1.91 (s, 3H), 1.76 (d, J=6.4 Hz, 3H); 1.73 (s, 3H), 1.18 (d, J=5.4 Hz, 3H), 1.07 (t, J=7.0 Hz, 3H), minor isomer: 9.31 (dd, J=16.6, 11.5 Hz, 1H), 7.25 (s, 1H), 6.83 (br d, J=6.4 Hz, 1H), 6.64 (d, J=11.5 Hz, 1H), 6.37 (dd, J=11.5, 11.5 Hz, 1H), 6.01 (d, J=16.6 Hz, 1H), 5.91 (br d, J=9.8 Hz, 1H), 5.27 (dq, J=6.4, 6.4 Hz, 1H), 5.08 (br s, 1H), 4.98 (dd, J=9.8, 1.2 Hz, 1H), 4.64 (q, J=5.4 Hz, 1H), 3.52-3.25 (m, 2H), 3.24 (d, J=14.6 Hz, 1H), 2.87 (d, J=14.6 Hz, 1H), 2.35-1.80 (m, 4H), 1.90 (s, 3H), 1.78 (d, J=6.6 Hz, 3H), 1.73 (br s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.12 (d, J=5.4 Hz, 3H)
FABMS m/z 583 (M+H).sup.+
HRFABMS calcd for C.sub.25 H.sub.35 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 583.1606, found 583.1600
EXAMPLE 20
Synthesis of Compound 20
DC107 (44 mg, 0.085 mmol) was dissolved in dichloromethane (5.0 ml), and then benzyl 2,2,2-trichloroacetimidate (0.22 ml, 1.18 mmol) and trifluoromethanesulfonic acid (0.011 ml, 0.13 mmol) were added thereto, followed by stirring at 25.degree. C. for 1 hour. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with ether/methanol=97/3) to obtain Compound 20 (7.0 mg, 14% yield).
IR (KBr) 3420, 2926, 1711, 1653, 1612, 1532, 1451, 1369, 1199, 1095, 1067, 997, 945, 799, 736, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.46 (dd, J=16.3, 11.5 Hz, 1H), 7.25-7.03 (m, 5H), 7.27 (s, 1H), 6.84 (br d, J=6.2 Hz, 1H), 6.68 (d, J=11.5 Hz, 1H), 6.41 (dd, J=11.5, 11.5 Hz, 1H), 6.06 (d, J=16.3 Hz, 1H), 5.93 (br d, J=9.5 Hz, 1H), 5.20 (dq, J=6.5, 6.2 Hz, 1H), 5.08 (br s, 1H), 4.68 (dd, J=9.5, 1.0 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.40 (d, J=11.6 Hz, 1H), 3.24 (d, J=14.5 Hz, 1H), 2.86 (d, J=14.5 Hz, 1H), 2.32-1.45 (m, 4H), 1.90 (s, 3H), 1.67 (d, J=1.0 Hz, 3H), 1.53 (d, J=6.5 Hz, 3H)
FABMS m/z 601 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.33 N.sub.2 O.sub.6 S.sub.3 (M+H).sup.+ 601.1501, found 601.1490
EXAMPLE 21
Synthesis of Compound 21
DC107 (50 mg, 0.098 mmol) was dissolved in dichloromethane (1.0 ml), and then pyridine (0.79 ml, 9.8 mmol), acetyl chloride (0.35 ml, 4.9 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.020 mmol) were added thereto, followed by stirring at 25.degree. C. for 20 minutes. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with ether/methanol=99/1) to obtain Compound 21 (43 mg, 74% yield).
IR (KBr) 3450, 2932, 1735, 1652, 1620, 1558, 1520, 1456, 1369, 1218, 1109, 1020, 950 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.33 (dd, J=16.6, 11.5 Hz, 1H), 7.28 (s, 1H), 6.66 (d, J=11.3 Hz, 1H), 6.39 (br d, J=6.6 Hz, 1H), 6.38 (dd, J=11.5, 11.3 Hz, 1H), 6.08 (d, J=16.6 Hz, 1H), 5.99 (d, J=9.3 Hz, 1H), 5.68 (br d, J=9.3 Hz, 1H), 5.50 (dq, J=6.6, 6.6 Hz, 1H), 3.39 (d, J=16.4 Hz, 1H), 2.95 (d, J=16.3 Hz, 1H), 2.12 (s, 3H), 2.10 (s, 3H), 2.10-1.72 (m, 4H), 2.01 (s, 3H), 1.75 (d, J=6.6 Hz, 3H), 1.68 (d, J=1.2 Hz, 3H)
FABMS m/z 595 (M+H).sup.+
HRFABMS calcd for C.sub.26 H.sub.31 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 595.1242, found 595.1224
EXAMPLE 22
Synthesis of Compound 22
DC107 (50 mg, 0.098 mmol) was dissolved in dichloromethane (1.0 ml) and pyridine (0.79 ml, 9.8 mmol), and then pivaloyl chloride (0.84 ml, 6.85 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.020 mmol) were added thereto, followed by stirring at 25.degree. C. for 24 hours. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with chloroform) to obtain Compound 22 (16 mg, 24% yield).
IR (KBr) 3420, 2976, 2936, 1730, 1653, 1620, 1520, 1479, 1447, 1395, 1368, 1277, 1146, 1101, 1030, 857 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.64 (br dd, J=16.8, 11.3 Hz, 1H), 7.29 (s, 1H), 6.63 (d, J=11.3 Hz, 1H), 6.38 (br s, 1H), 6.34 (dd, J=11.3, 11.3 Hz, 1H), 6.02 (d, J=16.8 Hz, 1H), 5.84 (br s, 2H), 5.45 (dq, J=6.7, 6.4 Hz, 1H), 3.33 (d, J=15.9 Hz, 1H), 2.91 (br d, J=15.9 Hz, 1H), 2.20-1.60 (m, 4H), 1.89 (s, 3H), 1.76 (d, J=6.7 Hz, 3H), 1.75 (br s, 3H), 1.21 (s, 9H), 1.16 (s, 9H)
FABMS m/z 679 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.43 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 679.2181, found 679.2164
EXAMPLE 23
Synthesis of Compounds 23 and 24
Compound 18 (77 mg, 0.13 mmol) was dissolved in chloroform (4.0 ml) and pyridine (2.9 ml, 35.9 mmol), and then acetic anhydride (0.68 ml, 7.2 mmol) and 4-dimethylaminopyridine (2.7 mg, 0.024 mmol) were added thereto, followed by stirring at 25.degree. C. for 5 hours. After subjecting the resulting mixture to the usual post-treatment, a mixture of Compounds 23 and 24 (76 mg, 91% yield) was obtained. Then, 36 mg of the resulting mixture was purified by thin layer chromatography (developed with ether/methanol=97/3) to obtain Compound 23 (13 mg) and Compound 24 (11 mg) which is a diastereomer of Compound 23.
Compound 23
IR (KBr) 3420, 3332, 3100, 2942, 2856, 1763, 1716, 1670, 1612, 1521, 1447, 1368, 1212, 1112, 1078, 1021, 969, 912, 867, 808 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.76 (br dd, J=16.5, 11.6 Hz, 1H), 7.24 (s, 1H), 6.63 (d, J=11.3 Hz, 1H), 6.59 (br d, J=7.0 Hz, 1H), 6.35 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.83 (br d, J=9.2 Hz, 1H), 5.44 (dq, J=7.0, 6.7 Hz, 1H), 5.18 (d, J=9.2 Hz, 1H), 4.56 (dd, J=4.9, 2.7 Hz, 1H), 3.87-3.82 (m, 1H), 3.50-3.47 (m, 1H), 3.19 (d, J=15.5 Hz, 1H), 2.94 (br d, J=15.5 Hz, 1H), 2.22-1.45 (m, 10H), 2.10 (s, 3H), 2.07 (s, 3H), 1.74 (d, J=1.2 Hz, 3H), 1.73 (d, J=6.7 Hz, 3H)
FABMS m/z 637 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 637.1712, found 637.1723
Compound 24
IR (KBr) 3450, 3330, 3100, 2942, 2860, 1759, 1718, 1653, 1615, 1522, 1447, 1368, 1212, 1104, 1078, 1019, 972, 910, 866, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.57 (br dd, J=16.5, 11.6 Hz, 1H), 7.24 (s, 1H), 6.62 (d, J=11.1 Hz, 1H), 6.49 (br d, J=6.6 Hz, 1H), 6.36 (dd, J=11.6, 11.1 Hz, 1H), 6.08 (d, J=16.5 Hz, 1H), 5.70 (br d, J=9.3 Hz, 1H), 5.42 (dq, J=6.7, 6.7 Hz, 1H), 5.11 (d, J=9.3 Hz, 1H), 4.68 (t, J=3.5 Hz, 1H), 3.78-3.74 (m, 1H), 3.46-3.42 (m, 1H), 3.22 (d, J=15.7 Hz, 1H), 2.81 (br d, J=15.7 Hz, 1H), 2.25-1.45 (m, 10H), 2.23 (s, 3H), 2.21 (s, 3H), 1.73 (d, J=1.2 Hz, 3H), 1.70 (d, J=6.7 Hz, 3H)
FABMS m/z 637 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 637.1712, found 637.1738
EXAMPLE 24
Synthesis of Compound 25
The unpurified mixture of Compounds 23 and 24 (30 mg, 0.047 mmol) obtained in Example 23 was dissolved in methanol (4.0 ml), and camphorsulfonic acid (22 mg, 0.094 mmol) was added thereto, followed by stirring at 0.degree. C. for 40 minutes. After subjecting the mixture to the usual post-treatment, the resulting mixture was purified by thin layer chromatography (developed with chloroform/methanol=99/3) to obtain Compound 25 (14 mg, 53% yield).
IR (KBr) 3450, 3300, 2930, 1760, 1716, 1654, 1614, 1528, 1446, 1372, 1218, 1104, 1066, 1010, 949, 842, 808 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.08 (ddd, J=16.5, 11.5, 1.0 Hz, 1H), 7.26 (s, 1H), 6.72 (dd, J=11.2, 1.0 Hz, 1H), 6.40 (dd, J=11.5, 11.2 Hz, 1H), 6.24 (br d, J=7.2 Hz, 1H), 6.20 (d, J=16.5 Hz, 1H), 5.51 (dq, J=7.2, 6.8 Hz, 1H), 5.48 (br d, J=9.0 Hz, 1H), 5.05 (d, J=9.0 Hz, 1H), 3.97 (br s, 1H), 3.46 (d, J=16.6 Hz, 1H), 3.00 (d, J=16.6 Hz, 1H), 2.12-1.82 (m, 3H), 2.09 (s, 3H), 1,98 (s, 3H), 1.75-1.65 (m, 1H), 1.74 (d, J=6.8 Hz, 3H), 1.64 (d, J=1.2 Hz, 3H)
FABMS m/z 553 (M+H).sup.+
HRFABMS calcd for C.sub.24 H.sub.29 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 553.1137, found 553.1143
EXAMPLE 25
Synthesis of Compound 26
DC107 (51 mg, 0.10 mmol) was dissolved in dichloromethane (10 ml), and N,N-diisopropylethylamine (0.69 ml, 4.0 mmol) and iodomethane (0.19 ml, 3.0 mmol) were added thereto, followed by stirring at 25.degree. C. for 5 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 26 (17 mg, 34% yield).
IR (KBr) 3430, 2930, 1720, 1680, 1610, 1448, 1364, 1264, 1155, 1089, 997, 753 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.45 (ddd, J=16.5, 11.6, 1.0 Hz, 1H), 7.47 (s, 1H), 6.58 (d, J=11.6 Hz, 1H), 6.23 (dd, J=11.6, 11.6 Hz, 1H), 6.17 (d, J=16.5 Hz, 1H), 5.73 (br d, J=8.5 Hz, 1H), 5.46 (br s, 1H), 5.41 (q, J=6.7 Hz, 1H), 4.94 (d, J=8.5 Hz, 1H), 3.93 (d, J=17.8 Hz, 1H), 2.28 (d, J=17.8 Hz, 1H), 2.38-1.92 (m, 4H), 2.23 (s, 3H), 2.03 (d, J=6.7 Hz, 3H), 1.78 (s, 3H), 1.75 (d, J=1.2 Hz, 3H)
FABMS m/z 525 (M+H).sup.+
HRFABMS calcd for C.sub.23 H.sub.29 N.sub.2 O.sub.6 S.sub.3 (M+H).sup.+ 525.1189, found 525.1187
EXAMPLE 26
Synthesis of Compound 27
DC107 (51 mg, 0.10 mmol) was dissolved in dimethylformamide (4.0 ml), and N,N-diisopropylethylamine (0.35 ml, 1.98 mmol), allyl bromide (0.086 ml, 0.99 mmol) and potassium iodide (82 mg, 0.50 mmol) were added thereto, followed by stirring at 25.degree. C. for 16 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 27 (26 mg, 49% yield).
IR (KBr) 3420, 2930, 1720, 1675, 1610, 1450, 1370, 1262, 1153, 1090, 987, 923 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.38 (dd, J=16.4, 11.3 Hz, 1H), 7.27 (s, 1H), 6.51 (br d, J=11.7 Hz, 1H), 6.16 (dd, J=11.7, 11.3 Hz, 1H), 6.10 (d, J=16.4 Hz, 1H), 5.68 (ddt, J=16.8, 10.1, 6.8 Hz, 1H), 5.65 (br d, J=9.0 Hz, 1H), 5.39 (br s, 1H), 5.34 (q, J=6.8 Hz, 1H), 5.17 (dd, J=16.8, 1.2 Hz, 1H), 5.04 (br d, J=10.1 Hz, 1H), 4.87 (d, J=9.0 Hz, 1H), 3.87 (d, J=18.0 Hz, 1H), 3.67 (br s, 1H), 3.40 (dd, J=14.2, 6.8 Hz, 1H), 3.35 (dd, J=14.2, 6.8 Hz, 1H), 2.28-1.72 (m, 4H), 2.21 (d, J=18.0 Hz, 1H), 1.95 (d, J=6.8 Hz, 3H), 1.71 (s, 3H), 1.68 (d, J=0.5 Hz, 3H)
FABMS m/z 551 (M+H).sup.+
HRFABMS calcd for C.sub.25 H.sub.31 N.sub.2 O.sub.6 S.sub.3 (M+H).sup.+ 551.1344, found 551.1336
EXAMPLE 27
Synthesis of Compounds 28 and 29
DC107 (100 mg, 0.20 mmol) was dissolved in dichloromethane (20 ml), and N,N-diisopropylethylamine (1.4 ml, 7.9 mmol) and chloromethyl methyl ether (0.30 ml, 4.0 mmol) were added thereto, followed by stirring at 25.degree. C. for 3 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with chloroform/methanol=99/1) to obtain Compound 28 (47 mg, 43% yield) and Compound 29 (37 mg, 31% yield). Compound 28 (Monomethoxymethyl compound)
IR (KBr) 3430, 2930, 1685, 1653, 1610, 1447, 1363, 1264, 1185, 1154, 1093, 1020, 982 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.46 (ddd, J=16.4, 11.2, 1.0 Hz, 1H), 7.34 (s, 1H), 6.58 (d, J=12.0 Hz, 1H), 6.23 (dd, J=12.0, 11.2 Hz, 1H), 6.17 (d, J=16.4 Hz, 1H), 5.73 (br d, J=8.5 Hz, 1H), 5.49 (br s, 1H), 5.42 (q, J=6.9 Hz, 1H), 5.00 (d, J=11.0 Hz, 1H), 4.94 (d, J=11.0 Hz, 1H), 4.94 (d, J=8.5 Hz, 1H), 3.95 (d, J=17.8 Hz, 1H), 3.70 (br s, 1H), 3.31 (s, 3H), 2.35-1.85 (m, 4H), 2.30 (d, J=17.8 Hz, 1H), 2.03 (d, J=6.9 Hz, 3H), 1.79 (s, 3H), 1.75 (d, J=1.5 Hz, 3H)
FABMS m/z 555 (M+H).sup.+
HRFABMS calcd for C.sub.24 H.sub.31 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 555.1293, found 555.1285
Compound 29 (Dimethoxymethyl compound)
IR (KBr) 3450, 2928, 1683, 1651, 1608, 1443, 1380, 1260, 1150, 1094, 1024, 982 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.53 (ddd, J=16.6, 11.4, 1.0 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.36 (dd, J=11.5, 11.4 Hz, 1H), 6.03 (d, J=16.6 Hz, 1H), 5.83 (br d, J=9.5 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 5.52 (br s, 1H), 5.03 (d, J=11.0 Hz, 1H), 4.93 (d, J=11.0 Hz, 1H), 4.80 (dd, J=9.5, 1.2 Hz, 1H), 4.63 (d, J=6.9 Hz, 1H), 4.59 (d, J=6.9 Hz, 1H), 4.10 (d, J=17.8 Hz, 1H), 3.33 (s, 3H), 3.29 (s, 3H), 2.43-2.30 (m, 2H), 2.33 (d, J=17.8 Hz, 1H), 1.92-1.38 (m, 2H), 1.90 (d, J=6.7 Hz, 3H), 1.75 (d, J=1.2 Hz, 3H), 1.72 (s, 3H)
FABMS m/z 599 (M+H).sup.+
HRFABMS calcd for C.sub.26 H.sub.35 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 599.1555, found 599.1553
EXAMPLE 28
Synthesis of Compound 30
DC107 (16 mg, 0.032 mmol) was dissolved in chloroform (1.0 ml), and N,N-diisopropylethylamine (0.20 ml, 1.2 mmol) and chloromethyl methyl ether (0.070 ml, 0.92 mmol) were added thereto, followed by stirring at 0.degree. C. for 1 hour. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=98/2) to obtain Compound 30 (8.3 mg, 48% yield). In this reaction, Compound 28 and Compound 29 were also produced.
IR (KBr) 3310, 2928, 1717, 1646, 1613, 1541, 1449, 1373, 1263, 1194, 1149, 1097, 1025, 946, 894, 808 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.10 (dd, J=16.5, 11.6 Hz, 1H), 7.26 (s, 1H), 6.85 (br d, J=6.4 Hz, 1H), 6.64 (d, J=11.6 Hz, 1H), 6.38 (t, J=11.6 Hz, 1H), 6.03 (d, J=16.5, 1.0 Hz, 1H), 5.88 (br d, J=9.4 Hz, 1H), 5.30 (dq, J=6.4, 6.4 Hz, 1H), 4.95 (br s, 1H), 4.92 (dd, J=9.4, 1.2 Hz, 1H), 4.59 (d, J=6.7 Hz, 1H), 4.54 (d, J=6.7 Hz, 1H), 3.25 (s, 3H), 3.21 (d, J=15.5 Hz, 1H), 2.92 (d, J=15.5 Hz, 1H), 2.33 (m, 1H), 2.09 (m, 1H), 1.88 (m, 2H), 1.87 (s, 3H), 1.74 (d, J=6.4 Hz, 3H), 1.73 (d, J=1.2 Hz, 3H)
SIMS m/z 555 (M+H).sup.+
HRFABMS calcd for C.sub.24 H.sub.31 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 555.1293, found 555.1305
EXAMPLE 29
Synthesis of Compound 31
DC107 (51 mg, 0.10 mmol) was dissolved in dichloromethane (3.0 ml), and N,N-diisopropylethylamine (1.1 ml, 6.0 mmol) and chloromethyl ethyl ether (0.28 ml, 3.0 mmol) were added thereto, followed by stirring at 25.degree. C. for 3 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with chloroform/methanol=99/1) to obtain Compound 31 (34 mg, 55% yield).
IR (KBr) 3440, 2980, 2920, 1684, 1652, 1610, 1455, 1362, 1263, 1150, 1096, 1022, 985 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.52 (ddd, J=16.5, 11.6, 0.9 Hz, 1H), 7.40 (s, 1H), 6.61 (d, J=11.3 Hz, 1H), 6.36 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.82 (dd, J=9.2, 0.9 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 5.50 (br s, 1H), 5.06 (d, J=11.0 Hz, 1H), 4.98 (d, J=11.0 Hz, 1H), 4.81 (dd, J=9.2, 1.2 Hz, 1H), 4.67 (d, J=7.0 Hz, 1H), 4.63 (d, J=7.0 Hz, 1H), 4.09 (d, J=17.7 Hz, 1H), 3.56-3.46 (m, 4H), 2.45-2.30 (m, 3H), 2.32 (d, J=17.7 Hz, 1H), 1.89 (d, J=6.7 Hz, 3H), 1.74 (d, J=1.2 Hz, 3H), 1.71 (s, 3H), 1.45-1.40 (m, 1H), 1.20 (t, J=7.0 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H)
FABMS m/z 627 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.39 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 627.1868, found 627.1861
EXAMPLE 30
Synthesis of Compound 32
DC107 (5.5 mg, 0.011 mmol) was dissolved in dichloromethane (0.5 ml), and N,N-diisopropylethylamine (0.019 ml, 0.11 mmol) and chloromethyl benzyl ether (0.0075 ml, 0.055 mmol) were added thereto, followed by stirring at 25.degree. C. for 6 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 32 (2.2 mg, 32% yield).
IR (KBr) 3400, 2934, 1684, 1652, 1611, 1453, 1375, 1264, 1089, 1018, 981, 807, 741, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.46 (ddd, J=16.2, 11.3, 1.0 Hz, 1H), 7.35-7.25 (m, 5H), 7.34 (s, 1H), 6.58 (d, J=11.6 Hz, 1H), 6.23 (dd, J=11.6, 11.3 Hz, 1H), 6.17 (d, J=16.2 Hz, 1H), 5.73 (br d, J=8.6 Hz, 1H), 5.43 (br s, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.08 (d, J=11.0 Hz, 1H), 5.03 (d, J=11.0 Hz, 1H), 4.94 (d, J=8.6 Hz, 1H), 4.53 (s, 2H), 3.94 (d, J=17.7 Hz, 1H), 3.74 (br s, 1H), 2.36-1.70 (m, 4H), 2.27 (d, J=17.7 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.79 (s, 3H), 1.74 (d, J=1.0 Hz, 3H)
FABMS m/z 631 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.35 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 631.1606, found 631.1624
EXAMPLE 31
Synthesis of Compound 33
DC107 (40 mg, 0.079 mmol) was dissolved in dimethylformamide (4.0 ml), and N,N-diisopropylethylamine (0.27 ml, 1.6 mmol), ethyl bromoacetate (0.088 ml, 0.79 mmol) and tetra-n-butylammonium iodide (291 mg, 0.79 mmol) were added thereto, followed by stirring at 25.degree. C. for 8 hours. After subjecting the resulting mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with chloroform) to obtain Compound 33 (36 mg, 77% yield).
IR (KBr) 3420, 2984, 2938, 1715, 1684, 1647, 1610, 1448, 1368, 1264, 1155, 1092, 1020, 991, 860 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.46 (ddd, J=16.5, 11.2, 1.0 Hz, 1H), 7.35 (s, 1H), 6.59 (d, J=11.7 Hz, 1H), 6.24 (dd, J=11.7, 11.2 Hz, 1H), 6.17 (d, J=16.5 Hz, 1H), 5.72 (dd, J=8.8, 1.0 Hz, 1H), 5.65 (br s, 1H), 5.42 (q, J=6.8 Hz, 1H), 4.93 (d, J=8.8 Hz, 1H), 4.16 (m, 2H), 3.98 (d, J=18.1 Hz, 1H), 3.69 (d, J=16.4 Hz, 1H), 3.50 (d, J=16.4 Hz, 1H), 2.47 (d, J=18.1 Hz, 1H), 2.35-1.75 (m, 4H), 2.03 (d, J=6.8 Hz, 3H), 1.80 (s, 3H), 1.73 (d, J=1.0 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H)
FABMS m/z 597 (M+H).sup.+
HRFABMS calcd for C.sub.26 H.sub.33 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 597.1399, found 597.1398
EXAMPLE 32
Synthesis of Compound 34
DC107 (48 mg, 0.093 mmol) was dissolved in acetonitrile (7.0 ml), and potassium carbonate (1.6 g, 11.2 mmol), chloromethyl pivalate (1.0 ml, 6.9 mmol) and potassium iodide (310 mg, 1.9 mmol) were added thereto, followed by stirring at 25.degree. C. for 2 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate=1/1) to obtain Compound 34 (34 mg, 59% yield).
IR (KBr) 3430, 3098, 2980, 2940, 2874, 1715, 1698, 1652, 1611, 1480, 1449, 1369, 1268, 1129, 974, 847, 807, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.48 (ddd, J=16.4, 11.2, 1.0 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=11.6 Hz, 1H), 6.24 (dd, J=11.6, 11.2 Hz, 1H), 6.17 (d, J=16.4 Hz, 1H), 5.75 (dd, J=8.6, 1.2 Hz, 1H), 5.51 (br s, 1H), 5.42 (q, J=7.1Hz, 1H), 5.41 (d, J=11.8 Hz, 1H), 5.35 (d, J=11.8 Hz, 1H), 4.93 (d, J=8.6 Hz, 1H), 3.59 (d, J=18.0 Hz, 1H), 2.33-2.15 (m, 3H), 2.25 (d, J=18.0 Hz, 1H), 2.02 (d, J=7.1 Hz, 3H), 2.02-1.93 (m, 1H), 1.78 (s, 3H), 1.74 (d, J=1.2 Hz, 3H), 1.16 (s, 9H)
FABMS m/z 625 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 625.1712, found 625.1708
EXAMPLE 33
Synthesis of Compound 35
DC107 (150 mg, 0.29 mmol) was dissolved in dimethylformamide (10 ml), and potassium carbonate (1.2 g, 8.9 mmol), 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (0.86 g, 5.8 mmol) and potassium iodide (245 mg, 1.47 mmol) were added thereto, followed by stirring at 25.degree. C. for 1 hour. After subjecting the mixture to the usual post-treatment, the mixture was purified by silica gel column chromatography (eluted with chloroform) to obtain Compound 35 (125 mg, 69% yield).
IR (KBr) 3420, 2936, 1819, 1680, 1647, 1611, 1450, 1375, 1265, 1208, 1150, 1092, 980, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.37 (ddd, J=16.3, 11.7, 1.0 Hz, 1H), 7.28 (s, 1H), 6.52 (d, J=11.7 Hz, 1H), 6.17 (dd, J=11.7, 11.7 Hz, 1H), 6.11 (d, J=16.3 Hz, 1H), 5.66 (br d, J=8.5 Hz, 1H), 5.34 (q, J=6.9 Hz, 1H), 4.88 (d, J=8.5 Hz, 1H), 3.83 (d, J=17.9 Hz, 1H), 3.69 (br s, 2H), 2.23-1.60 (m, 4H), 2.18 (d, J=17.9 Hz, 1H), 2.07 (s, 3H), 1.95 (d, J=6.9 Hz, 3H), 1.71 (s, 3H), 1.68 (d, J=1.2 Hz, 3H)
FABMS m/z 623 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.31 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 623.1192, found 623.1174
EXAMPLE 34
Synthesis of Compound 36
Compound 1 (20 mg, 0.036 mmol) was dissolved in dichloromethane (1.5 ml), and N,N-diisopropylethylamine (0.25 ml, 1.43 mmol) and chloromethyl methyl ether (0.054 ml, 0.71 mmol) were added thereto, followed by stirring at 25.degree. C. for 2 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed twice with chloroform/methanol=7/3) to obtain Compound 36 (16 mg, 76% yield).
IR (KBr) 3430, 2932, 1730, 1684, 1609, 1446, 1372, 1262, 1230, 1184, 1092, 1022, 983 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.28 (ddd, J=16.6, 11.4, 1.0 Hz, 1H), 7.42 (s, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.33 (dd, J=11.6, 11.4 Hz, 1H), 6.03 (dd, J=16.6, 1.0 Hz, 1H), 5.77 (br d, J=9.6 Hz, 1H), 5.66 (dd, J=9.6, 1.0 Hz, 1), 5.60 (q, J=6.7 Hz, 1H), 5.47 (br s, 1H), 5.03 (d, J=11.0 Hz, 1H), 4.94 (d, J=11.0 Hz, 1H), 4.09 (d, J=17.7 Hz, 1H), 3.33 (s, 3H), 2.46-2.33 (m, 3H), 2.33 (d, J=17.7 Hz, 1H), 2.02 (s, 3H), 1.93 (d, J=6.7 Hz, 3H), 1.78 (d, J=1.2 Hz, 3H), 1.73 (s, 3H), 1.51-1.43 (m, 1H)
FABMS m/z 597 (M+H).sup.+
HRFABMS calcd for C.sub.26 H.sub.33 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 597.1399, found 597.1407
EXAMPLE 35
Synthesis of Compounds 37 and 38
Compound 18 (a mixture of diastereomers, 48.5 mg, 0.082 mmol) was dissolved in dichloromethane (4.0 ml), and N,N-diisopropylethylamine (0.285 ml, 1.64 mmol), and chloromethyl methyl ether (0.062 ml, 0.82 mmol) were added thereto, followed by stirring at 25.degree. C. for 1.5 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=98/2) to obtain Compound 37 (21 mg, 39% yield) and Compound 38 (23 mg, 45% yield) which is a diastereomer thereof.
Compound 37
IR (KBr) 3404, 3096, 2940, 1690, 1648, 1607, 1442, 1374, 1259, 1186, 1152, 1094, 1023, 975, 894, 868, 810 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.59 (ddd, J=16.5, 11.6, 1.0 Hz, 1H), 7.40 (s, 1H), 6.61 (d, J=11.6 Hz, 1H), 6.34 (dd, J=11.6, 11.6 Hz, 1H), 6.00 (d, J=16.5 Hz, 1H), 5.83 (br d, J=9.2 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 5.53 (br s, 1H), 5.03 (d, J=11.0 Hz, 1H), 5.02 (dd, J=9.2, 1.2 Hz, 1H), 4.93 (d, J=11.0 Hz, 1H), 4.57 (t, J=4.3 Hz, 1H), 4.10 (d, J=17.7 Hz, 1H), 3.84-3.80 (m, 1H), 3.52-3.48 (m, 1H), 3.33 (s, 3H), 2.41-1.41 (m, 10H), 2.33 (d, J=17.7 Hz, 1H), 1.94 (d, J=6.7 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H), 1.71 (s, 3H)
FABMS m/z 639 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.39 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 639.1868, found 639.1876
Compound 38
IR (KBr) 3404, 3100, 2938, 1685, 1648, 1609, 1442, 1375, 1261, 1183, 1153, 1093, 1022, 974, 898, 868, 808 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.39 (ddd, J=16.5, 11.5, 1.0 Hz, 1H), 7.39 (s, 1H), 6.60 (d, J=11.5 Hz, 1H), 6.37 (dd, J=11.5, 11.5 Hz, 1H), 5.80 (br d, J=9.3 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.51 (br s, 1H), 5.03 (d, J=11.0 Hz, 1H), 4.93 (d, J=11.0 Hz, 1H), 4.74 (dd, J=9.3, 1.2 Hz, 1H), 4.70 (m, 1H), 4.09 (d, J=17.8 Hz, 1H), 3.77-3.71 (m, 1H), 3.47-3.42 (m, 1H), 3.34 (s, 3H), 2.40-1.41 (m, 10H), 2.34 (d, J=17.8 Hz, 1H), 1.88 (d, J=6.6 Hz, 3H), 1.73 (d, J=1.2 Hz, 3H), 1.71 (s, 3H)
FABMS m/z 639 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.39 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 639.1868, found 639.1860
EXAMPLE 36
Synthesis of Compound 39
According to the procedure as described in Example 1, Compound 39 (7.2 mg, 57% yield) was obtained from Compound 34 (12 mg, 0.019 mmol) prepared in Example 32, chloroform (1.0 ml), pyridine (0.15 ml, 1.9 mmol), acetic anhydride (0.036 ml, 0.38 mmol) and 4-dimethylaminopyridine (1.8 mg, 0.015 mmol).
IR (KBr) 3440, 3974, 2940, 1734, 1705, 1653, 1609, 1460, 1369, 1273, 1230, 1131, 1020, 974 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.21 (dd, J=16.6, 11.4 Hz, 1H), 7.35 (s, 1H), 6.55 (d, J=11.4 Hz, 1H), 6.26 (dd, J=11.4, 11.4 Hz, 1H), 5.95 (d, J=16.6 Hz, 1H), 5.70 (br d, J=9.7 Hz, 1H), 5.59 (d, J=9.7 Hz, 1H), 5.53 (q, J=6.6 Hz, 1H), 5.39 (br s, 1H), 5.36 (d, J=10.9 Hz, 1H), 5.28 (d, J=10.9 Hz, 1H), 3.28 (d, J=17.7 Hz, 1H), 2.40-2.24 (m, 3H), 2.20 (d, J=17.7 Hz, 1H), 1.95 (s, 3H), 1.85 (d, J=6.6 Hz, 3H), 1.71 (d, J=1.2 Hz, 3H), 1.64 (s, 3H), 1.45-1.35 (m, 1H), 1.12 (s, 9H)
FABMS m/z 667 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.39 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 667.1818, found 667.1818
EXAMPLE 37
Synthesis of Compound 40
According to the procedure as described in Example 1, Compound 40 (25 mg, 55% yield) was obtained from Compound 34 (42 mg, 0.067 mmol), dichloromethane (8.0 ml), pyridine (0.22 ml, 2.7 mmol), propionic anhydride (0.069 ml, 0.54 mmol) and 4-dimethylaminopyridine (4.9 mg, 0.040 mmol).
IR (KBr) 3430, 2982, 2940, 1735, 1700, 1654, 1610, 1457, 1363, 1273, 1130, 1073, 1016, 972, 806 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.27 (dd, J=16.8, 11.3 Hz, 1H), 7.42 (s, 1H), 6.61 (d, J=11.3 Hz, 1H), 6.33 (dd, J=11.3, 11.3 Hz, 1H), 6.02 (d, J=16.8 Hz, 1H), 5.77 (br d, J=10.0 Hz, 1H), 5.66 (d, J=10.0 Hz, 1H), 5.60 (q, J=6.4 Hz, 1H), 5.46 (br s, 1H), 5.43 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.03 (d, J=17.0 Hz, 1H), 2.43-2.30 (m, 3H), 2.29 (q, J=7.6 Hz, 2H), 2.28 (d, J=17.0 Hz, 1H), 1.92 (d, J=6.4 Hz, 3H), 1.78 (d, J=0.9 Hz, 3H), 1.71 (s, 3H), 1.55-1.45 (m, 1H), 1.19 (s, 9H), 1.08 (t, J=7.6 Hz, 3H)
FABMS m/z 681 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.41 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 681.1974, found 681.1987
EXAMPLE 38
Synthesis of Compound 41
According to the procedure as described in Example 1, Compound 41 (31 mg, 50% yield) was obtained from Compound 34 (55 mg, 0.088 mmol), dichloromethane (6.0 ml), pyridine (0.14 ml, 1.8 mmol) and ethyl chloroformate (0.084 ml, 0.88 mmol).
IR (KBr) 3430, 2984, 2938, 1735, 1698, 1654, 1609, 1478, 1456, 1370, 1320, 1260, 1129, 971, 873, 785 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.34 (ddd, J=16.8, 11.3, 0.9 Hz, 1H), 7.41 (s, 1H), 6.63 (d, J=11.3 Hz, 1H), 6.34 (dd, J=11.3, 11.3 Hz, 1H), 6.05 (d, J=16.8, 0.9 Hz, 1H), 5.80 (dd, J=9.8, 1.2 Hz, 1H), 5.61 (dd, J=9.8, 0.9 Hz, 1H), 5.57 (q, J=6.4 Hz, 1H), 5.49 (br s, 1H), 5.43 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.14 (q, 2H), 4.03 (d, J=17.7 Hz, 1H), 2.43-2.30 (m, 3H), 2.26 (d, J=17.7 Hz, 1H), 1.89 (d, J=6.4 Hz, 3H), 1.82 (d, J=1.2 Hz, 3H), 1.71 (s, 3H), 1.48-1.42 (m, 1H), 1.23 (t, 3H), 1.18 (s, 9H)
FABMS m/z 697 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.41 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 697.1923, found 697.1926
EXAMPLE 39
Synthesis of Compound 42
According to the procedure as described in Example 1, Compound 42 (27 mg, 73% yield) was obtained from Compound 34 (34 mg, 0.055 mmol), dichloromethane (3.0 ml), pyridine (0.044 ml, 0.54 mmol) and phenyl chloroformate (0.020 ml, 0.16 mmol).
IR (KBr) 3430, 2980, 1761, 1740, 1701, 1653, 1610, 1480, 1456, 1369, 1319, 1245, 1208, 1130, 1072, 1022, 973, 771 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.43 (dd, J=16.8, 11.5 Hz, 1H), 7.43 (s, 1H), 7.40-7.12 (m, 5H), 6.66 (d, J=11.5 Hz, 1H), 6.38 (dd, J=11.5, 11.5 Hz, 1H), 6.10 (d, J=16.8 Hz, 1H), 5.87 (br d, J=9.7 Hz, 1H), 5.73 (dd, J=9.7, 1.0 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 5.48 (br s, 1H), 5.43 (d, J=11.0 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 4.04 (d, J=17.8 Hz, 1H), 2.51-2.32 (m, 3H), 2.28 (d, J=17.8 Hz, 1H), 1.96 (d, J=6.7 Hz, 3H), 1.85 (d, J=1.2 Hz, 3H), 1.73 (s, 3H), 1.55-1.44 (m, 1H), 1.19 (s, 9H)
FABMS m/z 745 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.41 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 745.1923, found 745.1924
EXAMPLE 40
Synthesis of Compound 43
According to the procedure as described in Example 28, Compound 43 (10 mg, 36% yield) was obtained from Compound 34 (26 mg, 0.042 mmol), dichloromethane (4.0 ml), N,N-diisopropylethylamine (2.6 ml, 14.8 mmol), and chloromethyl methyl ether (0.93 ml, 12.2 mmol).
IR (KBr) 3440, 2986, 2936, 1735, 1696, 1647, 1609, 1457, 1364, 1272, 1133, 1094, 1027, 972 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.53 (ddd, J=16.5, 11.3, 0.9 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.36 (dd, J=11.6, 11.3 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.83 (br d, J=9.5 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 5.52 (br s, 1H), 5.43 (d, J=10.8 Hz, 1H), 5.36 (d, J=10.8 Hz, 1H), 4.80 (dd, J=9.5, 1.2 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.59 (d, J=6.7 Hz, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.29 (s, 3H), 2.42-2.32 (m, 3H), 2.28 (d, J=17.7 Hz, 1H), 1.90 (d, J=6.7 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H, 1.71 (s, 3H), 1.50-1.40 (m, 1H), 1.19 (s, 9H)
FABMS m/z 669 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.41 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 669.1974, found 669.1991
EXAMPLE 41
Synthesis of Compound 44
According to the procedure as described in Example 18, Compound 34 (54 mg, 0.86mmol) was dissolved in dichloromethane (10 ml), and 3,4-dihydro-2H-pyran (0.11 ml, 1.22 mmol) and camphorsulfonic acid (39 mg, 0.17 mmol) were added thereto, followed by stirring at 0.degree. C. for 5 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with ether/methanol=99/1) to obtain Compound 44 (21 mg, 34% yield). From .sup.1 H NMR, Compound 44 was found to be a mixture of diastereomers at a ratio of about 2:1.
IR (KBr) 3430, 2942, 2872, 1735, 1697, 1651, 1609, 1478, 1454, 1370, 1274, 1124, 1072, 1028, 971, 867, 799, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; major isomer: 9.40 (dd, J=16.8, 11.7 Hz, 1H), 7.40 (s, 1H), 6.60 (d, J=11.4 Hz, 1H), 6.37 (dd, J=11.7, 11.4 Hz, 1H), 6.05 (d, J=16.8 Hz, 1H), 5.80 (br d, J=10.0 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.51 (br s, 1H), 5.43 (d, J=10.7 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 4.74 (dd, J=10.0, 1.0 Hz, 1H), 4.71 (m, 1H), 4.03 (d, J=17.8 Hz, 1H), 3.81-3.69 (m, 1H), 3.47-3.40 (m, 1H), 2.43-1.40 (m, 10H), 2.28 (d, J=17.8 Hz, 1H), 1.88 (d, J=6.6 Hz, 3H), 1.74 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.19 (s, 9H); minor isomer: 9.59 (dd, J=16.8, 11.7 Hz, 1H), 7.40 (s, 1H), 6.61 (d, J=11.0 Hz, 1H), 6.34 (dd, J=11.7, 11.0 Hz, 1H), 6.00 (d, J=16.8 Hz, 1H), 5.83 (br d, J=10.0 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 5.52 (br s, 1H), 5.43 (d, J=10.7 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 5.02 (dd, J=10.0, 1.0 Hz, 1H), 4.57 (m, 1H), 4.04 (d, J=17.8 Hz, 1H), 3.87-3.80 (m, 1H), 3.55-3.40 (m, 1H), 2.43-1.40 (m, 10H), 2.27 (d, J=17.8 Hz, 1H), 1.94 (d, J=6.6 Hz, 3H), 1.76 (d, J=1.0H, 3H), 1.70 (s, 3H), 1.19 (s, 9H)
FABMS m/z 709 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.45 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 709.2287, found 709.2305
EXAMPLE 42
Synthesis of Compounds 45 and 46
Compound 35 (50 mg, 0.081 mmol) obtained in Example 33 was dissolved in chloroform (2.0 ml) and pyridine (0.66 ml, 8.1 mmol), and then acetic anhydride (0.15 ml, 1.6 mmol) and 4-dimethylaminopyridine (7.9 mg, 0.065 mmol) were added thereto, followed by stirring at 25.degree. C. for 30 minutes. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 45 (10.5 mg, 20% yield) and Compound 46 (26 mg, 46% yield).
Compound 45 (Monoacetyl compound)
IR (KBr) 3430, 2932, 1821, 1735, 1682, 1650, 1610, 1440, 1370, 1262, 1231, 1152, 1094, 1027, 978, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.26 (ddd, J=16.9, 11.3, 1.0 Hz, 1H), 7.42 (s, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.33 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (d, J=16.9 Hz, 1H), 5.77 (br d, J=9.5 Hz, 1H), 5.66 (d, J=6.8, 1.0 Hz, 1H), 5.60 (q, J=6.4 Hz, 1H), 5.44 (br s, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.78 (d, J=15.9 Hz, 1H), 3.77 (d, J=15.9 Hz, 1H), 2.48-2.25 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 2.03 (s, 3H), 1.92 (d, J=6.4 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.71 (s, 3H), 1.55-1.40 (m, 1H).
FABMS m/z 665 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.33 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 665.1297, found 665.1312
Compound 46 (Diacetyl compound)
IR (KBr) 3430, 2936, 1824, 1735, 1720, 1685, 1611, 1440, 1369, 1268, 1231, 1122, 1019, 974, 942, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.11 (dd, J=16.5, 11.4 Hz, 1H), 7.41 (s, 1H), 6.61 (d, J=11.4 Hz, 1H), 6.31 (dd, J=11.4, 11.4 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.74 (br d, J=9.5 Hz, 1H), 5.67 (d, J=9.5 Hz, 1H), 5.53 (q, J=6.4 Hz, 1H), 3.94 (d, J=17.8 Hz, 1H), 3.89 (br s, 2H), 2.55 (d, J=17.8 Hz, 1H), 2.38-1.95 (m, 3H), 2.14 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.95 (d, J=6.4 Hz, 3H), 1.74 (d, J=1.0 Hz, 3H), 1.60-1.48 (m, 1H)
FABMS m/z 707 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.35 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 707.1403, found 707.1389
EXAMPLE 43
Synthesis of Compound 47
According to the procedure as described in Example 1, Compound 47 (29 mg, 54% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), dichloromethane (2.4 ml), pyridine (0.23 ml, 2.8 mmol) and propionic anhydride (0.061 ml, 0.48 mmol).
IR (KBr) 3420, 2928, 1821, 1734, 1685, 1652, 1609, 1455, 1363, 1268, 1208, 1170, 1074, 1016, 978, 755 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.26 (ddd, J=16.8, 11.3, 1.0 Hz, 1H), 7.42 (s, 1H), 6.61 (d, J=11.6 Hz, 1H), 6.33 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (dd, J=16.8, 1.0 Hz, 1H), 5.77 (dd, J=9.5, 1.2 Hz, 1H), 5.66 (dd, J=9.5, 1.0 Hz, 1H), 5.60 (q, J=6.7 Hz, 1H), 5.44 (br s, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.80 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 2.47-2.30 (m, 3H), 2.29 (q, J=7.6 Hz, 2H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.92 (d, J=6.7 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H), 1.55-1.48 (m, 1H), 1.08 (t, J=7.6 Hz, 3H)
FABMS m/z 679 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.35 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 679.1454, found 679.1480
EXAMPLE 44
Synthesis of Compound 48
According to the procedure as described in Example 1, Compound 48 (24 mg, 55% yield) was obtained from Compound 35 (36 mg, 0.058 mmol), dichloromethane (3.0 ml), pyridine (0.050 ml, 0.62 mmol) and cyclohexanecarbonyl chloride (0.039 ml, 0.29 mmol).
IR (KBr) 3430, 2934, 2858, 1823, 1732, 1684, 1611, 1449, 1374, 1264, 1209, 1162, 1131, 977, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.19 (dd, J=16.5, 11.5 Hz, 1H), 7.41 (s, 1H), 6.60 (d, J=11.5 Hz, 1H), 6.32 (dd, J=11.5, 11.5 Hz, 1H), 6.00 (d, J=16.5 Hz, 1H), 5.76 (br d, J=9.5 Hz, 1H), 5.60 (d, J=9.5 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 5.45 (br s, 1H), 4.04 (d, J=17.8 Hz, 1H), 3.80 (d, J=15.2 Hz, 1H), 3.76 (d, J=15.2 Hz, 1H), 2.47-1.10 (m, 15H), 2.30 (d, J=17.8 Hz, 1H), 2.15 (s, 3H), 1.93 (d, J=6.6 Hz, 3H), 1.77 (d, J=0.7 Hz, 3H), 1.71 (s, 3H)
FABMS m/z 733 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.41 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 733.1923, found 733.1934
EXAMPLE 45
Synthesis of Compound 49
Compound 35 (51 mg 0.082 mmol), 1-naphthoic acid (42 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) were dissolved in dichloromethane (5.0 ml), followed by stirring at 25.degree. C. for 20 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 49 (18 mg, 28% yield).
IR (KBr) 3420, 2930, 1821, 1711, 1684, 1611, 1501, 1438, 1375, 1267, 1241, 1195, 1131, 978, 781 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.41 (dd, J=16.6, 11.3, 0.6 Hz, 1H), 8.80 (dd, J=8.7, 1.1 Hz, 1H), 8.12 (dd, J=7.5, 1.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.84 (dd, J=8.0, 1.4 Hz, 1H), 7.57-7.47 (m, 2H), 7.42 (s, 1H), 7.29 (dd, J=8.2, 7.5 Hz, 1H), 6.63 (d, J=11.6 Hz, 1H), 6.37 (dd, J=11.6, 11.3 Hz, 1H), 6.14 (d, J=16.6 Hz, 1H), 6.06 (dd, J=9.5, 0.9 Hz, 1H), 5.94 (br d, J=9.5 Hz, 1H), 5.45 (q, J=6.7 Hz, 1H), 5.44 (br s, 1H), 4.01 (d, J=17.7 Hz, 1H), 3.78 (br s, 2H), 2.50-2.25 (m, 3H), 2.28 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.91 (d, J=1.2 Hz, 3H), 1.72 (s, 3H), 1.63-1.55 (m, 1H), 1.56 (d, J=6.7 Hz, 3H)
FABMS m/z 777 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.37 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 777.1610, found 777.1639
EXAMPLE 46
Synthesis of Compound 50
According to the procedure as described in Example 45, Compound 50 (15 mg, 29% yield) was obtained from Compound 35 (40 mg, 0.065 mmol), 2-naphthoic acid (122 mg, 0.71 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg, 0.71 mmol), dichloromethane (5.0 ml) and 4-dimethylaminopyridine (3.2 mg, 0.026 mmol).
IR (KBr) 3430, 2932, 1821, 1713, 1685, 1610, 1440, 1389, 1371, 1356, 1269, 1227, 1195, 1129, 1090, 977, 866, 777 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.51 (dd, J=16.5, 11.3 Hz, 1H), 8.55 (s, 1H), 7.98 (dd, J=8.5, 1.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.55 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.46 (s, 1H), 7.46 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 6.65 (d, J=11.6 Hz, 1H), 6.38 (dd, J=11.6, 11.3 Hz, 1H), 6.12 (d, J=16.5 Hz, 1H), 6.08 (dd, J=9.5, 1.2 Hz, 1H), 5.96 (br d, J=9.5 Hz, 1H), 5.49 (q, J=6.4 Hz, 1H), 5.44 (br s, 1H), 4.02 (d, J=17.7 Hz, 1H), 3.78 (br s, 2H), 2.52-2.26 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.92 (d, J=1.2 Hz, 3H), 1.73 (s, 3H), 1.67 (d, J=6.7 Hz, 3H), 1.64-1.55 (m, 1H)
FABMS m/z 777 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.37 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 777.1610, found 777.1612
EXAMPLE 47
Synthesis of Compound 51
According to the procedure as described in Example 45, Compound 51 (18 mg, 29% yield) was obtained from Compound 35 (51 mg, 0.082 mmol), quinaldic acid (28 mg, 0.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol), dichloromethane (5.0 ml) and 4-dimethylaminopyridine (1.3 mg, 0.011 mmol).
IR (KBr) 3420, 2930, 1821, 1719, 1678, 1610, 1501, 1458, 1375, 1269, 1210, 1133, 1106, 977, 844, 776 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.42 (dd, J=16.3, 11.3 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.05 (dd, J=8.2, 1.0 Hz, 1H), 7.82 (dd, J=8.2, 1.0 Hz, 1H), 7.73 (ddd, J=8.2, 7.0, 1.0 Hz, 1H), 7.62 (ddd, J=8.2, 7.0, 1.0 Hz, 1H), 7.43 (s, 1H), 6.64 (d, J=11.6 Hz, 1H), 6.37 (dd, J=11.6, 11.3 Hz, 1H), 6.14 (d, J=16.3 Hz, 1H), 6.12 (d, J=8.8 Hz, 1H), 5.96 (br d, J=8.8 Hz, 1H), 5.45 (q, J=6.7 Hz, 1H), 5.45 (br s, 1H), 4.00 (d, J=17.7 Hz, 1H), 3.79 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 2.50-2.27 (m, 3H), 2.27 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.94 (d, J=1.2 Hz, 3H), 1.73 (s, 3H), 1.67 (d, J=6.7 Hz, 3H), 1.62-1.50 (m, 1H)
FABMS m/z 778 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.36 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 778.1563, found 778.1565
EXAMPLE 48
Synthesis of Compound 52
According to the procedure as described in Example 1, Compound 52 (38 mg, 61% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), dichloromethane (5.0 ml), pyridine (0.16 ml, 2.0 mmol) and 2-quinoxaloyl chloride (47 mg, 0.24 mmol).
IR (KBr) 3430, 2930, 1820, 1719, 1707, 1684, 1609, 1490, 1364, 1341, 1266, 1231, 1208, 1154, 1107, 977, 799, 775 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.44 (s, 1H), 9.41 (dd, J=16.8, 11.6 Hz, 1H), 8.13 (dd, J=8.2, 1.4 Hz, 1H), 8.09 (dd, J=8.2, 1.4 Hz, 1H), 7.88 (ddd, J=8.2, 6.7, 1.4 Hz, 1H), 7.82 (ddd, J=8.2, 6.7, 1.4 Hz, 1H), 7.44 (s, 1H), 6.65 (d, J=11.6 Hz, 1H), 6.37 (dd, J=11.6, 11.6 Hz, 1H), 6.17 (dd, J=9.8, 0.9 Hz, 1H), 6.14 (dd, J=16.8, 0.9 Hz, 1H), 5.97 (br d, J=9.8 Hz, 1H), 5.47 (q, J=6.4 Hz, 1H), 5.40 (br s, 1H), 4.01 (d, J=17.7 Hz, 1H), 3.78 (br s, 2H), 2.52-2.25 (m, 3H), 2.28 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.94 (d, J=1.2 Hz, 3H), 1.73 (s, 3H), 1.69 (d, J=6.4 Hz, 3H), 1.65-1.50 (m, 1H)
SIMS m/z 779 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.35 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 779.1515, found 779.1522
EXAMPLE 49
Synthesis of Compound 53
According to the procedure as described in Example 1, Compound 53 (26 mg, 63% yield) was obtained from Compound 35 (38 mg, 0.060 mmol), dichloromethane (3.0 ml), pyridine (0.049 ml, 0.060 mmol) and ethyl chloroformate (0.029 ml, 0.30 mmol).
IR (KBr) 3440, 2926, 1822, 1736, 1690, 1660, 1610, 1437, 1372, 1262, 1208, 1160, 1093, 978, 880, 787, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.32 (ddd, J=16.8, 11.3, 0.9 Hz, 1H), 7.41 (s, 1H), 6.63 (d, J=11.3 Hz, 1H), 6.34 (t, J=11.3 Hz, 1H), 6.06 (dd, J=16.7, 0.6 Hz, 1H), 5.79 (br d, J=9.5 Hz, 1H), 5.61 (dd, J=9.5, 0.9 Hz, 1H), 5.57 (q, J=6.7 Hz, 1H), 5.46 (br s, 1H), 4.15 (dq, J=7.2, 0.6 Hz, 2H), 4.03 (d, J=17.7 Hz, 1H), 3.78 (s, 2H), 2.27 (d, J=17.7 Hz, 1H), 2.48-1.45 (m, 4H), 2.15 (s, 3H), 1.89 (d, J=6.7 Hz, 3H), 1.82 (d, J=1.2 Hz, 3H), 1.71 (s, 3H), 1.24 (t, J=7.2 Hz, 3H)
FABMS m/z 695 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.35 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 695.1403, found 695.0392
EXAMPLE 50
Synthesis of Compound 54
According to the procedure as described in Example 1, Compound 54 (39 mg, 68% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), dichloromethane (5.0 ml), pyridine (0.065 ml, 0.80 mmol) and isobutyl chloroformate (0.052 ml, 0.40 mmol).
IR (KBr) 3430, 2980, 2934, 1823, 1733, 1694, 1651, 1608, 1460, 1380, 1260, 1240, 1209, 1072, 976, 770 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.36 (ddd, J=16.8, 11.3, 0.9 Hz, 1H), 7.41 (s, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.34 (dd, J=11.6, 11.3 Hz, 1H), 6.05 (dd, J=16.8, 0.6 Hz, 1H), 5.78 (br d, J=9.5 Hz, 1H), 5.58 (q, J=6.7 Hz, 1H), 5.57 (dd, J=9.5, 1.2 Hz, 1H), 5.47 (br s, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.91 (dd, J=10.4, 6.7 Hz, 1H), 3.84 (dd, J=10.4, 6.7 Hz, 1H), 3.78 (br s, 2H), 2.50-2.15 (m, 3H), 2.27 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.92-1.82 (m, 1H), 1.90 (d, J=6.7 Hz, 3H), 1.81 (d, J=1.2 Hz, 3H), 1.71 (s, 3H), 1.55-1.42 (m, 1H), 0.85 (d, J=6.7 Hz, 6H)
FABMS m/z 723 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.39 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 723.1716, found 723.1715
EXAMPLE 51
Synthesis of Compound 55
According to the procedure as described in Example 1, Compound 55 (36 mg, 57% yield) was obtained from Compound 35 (53 mg, 0.085 mmol), dichloromethane (5.0 ml), pyridine (0.069 ml, 0.85 mmol) and phenyl chloroformate (0.032 ml, 0.26 mmol).
IR (KBr) 3420, 2934, 1821, 1759, 1720, 1677, 1610, 1489, 1457, 1375, 1260, 1241, 1209, 1115, 1021, 977, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.41 (ddd, J=16.7, 11.2, 1.0 Hz, 1H), 7.43 (s, 1H), 7.37-7.05 (m, 5H), 6.66 (d, J=11.5 Hz, 1H), 6.38 (dd, J=11.5, 11.2 Hz, 1H), 6.10 (d, J=16.7, Hz, 1H), 5.87 (br d, J=9.7 Hz, 1H), 5.73 (dd, J=9.7, 1.0 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 5.46 (br s, 1H), 4.05 (d, J=17.8 Hz, 1H), 3.78 (s, 2H), 2.52-2.25 (m, 3H), 2.29 (d, J=17.8 Hz, 1H), 2.15 (s, 3H), 1.96 (d, J=6.6 Hz, 3H), 1.85 (d, J=1.0 Hz, 3H), 1.72 (s, 3H), 1.60-1.45 (m, 1H)
FABMS m/z 743 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.35 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 743.1403, found 743.1417
EXAMPLE 52
Synthesis of Compound 56
According to the procedure as described in Example 1, Compound 56 (15 mg, 39% yield) was obtained from Compound 35 (30 mg, 0.049 mmol), dichloromethane (3.0 ml), pyridine (1.27 ml, 15.7 mmol) and benzyl chloroformate (0.692 ml, a 30% toluene solution, 1.46 mmol).
IR (KBr) 3430, 2932, 1821, 1738, 1710, 1680, 1609, 1453, 1382, 1153, 1113, 1093, 976, 785, 768, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.34 (ddd, J=16.8, 11.5, 1.0 Hz, 1H), 7.40 (s, 1H), 7.40-7.25 (m, 5H), 6.62 (d, J=11.5 Hz, 1H), 6.32 (dd, J=11.5, 11.5 Hz, 1H), 6.03 (dd, J=16.8, 1.0 Hz, 1H), 5.79 (br d, J=9.5 Hz, 1H), 5.61 (dd, J=9.5, 1.0 Hz, 1H), 5.54 (q, J=6.5 Hz, 1H), 5.46 (br s, 1H), 5.11 (s, 2H), 4.03 (d, J=17.7 Hz, 1H), 3.77 (s, 2H), 2.48-2.25 (m, 3H), 2.26 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.84 (d, J=6.5 Hz, 3H), 1.81 (d, J=1.0 Hz, 3H), 1.71 (s, 3H), 1.55-1.42 (m, 1H)
FABMS m/z 757 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.37 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 757.1559, found 757.1538
EXAMPLE 53
Synthesis of Compound 57
According to the procedure as described in Example 1, Compound 57 (40 mg, 60% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), dichloromethane (4.0 ml), pyridine (0.078 ml, 0.96 mmol ) and 9-fluorenylmethyl chloroformate (83 ml, 0.32 mmol).
IR (KBr) 3420, 2920, 1822, 1733, 1680, 1610, 1449, 1384, 1263, 1209, 1152, 1092, 976, 759, 740 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.48 (dd, J=16.6, 11.6 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.34 (dd, J=7.6, 7.3 Hz, 1H), 7.29 (d, J=7.6, 7.3 Hz, 1H), 7.18 (dd, J=7.6, 7.3 Hz, 1H), 6.98 (dd, J=7.6, 7.3 Hz, 1H), 6.64 (d, J=11.3 Hz, 1H), 6.32 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.77 (br d, J=9.5 Hz, 1H), 5.57 (q, J=6.7 Hz, 1H), 5.50 (d, J=9.5 Hz, 1H), 5.49 (br s, 2H), 4.59 (dd, J=10.7, 6.7 Hz, 1H), 4.25 (dd, J=10.7, 7.0 Hz, 1H), 4.13 (br dd, J=7.0, 6.7 Hz, 1H), 4.06 (d, J=17.7 Hz, 1H), 3.79 (d, J=15.3 Hz, 1H), 3.77 (d, J=15.3 Hz, 1H), 2.53-2.29 (m, 3H), 2.26 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.78 (d, J=0.9 Hz, 3H), 1.77 (d, J=6.7 Hz, 3H), 1.72 (s, 3H), 1.43-1.37 (m, 1H)
FABMS m/z 845 (M+H).sup.+
HRFABMS calcd for C.sub.42 H.sub.41 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 845.1872, found 845.1859
EXAMPLE 54
Synthesis of Compound 58
According to the procedure as described in Example 28, Compound 58 (18 mg, 42% yield) was obtained from Compound 35 (41 mg, 0.065 mmol), dichloromethane (2.0 ml), N,N-diisopropylethylamine (3.8 ml, 22mmol) and chloromethyl methyl ether (0.83 ml, 11 mmol).
IR (KBr) 3430, 2932, 1821, 1720, 1684, 1647, 1608, 1437, 1374, 1262, 1209, 1150, 1093, 1026, 977, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.51 (dd, J=16.5, 11.3 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=11.3 Hz, 1H), 6.36 (dd, J=11.3, 11.3 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.83 (br d, J=9.2 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 5.50 (br s, 1H), 4.80 (dd, J=9.2, 1.2 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.60 (d, J=6.7 Hz, 1H), 4.04 (d, J=17.5 Hz, 1H), 3.80 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 3.29 (s, 3H), 2.46-2.22 (m, 3H), 2.29 (d, J=17.5 Hz, 1H), 2.15 (s, 3H), 1.90 (d, J=6.7 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H), 1.70 (s, 3H), 1.52-1.42 (m, 1H)
FABMS m/z 667 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.35 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 667.1454, found 667.1459
EXAMPLE 55
Synthesis of Compound 59
According to the procedure as described in Example 28, Compound 59 (9.8 mg, 42% yield) was obtained from Compound 35 (21 mg, 0.034 mmol), dichloromethane (1.5 ml), N,N-diisopropylethylamine (1.1 ml, 6.4 mmol) and chloromethyl ethyl ether (0.44 ml, 4.7 mmol).
IR (KBr) 3430, 2932, 1820, 1718, 1684, 1653, 1609, 1436, 1387, 1262, 1209, 1150, 1092, 1025, 978, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.51 (ddd, J=16.5, 11.6, 0.9 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=11.3 Hz, 1H), 6.36 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (dd, J=16.5, 0.9 Hz, 1H), 5.82 (br d, J=9.5 Hz, 1H), 5.58 (q, J=6.4 Hz, 1H), 5.50 (br s, 1H), 4.82 (dd, J=9.5, 1.2 Hz, 1H), 4.68 (d, J=9.9 Hz, 1H), 4.64 (d, J=9.9 Hz, 1H), 4.04 (d, J=17.5 Hz, 1H), 3.80 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 3.56-3.46 (m, 2H), 2.44-2.24 (m, 3H), 2.29 (d, J=17.5 Hz, 1H), 2.15 (s, 3H), 1.90 (d, J=6.4 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H), 1.70 (s, 3H), 1.52-1.41 (m, 1H), 1.14 (t, J=7.0 Hz, 3H)
FABMS m/z 681 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.37 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 681.1610, found 681.1622
EXAMPLE 56
Synthesis of Compound 60
According to the procedure as described in Example 28, Compound 60 (17 mg, 25% yield) was obtained from Compound 35 (56 mg, 0.090 mmol), dichloromethane (4.0 ml), N,N-diisopropylethylamine (1.3 ml, 7.2mmol) and chloromethyl octyl ether (0.70 ml, 3.6 mmol).
IR (KBr) 3430, 3055, 2934, 2858, 1822, 1699, 1650, 1607, 1454, 1380, 1260, 1208, 1160, 1105, 1016, 980, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.50 (ddd, J=16.5, 11.3, 1.0 Hz, 1H), 7.39 (s, 1H), 6.61 (d, J=11.3 Hz, 1H), 6.35 (dd, J=11.3, 11.3 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.82 (dd, J=9.2, 1.0 Hz, 1H), 5.58 (q, J=6.4 Hz, 1H), 5.51 (br s, 1H), 4.81 (dd, J=9.2, 1.0 Hz, 1H), 4.67 (d, J=6.7 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.79 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 3.46 (dt, J=9.5, 6.7 Hz, 1H), 3.41 (dt, J=9.5, 6.7 Hz, 1H), 2.45-2.22 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.89 (d, J=6.4 Hz, 3H), 1.76 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.55-1.43 (m, 3H), 1.31-1.20 (m, 10H), 0.88 (t, J=7.0 Hz, 3H)
FABMS m/z 765 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.49 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 765.2549, found 765.2557
EXAMPLE 57
Synthesis of Compound 61
According to the procedure as described in Example 28, Compound 61 (16 mg, 25% yield) was obtained from Compound 35 (54 mg, 0.086 mmol), dichloromethane (4.0 ml), N,N-diisopropylethylamine (0.75 ml, 4.3 mmol) and chloromethyl benzyl ether (0.30 ml, 2.2 mmol).
IR (KBr) 3420, 2940, 1817, 1695, 1650, 1607, 1454, 1380, 1260, 1209, 1160, 1094, 1025, 980, 768, 736, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.52 (ddd, J=16.5, 11.6, 1.0 Hz, 1H), 7.40-7.24 (m, 5H), 7.40 (s, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.34 (dd, J=11.6, 11.6 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.84 (dd, J=9.2, 1.0 Hz, 1H), 5.59 (q, J=6.4 Hz, 1H), 5.50 (br s, 1H), 4.89 (dd, J=6.2, 1.0 Hz, 1H), 4.76 (d, J=6.7 Hz, 1H), 4.73 (d, J=6.7 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.79 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 2.46-2.25 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.91 (d, J=6.4 Hz, 3H), 1.76 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.54-1.45 (m, 1H)
FABMS m/z 743 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.39 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 743.1767, found 743.1773
EXAMPLE 58
Synthesis of Compound 62
According to the procedure as described in Example 28, Compound 62 (22 mg, 38% yield) was obtained from Compound 35 (51 mg, 0.082 mmol), dichloromethane (3.0 ml), N,N-diisopropylethylamine (2.1 ml, 12 mmol) and 2-methoxyethoxymethyl chloride (0.84 ml, 7.4 mmol).
IR (KBr) 3420, 2932, 1820, 1705, 1679, 1648, 1608, 1447, 1364, 1261, 1208, 1105, 1094, 1019, 977, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.48 (dd, J=16.8, 11.3 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=11.6 Hz, 1H), 6.36 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (d, J=16.8 Hz, 1H), 5.82 (br d, J=9.2 Hz, 1H), 5.58 (q, J=6.4 Hz, 1H), 5.50 (br s, 1H), 4.84 (dd, J=9.2, 1.2 Hz, 1H), 4.72 (d, J=6.9 Hz, 1H), 4.69 (d, J=6.9 Hz, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.80 (d, J=15.6 Hz, 1H), 3.76 (d, J=15.6 Hz, 1H), 3.62-3.45 (m, 4H), 3.35 (s, 3H), 2.46-2.24 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.89 (d, J=6.4 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H), 1.70 (s, 3H), 1.50-1.42 (m, 1H)
FABMS m/z 711 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.39 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 711.1716, found 711.1724
EXAMPLE 59
Synthesis of Compounds 63 and 64
According to the procedure as described in Example 18, Compound 35 (53 mg, 0,085 mmol) was dissolved in dichloromethane (4.7 ml), and 3,4-dihydro-2H-pyran (0.035 ml, 0.39 mmol) and camphorsulfonic acid (13.5 mg, 0.058 mmol) were added thereto, followed by stirring at 0.degree. C. for 2 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed seven times with chloroform/methanol=98/2) to obtain Compound 63 (14 mg, 23% yield) and Compound 64 (22 mg, 37% yield) as a diastereomer thereof.
Compound 63
IR (KBr) 3420, 2930, 1820, 1710, 1686, 1647, 1607, 1437, 1387, 1260, 1207, 1116, 1073, 1021, 973, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.58 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.40 (s, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.34 (dd, J=11.5, 11.5 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.83 (br d, J=9.0 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 5.50 (s, 1H), 5.02 (dd, J=9.0, 1.0 Hz, 1H), 4.57 (m, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.88-3.80 (m, 1H), 3.78 (s, 2H), 3.53-3.47 (m, 1H), 2.46-1.40 (m, 10H), 2.30 (d, J=17.8 Hz, 1H), 2.15 (s, 3H), 1.94 (d, J=6.6 Hz, 3H), 1.77 (d, J=1.0 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 707 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.39 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 707.1767, found 707.1793
Compound 64
IR (KBr) 3420, 2940, 1822, 1715, 1690, 1650, 1610, 1441, 1375, 1262, 1207, 1117, 3073, 1028, 973, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.39 (ddd, J=16.5, 11.2, 1.0 Hz, 1H), 7.39 (s, 1H), 6.60 (d, J=11.7 Hz, 1H), 6.37 (dd, J=11.7, 11.2 Hz, 1H), 6.05 (d, J=16.5 Hz, 1H), 5.80 (br d, J=9.2 Hz, 1H), 5.57 (q, J=6.5 Hz, 1H), 5.48 (br s, 1H), 4.74 (dd, J=9.2, 1.0 Hz, 1H), 4.70 (m, 1H), 4.04 (d, J=17.7 Hz, 1H), 3.80 (d, J=15.2 Hz, 1H), 3.83-3.72 (m, 1H), 3.75 (d, J=15.2 Hz, 1H), 3.47-3.38 (m, 1H), 2.45-1.40 (m, 10H), 2.29 (d, J=17.7 Hz, 1H), 2.15 (s, 3H), 1.88 (d, J=6.5 Hz, 3H), 1.74 (d, J=1.0 Hz, 3H), 1.69 (s, 3H)
FABMS m/z 707 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.39 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 707.1767, found 707.1783
EXAMPLE 60
Synthesis of Compound 65
DC107 (5.8 mg, 0.011 mmol) was dissolved in methanol (0.50 ml), and then, pyridine (0.0046 ml, 0.057 mmol) and hydroxylamine hydrochloride (1.6 mg, 0.022 mmol) were added thereto, followed by stirring at 0.degree. C. for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 65 (3.0 mg, 52% yield).
IR (KBr) 3370, 2932, 1713, 1641, 1527, 1449, 1376, 1298, 1211, 1094, 951, 889, 798 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.78 (dd, J=16.5, 11.2 Hz, 1H), 7.12 (s, 1H), 7.02 (br d, J=6.3 Hz, 1H), 6.41 (d, J=11.3 Hz, 1H), 6.34 (dd, J=11.3, 11.2 Hz, 1H), 6.20 (dd, J=9.8, 1.0 Hz, 1H), 6.18 (d, J=16.5 Hz, 1H), 6.00 (br d, J=9.8 Hz, 1H), 5.27 (br s, 1H), 5.24 (dq, J=6.6, 6.3 Hz, 1H), 3.25 (d, J=14.6 Hz, 1H), 2.85 (d, J=14.6 Hz, 1H), 2.34 (m, 4H), 1.91 (s, 3H), 1.75 (s, 3H), 1.74 (d, J=6.6 Hz, 3H)
FABMS m/z 526 (M+H).sup.+
HRFABMS calcd for C.sub.22 H.sub.28 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 526.1140, found 526.1152
EXAMPLE 61
Synthesis of Compounds 66 and 67
According to the procedure as described in Example 60, Compound 66 (1.4 mg, 24% yield) and Compound 67 (3.6 mg, 61% yield) which is a geometrical isomer thereof were obtained from DC107 (5.7 mg, 0.011 mmol), methanol (0.5 ml), pyridine (0.030 ml, 0.37 mmol) and 0-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol).
Compound 66
IR (KBr) 3420, 2938, 1710, 1643, 1530, 1449, 1372, 1093, 1047, 951, 928, 795 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.75 (dd, J=16.5, 11.0 Hz, 1H), 7.11 (s, 1H), 6.95 (br d, J=6.5 Hz, 1H), 6.40 (d, J=11.5 Hz, 1H), 6.34 (dd, J=11.5, 11.0 Hz, 1H), 6.19 (d, J=16.5 Hz, 1H), 6.09 (dd, J=9.8, 1.0 Hz, 1H), 5.98 (br d, J=9.8 Hz, 1H), 5.24 (dq, J=6.5, 6.5 Hz, 1H), 3.93 (s, 3H), 3.27 (dd, J=14.6, 1.2 Hz, 1H), 2.84 (d, J=14.6 Hz, 1H), 2.31-1.75 (m, 4H), 1.92 (s, 3H), 1.74 (d, J=6.5 Hz, 3H), 1.72 (d, J=1.0 Hz, 3H)
FABMS m/z 540 (M+H).sup.+
HRFABMS calcd for C.sub.23 H.sub.30 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 540.1297, found 540.1284
Compound 67
IR (KBr) 3420, 2938, 1705, 1643, 1530, 1450, 1374, 1096, 1052, 949, 889,799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.13 (dd, J=16.6, 11.5 Hz, 1H), 7.14 (s, 1H), 6.99 (br d, J=6.6 Hz, 1H), 6.78 (d, J=16.6 Hz, 1H), 6.51 (d, J=11.5 Hz, 1H), 6.39 (dd, J=11.5, 11.5 Hz, 1H), 5.86 (br d, J=9.4 Hz, 1H), 5.32 (dq, J=6.6, 6.6 Hz, 1H), 5.13 (d, J=9.4 Hz, 1H), 3.93 (s, 3H), 3.11 (d, J=15.3 Hz, 1H), 3.01 (d, J=15.3 Hz, 1H), 2.32 (dt, J=12.5, 4.1 Hz, 1H), 1.99-1.80 (m, 3H), 1.81 (s, 3H), 1.74 (d, J=6.6 Hz, 3H), 1.66 (d, J=1.2 Hz, 3H)
FABMS m/z 540 (M+H).sup.+
HRFABMS calcd for C.sub.23 H.sub.30 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 540.1297, found 540.1284
EXAMPLE 62
Synthesis of Compounds 68 and 69
According to the procedure as described in Example 60, Compound 68 (29 mg, 47% yield) and Compound 69 (26 mg, 43% yield) which is a geometrical isomer thereof were obtained from DC107 (50 mg, 0.10 mmol), methanol (5.0 ml), pyridine (0.040 ml, 0.50 mmol) and O-benzylhydroxylamine hydrochloride (32 mg, 0.20 mmol).
Compound 68
IR (KBr) 3420, 2924, 1719, 1648, 1540, 1451, 1363, 1084, 1015, 952, 795, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.78 (dd, J=16.8, 11.0 Hz, 1H), 7.37-7.30 (m, 5H), 7.10 (s, 1H), 6.97 (d, J=6.2 Hz, 1H), 6.39 (d, J=11.5 Hz, 1H), 6.33 (dd, J=11.5, 11.0 Hz, 1H), 6.20 (d, J=16.8 Hz, 1H), 6.14 (dd, J=9.7, 1.2 Hz, 1H), 5.97 (br d, J=9.7 Hz, 1H), 5.23 (dq, J=6.3, 6.0 Hz, 1H), 5.17 (d, J=12.0 Hz, 1H), 5.13 (d, J=12.0 Hz, 1H), 3.26 (dd, J=14.6, 1.4 Hz, 1H), 2.83 (d, J=14.6 Hz, 1H), 2.27 (dt, J=12.7, 2.9 Hz, 1H), 2.06 (dt, J=12.7, 6.3 Hz, 1H), 1.92 (s, 3H), 1.92 (ddd, J=14.7, 12.7, 2.9 Hz, 1H), 1.82 (ddd, J=14.7, 12.7, 6.3 Hz, 1H), 1.73 (d, J=6.3 Hz, 3H), 1.63 (s, 3H)
FABMS m/z 616 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.34 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 616.1610, found 616.1612
Compound 69
IR (KBr) 3400, 2930, 1720, 1652, 1539, 1451, 1369, 1209, 1097, 1016, 952, 878, 799, 730, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.25 (dd, J=16.3, 11.2 Hz, 1H), 7.38-7.28 (m, 5H), 7.11 (s, 1H), 6.83 (d, J=16.3 Hz, 1H), 6.82 (br d, J=6.6 Hz, 1H), 6.50 (d, J=11.3 Hz, 1H), 6.36 (dd, J=11.3, 11.2 Hz, 1H), 5.91 (br d, J=9.4 Hz, 1H), 5.29 (dq, J=6.9, 6.6 Hz, 1H), 5.16 (br s, 2H), 5.15 (d, J=9.4 Hz, 1H), 4.59 (br s, 1H), 3.10 (d, J=15.0 Hz, 1H), 2.98 (d, J=15.0 Hz, 1H), 2.38 (br s, 1H), 2.36-2.26 (m, 1H), 2.01-1.82 (m, 3H), 1.82 (s, 3H), 1.73 (d, J=6.9 Hz, 3H), 1.64 (d, J=1.2 Hz, 3H)
FABMS m/z 616 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.34 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 616.1610, found 616.1605
EXAMPLE 63
Synthesis of Compounds 70 and 71
According to the procedure as described in Example 60, Compound 70 (27 mg, 49% yield) and Compound 71 (14 mg, 26% yield) which is a geometrical isomer thereof were obtained from DC107 (51 mg, 0.10 mmol), methanol (5.0 ml), pyridine (0.040 ml, 0.50 mmol) and O-allylhydroxylamine hydrochloride (33 mg, 0.30 mmol).
Compound 70
IR (KBr) 3420, 2926, 1719, 1647, 1539, 1448, 1370, 1096, 1025, 1001, 945, 888, 798 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.79 (dd, J=16.4, 11.2 Hz, 1H), 7.11 (s, 1H), 6.92 (d, J=6.1 Hz, 1H), 6.40 (d, J=11.2 Hz, 1H), 6.33 (dd, J=11.2, 11.2 Hz, 1H), 6.20 (d, J=16.4 Hz, 1H), 6.14 (dd, J=10.0, 2.0 Hz, 1H), 6.02-5.91 (m, 1H), 5.99 (br d, J=10.0 Hz, 1H), 5.31-5.20 (m, 3H), 5.23 (br s, 1H), 4.62 (dd, J=5.6, 1.2 Hz, 2H), 3.26 (d, J=14.7 Hz, 1H), 2.83 (d, J=14.7 Hz, 1H), 2.28 (dt, J=12.7, 3.0 Hz, 1H), 2.09 (dt, J=12.7, 6.3 Hz, 1H), 1.98-1.78 (m, 3H), 1.92 (s, 3H), 1.74 (d, J=6.6 Hz, 3H), 1.73 (br s, 3H)
FABMS m/z 566 (M+H).sup.+
HRFABMS calcd for C.sub.25 H.sub.32 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 566.1453, found 566.1438
Compound 71
IR (KBr) 3420, 2928, 1711, 1647, 1538, 1447, 1369, 1097, 1032, 996, 949, 924, 887, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.26 (dd, J=16.5, 11.6 Hz, 1H), 7.12 (s, 1H), 6.82 (d, J=16.5 Hz, 1H), 6.75 (d, J=6.7 Hz, 1H), 6.51 (d, J=11.3 Hz, 1H), 6.38 (dd, J=11.6, 11.3 Hz, 1H), 6.01 (ddt, J=17.4, 10.4, 5.5 Hz, 1H), 5.91 (br d, J=9.5 Hz, 1H), 5.31 (dq, J=17.4, 1.5 Hz, 1H), 5.30 (dq, J=6.7, 6.4 Hz, 1H), 5.23 (dq, J=10.4, 1.5 Hz, 1H), 5.15 (dd, J=9.5, 2.8 Hz, 1H), 4.63 (dt, J=5.5, 1.5 Hz, 2H), 4.58 (br s, 1H), 3.11 (d, J=15.0 Hz, 1H), 2.98 (d, J=15.0 Hz, 1H), 2.37-1.82 (m, 5H), 1.83 (s, 3H), 1.74 (d, J=6.4 Hz, 3H), 1.68 (d, J=1.0 Hz, 3H)
FABMS m/z 566 (M+H).sup.+
HRFABMS calcd for C.sub.25 H.sub.32 N.sub.3 O.sub.6 S.sub.3 (M+H).sup.+ 566.1453, found 566.1464
EXAMPLE 64
Synthesis of Compounds 72 and 73
According to the procedure as described in Example 60, Compound 72 (16 mg, 23% yield) and Compound 73 (15 mg, 22% yield) which is a geometrical isomer thereof were obtained from Compound 35 (60 mg, 0.096 mmol), methanol (3.0 ml), pyridine (0.039 ml, 0.48 mmol) and O-benzylhydroxylamine hydrochloride (47 mg, 0.29 mmol).
Compound 72
IR (KBr) 3440, 2928, 1820, 1720, 1684, 1452, 1364, 1263, 1208, 1147, 1017, 983, 871, 797, 768, 732, 699 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.94 (dd, J=16.6, 11.2 Hz, 1H), 7.37-7.25 (m, 5H), 7.25 (s, 1H), 6.38 (d, J=11.2 Hz, 1H), 6.31 (dd, J=11.2, 11.2 Hz, 1H), 6.21 (d, J=16.6 Hz, 1H), 6.12 (dd, J=8.6, 5.6 Hz, 1H), 5.86 (br d, J=8.6 Hz, 1H), 5.58 (br s, 1H), 5.54 (q, J=6.6 Hz, 1H), 5.18 (br s, 2H), 4.03 (d, J=17.6 Hz, 1H), 3.78 (br s, 2H), 2.38-1.40 (m, 4H), 2.30 (d, J=17.6 Hz, 2H), 2.15 (s, 3H), 1.88 (d, J=6.6 Hz, 3H), 1.72 (d, J=1.2 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 728 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.38 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 728.1770, found 728.1768
Compound 73
IR (KBr) 3440, 2930, 1820, 1720, 1684, 1451, 1363, 1262, 1207, 1150, 1012, 980, 928, 877, 799, 767, 732, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.89 (dd, J=16.6, 11.5 Hz, 1H), 7.42-7.25 (m, 5H), 7.28 (s, 1H), 6.83 (d, J=16.6 Hz, 1H), 6.47 (d, J=11.5 Hz, 1H), 6.34 (dd, J=11.5, 11.5 Hz, 1H), 5.98 (br d, J=8.3 Hz, 1H), 5.57 (br s, 1H), 5.55 (q, J=6.6 Hz, 1H), 5.17 (br s, 2H), 5.11 (dd, J=8.3, 5.9 Hz, 1H), 4.02 (d, J=17.5 Hz, 1H), 3.78 (br s, 2H), 2.40-1.45 (m, 4H), 2.35 (d, J=17.5 Hz, 1H), 2.14 (s, 3H), 1.98 (d, J=3.9 Hz, 1H), 1.89 (d, J=6.6 Hz, 3H), 1.74 (s, 3H), 1.71 (s, 3H)
FABMS m/z 728 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.38 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 728.1770, found 728.1768
EXAMPLE 65
Synthesis of Compound 74
DC107 (20 mg, 0.039 mmol) was dissolved in methanol (3.0 ml), and p-toluenesulfonyl hydrazide (102 mg, 0.55 mmol) was added thereto, followed by stirring at 25.degree. C. for 5.5 hours. After distilling off the solvent under reduced pressure, the residue was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 74 (14 mg, 53% yield).
IR (KBr) 3400, 2930, 2930, 1707, 1647, 1597, 1558, 1449, 1375, 1334, 1292, 1209, 1186, 1092, 999, 949, 886, 811, 704, 662 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.18 (dd, J=15.6, 11.3 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.16 (s, 1H), 6.82 (br d, J=6.7 Hz, 1H), 6.56 (d, J=11.6 Hz, 1H), 6.31 (dd, J=11.6, 11.3 Hz, 1H), 6.22 (d, J=15.6 Hz, 1H), 5.65 (br d, J=9.2 Hz, 1H), 5.31 (dq, J=6.7, 6.7 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.30 (br s, 1H), 3.06 (d, J=15.3 Hz, 1H), 3.00 (d, J=15.3 Hz, 1H), 2.46-2.21 (m, 2H), 2.43 (s, 3H), 1.90-1.60 (m, 2H), 1.74 (s, 3H), 1.71 (d, J=6.7 Hz, 3H), 1.48 (s, 3H)
FABMS m/z 679 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.35 N.sub.4 O.sub.7 S.sub.4 (M+H).sup.+ 679.1388, found 679.1379
EXAMPLE 66
Synthesis of Compound 75
DC107 (50 mg, 0.098mmol) was dissolved in methanol (10 ml), and methyl hydrazinocarboxylate (44 mg, 0.49 mmol) and pyridinium p-toluenesulfonate (74 mg, 0.29 mmol) were added thereto, followed by stirring at 25.degree. C. for 40 minutes. After distilling off the solvent under reduced pressure, the residue was purified by thin layer chromatography (developed with chloroform/methanol=94/6) to obtain Compound 75 (8.8 mg, 15% yield).
IR (KBr) 3400, 2932, 1721, 1650, 1527, 1449, 1374, 1241, 1095, 950, 894, 799, 767 cm.sup.-1
.sup.1 H NMR (CDOD.sub.3, 400 MHz) .delta. ppm; 8.95 (br d, J=6.8 Hz, 1H), 8.03 (br dd, J=15.9, 11.7 Hz, 1H), 7.45 (s, 1H), 6.59 (d, J=11.5 Hz, 1H), 6.53 (d, J=15.9 Hz, 1H), 6.38 (dd, J=11.7, 11.5 Hz, 1H), 5.65 (br d, J=9.0 Hz, 1H), 5.32 (dq, J=6.8, 6.6 Hz, 1H), 5.15 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.21 (d, J=15.8 Hz, 1H), 2.98 (d, J=15.8 Hz, 1H), 2.45-1.78 (m, 4H), 1.70 (d, J=6.8 Hz, 3H), 1.68 (s, 3H), 1.61 (s, 3H)
FABMS m/z 583 (M+H).sup.+
HRFABMS calcd for C.sub.24 H.sub.31 N.sub.4 O.sub.7 S.sub.3 (M+H).sup.+ 583.1355, found 583.1371
EXAMPLE 67
Synthesis of Compound 76
According to the procedure as described in Example 22, Compound 76 (11 mg, 26% yield) was obtained from DC107 (30 mg, 0.058 mmol), pyridine (0.72 ml, 8.8 mmol), benzoyl chloride (0.30 ml, 2.6 mmol) and 4-dimethylaminopyridine (2.1 mg, 0.017 mmol).
IR (KBr) 3400, 2928, 1721, 1670, 1614, 1517, 1450, 1375, 1316, 1267, 1176, 1096, 1068, 1025, 996, 952, 853, 799, 711 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.60 (br s, 1H), 8.02-7.95 (m, 4H), 7.65-7.34 (m, 6H), 7.28 (s, 1H), 6.58 (d, J=11.2 Hz, 1H), 6.47 (br s, 1H), 6.17 (d, J=9.5 Hz, 1H), 6.16 (br s, 1H), 6.01 (d, J=16.6 Hz, 1H), 5.78 (br d, J=9.5 Hz, 1H), 5.46 (dq, J=7.0, 6.8 Hz, 1H), 3.49 (d, J=16.1 Hz, 1H), 3.16 (br s, 1H), 2.32-1.90 (m, 4H), 2.06 (s, 3H), 1.75 (s, 3H), 1.68 (d, J=6.8 Hz, 3H)
FABMS m/z 719 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.35 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 719.1555, found 719.1564
EXAMPLE 68
Synthesis of Compound 77
According to the procedure as described in Example 32, Compound 77 (24 mg, 25% yield) was obtained from DC107 (82 mg, 0.16 mmol), potassium carbonate (220 mg, 1.6 mmol), chloromethyl cyclopropanecarboxylate (280 mg, 2.1 mmol) and potassium iodide (26 mg, 0.16 mmol).
IR (KBr) 3408, 3100, 2936, 1725, 1693, 1649, 1611, 1453, 1414, 1387, 1264, 1154, 1099, 1063, 979, 887, 809, 750 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.46 (ddd, J=16.3, 11.5, 1.0 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=12.0 Hz, 1H), 6.23 (dd, J=12.0, 11.5 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.73, (br d, J=8.5 Hz, 1H), 5.44 (br s, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.41 (d, J=11.0 Hz, 1H), 5.37 (d, J=11.0 Hz, 1H), 4.94 (dd, J=8.5, 3.9 Hz, 1H), 3.90 (d, J=17.8 Hz, 1H), 3.73 (d, J=3.9 Hz, 1H), 2.37-1.55 (m, 5H), 2.28 (d, J=17.8 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.80 (s, 3H), 1.75 (d, J=1.2 Hz, 3H), 1.05-0.85 (m, 4H)
FABMS m/z 609 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.33 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 609.1399, found 609.1399
EXAMPLE 69
Synthesis of Compound 78
According to the procedure as described in Example 32, Compound 78 (27 mg, 43% yield) was obtained from DC107 (51 mg, 0.10 mmol), potassium carbonate (140 mg, 1.0 mmol), chloromethyl cyclobutanecarboxylate (250 mg, 1.7 mmol) and potassium iodide (17 mg, 0.10 mmol).
IR (KBr) 3430, 2950, 1730, 1694, 1648, 1610, 1450, 1365, 1254, 1154, 1090, 1051, 986, 730 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.46 (ddd, J=16.3, 11.3, 1.0 Hz, 1H), 7.34 (s, 1H), 6.58 (d, J=11.6 Hz, 1H), 6.23 (dd, J=11.6, 11.3 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.73 (dd, J=8.5, 1.0 Hz, 1H), 5.51 (br s, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.41 (d, J=11.0 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 4.94 (dd, J=8.5, 3.7 Hz, 1H), 3.89 (d, J=17.7 Hz, 1H), 3.73 (d, J=3.7 Hz, 1H), 3.17-3.08 (m, 1H), 2.36-1.80 (m, 10H), 2.26 (d, J=17.7 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.78 (s, 3H), 1.74 (d, J=1.0 Hz, 3H)
FABMS m/z 623 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.35 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 623.1555, found 623.1569
EXAMPLE 70
Synthesis of Compound 79
According to the procedure as described in Example 32, Compound 79 (24 mg, 26% yield) was obtained from DC107 (75 mg, 0.15 mmol), potassium carbonate (250 mg, 1.8 mmol), chloromethyl cyclopentanecarboxylate (330 mg, 2.0 mmol) and potassium iodide (30 mg, 0.18 mmol).
IR (KBr) 3420, 3106, 2960, 2874, 1720, 1691, 1648, 1610, 1452, 1411, 1372, 1263, 1143, 1105, 1087, 980, 859, 807, 730 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.47 (ddd, J=16.5, 11.5, 1.2 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=11.9 Hz, 1H), 6.23 (dd, J=11.9, 11.5 Hz, 1H), 6.17 (d, J=16.5 Hz, 1H), 5.74 (br d, J=8.8 Hz, 1H), 5.51 (br s, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.41 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.94 (br d, J=8.8 Hz, 1H), 3.89 (d, J=17.7 Hz, 1H), 3.74 (br s, 1H), 2.77-2.66 (m, 1H), 2.36-1.50 (m, 12H), 2.25 (d, J=17.7 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.78 (s, 3H), 1.75 (d, J=1.2 Hz, 3H)
FABMS m/z 637 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 637.1712, found 637.1695
EXAMPLE 71
Synthesis of Compound 80
According to the procedure as described in Example 32, Compound 80 (37 mg, 35% yield) was obtained from DC107 (84 mg, 0.16 mmol), potassium carbonate (220 mg, 1.6 mmol), chloromethyl cyclohexanecarboxylate (280 mg, 1.6 mmol) and potassium iodide (26 mg, 0.16 mmol).
IR (KBr) 3420, 3106, 2936, 2858, 1725, 1692, 1648, 1610, 1451, 1376, 1267, 1157, 1120, 1090, 1020, 974, 804, 728 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.47 (ddd, J=16.3, 11.5, 1.0 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=12.0 Hz, 1H), 6.23 (dd, J=12.0, 11.5 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.74 (br d, J=8.5 Hz, 1H), 5.50 (br s, 1H), 5.41 (q, J=6.8 Hz, 1H), 5.40 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.94 (br d, J=8.5 Hz, 1H), 3.89 (d, J=17.8 Hz, 1H), 3.75 (br s, 1H), 2.35-1.20 (m, 15H), 2.26 (d, J=17.8 Hz, 1H), 2.20 (d, J=6.8 Hz, 3H), 1.78 (s, 3H), 1.75 (d, J=1.2 Hz, 3H)
FABMS m/z 651 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.39 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 651.1868, found 651.1868
EXAMPLE 72
Synthesis of Compound 81
According to the procedure as described in Example 32, Compound 81 (25 mg, 35% yield) was obtained from DC107 (60 mg, 0.12 mmol), potassium carbonate (290 mg, 2.1 mmol), chloromethyl isobutyrate (320 mg, 2.3 mmol) and potassium iodide (58 mg, 0.35 mmol).
IR (KBr) 3420, 3106, 2980, 2936, 1720, 1694, 1648, 1611, 1469, 1454, 1373, 1265, 1183, 1146, 1101, 974, 807, 754 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.47 (ddd, J=16.4, 11.2, 1.0 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=11.7 Hz, 1H), 6.23 (dd, J=11.7, 11.2 Hz, 1H), 6.17 (d, J=16.4 Hz, 1H), 5.74 (br d, J=16.4 Hz, 1H), 5.52 (br s, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.41 (d, J=11.0 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 4.94 (dd, J=8.5, 3.9 Hz, 1H), 3.89 (d, J=17.8 Hz, 1H), 3.74 (d, J=3.9 Hz, 1H), 2.60-2.45 (m, 1H), 2.35-1.90 (m, 4H), 2.26 (d, J=17.8 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.78 (s, 3H), 1.74 (d, J=1.2 Hz, 3H), 1.13 (d, J=7.1 Hz, 6H)
FABMS m/z 611 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.35 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 611.1555, found 611.1547
EXAMPLE 73
Synthesis of Compound 82
According to the procedure as described in Example 32, Compound 82 (22 mg, 28% yield) was obtained from DC107 (65 mg, 0.13 mmol), potassium carbonate (170 mg, 1.2 mmol), chloromethyl isovalerate (320 mg, 2.1 mmol) and potassium iodide (30 mg, 0.18 mmol).
IR (KBr) 3430, 3105, 2936, 2880, 1720, 1697, 1650, 1611, 1453, 1408, 1371, 1265, 1160, 1091, 979, 804, 730 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.47 (ddd, J=16.3, 11.3, 1.0 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=11.9 Hz, 1H), 6.23 (dd, J=11.9, 11.3 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.74 (br d, J=8.5 Hz, 1H), 5.53 (br d, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.41 (d, J=11.0 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 4.94 (dd, J=8.5, 3.7 Hz, 1H), 3.88 (d, J=17.7 Hz, 1H), 3.73 (d, J=3.7 Hz, 1H), 2.41-1.92 (m, 7H), 2.26 (d, J=17.7 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.78 (s, 3H), 1.75 (d, J=1.0 Hz, 3H), 0.93 (d, J=6.4 Hz, 6H)
FABMS m/z 625 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 625.1712, found 625.1732
EXAMPLE 74
Synthesis of Compound 83
According to the procedure as described in Example 32, Compound 83 (23 mg, 38% yield) was obtained from DC107 (50 mg, 0.098 mmol), potassium carbonate (244 mg, 1.8 mmol), chloromethyl n-valerinate (300 mg, 2.0 mmol) and potassium iodide (50 mg, 0.30 mmol).
IR (KBr) 3430, 2960, 2936, 1720, 1693, 1650, 1611, 1452, 1374, 1260, 1154, 1105, 1089, 1018, 981, 727 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.46 (ddd, J=16.3, 11.3, 1.0 Hz, 1H),7.35 (s, 1H), 6.58 (d, J=11.7 Hz, 1H), 6.23 (dd, J=11.7, 11.3 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.73 (br d, J=8.5 Hz, 1H), 5.52 (br s, 1H), 5.41 (q, J=6.8 Hz, 1H), 5.40 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.94 (dd, J=8.5, 3.9 Hz, 1H), 3.89 (d, J=17.8 Hz, 1H), 3.73 (d, J=3.9 Hz, 1H), 2.38-1.23 (m, 10H), 2.26 (d, J=17.8 Hz, 1H), 2.02 (d, J=6.8 Hz, 3H), 1.79 (s, 3H), 1.75 (d, J=1.2 Hz, 3H), 0.89 (t, J=7.3 Hz, 3H)
FABMS m/z 625 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 625.1712, found 625.1741
EXAMPLE 75
Synthesis of Compound 84
According to the procedure as described in Example 32, Compound 84 (30 mg, 36% yield) was obtained from DC107 (63 mg, 0.12 mmol), potassium carbonate (310 mg, 2.2 mmol), chloromethyl n-octanoate (240 mg, 1.2 mmol) and potassium iodide (61 mg, 0.37 mmol).
IR (KBr) 3420, 2930, 2858, 1721, 1698, 1650, 1612, 1456, 1411, 1375, 1264, 1153, 1107, 1018, 978, 807, 727 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.47 (ddd, J=16.3, 11.2, 0.8 Hz, 1H), 7.35 (s, 1H), 6.58 (d, J=11.7 Hz, 1H), 6.23 (dd, J=11.7, 11.2 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.74 (br d, J=8.5 Hz, 1H), 5.52 (br s, 1H), 5.41 (q, J=7.0 Hz, 1H), 5.39 (d, J=11.0 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 4.94 (dd, J=8.5, 3.7 Hz, 1H), 3.89 (d, J=17.8 Hz, 1H), 3.73 (d, J=3.9 Hz, 1H), 2.36-1.20 (m, 14H), 2.29 (t, J=7.3 Hz, 2H), 2.27 (d, J=17.8 Hz, 1H), 2.02 (d, J=7.0 Hz, 3H), 1.79 (s, 3H), 1.75 (d, J=1.2 Hz, 3H), 0.87 (t, J=6.8 Hz, 3H)
FABMS m/z 667 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.43 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 667.2181, found 667.2172
EXAMPLE 76
Synthesis of Compound 85
According to the procedure as described in Example 32, Compound 85 (29 mg, 28% yield) was obtained from Compound 18 (85 mg, 0.14 mmol), potassium carbonate (197 mg, 1.4 mmol), chloromethyl cyclohexanecarboxylate (250 mg, 1.4 mmol) and potassium iodide (25 mg, 0.14 mmol). From .sup.1 H NMR data, Compound 85 was found to be a mixture of diastereomers at about 1:1 due to the asymmetric carbon of the tetrahydropyranyl group.
IR (KBr) 3420, 2936, 2858, 1730, 1698, 1651, 1609, 1452, 1375, 1262, 1156, 1123, 1074, 1020, 971, 869 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.59, 9.39 (dd, J=16.4, 11.2 Hz, 1H), 7.40, 7.39 (s, 1H), 6.61, 6.60 (d, J=11.5 Hz, 1H), 6.37, 6.60 (dd, J=11.5, 11.2 Hz, 1H), 6.04, 6.00 (d, J=16.4 Hz, 1H), 5.83, 5.80 (d, J=9.3 Hz, 1H), 5.58, 5.56 (q, J=6.6 Hz, 1H), 5.52, 5.50 (br s, 1H), 5.42 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 5.02, 4.74 (dd, J=9.3, 1.0 Hz, 1H), 4.72-4.53 (m, 1H), 4.04, 4.03 (d, J=17.8 Hz, 1H), 3.88-3.70 (m, 1H), 3.54-3.40 (m, 1H), 2.45-1.20 (m, 21H), 2.29, 2.28 (d, J=17.8 Hz, 1H), 1.94, 1.88 (d, J=6.6 Hz, 3H), 1.77, 1.74 (d, J=1.2 Hz, 3H), 1.70, 1.69 (s, 3H)
FABMS m/z 735 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.47 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 735.2443, found 735.2463
EXAMPLE 77
Synthesis of Compound 86
According to the procedure as described in Example 32, Compound 86 (34 mg, 34% yield) was obtained from Compound 18 (85 mg, 0.14 mmol), potassium carbonate (197 mg, 1.4 mmol), chloromethyl isovalerinate (323 mg, 2.1 mmol) and potassium iodide (25 mg, 0.14 mmol). From .sup.1 H NMR data, Compound 86 was found to be a mixture of diastereomers at about 1:1 due to the asymmetric carbon of the tetrahydropyranyl group.
IR (KBr) 3420, 2960, 2930, 1740, 1700, 1649, 1609, 1454, 1370, 1262, 1155, 1115, 1074, 1019, 974, 868 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.59, 9.40 (dd, J=16.6, 11.7 Hz, 1H), 7.40, 7.39 (s, 1H), 6.61, 6.60 (d, J=11.5 Hz, 1H), 6.37, 6.35 (dd, J=11.7, 11.5 Hz, 1H), 6.05, 6.00 (d, J=16.6 Hz, 1H), 5.83, 5.80 (d, J=9.3 Hz, 1H), 5.59, 5.57 (q, J=6.6 Hz, 1H), 5.55, 5.53 (br s, 1H), 5.42 (d, J=11.0 Hz, 1H), 5.36 (d, J=11.0 Hz, 1H), 5.02, 4.74 (dd, J=9.3, 1.2 Hz, 1H), 4.73-4.55 (m, 1H), 4.04, 4.02 (d, J=17.7 Hz, 1H), 3.87-3.70 (m, 1H), 3.54-3.40 (m, 1H), 2.45-1.40 (m, 13H), 2.30, 2.29 (d, J=17.7 Hz, 1H), 1.94, 1.88 (d, J=6.6 Hz, 3H), 1.77, 1.74 (d, J=1.2 Hz, 3H), 1.71, 1.70 (s, 3H), 0.96, 0.95 (d, J=6.6 Hz, 6H)
FABMS m/z 709 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.45 N.sub.2 O.sub.9 S.sub.3 (M+H).sup.+ 709.2287, found 709.2289
EXAMPLE 78
Synthesis of Compound 87
According to the procedure as described in Example 19, Compound 87 (37 mg, 54% yield) was obtained from Compound 35 (61 mg, 0.098 mmol), ethyl vinyl ether (0.056 ml, 0.59 mmol) and camphorsulfonic acid (22 mg, 0.098 mmol). From .sup.1 H NMR data, Compound 87 was found to be a mixture of diastereomers at about 10:9 due to the asymmetric carbon of the 1-ethoxyethyl group.
IR (KBr) 3420, 3096, 2984, 2934, 1820, 1705, 1688, 1648, 1608, 1447, 1391, 1377, 1308, 1263, 1208, 1090, 1054, 976, 784 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; major isomer: 9.49 (dd, J=16.5, 11.5 Hz, 1H), 7.38 (s, 1H), 6.60 (d, J=11.2 Hz, 1H), 6.35 (dd, J=11.5, 11.2 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.80 (br d, J=9.0 Hz, 1H), 5.57 (q, J=6.3 Hz, 1H), 5.52 (br s, 1H), 4.68 (dd, J=9.0, 1.0 Hz, 1H), 4.66 (q, J=5.5 Hz, 1H), 4.04 (d, J=17.6 Hz, 1H), 3.83-3.72 (m, 2H), 3.58-3.31 (m, 2H), 2.46-1.40 (m, 4H), 2.28 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.90 (d, J=6.3 Hz, 3H), 1.74 (d, J=1.0 Hz, 3H), 1.69 (s, 3H), 1.25 (d, J=5.5 Hz, 3H), 1.90 (t, J=7.1 Hz, 3H); minor isomer: 9.63 (dd, J=16.3, 11.5 Hz, 1H), 7.40 (s, 1H), 6.62 (d, J=11.2 Hz, 1H), 6.35 (dd, J=11.5, 11.2 Hz, 1H), 6.00 (d, J=16.3 Hz, 1H), 5.82 (br d, J=9.3 Hz, 1H), 5.58 (q, J=6.3 Hz, 1H), 5.55 (br s, 1H), 4.91 (dd, J=9.0, 1.0 Hz, 1H), 4.72 (q, J=5.5 Hz, 1H), 4.04 (d, J=17.6 Hz, 1H), 3.83-3.72 (m, 2H), 3.58-3.31 (m, 2H), 2.46-1.40 (m, 4H), 2.27 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.92 (d, J=6.3 Hz, 3H), 1.75 (d, J=1.0 Hz, 3H), 1.69 (s, 3H), 1.21 (d, J=5.5 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H).
FABMS m/z 695 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.39 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 695.1767, found 695.1761
EXAMPLE 79
Synthesis of Compounds 88 and 89
According to the procedure as described in Example 60, Compound 88 (14 mg, 45% yield) and its geometrical isomer, Compound 89 (7.4 mg, 24% yield) were obtained from Compound 63 (30 mg, 0.042 mmol), methanol (4.0 ml), pyridine (0.034 ml, 0.42 mmol) and O-methylhydroxylamine hydrochloride (17.5 mg, 0.21 mmol).
Compound 88
IR (KBr) 3420, 2940, 1822, 1720, 1686, 1440, 1376, 1262, 1208, 1047, 973, 928, 871, 799, 766, 730 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.99 (dd, J=16.4, 11.0 Hz, 1H), 7.24 (s, 1H), 6.35 (d, J=11.5 Hz, 1H), 6.29 (dd, J=11.5, 11.0 Hz, 1H), 6.17 (d, J=16.4 Hz, 1H), 6.11 (dd, J=9.2, 1.2 Hz, 1H), 5.82 (br d, J=9.2 Hz, 1H), 5.58 (br s, 1H), 5.58 (q, J=6.6 Hz, 1H), 4.47 (br s, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.93 (s, 3H), 3.88-3.72 (m, 3H), 3.55-3.47 (m, 1H), 2.44-1.30 (m, 10H), 2.27 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.90 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 736 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.42 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 736.2032, found 736.2015
Compound 89
IR (KBr) 3420, 2938, 1823, 1715, 1683, 1441, 1377, 1262, 1208, 1048, 973, 887, 798, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.00 (dd, J=16.6, 11.5 Hz, 1H), 7.28 (s, 1H), 6.76 (d, J=16.6 Hz, 1H), 6.44 (d, J=11.3 Hz, 1H), 6.33 (dd, J=11.5, 11.3 Hz, 1H), 5.96 (br d, J=9.0 Hz, 1H), 5.58 (br s, 1H), 5.58 (q, J=6.6 Hz, 1H), 5.11 (dd, J=9.0, 1.0 Hz, 1H), 4.61 (br s, 1H), 4.04 (d, J=17.6 Hz, 1H), 3.94 (s, 3H), 3.90-3.81 (m, 1H), 3.78 (br s, 2H), 3.58-3.50 (m, 1H), 2.45-1.30 (m, 10H), 2.26 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.90 (d, J=6.6 Hz, 3H), 1.78 (d, J=1.0 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 736 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.42 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 736.2032, found 736.2020
EXAMPLE 80
Synthesis of Compound 90
According to the procedure as described in Example 18, Compound 90 (30 mg, 49% yield) was obtained from DC107 (50 mg, 0.1mmol), 5,6-dihydro-4-methoxy-2H-pyran (0.056 ml, 0.50 mmol) and camphorsulfonic acid (23 mg, 0.1 mmol).
IR (KBr) 3420, 3330, 2944, 1726, 1642, 1609, 1529, 1453, 1357, 1306, 1261, 1231, 1142, 1097, 1048, 949, 886, 807, 732 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.31 (ddd, J=16.5, 11.5, 1.0 Hz, 1H), 7.29 (s, 1H), 6.88 (br d, J=6.3 Hz, 1H), 6.65 (d, J=11.5 Hz, 1H), 6.39 (t, J=11.5 Hz, 1H), 6.01 (d, J=16.5 Hz, 1H), 5.95 (br d, J=9.8 Hz, 1H), 5.26 (dq, J=6.3, 6.5 Hz, 1H), 5.22 (br s, 1H), 5.03 (dd, J=9.8, 1.2 Hz, 1H), 3.64-3.44 (m, 4H), 3.24 (d, J=14.8 Hz, 1H), 3.06 (s, 3H), 2.86 (d, J=14.8 Hz, 1H), 2.35-1.50 (m, 8H), 1.90 (s, 3H), 1.80 (d, J=6.5 Hz, 3H), 1.74 (d, J=1.2 Hz, 3H)
FABMS m/z 625 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.37 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 625.1712, found 625.1738
EXAMPLE 81
Synthesis of Compound 91
According to the procedure as described in Example 18, Compound 91 (40 mg, 58% yield) was obtained from DC107 (58 mg, 0.11 mmol), 1-methoxy-1-cyclohexene (64 mg, 0.56 mmol) and camphorsulfonic acid (5 mg, 0.02 mmol).
IR (KBr) 3400, 2938, 2938, 1720, 1644, 1610, 1525, 1450, 1369, 1270, 1247, 1180, 1153, 1091, 1022, 926, 800 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.29 (dd, J=16.6, 11.5 Hz, 1H), 7.27 (s, 1H), 6.94 (br d, J=5.9 Hz, 1H), 6.64 (d, J=11.3 Hz, 1H), 6.38 (dd, J=11.5, 11.3 Hz, 1H), 5.98 (d, J=16.6 Hz, 1H), 5.93 (br d, J=9.8 Hz, 1H), 5.26 (br s, 1H), 5.26 (dq, J=5.9, 6.6 Hz, 1H), 5.01 (dd, J=9.8, 1.2 Hz, 1H), 3.24 (d, J=14.5 Hz, 1H), 3.02 (s, 3H), 2.85 (d, J=14.5 Hz, 1H), 2.35-1.20 (m, 14H), 1.90 (s, 3H), 1.81 (d, J=6.6 Hz, 3H), 1.73 (d, J=1.2 Hz, 3H)
FABMS m/z 623 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.39 N.sub.2 O.sub.7 S.sub.3 (M+H).sup.+ 623.1919, found 623.1890
EXAMPLE 82
Synthesis of Compound 92
According to the procedure as described in Example 18, Compound 93 (15 mg, 30% yield) was obtained from DC107 (41 mg, 0.08 mmol), 5,6-dihydro-4-methoxy-2H-thiopyran (52 mg, 0.40 mmol) and camphorsulfonic acid (4.6 mg, 0.02 mmol).
IR (KBr) 3322, 2928, 1721, 1642, 1611, 1530, 1452, 1362, 1247, 1208, 1096, 1031, 950, 881, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.27 (ddd, J=16.5, 11.5, 1.0 Hz, 1H), 7.29 (s, 1H), 6.87 (br d, J=6.2 Hz, 1H), 6.65 (d, J=11.3 Hz, 1H), 6.39 (dd, J=11.5, 11.3 Hz, 1H), 6.00 (d, J=16.5 Hz, 1H), 5.94 (br d, J=9.8 Hz, 1H), 5.26 (dq, J=6.2, 6.5 Hz, 1H), 5.22 (br s, 1H), 5.00 (dd, J=9.8, 1.2 Hz, 1H), 3.25 (d, J=14.8 Hz, 1H), 3.03 (s, 3H), 2.85 (d, J=14.8 Hz, 1H), 2.70-1.60 (m, 12H), 1.91 (s, 3H), 1.81 (d, J=6.5 Hz, 3H), 1.74 (d, J=1.0 Hz, 3H)
FABMS m/z 641 (M+H).sup.+
HRFABMS calcd for C.sub.28 H.sub.37 N.sub.2 O.sub.7 S.sub.4 (M+H).sup.+ 641.1483, found 641.1483
EXAMPLE 83
Synthesis of Compound 93
According to the procedure as described in Example 18, Compound 93 (33 mg, 76% yield) was obtained from DC107 (32 mg, 0.063 mmol), 1-ethoxycarbonyl-4-methoxy-1,2,5,6-tetrahydropyridine (58 mg, 0.31 mmol) and camphorsulfonic acid (7 mg, 0.031 mmol).
IR (KBr) 3290, 2934, 1680, 1642, 1611, 1637, 1442, 1354, 1240, 1100, 1025, 951, 892, 799, 766 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.28 (dd, J=16.6, 11.5 Hz, 1H), 7.29 (s, 1H), 6.95 (br d, J=5.8 Hz, 1H), 6.64 (d, J=11.2 Hz, 1H), 6.37 (dd, J=11.5, 11.2 Hz, 1H), 5.99 (d, J=16.6 Hz, 1H), 5.95 (br d, J=9.8 Hz, 1H), 5.27 (br s, 1H), 5.25 (dq, J=5.8, 6.4 Hz, 1H), 5.03 (br d, J=9.8 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.58-3.45 (m, 2H), 3.24 (d, J=14.8 Hz, 1H), 3.25-3.03 (m, 2H), 3.06 (s, 3H), 2.87 (d, J=14.8 Hz, 1H), 2.36-1.35 (m, 8H), 1.90 (s, 3H), 1.79 (d, J=6.4 Hz, 3H), 1.74 (s, 3H), 1.20 (t, J=7.1 Hz, 3H)
FABMS m/z 696 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.42 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 696.2083, found 696.2065
EXAMPLE 84
Synthesis of Compound 94
DC107 (51 mg, 0.099mmol) and 2-pyrazinecarboxylic acid (55 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.44 mmol) and 4-dimethylaminopyridine (3.6 mg, 0.029 mmol) were added thereto, followed by stirring at room temperature for 30 minutes. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 94 (45 mg, 74% yield).
IR (KBr) 3400, 2930, 1721, 1661, 1613, 1529, 1447, 1371, 1308, 1274, 1200, 1134, 1100, 1048, 1017, 895, 806, 771 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.20 (d, J=1.2 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.69 (dd, J=16.5, 11.6 Hz, 1H), 8.59 (dd, J=2.4, 1.2 Hz, 1H), 7.29 (s, 1H), 6.67 (d, J=11.3 Hz, 1H), 6.57 (br d, J=6.7 Hz, 1H), 6.38 (dd, J=11.6, 11.3 Hz, 1H), 6.22 (d, J=9.8 Hz, 1H), 6.11 (d, J=16.5 Hz, 1H), 5.90 (d, J=9.8 Hz, 1H), 5.40 (dq, J=6.7, 6.7 Hz, 1H), 4.05 (br s, 1H), 3.16 (d, J=15.5 Hz, 1H), 2.99 (d, J=15.5 Hz, 1H), 2.42 (dt, J=13.0, 4.3 Hz, 1H), 2.09 (td, J=12.5, 4.3 Hz, 1H), 1.93 (dt, J=4.6, 13.0 Hz, 1H), 1.82-1.72 (m, 1H), 1.81 (d, J=1.2 Hz, 3H), 1.73 (s, 3H), 1.69 (d, J=6.7 Hz, 3H)
FABMS m/z 617 (M+H).sup.+
HRFABMS calcd for C.sub.27 H.sub.29 N.sub.4 O.sub.7 S.sub.3 (M+H).sup.+ 617.1198, found 617.1218
EXAMPLE 85
Synthesis of Compound 95
According to the procedure as described in Example 45, Compound 95 (51 mg, 91% yield) was obtained from DC107 (41 mg, 0.080 mmol), N-Boc-L-proline (173 mg, 0.80mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol), dichloromethane (4 ml) and 4-dimethylaminopyridine (3 mg, 0.025 mmol).
IR (KBr) 3430, 3300, 2980, 2936, 1740, 1700, 1674, 1610, 1537, 1476, 1408, 1367, 1257, 1200, 1164, 1128, 1090, 999, 891, 854, 771 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.53, 8.45 (dd, J=16.5, 11.6 Hz, 1H), 7.28 (s, 1H), 6.65, 6.63 (d, J=11.3 Hz, 1H), 6.57, 6.71 (br d, J=6.4 Hz, 1H), 6.34 (dd, J=11.6, 11.3 Hz, 1H), 6.03, 6.04 (d, J=16.5 Hz, 1H), 5.91, 5.85 (d, J=9.5 Hz, 1H), 5.79, 5.73 (br d, J=9.5 Hz, 1H), 5.42, 5.43 (dq, J=6.4, 6.4 Hz, 1H), 4.25 (dd, J=8.5, 4.0 Hz, 1H), 4.00, 4.04 (br s, 1H), 3.42-3.28 (m, 2H), 3.17, 3.20 (d, J=15.6 Hz, 1H), 2.97, 2.95 (d, J=15.6 Hz, 1H), 2.45-1.60 (m, 8H), 1.77, 1.75 (d, J=6.4 Hz, 3H), 1.70 (s, 3H), 1.70 (s, 3H), 1.36 (s, 9H).
FABMS m/z 708 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.42 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 708.2083, found 708.2108
EXAMPLE 86
Synthesis of Compound 96
According to the procedure as described in Example 45, Compound 96 (42 mg, 78% yield) was obtained from DC107 (41 mg, 0.080 mmol), N-Boc-glycine (43 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (2 mg, 0.016 mmol).
IR (KBr) 3400, 2980, 2936, 1711, 1695, 1660, 1615, 1531, 1452, 1368, 1256, 1162, 1102, 1055, 997, 949, 896, 859, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.79 (dd, J=16.6, 11.2 Hz, 1H), 7.30 (s, 1H), 6.97 (br d, J=6.6 Hz, 1H), 6.64 (d, J=11.2 Hz, 1H), 6.32 (dd, J=11.5, 11.2 Hz, 1H), 6.03 (d, J=16.6 Hz, 1H), 5.80 (br s, 2H), 5.43 (dq, J=6.6, 6.8 Hz, 1H), 5.03 (br s, 1H), 4.25 (br s, 1H), 3.97 (dd, J=18.2, 5.3 Hz, 1H), 3.77 (dd, J=18.2, 5.3 Hz, 1H), 3.08 (br s, 2H), 2.40-1.35 (m, 4H), 1.75 (d, J=6.8 Hz, 3H), 1.73 (d, J=1.4 Hz, 3H), 1.73 (s, 3H), 1.42 (s, 9H)
FABMS m/z 668 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.38 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 668.1770, found 668.1790
EXAMPLE 87
Synthesis of Compound 97
According to the procedure as described in Example 45, Compound 97 (43 mg, 80% yield) was obtained from DC107 (40 mg, 0.077 mmol), N-Cbz-glycine (82 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg, 0.39 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (3 mg, 0.025 mmol).
IR (KBr) 3380, 2932, 1712, 1660, 1614, 1543, 1454, 1373, 1264, 1188, 1102, 1055, 998, 896 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.76 (dd, J=16.6, 11.5 Hz, 1H), 7.37-7.26 (m, 5H), 7.28 (s, 1H), 6.98 (br d, J=6.6 Hz, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.33 (t, J=11.5 Hz, 1H), 6.04 (d, 16.6 Hz, 1H), 5.84 (d, J=9.7 Hz, 1H), 5.80 (d, J=9.7 Hz, 1H), 5.43 (dq, J=6.6, 6.6 Hz, 1H), 5.26 (br dd, J=5.9, 5.4 Hz, 1H), 5.01 (d, J=12.3 Hz, 1H), 4.96 (d, J=12.3 Hz, 1H), 4.25 (br s, 1H), 4.00 (dd, J=18.2, 5.9 Hz, 1H), 3.90 (dd, J=18.2, 5.4 Hz, 1H), 3.12 (d, J=16.1 Hz, 1H), 3.07 (d, J=16.1 Hz, 1H), 2.41-2.30 (m, 1H), 2.15-2.06 (m, 1H), 1.93-1.52 (m, 2H), 1.74 (d, J=6.6 Hz, 3H), 1.73 (s, 3H), 1.73 (s, 3H)
FABMS m/z 702 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.36 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 702.1634, found 702.1631
EXAMPLE 88
Synthesis of Compound 98
According to the procedure as described in Example 45, Compound 98 (60 mg, 76% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Fmoc-glycine (44 mg, 0.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg, 0.15 mmol), dichloromethane (6 ml) and 4-dimethylaminopyridine (1.2 mg, 0.01 mmol).
IR (KBr) 3400, 2932, 1711, 1661, 1613, 1523, 1449, 1373, 1266, 1189, 1102, 1051, 996, 940, 896,799, 759,740 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.70 (dd, J=16.5, 11.5 Hz, 1H), 7.80-7.28 (m, 8H), 7.12 (s, 1H), 7.03 (br d, J=7.0 Hz, 1H), 6.47 (d, J=11.3 Hz, 1H), 6.22 (dd, J=11.5, 11.3 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.83 (d, J=9.0 Hz, 1H), 5.79 (d, J=9.0 Hz, 1H), 5.42 (dq, J=7.0, 6.7 Hz, 1H), 5.31 (br t, J=5.5 Hz, 1H), 4.32 (dd, J=10.4, 6.7 Hz, 1H), 4.22 (br s, 1H), 4.15 (br t, J=6.7 Hz, 1H), 4.03 (dd, J=10.4, 6.7 Hz, 1H), 3.98 (dd, J=18.0, 5.8 Hz, 1H), 3.93 (dd, J=18.0, 5.5 Hz, 1H), 3.13 (d, J=16.3 Hz, 1H), 3.07 (d, J=16.3 Hz, 1H), 2.40-2.30 (m, 1H), 2.15-2.06 (m, 1H), 1.93-1.72 (m, 2H), 1.74 (s, 3H), 1.72 (s, 3H), 1.68 (d, J=6.7 Hz, 3H)
FABMS m/z 790 (M+H).sup.+
HRFABMS calcd for C.sub.39 H.sub.40 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 790.1926, found 790.1933
EXAMPLE 89
Synthesis of Compound 99
According to the procedure as described in Example 45, Compound 99 (34 mg, 57% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-formylglycine (31 mg, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol), dichloromethane (10 ml) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol).
IR (KBr) 3330, 2932, 1748, 1665, 1612, 1529, 1447, 1376, 1265, 1187, 1097, 999, 949, 896, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.55 (dd, J=16.5, 11.5 Hz, 1H), 8.03 (s, 1H), 6.60 (d, J=11.3 Hz, 1H), 6.27 (dd, J=11.5, 11.3 Hz, 1H), 5.96 (d, J=16.5 Hz, 1H), 5.87 (d, J=9.8 Hz, 1H), 5.68 (br d, J=9.8 Hz, 1H), 5.30 (q, J=6.7 Hz, 1H), 4.02 (d, J=18.3 Hz, 1H), 3.96 (d, J=18.3 Hz, 1H), 3.13 (d, J=16.2 Hz, 1H), 2.85 (d, J=16.2 Hz, 1H), 2.33 (dt, J=6.1, 12.2 Hz, 1H), 1.96 (td, J=12.2, 3.1 Hz, 1H), 1.85-1.50 (m, 2H), 1.66 (d, J=6.7 Hz, 3H), 1.62 (s, 3H), 1.58 (s, 3H)
FABMS m/z 596 (M+H).sup.+
HRFABMS calcd for C.sub.25 H.sub.30 N.sub.3 O.sub.8 S.sub.3 (M+H).sup.+ 596.1195, found 596.1199
Anal calcd for C.sub.25 H.sub.29 N.sub.3 O.sub.8 S.sub.3.1.4H.sub.2 O: C, 48.36; H, 5.16; N, 6.77; found: C, 48.44; H, 4.95; N, 6.43
EXAMPLE 90
Synthesis of Compound 100
According to the procedure as described in Example 45, Compound 100 (34 mg, 56% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-acetylglycine (117 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.0 mmol), dichloromethane (10 ml) and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol).
IR (KBr) 3400, 2936, 1715, 1557, 1612, 1540, 1446, 1375, 1270, 1189, 1100, 1034, 999, 894, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.69 (dd, J=16.6, 11.5 Hz, 1H), 8.24 (br d, J=7.1 Hz, 1H), 7.32 (s, 1H), 6.61 (d, J=11.7 Hz, 1H), 6.28 (dd, J=11.7, 11.5 Hz, 1H), 6.09 (br dd, J=4.9, 5.5 Hz, 1H), 6.05 (d, J=16.6 Hz, 1H), 5.82 (d, J=8.5 Hz, 1H), 5.74 (d, J=8.5 Hz, 1H), 5.49 (dq, J=6.8, 7.1 Hz, 1H), 4.24 (br s, 1H), 3.95 (dd, J=17.3, 4.9 Hz, 1H), 3.86 (dd, J=17.3, 5.5 Hz, 1H), 3.18 (br s, 2H), 2.43-1.65 (m, 4H), 1.77 (s, 3H), 1.75 (s, 3H), 1.74 (d, J=6.8 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 610 (M+H).sup.+
HRFABMS calcd for C.sub.26 H.sub.32 N.sub.3 O.sub.8 S.sub.3 (M+H).sup.+ 610.1351, found 610.1357
EXAMPLE 91
Synthesis of Compound 101
According to the procedure as described in Example 45, Compound 101 (31 mg, 55% yield) was obtained from DC107 (41 mg, 0.080 mmol), N-Cbz-sarcosine (89.mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg, 0.40 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (2 mg, 0.016 mmol).
IR (KBr) 3400, 2938, 1701, 1687, 1655, 1612, 1528, 1482, 1449, 1404, 1364, 1194, 1151, 1100, 1000, 947, 895, 799, 770, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; major isomer 8.75 (dd, J=16.5, 11.6 Hz, 1H), 7.38-7.24 (m, 6H), 6.60 (d, J=11.3 Hz, 1H), 6.31 (dd, J=11.6, 11.3 Hz, 1H), 6.06 (d, J=16.5 Hz, 1H), 5.81 (d, J=9.0 Hz, 1H), 5.80 (d, J=9.0 Hz, 1H), 5.50 (dq, J=7.0, 6.7 Hz, 1H), 4.97 (d, J=12.2 Hz, 1H), 4.87 (d, J=12.2 Hz, 1H), 4.13 (br s, 1H), 4.09 (d, J=17.7 Hz, 1H), 3.92 (d, J=17.7 Hz, 1H), 3.14 (d, J=16.5 Hz, 1H), 3.09 (d, J=16.5 Hz, 1H), 2.99 (s, 3H), 2.42-1.70 (m, 4H), 1.75 (s, 3H), 1.74 (d, J=6.8 Hz, 3H), 1.68 (s, 3H); minor isomer 8.62 (dd, J=16.5, 11.6 Hz, 1H), 7.38-7.24 (m, 6H), 6.61 (d, J=11.5 Hz, 1H), 6.55 (br d, J=6.4 Hz, 1H), 6.30 (dd, J=11.6, 11.3 Hz, 1H), 6.00 (d, J=16.5 Hz, 1H), 5.87 (d, J=10.0 Hz, 1H), 5.79 (d, J=10.0 Hz, 1H), 5.40 (dq, J=6.4, 6.8 Hz, 1H), 5.06 (s, 2H), 4.03 (br s, 1H), 4.02 (d, J=17.7 Hz, 1H), 3.96 (d, J=17.7 Hz, 1H), 3.1-2.977 (m, 2H), 2.93 (s, 3H), 2.42-1.70 (m, 4H), 1.74 (s, 3H), 1.73 (d, J=6.8 Hz, 3H), 1.67 (s, 3H)
FABMS m/z 716 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.38 N.sub.3 O.sub.3 (M+H).sup.+ 716.1770, found 716.1770
EXAMPLE 92
Synthesis of Compound 102
According to the procedure as described in Example 45, Compound 102 (45 mg, 67% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Boc-L-alanine (95 mg, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (6 mg, 0.050 mmol).
IR (KBr) 3400, 2982, 2936, 1711, 1660, 1616, 1522, 1452, 1368, 1256, 1165, 1102, 1067, 996, 894, 856, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.08 (br, 1H), 7.29 (s, 1H), 6.67 (br d, J=6.4 Hz, 1H), 6.64 (d, J=11.3 Hz, 1H), 6.34 (dd, J=11.3, 11.3 Hz, 1H), 6.03 (d, J=16.8 Hz, 1H), 5.81 (m, 2H), 5.40 (dq, J=6.7, 6.4 Hz, 1H), 5.01 (br, 1H), 4.30 (br, 1H), 4.23 (br, 1H), 3.09 (br d, J=15.6 Hz, 1H), 3.04 (br d, J=15.6 Hz, 1H), 2.37 (dt, J=12.5, 4.6 Hz, 1H), 2.08 (dt, J=12.5, 4.6 Hz, 1H), 1.91-1.75 (m, 2H), 1.77 (d, J=6.7 Hz, 3H), 1.75 (br s, 3H), 1.72 (s, 3H), 1.38 (s, 9H), 1.33 (d, J=7.3 Hz, 3H)
FABMS m/z 682 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.40 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 682.1926, found 682.1926
EXAMPLE 93
Synthesis of Compound 103
According to the procedure as described in Example 45, Compound 103 (53 mg, 76% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Cbz-L-alanine (66 mg, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (2.4 mg, 0.020 mmol).
IR (KBr) 3324, 3068, 2984, 2938, 1705, 1658, 1613, 1528, 1452, 1375, 1342, 1260, 1202, 1098, 1068, 996, 947, 896, 858, 807, 777, 733, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.73 (br dd, J=16.8, 11.3 Hz, 1H), 7.36-7.18 (m, 5H), 7.32 (s, 1H), 7.20 (br d, J=6.7 Hz, 1H), 6.59 (d, J=11.6 Hz, 1H), 6.31 (dd, J=11.6, 11.3 Hz, 1H), 6.06 (d, J=16.8 Hz, 1H), 5.84 (br d, J=8.8 Hz, 1H), 5.76 (d, J=8.8 Hz, 1H), 5.47 (dq, J=6.7, 6.7 Hz, 1H), 5.21 (br d, J=6.0 Hz, 1H), 4.89 (d, J=12.2 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 4.33 (br s, 1H), 4.28 (dq, J=7.0, 6.0 Hz, 1H), 3.17 (d, J=16.2 Hz, 1H), 3.12 (d, J=16.2 Hz, 1H), 2.43-1.70 (m, 4H), 1.74 (d, J=6.7 Hz, 3H), 173 (s, 3H), 1.73 (s, 3H), 1.40 (d, J=7.0 Hz, 3H)
FABMS m/z 716 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.38 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 716.1770, found 716.1770
EXAMPLE 94
Synthesis of Compound 104
According to the procedure as described in Example 45, tert-butyldimethylsilyl ether compound of Compound 104 (59 mg, 88% yield) was obtained from DC107 (41 mg, 0.080 mmol), N-Cbz-O-tert-butyldimethylsilyl-L-serine (351 mg, 0.97 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (185 mg, 0.97 mmol), tetrahydrofuran (8 ml) and 4-dimethylaminopyridine (6.8 mg, 0.06 mmol).
The obtained tert-butyldimethylsilyl ether compound (50 mg, 0.059 mmol) was dissolved in methanol (5 ml), and 3N hydrochloric acid (0.2 ml) was added thereto, followed by stirring for 1.5 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 104 (19 mg, 44% yield).
IR (KBr) 3400, 2930, 1718, 1708, 1654, 1611, 1529, 1452, 1375, 1340, 1261, 1199, 1083, 995, 892 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.61 (br dd, J=16.6, 11.7 Hz, 1H), 7.43-7.25 (m, 7H), 6.64 (d, J=11.5 Hz, 1H), 6.32 (dd, J=11.7, 11.5 Hz, 1H), 6.07 (d, J=16.6 Hz, 1H), 5.89 (d, J=8.5 Hz, 1H), 5.78 (br d, J=8.5 Hz, 1H), 5.65 (br d, J=7.1 Hz, 1H), 5.48 (dq, J=7.1, 6.6 Hz, 1H), 5.06 (d, J=12.2 Hz, 1H), 4.97 (br d, J=12.2 Hz, 1H), 4.40-4.13 (m, 1H), 4.04 (br d, J=11.0 Hz, 1H), 3.91 (br d, J=11.0 Hz, 1H), 3.79 (br s, 1H), 3.72 (br s, 1H), 3.22 (d, J=16.6 Hz, 1H), 3.02 (br d, J=16.6 Hz, 1H), 2.43-1.50 (m, 4H), 1.72 (d, J=6.6 Hz, 3H), 1.71 (s, 3H), 1.63 (s, 3H)
FABMS m/z 732 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.38 N.sub.30 O.sub.10 S.sub.3 (M+H).sup.+ 732.1719, found 732.1726
EXAMPLE 95
Synthesis of Compound 105
According to the procedure as described in Example 45, Compound 105 (55 mg, 77% yield) was obtained from DC107 (50 mg, 0.099 mmol), N-Cbz-.beta.-alanine (66 mg, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (2.4 mg, 0.020 mmol).
IR (KBr) 3330, 2934, 1709, 1658, 1614, 1524, 1454, 1373, 1255, 1179, 1101, 1000, 947, 896, 858, 799, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.67 (br dd, J=16.7, 11.6 Hz, 1H), 7.38-7.26 (m, 5H), 7.27 (s, 1H), 6.63 (d, J=11.3 Hz, 1H), 6.51 (br d, J=6.6 Hz, 1H), 6.33 (dd, J=11.6, 11.3 Hz, 1H), 6.03 (d, J=16.8 Hz, 1H), 5.88 (d, J=9.8 Hz, 1H), 5.76 (br d, J=9.8 Hz, 1H), 5.50 (m, 1H), 5.39 (dq, J=6.6, 6.6 Hz, 1H), 5.07 (s, 2H), 4.11 (br s, 1H), 3.44 (m, 2H), 3.13 (d, J=15.4 Hz, 1H), 2.98 (d, J=15.4 Hz, 1H), 2.50 (m, 2H), 2.35 (dt, J=13.0, 4.3 Hz, 1H), 2.06 (dt, J=13.0, 4.3 Hz, 1H), 1.96-1.65 (m, 2H), 1.75 (d, J=6.6 Hz, 3H), 1.73 (s, 3H), 1.69 (d, J=1.2 Hz, 3H)
FABMS m/z 716 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.38 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 716.1770, found 716.1794
EXAMPLE 96
Synthesis of Compound 106
According to the procedure as described in Example 45, Compound 106 (39 mg, 54% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Cbz-.gamma.-amino-n-butyric acid (71 mg, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (2.4 mg, 0.020 mmol).
IR (KBr) 3332, 3300, 2936, 1710, 1656, 1614, 1527, 1454, 1373, 1250, 1167, 1000, 948, 896, 858, 799, 775, 737, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.73 (br dd, J=16.8, 11.9 Hz, 1H), 7.38-7.26 (m, 5H), 7.22 (br s, 1H), 6.79 (br d, J=6.7 Hz, 1H), 6.61 (d, J=11.3 Hz, 1H), 6.33 (dd, J=11.9, 11.3 Hz, 1H), 6.03 (d, J=16.8 Hz, 1H), 5.79 (br s, 2H), 5.37 (dq, J=6.7, 6.7 Hz, 1H), 4.98 (m, 2H), 4.83 (br, 1H), 4.34 (br, 1H), 3.25-3.33 (m, 4H), 2.42-2.30 (m, 3H), 2.12-1.70 (m, 5H), 1.75 (s, 3H), 1.74 (d, J=6.7 Hz, 3H), 1.71 (br s, 3H)
FABMS m/z 730 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.40 N.sub.3 O.sub.9 S.sub.3 (M+H).sup.+ 730.1926, found 730.1946
EXAMPLE 97
Synthesis of Compound 107
According to the procedure as described in Example 45, Compound 107 (42 mg, 55% yield) was obtained from DC107 (60 mg, 0.11mmol), N-Boc-glycylglycine (167 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.72 mmol), dichloromethane (6 ml) and 4-dimethylaminopyridine (7.2 mg, 0.059 mmol).
IR (KBr) 3292, 1707, 1686, 1656, 1544, 1369, 1169, 1103, 945, 895, 859 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.67 (dd, J=16.5, 11.6 Hz, 1H), 7.87 (br, 1H), 7.34 (s, 1H), 6.87 (br, 1H), 6.63 (d, J=11.6 Hz, 1H), 6.31 (t, J=11.6 Hz, 1H), 6.05 (d, J=16.5 Hz, 1H), 5.79 (d, J=9.2 Hz, 1H), 5.77 (d, J=9.2 Hz, 1H), 5.48 (dq, J=7.0, 6.7 Hz, 1H), 4.90 (br, 1H), 4.29 (br, 1H), 3.98 (dd, J=17.4, 5.5 Hz, 1H), 3.95 (dd, J=17.4, 5.5 Hz, 1H), 3.61 (dd, J=17.0, 6.1 Hz, 1H), 3.59 (dd, J=17.0, 6.1 Hz, 1H), 3.18 (d, J=16.5 Hz, 1H), 3.12 (d, J=16.5 Hz, 1H), 2.36 (m, 1H), 2.12 (m, 1H), 1.92-1.75 (m, 2H), 1.74 (d, J=6.71 Hz, 3H), 1.74 (s, 3H), 1.71 (s, 3H), 1.43 (s, 9H)
FABMS m/z 725 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.41 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 725.1985, found 725.2009
EXAMPLE 98
Synthesis of Compound 108
According to the procedure as described in Example 45, Compound 108 (53 mg, 47% yield) was obtained from DC107 (81 mg, 0.15 mmol), N-Cbz-glycylglycine (420 mg, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (303 mg, 1.58 mmol), tetrahydrofuran (17 ml) and 4-dimethylaminopyridine (11 mg, 0.090 mmol).
IR (KBr) 3400, 2930, 1710, 1662, 1614, 1526, 1452, 1378, 1257, 1190, 1100, 1049, 990, 893 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.65 (dd, J=16.8, 11.6 Hz, 1H), 7.74 (br, 1H), 7.40-7.30 (m, 5H), 7.30 (s, 1H), 6.73 (br, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.29 (dd, J=11.6, 11.5 Hz, 1H), 6.03 (d, J=16.8 Hz, 1H), 5.78 (br s, 2H), 5.47 (dq, J=7.0, 7.0 Hz, 1H), 5.17 (br, 1H), 5.10 (d, J=12.2 Hz, 1H), 5.08 (d, J=12.2 Hz, 1H), 4.24 (br s, 1H), 3.98 (dd, J=18.5, 5.2 Hz, 1H), 3.93 (dd, J=18.0, 4.9 Hz, 1H), 3.69 (d, J=5.8 Hz, 2H), 3.18 (d, J=16.5 Hz, 1H), 3.10 (d, J=16.5 Hz, 1H), 2.39-2.32 (m, 1H), 2.14-2.08 (m, 1H), 1.92-1.70 (m, 2H), 1.73 (s, 3H), 1.71 (d, J=7.0 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 759 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.39 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 759.1828, found 759.1810
EXAMPLE 99
Synthesis of Compound 109
According to the procedure as described in Example 45, Compound 109 (42 mg, 55% yield) was obtained from DC107 (60 mg, 0.11 mmol), N-benzoylglycylglycine (418 mg, 1.77 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (339 mg, 1.77 mmol), dichloromethane (15 ml) and 4-dimethylaminopyridine (13 mg, 0.11 mmol).
IR (KBr) 3340, 3064, 2936, 2472, 1759, 1711, 1655, 1641, 1616, 1576, 1544, 1528, 1451, 1377, 1290, 1189, 997, 970, 932, 908, 799, 727 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.68 (dd, J=16.5, 11.5 Hz, 1H), 7.75-7.40 (m, 5H), 7.63 (br d, J=7.0 Hz, 1H), 7.32 (s, 1H), 6.89 (br t, J=5.4 Hz, 1H), 6.67 (br t, J=5.4 Hz, 1H), 6.64 (d, J=11.7 Hz, 1H), 6.30 (dd, J=11.7, 11.5 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5.79 (br s, 2H), 5.46 (dq, J=7.0, 6.8 Hz, 1H), 4.22 (br s, 1H), 4.00 (d, J=5.4 Hz, 2H), 3.98 (d, J=5.4 Hz, 2H), 3.18 (d, J=16.4 Hz, 1H), 3.11 (d, J=16.4 Hz, 1H), 2.42-1.50 (m, 4H), 1.74 (s, 3H), 1.71 (d, J=6.8 Hz, 3H), 1.71 (s, 3H)
FABMS m/z 729 (M+H).sup.+
HRFABMS calcd for C.sub.3 H.sub.37 N.sub.4 O.sub.9 S.sub.3 (M+H).sup.+ 729.1722, found 729.1735
EXAMPLE 100
Synthesis of Compound 110
According to the procedure as described in Example 45, Compound 110 (39 mg, 50% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Cbz-L-alanylglycine (280 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.0 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol).
IR (KBr) 3420, 2938, 1704, 1658, 1612, 1529, 1453, 1376, 1255, 1188, 1099, 997, 947, 897, 859, 799, 739, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.65 (dd, J=16.5, 11.2 Hz, 1H), 7.45 (br d, J=6.3 Hz, 1H), 7.38-7.25 (m, 5H), 7.28 (s, 1H), 6.83 (br, 1H), 6.62 (d, J=11.4 Hz, 1H), 6.31 (dd, J=11.4, 11.2 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5.80 (d, J=9.3 Hz, 1H), 5.78 (d, J=9.3 Hz, 1H), 5.45 (dq, J=6.3, 6.8 Hz, 1H), 5.24 (d, J=7.6 Hz, 1H), 5.12 (d, J=12.0 Hz, 1H), 5.07 (br s, 1H), 5.06 (d, J=12.2 Hz, 1H), 4.19 (m, 1H), 4.02 (dd, J=17.8, 5.6 Hz, 1H), 3.89 (dd, J=17.8, 4.6 Hz, 1H), 3.13 (d, J=16.1 Hz, 1H), 3.04 (d, J=16.1 Hz, 1H), 2.42-1.50 (m, 4H), 1.72 (d, J=6.8 Hz, 3H), 1.71 (s, 3H), 1.68 (s, 3H), 1.29 (d, J=7.0 Hz, 3H)
FABMS m/z 773 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.41 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 773.1985, found 773.1982
EXAMPLE 101
Synthesis of Compound 111
According to the procedure as described in Example 45, Compound 111 (38 mg, 41% yield) was obtained from DC107 (62 mg, 0.12 mmol), N-Cbz-.beta.-alanylglycine (339 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (232 mg, 1.2 mmol), tetrahydrofuran (11 ml) and 4-dimethylaminopyridine (8.8 mg, 0.07 mmol).
IR (KBr) 3312, 2934, 1702, 1660, 1613, 1528, 1452, 1374, 1258, 1183, 1099, 996, 948, 895, 858, 799, 774, 739, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3 +CD.sub.3 OD, 500 MHz) .delta. ppm; 8.61 (br dd, J=16.5, 11.6 Hz, 1H), 7.37-7.28 (m, 5H), 7.33 (s, 1H), 6.66 (d, J=11.3 Hz, 1H), 6.33 (d, J=11.6, 11.3 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.89 (d, J=9.5 Hz, 1H), 5.74 (br d, J=9.5 Hz, 1H), 5.38 (q, J=6.7 Hz, 1H), 5.07 (br s, 2H), 3.99 (d, J=18.0 Hz, 1H), 3.94 (d, J=18.0 Hz, 1H), 3.35 (dd, J=5.9, 5.3 Hz, 2H), 3.18 (d, J=16.2 Hz, 1H), 2.96 (d, J=16.2 Hz, 1H), 2.43-2.28 (m, 3H), 2.05-1.55 (m, 3H), 1.73 (d, J=6.7 Hz, 3H), 1.70 (d, J=0.7 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 773 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.41 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 773.1985, found 773.1990
EXAMPLE 102
Synthesis of Compound 112
According to the procedure as described in Example 45, Compound 112 (31 mg, 42% yield) was obtained from DC107 (51 mg, 0.10mmol), N-Boc-.beta.-alanylglycine (244 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.0 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (12 mg, 0.10 mmol).
IR (KBr) 3400, 2980, 2932, 1704, 1656, 1615, 1545, 1450, 1368, 1270, 1254, 1181, 1098, 997, 894, 857, 799 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400MHz) .delta. ppm; 8.65 (dd, J=16.9, 11.2 Hz, 1H), 8.11 (br s, 1H), 7.33 (s, 1H), 7.16 (br, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.30 (dd, J=11.5, 11.2 Hz, 1H), 6.05 (d, J=16.9 Hz, 1H), 5.79 (d, J=8.8 Hz, 1H), 5.75 (d, J=8.8 Hz, 1H), 5.49 (dq, J=6.8, 6.5 Hz, 1H), 4.86 (br, 1H), 4.29 (br s, 1H), 3.95 (dd, J=17.6, 5.1 Hz, 1H), 3.90 (dd, J=17.6, 5.3 Hz, 1H), 3.44-3.19 (m, 2H), 3.18 (d, J=16.5 Hz, 1H), 3.14 (d, J=16.5 Hz, 1H), 2.42-1.70 (m, 6H), 1.74 (s, 3H), 1.73 (d, J=6.5 Hz, 3H), 1.70 (s, 3H), 1.41 (s, 9H)
FABMS m/z 739 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.43 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 739.2141, found 739.2168
EXAMPLE 103
Synthesis of Compound 113
According to the procedure as described in Example 45, Compound 113 (16 mg, 20% yield) was obtained from DC107 (51 mg, 0.12 mmol), N-Cbz-.gamma.-aminobutyrylglycine (295 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.0 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol).
IR (KBr) 3350, 2932, 1718, 1658, 1544, 1452, 1375, 1260, 1186, 1098, 998, 945, 896, 799, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.67 (dd, J=16.8, 11.2 Hz, 1H), 8.13 (br s, 1H), 7.39-7.26 (m, 5H), 7.30 (s, 1H), 6.92 (br, 1H), 6.59 (d, J=11.5 Hz, 1H), 6.27 (dd, J=11.5, 11.2 Hz, 1H), 6.05 (d, J=16.8 Hz, 1H), 5.81 (br d, J=8.8 Hz, 1H), 5.74 (d, J=8.8 Hz, 1H), 5.49 (dq, J=7.0, 6.6 Hz, 1H), 5.08 (br s, 2H), 4.89 (br t, J=4.6 Hz, 1H), 4.27 (br s, 1H), 3.90 (br d, J=4.6 Hz, 2H), 3.20-3.10 (m, 4H), 2.43-1.50 (m, 8H), 1.74 (s, 3H), 1.73 (d, J=6.6 Hz, 3H), 1.69 (s, 3H)
FABMS m/z 787 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.43 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 787.2141, found 787.2137
EXAMPLE 104
Synthesis of Compound 114
According to the procedure as described in Example 45, Compound 114 (41 mg, 54% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Cbz-sarcosylglycine (278 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.0 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (7.2 mg, 0.06 mmol).
IR (KBr) 3400, 2938, 1700, 1688, 1665, 1534, 1451, 1405, 1365, 1189, 1153, 1103, 989, 939, 895, 799, 769, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.67 (br dd, J=16.5, 11.3 Hz, 1H), 7.69 (br s, 1H), 7.34 (br s, 5H), 7.31 (s, 1H), 6.69 (br, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.29 (dd, J=11.5, 11.3 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5.80 (br d, J=9.5 Hz, 1H), 5.77 (d, J=9.5 Hz, 1H), 5.47 (dq, J=6.8, 6.6 Hz, 1H), 5.13 (s, 2H), 4.20 (br s, 1H), 4.02-3.55 (m, 4H), 3.18 (d, J=16.4 Hz, 1H), 3.11 (d, J=16.4 Hz, 1H), 2.93 (s, 3H), 2.42-1.70 (m, 4H), 1.74 (s, 3H), 1.73 (d, J=6.6 Hz, 3H), 1.71 (s, 3H)
FABMS m/z 773 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.41 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 773.1985, found 773.1997
Anal calcd for C.sub.35 H.sub.40 N.sub.4 O.sub.10 S.sub.3.1.0H.sub.2 O: C, 53.15; H, 5.35; N, 7.08; found: C, 53.22; H, 5.21; N, 7.10
EXAMPLE 105
Synthesis of Compound 115
According to the procedure as described in Example 45, Compound 115 (39 mg, 43% yield) was obtained from DC107 (60 mg, 0.11 mmol), N-Cbz-leucylglycine (380 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg, 1.2 mmol), tetrahydrofuran (11 ml) and 4-dimethylaminopyridine (8.6 mg, 0.07 mmol).
IR (KBr) 3400, 2960, 1706, 1664, 1615, 1528, 1452, 1370, 1261, 1190, 1100, 1043, 996, 896 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.73 (dd, J=16.8, 11.3 Hz, 1H), 7.38-7.27 (m, 6H), 7.30 (s, 1H), 6.78 (br, 1H), 6.63 (d, J=11.6 Hz, 1H), 6.31 (dd, J=11.6, 11.3 Hz, 1H), 6.03 (d, J=16.8 Hz, 1H), 5.81 (d, J=9.2 Hz, 1H), 5.79 (d, J=9.2 Hz, 1H), 5.46 (dq, J=7.0, 6.7 Hz, 1H), 5.12 (d, J=12.2 Hz, 1H), 5.08 (d, J=12.2 Hz, 1H), 5.00 (br, 1H), 4.21 (br s, 1H), 4.11 (m, 1H), 4.01 (dd, J=18.0, 5.5 Hz, 1H), 3.89 (br dd, J=18.0, 4.9 Hz, 1H), 3.12 (d, J=16.5 Hz, 1H), 3.07 (d, J=16.5 Hz, 1H), 2.40-2.31 (m, 1H), 2.34 (m, 1H), 1.93-1.45 (m, 5H), 1.73 (d, J=6.7 Hz, 3H), 1.72 (s, 3H), 1.70 (s, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.85 (d, J=7.0 Hz, 3H)
FABMS m/z 815 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.47 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 815.2454, found 815.2435
EXAMPLE 106
Synthesis of Compound 116
According to the procedure as described in Example 45, tert-butyldimethylsilyl ether compound of Compound 116 (74 mg, 68% yield) was obtained from DC107 (60 mg, 0.12 mmol), N-Cbz-O-tert-butyldimethylsilyl-L-serylglycine (485 mg, 0.97 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg, 0.97 mmol), tetrahydrofuran (10 ml) and 4-dimethylaminopyridine (8.6 mg, 0.07 mmol).
The obtained tert-butyldimethylsilyl ether compound (74 mg, 0.081 mmol) was dissolved in methanol (7.4 ml), and 3N hydrochloric acid (0.3 ml) was added thereto, followed by stirring for 1 hour. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 116 (22 mg, 34% yield).
IR (KBr) 3402, 2926, 1719, 1655, 1539, 1448, 1384, 1260, 1194, 1090, 892 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.61 (dd, J=16.6, 11.2 Hz, 1H), 7.40-7.10 (m, 7H), 7.25 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.31 (dd, J=11.5, 11.2 Hz, 1H), 6.03 (d, J=16.6 Hz, 1H), 5.82 (d, J=9.3 Hz, 1H), 5.81 (br s, 1H), 5.75 (br d, J=9.3 Hz, 1H), 5.46 (dq, J=7.0, 6.9 Hz, 1H), 5.10 (d, J=12.0 Hz, 1H), 5.07 (d, J=12.0 Hz, 1H), 4.26-3.58 (m, 6H), 3.19 (d, J=16.2 Hz, 1H), 3.02 (d, J=16.2 Hz, 1H), 2.94 (br s, 1H), 2.40-1.60 (m, 4H), 1.71 (d, J=6.9 Hz, 3H), 1.70 (s, 3H), 1.68 (s, 3H)
FABMS m/z 789 (M+H).sup.+.
HRFABMS calcd for C.sub.35 H.sub.41 N.sub.4 O.sub.11 S.sub.3 (M+H).sup.+ 789.1934, found 789.1918
EXAMPLE 107
Synthesis of Compound 117
According to the procedure as described in Example 45, Compound 117 (32 mg, 42% yield) was obtained from DC107 (50 mg, 0.098 mmol), N-Cbz-.beta.-alanylsarcosine (148 mg, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg, 0.50 mmol), tetrahydrofuran (15 ml) and 4-dimethylaminopyridine (3.6 mg, 0.03 mmol).
IR (KBr) 3400, 2938, 1709, 1656, 1647, 1527, 1511, 1453, 1405, 1372, 1255, 1187, 1101, 997, 942, 895 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.65 (dd, J=16.5, 11.6 Hz, 1H), 7.55 (br d, J=6.7 Hz, 1H), 7.39-7.27 (m, 5H), 7.29 (s, 1H), 6.60 (d, J=11.3 Hz, 1H), 6.30 (dd, J=11.6, 11.3 Hz, 1H), 6.05 (d, J=16.5 Hz, 1H), 5.80-5.73 (m, 2H), 5.47 (dq, J=7.0, 6.7 Hz, 1H), 5.17 (br, 1H), 5.06 (br s, 2H), 4.15 (br s, 1H), 4.10-3.90 (m, 2H), 3.30-3.00 (m, 2H), 3.16 (d, J=16.8 Hz, 1H), 3.07 (d, J=16.8 Hz, 1H), 3.03 (s, 3H), 2.60-1.70 (m, 6H), 1.74 (d, J=7.0 Hz, 3H), 1.73 (s, 3H), 1.67 (s, 3H)
FABMS m/z 787 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.43 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 787.2141, found 787.2163
EXAMPLE 108
Synthesis of Compound 118
According to the procedure as described in Example 45, Compound 118 (45 mg, 53% yield) was obtained from DC107 (51 mg, 0.10mmol), N-Cbz-glycyl-.beta.-alanine (282 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.1 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol).
IR (KBr) 3330, 3072, 2936, 1720, 1658, 1613, 1537, 1454, 1375, 1255, 1175, 1098, 1060, 998, 946, 896, 859, 799, 776, 737, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.45 (br dd, J=16.5, 11.6 Hz, 1H), 7.38-7.28 (m, 5H), 7.27 (s, 1H), 6.99 (br, 1H), 6.73 (br d, J=6.7 Hz, 1H), 6.66 (d, J=11.6 Hz, 1H), 6.32 (t, J=11.6 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.98 (d, J=9.5 Hz, 1H), 5.70 (br d, J=9.5 Hz, 1H), 5.60 (br, 1H), 5.43 (dq, J=6.7, 6.7 Hz, 1H), 5.10 (s, 2H), 4.02 (br, 1H), 3.84 (br, 2H), 3.59-3.48 (m, 2H), 3.25 (d, J=15.9 Hz, 1H), 2.90 (d, J=15.9 Hz, 1H), 2.57-2.47 (m, 2H), 2.37 (dt, J=4.8, 12.8 Hz, 1H), 2.04-1.60 (m, 3H), 1.74 (d, J=6.7 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H)
FABMS m/z 773 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.41 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 773.1985, found 773.2009
EXAMPLE 109
Synthesis of Compound 119
According to the procedure as described in Example 45, Compound 119 (42 mg, 53% yield) was obtained from DC107 (51 mg, 0.10 mmol), N-Cbz-.beta.-alanyl-.beta.-alanine (205 mg, 0.70 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (4.9 mg, 0.040 mmol).
IR (KBr) 3400, 2936, 1720, 1656, 1531, 1454, 1373, 1259, 1174, 1098, 896, 859, 799, 738, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.51 (dd, J=16.6, 11.5 Hz, 1H), 7.37-7.21 (m, 5H), 7.34 (s, 1H), 6.70 (br t, J=8.0 Hz, 1H), 6.66 (d, J=11.5 Hz, 1H), 6.57 (d, J=6.8 Hz, 1H), 6.34 (t, J=11.5 Hz, 1H), 6.05 (d, J=16.6 Hz, 1H), 5.98 (d, J=9.5 Hz, 1H), 5.73 (br d, J=9.5 Hz, 1H), 5.50 (br, 1H), 5.43 (dq, J=6.8, 6.8 Hz, 1H), 5.07 (br s, 2H), 3.92 (br s, 1H), 3.58-3.40 (m, 4H), 3.24 (d, J=16.1 Hz, 1H), 2.90 (d, J=16.1 Hz, 1H), 2.57-2.30 (m, 5H), 2.08-1.70 (m, 3H), 1.75 (d, J=6.8 Hz, 3H), 1.67 (d, J=1.2 Hz, 3H), 1.66 (s, 3H)
FABMS m/z 787 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.43 N.sub.4 O.sub.10 S.sub.3 (M+H).sup.+ 787.2141, found 787.2153
EXAMPLE 110
Synthesis of Compound 120
According to the procedure as described in Example 18, Compound 120 (7.6 mg, 17% yield) was obtained from Compound 80 (40 mg, 0.062 mmol), 2-methoxypropene (0.029 ml, 0.31mmol) and camphorsulfonic acid (14 mg, 0.062 mmol).
IR (KBr) 3420, 2938, 1720, 1649, 1609, 1452, 1374, 1256, 1211, 1154, 1124, 1070, 1021, 975, 887 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.51 (ddd, J=16.4, 11.5, 1.0 Hz, 1H), 7.41 (s, 1H), 6.61 (d, J=11.3 Hz, 1H), 6.36 (dd, J=11.5, 11.3 Hz, 1H), 5.98 (d, J=16.4 Hz, 1H), 5.81 (dd, J=9.5, 1.2 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.47 (br s, 1H), 5.41 (d, J=11.0 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 4.92 (dd, J=9.5, 1.2 Hz, 1H), 4.04 (d, J=17.8 Hz, 1H), 3.09 (s, 3H), 2.29 (d, J=17.8 Hz, 1H), 2.42-1.20 (m, 15H), 1.97 (d, J=6.6 Hz, 3H), 1.77 (d, J=1.2 Hz, 3H), 1.69 (s, 3H), 1.28 (s, 6H)
FABMS m/z 723 (M+H).sup.+
EXAMPLE 111
Synthesis of Compound 121
According to the procedure as described in Example 18, Compound 121 (12 mg, 66% yield) was obtained from Compound 35 (16 mg, 0.026mmol), 2-methoxypropene (0.012 ml, 0.13 mmol) and camphorsulfonic acid (3 mg, 0.013 mmol).
IR (KBr) 3400, 3224, 2938, 1819, 1730, 1705, 1680, 1642, 1608, 1448, 1374, 1258, 1208, 1146, 1070, 1029, 977, 888, 769, 732 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.50 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.41 (s, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.36 (t, J=11.5 Hz, 1H), 5.99 (d, J=16.6 Hz, 1H), 5.82 (br d, J=9.2 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.46 (br s, 1H), 4.92 (dd, J=9.5, 1.2 Hz, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.80 (d, J=15.1 Hz, 1H), 3.75 (d, J=15.1 Hz, 1H), 3.10 (s, 3H), 2.43-1.35 (m, 4H), 2.29 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.97 (d, J=6.6 Hz, 3H), 1.78 (d, J=1.4 Hz, 3H), 1.69 (s, 3H), 1.28 (s, 3H), 1.28 (s, 3H)
FABMS m/z 695 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.39 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 695.1767, found 695.1757
EXAMPLE 112
Synthesis of Compound 122
According to the procedure as described in Example 18, Compound 122 (54 mg, 81% yield) was obtained from Compound 35 (56 mg, 0.090 mmol), 5,6-dihydro-4-methoxy-2H-pyran (0.030 ml, 0.27 mmol) and camphorsulfonic acid (9.3 mg, 0.045 mmol).
IR (KBr) 3412, 2938, 2870, 1818, 1710, 1685, 1642, 1608, 1450, 1356, 1262, 1233, 1208, 1141, 1095, 977, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.53 (dd, J=16.5, 11.3 Hz, 1H), 7.43 (s, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.37 (dd, J=11.5, 11.3 Hz, 1H), 6.00 (d, J=16.5 Hz, 1H), 5.86 (br d, J=9.5 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.44 (br s, 1H), 4.98 (dd, J=9.5, 1.2 Hz, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.81 (d, J=15.4 Hz, 1H), 3.74 (d, J=15.4 Hz, 1H), 3.70-3.49 (m, 4H), 3.11 (s, 3H), 2.44-2.23 (m, 3H), 2.29 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.95 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.2 Hz, 3H), 1.80-1.35 (m, 5H), 1.68 (s, 3H)
FABMS m/z 737 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.41 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 737.1872, found 737.1848
EXAMPLE 113
Synthesis of Compounds 123 and 124
According to the procedure as described in Example 60, Compound 123 (13 mg, 33% yield) and its geometrical isomer, Compound 124 (13 mg, 33% yield), were obtained from Compound 122 (38 mg, 0.052 mmol), methanol (3 ml), pyridine (0.05 mol) and hydroxylamine hydrochloride (18 mg, 0.26 mmol).
Compound 123
IR (KBr) 3400, 2932, 1817, 1720, 1680, 1448, 1355, 1263, 1207, 1140, 1094, 886, 838 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.05 (dd, J=16.6, 11.3 Hz, 1H), 7.32 (s, 1H), 6.87 (d, J=16.6 Hz, 1H), 6.50 (d, J=11.6 Hz, 1H), 6.39 (dd, J=11.6, 11.3 Hz, 1H), 6.03 (br d, J=9.8 Hz, 1H), 5.55 (q, J=6.6 Hz, 1H), 5.51 (br s, 1H), 5.28 (dd, J=9.8, 1.2 Hz, 1H), 4.06 (d, J=17.6 Hz, 1H), 3.80 (d, J=15.1 Hz, 1H), 3.75 (d, J=15.1 Hz 1H), 3.65-3.54 (m, 4H), 3.13 (s, 3H), 2.35-1.20 (m, 8H), 2.20 (d, J=17.6 Hz, 1H), 2.08 (s, 3H), 1.85 (d, J=6.6 Hz, 3H), 1.75 (d, J=1.2 Hz, 3H), 1.62 (s, 3H)
FABMS m/z 752 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.42 N.sub.3 O.sub.11 S.sub.3 (M+H).sup.+ 752.1981, found 752.1957
Compound 124
IR (KBr) 3400, 2940, 1819, 1720, 1687, 1444, 1356, 1262, 1208, 1141, 1094, 837 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.03 (dd, J=16.6, 11.0 Hz, 1H), 7.22 (s, 1H), 6.33 (d, J=11.3 Hz, 1H), 6.27 (dd, J=11.3, 11.0 Hz, 1H), 6.14 (dd, J=9.8, 1.2 Hz, 1H), 6.09 (d, J=16.6 Hz, 1H), 5.84 (br d, J=9.8 Hz, 1H), 5.49 (q, J=6.6 Hz, 1H), 5.44 (br s, 1H), 3.98 (d, J=17.6 Hz, 1H), 3.74 (d, J=15.1 Hz, 1H), 3.67 (d, J=15.1 Hz, 1H), 3.60-3.45 (m, 4H), 3.07 (s, 3H), 2.42-1.25 (m, 8H), 2.30 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.92 (d, J=6.6 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 752 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.42 N.sub.3 O.sub.11 S.sub.3 (M+H).sup.+ 752.1981, found 752.1973
EXAMPLE 114
Synthesis of Compound 125
According to the procedure as described in Example 60, Compound 125 (13 mg, 91% yield) was obtained from Compound 63 (14 mg, 0.020mmol), methanol (1.0 ml), pyridine (0.020 ml) and hydroxylamine hydrochloride (6.9 mg, 0.10 mmol). From .sup.1 H NMR, Compound 125 was found to be a mixture of geometrical isomers at a ratio of about 3:2.
IR (KBr) 3400, 2932, 1820, 1720, 1680, 1440, 1370, 1261, 1207, 975, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; major isomer 8.96 (dd, J=16.6, 11.5 Hz, 1H), 7.19 (s, 1H), 6.36-6.15 (m, 2H), 6.17 (dd, J=9.3, 1.5 Hz, 1H), 6.10 (d, J=16.6 Hz, 1H), 5.79 (br d, J=9.3 Hz, 1H), 5.51 (br s, 1H), 5.51 (q, J=6.6 Hz, 1H), 4.45 (br s, 1H), 3.98 (d, J=17.6 Hz, 1H), 3.85-3.45 (m, 4H), 2.40-1.30 (m, 10H), 2.08 (s, 3H), 1.84 (d, J=6.6 Hz, 3H), 1.75 (d, J=1.2 Hz, 3H), 1.63 (s, 3H); minor isomer 8.97 (dd, J=16.6, 11.5 Hz, 1H), 7.23 (s, 1H), 6.79 (d, J=16.6 Hz, 1H), 6.41 (d, 11.7 Hz, 1H), 6.23 (dd, J=11.7, 11.0 Hz, 1H), 5.90 (br d, J=9.3 Hz, 1H), 5.51 (br s, 1H), 5.51 (q, J=6.6 Hz, 1H), 5.06 (dd, J=9.0, 1.2 Hz, 1H), 4.54 (br s, 1H), 4.00 (d, J=17.6 Hz, 1H), 3.85-3.45 (m, 4H), 2.40-1.30 (m, 10H), 2.08 (s, 3H), 1.83 (d, J=6.6 Hz, 3H), 1.70 (d, J=1.2 Hz, 3H), 1.62 (s, 3H)
FABMS m/z 722 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.39 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 722.1876, found 722.1881
EXAMPLE 115
Synthesis of Compound 126
According to the procedure as described in Example 18, Compound 126 (25 mg, 71% yield) was obtained from Compound 35 (30 mg, 0.048mmol), 1-methoxy-1-cyclohexene (27 mg, 0.24 mmol) and camphorsulfonic acid (2.2 mg, 0.01 mmol).
IR (KBr) 3420, 2940, 2860, 1820, 1720, 1680, 1649, 1609, 1450, 1369, 1255, 1208, 1152, 1090, 1017, 977, 926, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.52 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.41 (s, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.36 (t, J=11.5 Hz, 1H), 5.99 (d, J=16.6 Hz, 1H), 5.84 (br dd, J=9.8, 1.2 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.46 (dd, J=9.8, 1.4 Hz, 1H), 4.05 (d, J=17.8 Hz, 1H), 3.80 (dd, J=15.1, 0.7 Hz, 1H), 3.75 (dd, J=15.1, 0.7 Hz, 1H), 3.07 (s, 3H), 2.41-1.20 (m, 14H), 2.28 (d, J=17.8 Hz, 1H), 2.15 (s, 3H), 1.97 (d, J=6.6 Hz, 3H), 1.78 (d, J=1.4 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 735 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.43 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 735.2080, found 735.2067
EXAMPLE 116
Synthesis of Compound 127
According to the procedure as described in Example 18, Compound 127 (32 mg, 91% yield) was obtained from Compound 35 (29 mg, 0.047 mmol), 5,6-dihydro-4-methoxy-2H-thiopyran (60 mg, 0.46 mmol) and camphorsulfonic acid (8 mg, 0.034 mmol).
IR (KBr) 3400, 3090, 2930, 1820, 1710, 1678, 1642, 1609, 1427, 1376, 1248, 1207, 1147, 1094, 1030, 978, 879, 809, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.49 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.43 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.37 (t, J=11.5 Hz, 1H), 6.00 (s, J=16.6 Hz, 1H), 5.84 (dd, J=9.8, 1.0 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.43 (br s, 1H), 4.95 (dd, J=9.8, 1.2 Hz, 1H), 4.04 (d, J=17.8 Hz, 1H), 3.81 (d, J=15.4 Hz, 1H), 3.74 (d, J=15.4 Hz, 1H), 3.08 (s, 3H), 2.72-1.35 (m, 12H), 2.30 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.96 (d, J=6.6 Hz, 3H), 1.78 (d, J=1.2 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 753 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.41 N.sub.2 O.sub.10 S.sub.4 (M+H).sup.+ 753.1644, found 753.1618
EXAMPLE 117
Synthesis of Compounds 128 and 129
Compound 127 (80 mg, 0.11 mmol) was dissolved in dichloromethane (7 ml), and m-chloroperbenzoic acid (40 mg, 0.16 mmol) was gradually added thereto at 0.degree. C. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 128 (16 mg, 20% yield) and Compound 129 (44 mg, 53% yield).
Compound 128
IR (KBr) 3450, 2936, 1817, 1710, 1680, 1643, 1608, 1450, 1362, 1263, 1205, 1095, 1035, 982, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; major isomer 9.51 (ddd, J=16.6, 11.5, 0.7 Hz, 1H), 7.43 (s, 1H), 6.62 (d, J=11.2 Hz, 1H), 6.35 (dd, J=11.5, 11.2 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.86 (br d, J=9.0 Hz, 1H), 5.56 (q, J=6.6 Hz, 1H), 5.46 is, 1H), 4.99 (dd, J=9.0, 1.2 Hz, 1H), 4.05 (d, J=17.8 Hz, 1H), 3.82 (dd, J=15.4, 1.0 Hz, 1H), 3.73 (d, J=15.4 Hz, 1H), 3.13 is, 3H), 2.92-1.35 (m, 12H), 2.31 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.97 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.2 Hz, 3H), 1.68 (s, 3H); minor isomer 9.45 (ddd, J=16.6, 11.5, 0.7 Hz, 1H), 7.46 (s, 1H), 6.65 (d, J=11.2 Hz, 1H), 6.35 (dd, J=11.5, 11.2 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.85 (br d, J=9.0 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.40 (s, 1H), 4.97 (dd, J=9.0, 1.2 Hz, 1H), 4.05 (d, J=17.8 Hz, 1H), 3.81 (dd, J=15.4, 0.7 Hz, 1H), 3.74 (d, J=15.4 Hz, 1H), 3.17 (s, 3H), 2.92-1.35 (m, 12H), 2.29 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.95 (d, J=6.6 Hz, 3H), 1.80 (d, J=1.2 Hz, 3H), 1.67 (s, 3H)
FABMS m/z 769 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.41 N.sub.2 O.sub.11 S.sub.4 (M+H).sup.+ 769.1593, found 769.1584
Compound 129
IR (KBr) 3420, 2944, 1819, 1720, 1679, 1645, 1608, 1450, 1290, 1267, 1205, 1095, 1032, 978, 851 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.46 (ddd, J=16.6, 11.5, 0.8 Hz, 1H), 7.46 (s, 1H), 6.66 (d, J=11.5 Hz, 1H), 6.37 (t, J=11.5 Hz, 1H), 6.01 (d, J=16.6 Hz, 1H), 5.86 (br dd, J=9.5, 1.0 Hz, 1H), 5.57 (q, J=6.4 Hz, 1H), 5.38 (br s, 1H), 4.95 (dd, J=9.5, 1.2 Hz, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.83 (d, J=15.3 Hz, 1H), 3.73 (d, J=15.3 Hz, 1H), 3.15 (s, 3H), 3.15-2.80 (m, 4H), 2.45-1.40 (m, 8H), 2.31 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.94 (d, J=6.4 Hz, 3H), 1.79 (d, J=1.2 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 785 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.41 N.sub.2 O.sub.12 S.sub.4 (M+H).sup.+ 785.1542, found 785.1564
EXAMPLE 118
Synthesis of Compound 130
According to the procedure as described in Example 18, Compound 130 (37 mg, 71% yield) was obtained from Compound 35 (40 mg, 0.064 mmol), 1-ethoxycarbonyl-4-methoxy-1,2,5,6-tetrahydropyridine (59 mg, 0.32 mmol) and camphorsulfonic acid (7.4 mg, 0.032 mmol).
IR (KBr) 3420, 2936, 1821, 1667, 1640, 1608, 1440, 1381, 1354, 1241, 1208, 1143, 1105, 1019, 976, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.50 (dd, J=16.4, 11.5 Hz, 1H), 7.42 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.36 (t, J=11.5 Hz, 1H), 5.99 (d, J=16.6 Hz, 1H), 5.85 (br d, J=9.7 Hz, 1H), 5.56 (q, J=6.6 Hz, 1H), 5.43 (br s, 1H), 4.98 (dd, J=9.7, 1.3 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 4.04 (d, J=17.8 Hz, 1H), 3.81 (d, J=15.4 Hz, 1H), 3.74 (d, J=15.4 Hz, 1H), 3.61-3.50 (m, 2H), 3.27 (m, 2H), 3.11 (s, 3H), 2.44-1.35 (m, 8H), 2.29 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.94 (d, J=6.6 Hz, 3H), 1.78 (d, J=1.3 Hz, 3H), 1.68 (s, 3H), 1.22 (t, J=7.0 Hz, 3H)
FABMS m/z 808 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.46 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 808.2243, found 808.2223
EXAMPLE 119
Synthesis of Compound 131
According to the procedure as described in Example 18, Compound 131 (20 mg, 31% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), 1-phenyl-4-methoxy-1,2,5,6-tetrahydropyridine (150 mg, 0.80mmol) and trifluoroacetic acid (0.055 mg, 0.70 mmol).
IR (KBr) 3400, 2936, 1821, 1720, 1680, 1648, 1598, 1496, 1451, 1339, 1260, 1209, 1092, 1031, 977, 760 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.52 (dd, J=16.5, 11.5 Hz, 1H), 7.41 (s, 1H), 7.25-7.18 (m, 2H), 6.89-6.76 (m, 3H), 6.61 (d, J=11.5 Hz, 1H), 6.34 (t, J=11.5 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.87 (br d, J=9.8 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.45 (br s, 1H), 5.02 (dd, J=9.8, 1.2 Hz, 1H), 4.05 (d, J=17.8 Hz, 1H), 3.81 (d, J=15.2 Hz, 1H), 3.74 (d, J=15.2 Hz, 1H), 3.30-2.93 (m, 4H), 3.14 (s, 3H), 2.43-1.40 (m, 8H), 2.15 (s, 3H), 1.96 (d, J=6.6 Hz, 3H), 1.80 (d, J=1.2 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 812 (M+H).sup.+
HRFABMS calcd for C.sub.39 H.sub.45 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 812.2345, found 812.2333
EXAMPLE 120
Synthesis of Compound 132
DC107 (110 mg, 0.22 mmol) was dissolved in acetonitrile (10 ml), and p-nitrobenzylbromide (140 mg, 0.64 mmol) and potassium carbonate (150 mg, 1.1 mmol) were added thereto, followed by stirring at room temperature for 14 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 132 (90 mg, 65% yield).
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.44 (ddd, J=16.3, 11.5, 1.0 Hz, 1H), 8.15 (br d, J=8.8 Hz, 2H), 7.45 (br d, J=8.8 Hz, 2H), 7.34 (s, 1H), 6.58 (d, J=11.5 Hz, 1H), 6.23 (t, J=11.5 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.72 (br d, J=9.0 Hz, 1H), 5.47 (br s, 1H), 5.40 (q, J=6.8 Hz, 1H), 4.94 (dd, J=9.0, 3.7 Hz, 1H), 4.12-4.03 (m, 2H), 3.88 (d, J=17.6 Hz, 1H), 3.75 (br d, J=3.7 Hz, 1H), 2.18 (d, J=17.6 Hz, 1H), 2.35-1.85 (m, 4H), 2.01 (d, J=6.8 Hz, 3H), 1.76 (s, 3H), 1.74 (d, J=1.2 Hz, 3H)
FABMS m/z 646 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.32 N.sub.3 O.sub.8 S.sub.3 (M+H).sup.+ 646.1351, found 646.1350
EXAMPLE 121
Synthesis of Compound 133
According to the procedure as described in Example 18, Compound 133 (49 mg, 74% yield) was obtained from Compound 132 (56 mg, 0.087 mmol), 5,6-dihydro-4-methoxy-2H-pyran (0.029 ml, 0.26 mmol) and camphorsulfonic acid (10 mg, 0.044 mmol).
IR (KBr) 3400, 3088, 2938, 2870, 1720, 1680, 1640, 1607, 1519, 1491, 1453, 1345, 1260, 1140, 1100, 988, 840, 810, 730 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.52 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 8.16 (br d, J=8.8 Hz, 2H), 7.46 (br d, J=8.8 Hz, 2H), 7.42 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.36 (dd, J=11.5 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.84 (br d, J=9.8 Hz, 1H), 5.56 (q, J=6.3 Hz, 1H), 5.46 (br s, 1H), 4.97 (dd, J=9.8, 1.5 Hz, 1H), 4.08 (br s, 2H), 4.03 (d, J=17.6 Hz, 1H), 3.70-3.48 (m, 4H), 3.10 (s, 3H), 2.41-1.60 (m, 8H), 2.19 (d, J=17.6 Hz, 1H), 1.94 (d, J=6.6 Hz, 3H), 1.77 (d, J=1.2 Hz, 3H), 1.67 (s, 3H)
FABMS m/z 760 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.42 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 760.2032, found 760.2033
EXAMPLE 122
Synthesis of Compound 134
DC107 (100 mg, 0.20 mmol) was dissolved in acetonitrile (10 ml), and p-acetoxybenzylchloride (110 mg, 0.59 mmol), potassium carbonate (150 mg, 1.1 mmol) and potassium iodide (17 mg, 0.10 mmol) were added thereto, followed by stirring at room temperature for 12 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 134 (71 mg, 54% yield).
IR (KBr) 3420, 2930, 1760, 1720, 1670, 1647, 1710, 1610, 1505, 1460, 1370, 1260, 1192, 1052, 985, 913, 731 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.45 (ddd, J=16.3, 11.0, 1.0 Hz, 1H), 7.27 (s, 1H), 7.28-7.25 (m, 2H), 7.05-6.95 (m, 2H), 6.58 (d, J=11.7 Hz, 1H), 6.23 (dd, J=11.7, 11.0 Hz, 1H), 6.17 (d, J=16.3 Hz, 1H), 5.71 (br d, J=8.6 Hz, 1H), 5.41 (br s, 1H), 5.40 (q, J=6.8 Hz, 1H), 4.94 (dd, J=8.6, 3.7 Hz, 1H), 4.01 (br s, 2H), 3.90 (d, J=17.8 Hz, 1H), 3.72 (d, J=3.7 Hz, 1H), 2.28 (s, 3H), 2.35-1.85 (m, 4H), 2.21 (d, J=17.8 Hz, 1H), 2.01 (d, J=6.8 Hz, 3H), 1.78 (s, 3H), 1.73 (d, J=1.2 Hz, 3H)
FABMS m/z 659 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.35 N.sub.2 O.sub.8 S.sub.3 (M+H).sup.+ 659.1555, found 659.1553
EXAMPLE 123
Synthesis of Compound 135
Compound 134 (23 mg, 0.035 mmol) obtained in Example 122 was dissolved in dichloromethane (4.0 ml), and 3,4-dihydro-2H-pyran (0.10 ml) and camphorsulfonic acid (3 mg) were added thereto, followed by stirring at 20.degree. C. for 15 minutes. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=30/1) to obtain Compound 135 (10 mg, 38% yield). From .sup.1 H NMR, Compound 135 was found to be a mixture of diastereomers at a ratio of about 1:1.
IR (KBr) 2922, 1763, 1718, 1676, 1655, 1610, 1508, 1371, 1259, 1203, 1117, 1018, 980 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 270 MHz) .delta. ppm; 9.59 (dd, J=11.6, 16.1 Hz) and 9.40 (dd, J=11.4, 16.3 Hz) (total 1H), 7.29 (m, 2H), 7.40 (s) and 7.39 (s) (total 1H), 6.61 (d, J=11.4 Hz) and 6.60 (d, J=11.4 Hz) (total 1H), 7.02 (m, 2H), 6.36 (t, J=11.4 Hz) and 6.34 (t, J=11.4 Hz) (total 1H), 6.04 (d, J=16.8 Hz) and 6.00 (d, J=16.3 Hz) (total 1H), 5.82 (br d, J=9.4 Hz) and 5.79 (br d, J=9.4 Hz) (total 1H), 5.58 (q, J=6.9 Hz) and 5.56 (q, J=6.9 Hz) (total 1H), 5.46 (br s) and 5.43 (br s) (total 1H), 5.02 (d, J=9.4 Hz) and 4.74 (d, J=9.4 Hz) (total 1H), 4.71 (br s) and 4.57 (br s) (total 1H), 4.04 (d, J=17.8 Hz) and 4.03 (d, J=17.8 Hz) (total 1H), 4.01 (s, 2H), 3.9-3.3 (m, 2H), 2.5-1.3 (m, 10H), 2.33 (s, 3H), 2.21 (d, J=17.8 Hz, 1H), 1.93 (d, J=6.9 Hz) and 1.87 (d, J=6.9 Hz) (total 3H), 1.76 (d, J=1.0 Hz) and 1.72 (d, J=1.0 Hz) (total 3H), 1.69 (s, 3H)
FABMS m/z 743 (M+H).sup.+
EXAMPLE 124
Synthesis of Compound 136
According to the procedure as described in Example 18, Compound 136 (48 mg, 82% yield) was obtained from Compound 134 (50 mg, 0.076 mmol), 5,6-dihydro-4-methoxy-2H-pyran (0.042 ml, 0.38 mmol) and camphorsulfonic acid (8.8 mg, 0.038 mmol).
IR (KBr) 3400, 2970, 1760, 1720, 1680, 1610, 1510, 1450, 1370, 1260, 1190, 1160, 1100, 1005, 910 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.45 (dd, J=16.6, 11.5 Hz, 1H), 7.42 (s, 1H), 7.32-7.26 (m, 2H), 7.06-6.97 (m, 2H), 6.62 (d, J=11.5 Hz, 1H), 6.36 (t, J=11.5 Hz, 1H), 6.00 (d, J=16.0 Hz, 1H), 5.84 (br d, J=9.5 Hz, 1H), 5.56 (q, J=6.3 Hz, 1H), 5.37 (br s, 1H), 4.97 (dd, J=9.5, 1.2 Hz, 1H), 4.06-3.95 (m, 2H), 4.03 (d, J=17.6 Hz, 1H), 3.70-3.46 (m, 4H), 3.10 (s, 3H), 2.36-1.25 (m, 8H), 2.28 (s, 3H), 2.21 (d, J=17.6 Hz, 1H), 1.94 (d, J=6.3 Hz, 3H), 1.77 (d, J=1.3 Hz, 3H), 1.67 (s, 3H)
FABMS m/z 773 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.45 N.sub.2 O.sub.10 S.sub.3 (M+H).sup.+ 773.2236, found 773.2211
EXAMPLE 125
Synthesis of Compound 137
Compound 134 (185 mg, 0.281 mmol) produced in Example 122 was dissolved in methanol (20 ml), and hydrochloric acid (2M, 6.0 ml) was added thereto, followed by stirring at 20.degree. C. for 4 hours. A phosphoric acid buffer (pH 7) was added to the reaction mixture and extracted with chloroform. After subjecting the mixture to the usual post-treatment, the mixture was purified by fractional HPLC (acetonitrile/water=45/5) to obtain Compound 137 (57 mg, 33% yield).
IR (KBr) 2933, 1734, 1701, 1670, 1612, 1516, 1458, 1267, 1099, 991 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 270 MHz) .delta. ppm; 8.06 (dd, J=11.1, 16.2 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 6.61 (d, J=11.9 Hz, 1H), 6.25 (t, J=11.4 Hz, 1H), 6.2-6.1 (br, 1H), 6.18 (d, J=16.2 Hz, 1H), 5.39 (br d, J=9.0 Hz, 1H), 5.36 (q, J=6.9 Hz, 1H), 4.88 (dd, J=3.2, 9.0 Hz, 1H), 4.7 (br s, 1H), 4.18 (br s, 1H), 4.04 (d, J=13.7 Hz, 1H), 3.89 (d, J=13.7 Hz, 1H), 3.76 (br d, J=17.6 Hz, 1H), 2.17 (d, J=17.6 Hz, 1H), 2.02 (d, J=6.9 Hz, 3H), 2.0-1.5 (m, 4H), 1.76 (s, 3H), 1.62 (d, J=1.0 Hz, 3H)
FABMS m/z 617 (M+H).sup.+
EXAMPLE 126
Synthesis of Compound 138
DC107 (57 mg, 0.11 mmol) was dissolved in acetonitrile (6 ml), and p-(N,N-dimethylcarbamoyloxy)benzyl chloride (48 mg, 0.23 mmol), potassium carbonate (31 mg, 0.23 mmol) and potassium iodide (9 mg, 0.057 mmol) were added thereto, followed by stirring at room temperature for 15 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 138 (22 mg, 54% yield).
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.45 (ddd, J=16.4, 11.5, 1.0 Hz, 1H), 7.33 (s, 1H), 7.28-7.23 (m, 2H), 7.04-6.98 (m, 2H), 6.58 (d, J=11.5 Hz, 1H), 6.23 (t, J=11.5 Hz, 1H), 6.17 (d, J=6.3 Hz, 1H), 5.72 (br d, J=8.8 Hz, 1H), 5.40 (q, J=6.8 Hz, 1H), 5.39 (br s, 1H), 4.93 (dd, J=8.8, 3.9 Hz, 1H), 4.00 (br s, 2H), 3.90 (d, J=17.8 Hz, 1H), 3.72 (d, J=3.9 Hz, 1H), 3.08 (s, 3H), 2.99 (s, 3H), 2.33-1.70 (m, 4H), 2.22 (d, J=17.8 Hz, 1H), 2.01 (d, J=6.8 Hz, 3H), 1.77 (s, 3H), 1.73 (d, J=1.2 Hz, 3H)
FABMS m/z 688 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.38 N.sub.3 O.sub.8 S.sub.3 (M+H).sup.+ 688.1821, found 688.1814
EXAMPLE 127
Synthesis of Compound 139
According to the procedure as described in Example 18, Compound 139 (20 mg, 84% yield) was obtained from Compound 138 (20 mg, 0.029 mmol), 5,6-dihydro-4-methoxy-2H-pyran (0.016 ml, 0.15 mmol) and camphorsulfonic acid (3.4 mg, 0.015 mmol).
IR (KBr) 3400, 3092, 2938, 1720, 1680, 1643, 1609, 1445, 1386, 1210, 1175, 910, 753 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.54, (dd, J=16.3, 11.5 Hz, 1H), 7.42 (s, 1H), 7.30-7.24 (m, 2H), 7.07-7.01 (m, 2H), 6.62 (d, J=11.5 Hz, 1H), 6.36 (t, J=11.5 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.85 (br d, J=9.8 Hz, 1H), 5.56 (q, J=6.6 Hz, 1H), 5.39 (br s, 1H), 4.97 (dd, J=9.8, 1.5 Hz, 1H), 4.05 (d, J=17.8 Hz, 1H), 4.05-3.96 (m, 2H), 3.70-3.48 (m, 4H), 3.10 (s, 3H), 3.09 (s, 3H), 3.00 (s, 3H), 2.39-1.20 (m, 8H), 2.24 (d, J=17.8 Hz, 1H), 1.94 (d, J=6.6 Hz, 3H), 1.78 (d, J=1.2 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 802 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.48 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 802.2502, found 802.2472
EXAMPLE 128
Synthesis of Compound 140
DC107 (26 mg, 0.051 mmol) was dissolved in dimethylformamide (0.50 ml), and 4-(chloromethyl)phenyl N-acetylhexahydroisonicotinate a total amount of 4-(hydroxymethyl)phenyl N-acetylhexahydroisonicotinate (54 mg, 0.19 mmol) treated with thionyl chloride (0.50 ml)!, N,N-diisopropylethylamine (0.10 ml) and potassium iodide (26 mg, 0.16 mmol) were added thereto, followed by stirring at 20.degree. C. for 8 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=20/1) to obtain Compound 140 (9.3 mg, 24% yield).
IR (KBr) 2933, 1751, 1718, 1655, 1618, 1508, 1458, 1273, 1167 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 270 MHz) .delta. ppm; 8.44 (dd, J=11.4, 16.8 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.59 (d, J=11.4 Hz, 1H), 6.25 (t, J=11.4 Hz, 1H), 6.17 (d, J=16.8 Hz, 1H), 5.71 (d, J=8.7 Hz, 1H), 5.44 (br s, 1H), 5.40 (q, J=6.9 Hz, 1H), 4.94 (dd, J=3.0, 8.7 Hz, 1H), 4.46 (br d, J=13.9 Hz, 1H), 4.01 (s, 2H), 3.90 (d, J=17.8 Hz, 1H), 3.79 (d, J=13.9 Hz, 1H), 3.76 (br d, J=3.0 Hz, 1H), 3.21 (ddd, J=3.0, 10.9, 13.9 Hz, 1H), 2.9-2.7 (m, 1H), 2.89 (ddd, J=3.0, 10.9, 13.9 Hz, 1H), 2.4-1.7 (m, 8H), 2.19 (d, J=17.8 Hz, 1H), 2.12 (s, 3H), 2.01 (d, J=6.9 Hz, 3H), 1.78 (s, 3H), 1.73 (s, 3H)
FABMS m/z 770 (M+H).sup.+
EXAMPLE 129
Synthesis of Compound 141
According to the procedure as described in Example 18, Compound 140 (20 mg, 0.026 mmol) was dissolved in dichloromethane (2.0 ml), and 3,4-dihydro-2H-pyran (0.050 ml) and camphorsulfonic acid (10 mg) were added thereto, followed by stirring at 20.degree. C. for 5 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=20/1) to obtain Compound 141 (20 mg, 89% yield). From .sup.1 H NMR, Compound 141 was found to be a mixture of diastereomers at a ratio of about 1:1.
IR (KBr) 1751, 1718, 1676, 1653, 1618, 1508, 1450, 1273, 1203, 1167, 1151, 1132, 1028, 980 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 270 MHz) .delta. ppm; 9.60 (dd, J=11.4, 16.8 Hz) and 9.40 (dd, J=11.4, 16.8 Hz) (total 1H), 7.40 (s) and 7.39 (s) (total 1H), 7.30 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.61 (br d, J=11.4 Hz, 1H), 6.37 (t, J=11.4 Hz) and 6.34 (t, J=11.4 Hz) (total 1H), 6.04 (d, J=16.8 Hz) and 6.00 (d, J=16.8 Hz) (total 1H), 5.82 (br d, J=ca. 10 Hz) and 5.79 (br d, J=ca. 10 Hz) (total 1H), 5.58 (q, J=6.4 Hz) and 5.56 (q, J=6.4 Hz) (total 1H), 5.48 (s) and 5.45 (s) (total 1H), 5.02 (d, J=ca. 10 Hz) and 4.74 (br d, J=ca. 10 Hz) (total 1H), 4.70 (br s) and 4.56 (br s) (total 1H), 4.47 (br d, J=10.4 Hz, 1H), 4.03 (d, J=17.6 Hz) and 4.02 (d, J=17.6 Hz) (total 1H), 4.02 (s, 2H), 3.9-3.4 (m, 2H), 3.85 (br d, J=14.8 Hz, 1H), 3.21 (br t, J=11.4 Hz, 1H), 2.89 (br t, J=11.4 Hz, 1H), 2.80 (m, 1H), 2.4-1.4 (m, 14H), 2.21 (d, J=17.6 Hz) and 2.20 (d, J=17.6 Hz) (total 1H), 2.12 (s, 3H), 1.93 (d, J=6.4 Hz) and 1.87 (d, J=6.4 Hz) (total 3H), 1.76 (s) and 1.73 (s) (total 3H), 1.69 (s, 3H)
FABMS m/z 877 (M+Na).sup.+
EXAMPLE 130
Synthesis of Compound 142
According to the procedure as described in Example 18, Compound 140 (10 mg, 0.013 mmol) was dissolved in dichloromethane (1.0 ml), and 5,6-dihydro-4-methoxy-2H-pyran (0.030 ml) and camphorsulfonic acid (8.0 mg) were added thereto, followed by stirring at 0.degree. C. for 0.5 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=20/1) to obtain Compound 142 (11 mg, 100% yield).
IR (KBr) 2930, 1750, 1716, 1676, 1647, 1618, 1508, 1450, 1271, 1167, 1144, 1109, 985 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 270 MHz) .delta. ppm; 9.56 (dd, J=11.4, 16.8 Hz, 1H), 7.43 (s, 1H), 7.29 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 6.63 (d, J=11.9 Hz, 1H), 6.37 (t, J=11.7 Hz, 1H), 6.01 (d, J=16.8 Hz, 1H), 5.85 (d, J=9.7 Hz, 1H), 5.56 (q, J=6.7 Hz, 1H), 5.43 (s, 1H), 4.97 (dd, J=1.0, 9.7 Hz, 1H), 4.47 (br d, J=13.9 Hz, 1H), 4.05 (d, J=17.8 Hz, 1H), 4.01 (s, 2H), 3.85 (br d, J=13.9 Hz, 1H), 3.7-3.5 (m, 4H), 3.21 (ddd, J=2.5, 11.4, 13.9 Hz, 1H), 3.10 (s, 3H), 2.89 (ddd, J=2.5, 11.4, 13.9 Hz, 1H), 2.79 (m, 1H), 2.4-1.6 (m, 12H), 2.23 (d, J=17.8 Hz, 1H), 2.12 (s, 3H), 1.94 (d, J=6.7 Hz, 3H), 1.77 (d, J=1.0 Hz, 3H), 1.68 (s, 3H)
FABMS m/z 852 (M--CH.sub.3 O)+H!.sup.+
EXAMPLE 131
Synthesis of Compound 143
According to the procedure as described in Example 45, Compound 143 (32 mg, 74% yield) was obtained from Compound 35 (37 mg, 0.059 mmol), picolinic acid (22 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg, 0.18 ml), dichloromethane (3 ml) and 4-dimethylaminopyridine (7 mg, 0.059 mmol).
IR (KBr) 3420, 3104, 2930, 1820, 1720, 1680, 1649, 1610, 1439, 1380, 1205, 1130, 970, 863, 747 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.19 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 8.68 (m, 1H), 8.04 (m, 1H), 7.73 (m, 1H), 7.42 (m, 1H), 7.41 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.34 (t, J=11.5 Hz, 1H), 6.12 (dd, J=16.6, 1.0 Hz, 1H), 6.07 (dd, J=9.5, 1.0 Hz, 1H), 5.88 (br d, J=9.5 Hz, 1H), 5.46 (q, J=6.6 Hz, 1H), 5.42 (br s, 1H), 3.99 (d, J=17.8 Hz, 1H), 3.82-3.74 (m, 2H), 2.48-1.52 (m, 4H), 2.27 (d, J=17.8 Hz, 1H), 2.15 (s, 3H), 1.91 (br s, 3H), 1.72 (s, 3H), 1.71 (d, J=6.6 Hz, 3H)
FABMS m/z 728 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.34 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 728.1406, found 728.1408
EXAMPLE 132
Synthesis of Compound 144
According to the procedure as described in Example 45, Compound 144 (26 mg, 56% yield) was obtained from Compound 35 (40 mg, 0.064 mmol), nicotinic acid (23 mg, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37 mg, 0.19 mmol), dichloromethane (3 ml) and 4-dimethylaminopyridine (8 mg, 0.064 mmol).
IR (KBr) 3400, 3200, 2932, 1820, 1720, 1680, 1649, 1610, 1589, 1422, 1380, 1270, 1205, 1100, 971, 863, 768, 740, 701 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.35 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 9.17 (m, 1H), 8.73 (dd, J=4.9 Hz, 1H), 8.26 (ddd, J=7.8, 2.2, 1.7 Hz, 1H), 7.45 (s, 1H), 7.34 (ddd, J=7.8, 4.9, 1.0 Hz, 1H), 6.65 (d, J=11.5 Hz, 1H), 6.36 (t, J=11.5 Hz, 1H), 6.10 (d, J=16.6 Hz, 1H), 6.09 (dd, J=9.5, 1.0 Hz, 1H), 5.92 (br d, J=9.5 Hz, 1H), 5.47 (q, J=6.6 Hz, 1H), 5.44 (br s, 1H), 4.01 (d, J=17.6 Hz, 1H), 3.78 (br s, 2H), 2.50-1.50 (m, 4H), 2.28 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.90 (d, J=1.2 Hz, 3H), 1.71 (s, 3H), 1.66 (d, J=6.6 Hz, 3H)
FABMS m/z 728 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.34 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 728.1406, found 728.1414
EXAMPLE 133
Synthesis of Compound 145
According to the procedure as described in Example 45, Compound 145 (26 mg, 54% yield) was obtained from Compound 35 (42 mg, 0.067 mmol), 2-pyrazinecarboxylic acid (25 mg, 0.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (39 mg, 0.20 ml), dichloromethane (8 ml) and 4-dimethylaminopyridine (1.7 mg, 0.013 mmol).
IR (KBr) 3420, 2930, 1819, 1717, 1678, 1609, 1448, 1395, 1374, 1270, 1208, 1133, 1047, 1017, 978, 864, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.25 (d, J=1.5 Hz, 1H), 9.23 (ddd, J=16.6, 11.2, 1.0 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 8.69 (dd, J=2.7, 1.5 Hz, 1H), 7.44 (s, 1H), 6.65 (d, J=11.5 Hz, 1H), 6.35 (dd, J=11.5, 11.2 Hz, 1H), 6.14 (dd, J=16.6, 1.0 Hz, 1H), 6.13 (d, J=9.5 Hz, 1H), 5.93 (br d, J=9.5 Hz, 1H), 5.49 (q, J=6.6 Hz, 1H), 5.40 (br s, 1H), 4.02 (d, J=17.5 Hz, 1H), 3.79 (s, 2H), 2.50-1.50 (m, 4H), 2.29 (d, J=17.5 Hz, 1H), 2.16 (s, 3H), 1.92 (d, J=1.0 Hz, 3H), 1.74 (d, J=6.0 Hz, 3H), 1.74 (s, 3H)
FABMS m/z 729 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.33 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 729.1359, found 729.1377
EXAMPLE 134
Synthesis of Compound 146
Compound 35 (40 mg, 0.064 mmol) and phthalic anhydride (28 mg, 0.19 mmol) were dissolved in dichloromethane (4 ml), and 4-dimethylaminopyridine (23 mg, 0.19 mmol) was added thereto, followed by stirring at room temperature for 4 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 146 (16 mg, 32% yield).
IR (KBr) 3420, 2928, 1820, 1720, 1680, 1648, 1610, 1448, 1380, 1250, 1205, 1071, 977, 748 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.18 (br dd, J=16.6, 11.2 Hz, 1H), 7.83-7.30 (m, 4H), 7.37 (s, 1H), 6.60 (d, J=11.5 Hz, 1H), 6.31 (dd, J=11.5, 11.2 Hz, 1H), 6.07 (d, J=16.6 Hz, 1H), 5.96 (br d, J=9.3 Hz, 1H), 5.78 (br d, J=9.3 Hz, 1H), 5.39 (q, J=6.5 Hz, 1H), 3.99 (d, J=17.8 Hz, 1H), 3.74 (br s, 2H), 2.50-1.60 (m, 4H), 2.26 (d, J=17.8 Hz, 1H), 2.12 (s, 3H), 1.75 (br s, 3H), 1.64 (s, 3H), 1.45 (br d, J=6.5 Hz, 3H)
FABMS m/z 771 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.35 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 771.1352, found 771.1382
EXAMPLE 135
Synthesis of Compound 147
According to the procedure as described in Example 45, Compound 147 (28 mg, 47% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), 3-pyridylacetic acid hydrochloride (42 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24mmol), dichloromethane (4 ml) and 4-dimethylaminopyridine (10 mg, 0.080 mmol).
IR (KBr) 3400, 2932, 1810, 1720, 1680, 1611, 1429, 1370, 1265, 978, 862, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.06 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 8.43 (dd, J=4.9, 1.5 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.56 (ddd, J=7.3, 4.9, 2.0 Hz, 1H), 7.43 (s, 1H), 7.15 (dd, J=7.3, 4.9 Hz, 1H), 6.60 (d, J=11.5 Hz, 1H), 6.25 (t, J=11.5 Hz, 1H), 5.96 (d, J=16.6 Hz, 1H), 5.76 (br d, J=9.3 Hz, 1H), 5.71 (dd, J=9.3, 1.0 Hz, 1H), 5.60 (br s, 1H), 5.57 (q, J=6.6 Hz, 1H), 4.03 (d, J=17.8 Hz, 1H), 3.77 (br s, 2H), 3.61 (br s, 2H), 2.46-1.55 (m, 4H), 2.30 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.94 (d, J=6.6 Hz, 3H), 1.77 (d, J=1.0 Hz, 3H), 1.69 (s, 3H)
FABMS m/z 742 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.36 N.sub.3 O.sub.10 S.sub.3 (M+H).sup.+ 742.1563, found 742.1591
EXAMPLE 136
Synthesis of Compound 148
According to the procedure as described in Example 45, Compound 148 (41 mg, 61% yield) was obtained from Compound 35 (51 mg, 0.081 mmol), N-Boc-L-proline (350 mg, 1.63 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (311 mg, 1.63 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (6 mg, 0.049 mmol).
IR (KBr) 3420, 2970, 1821, 1735, 1685, 1400, 1369, 1263, 1208, 1161, 1120, 1089, 977 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; major isomer 8.91 (dd, J=16.5, 11.3 Hz, 1H), 7.40 (s, 1H), 6.60 (d, J=11.3 Hz, 1H), 6.27 (dd, J=11.3, 11.3 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.77 (br s, 2H), 5.53 (q, J=6.7 Hz, 1H), 5.43 (br s, 1H), 4.25 (dd, J=8.7, 3.5 Hz, 1H), 3.98 (d, J=17.8 Hz, 1H), 3.78 (d, J=15.6 Hz, 1H), 3.76 (d, J=15.6 Hz, 1H), 3.51-3.30 (m, 2H), 2.38-1.40 (m, 8H), 2.32 (d, J=14.8 Hz, 1H), 2.14 (s, 3H), 1.96 (d, J=6.7 Hz, 3H), 1.78 (s, 3H), 1.70 (s, 3H), 1.36 (s, 9H); minor isomer (main peaks); 8.83 (dd, J=16.5, 11.3 Hz, 1H), 7.37 (s, 1H), 6.58 (d, J=11.3 Hz, 1H), 6.29 (dd, J=11.3, 11.3 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5.73 (br, 2H), 4.33 (m, 1H), 1.42 (s, 9H)
FABMS m/z 820 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.46 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 820.2243, found 820.2251
EXAMPLE 137
Synthesis of Compound 149
According to the procedure as described in Example 45, Compound 149 (23 mg, 42% yield) was obtained from Compound 35 (46 mg, 0.074 mmol), pyroglutamic acid (47 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (9 mg, 0.074 mmol).
IR (KBr) 3400, 3220, 2932, 1813, 1740, 1720, 1680, 1649, 1610, 1450, 1377, 1260, 1200, 1105, 977, 863, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.94 (dd, J=16.6, 11.5 Hz, 1H), 7.44 (s, 1H), 6.65 (d, J=11.7 Hz, 1H), 6.31 (dd, J=11.7, 11.5 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.91 (br s, 1H), 5.74 (br s, 2H), 5.56 (q, J=6.6 Hz, 1H), 5.41 (br s, 1H), 4.25-4.20 (m, 1H), 3.99 (d, J=17.6 Hz, 1H), 3.83-3.70 (m, 2H), 2.48-1.60 (m, 8H), 2.32 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.94 (d, J=6.6 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H)
FABMS m/z 734 (M+H).sup.+
HRFABMS calcd for C.sub.32 H.sub.36 N.sub.3 O.sub.11 S.sub.3 (M+H).sup.+ 734.1512, found 734.1541
EXAMPLE 138
Synthesis of Compound 150
Compound 35 (50 mg, 0.080 mmol) and phthalic anhydride (32 mg, 0.32 mmol) were dissolved in dichloromethane (4 ml), and 4-dimethylaminopyridine (10 mg, 0.080 mmol) was added thereto, followed by stirring at room temperature for 10 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 150 (35 mg, 61% yield).
IR (KBr) 3400, 2936, 1820, 1735, 1670, 1609, 1372, 979, 755 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.20 (dd, J=16.6, 11.5 Hz, 1H), 7.42 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.32 (t, J=11.5 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.77 (br d, J=9.4 Hz, 1H), 5.72 (d, J=9.4 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.78 (br s, 2H), 2.74-1.48 (m, 8H), 2.30 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.93 (d, J=6.6 Hz, 3H), 1.78 (br s, 3H), 1.67 (s, 3H)
FABMS m/z 723 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.35 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 723.1352, found 723.1378
EXAMPLE 139
Synthesis of Compound 151
Compound 35 (35 mg, 0.056 mmol) was dissolved in dichloromethane (3 ml), and pyridine (0.20 ml, 0.28 mmol) and methylmalonyl chloride (0.009 ml, 0.084 mmol) were added thereto, followed by stirring at room temperature for 50 minutes. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 151 (12 mg, 29% yield).
IR (KBr) 3420, 2934, 1814, 1720, 1680, 1648, 1609, 1438, 1260, 1205, 1145, 977, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.18 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.42 (s, 1H), 6.62 (d, J=11.5 Hz, 1H), 6.34 (t, J=11.5 Hz, 1H), 6.03 (d, J=16.6 Hz, 1H), 5.57 (br d, J=9.3 Hz, 1H), 5.73 (dd, J=9.3, 1.0 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.42 (br s, 1H), 4.03 (d, J=17.6 Hz, 1H), 3.78 (br s, 2H), 3.63 (s, 3H), 3.35 (br s, 2H), 2.47-1.45 (m, 4H), 2.28 (d, J=17.6 Hz, 1H), 2.14 (s. 3H), 1.88 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.71 (s, 3H)
FABMS m/z 723 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.35 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 723.1352, found 723.1322
EXAMPLE 140
Synthesis of Compound 152
According to the procedure as described in Example 45, tert-butyl ester of Compound 151 (30 mg, 41% yield) was obtained from Compound 35 (60 mg, 0.096 mmol), mono-tert-butyl malonate (77 mg, 0.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg, 0.48 mmol), dichloromethane (3 ml) and 4-dimethylaminopyridine (12 mg, 0.096 mmol).
The obtained tert-butyl ester (26 mg, 0.034 mmol) was dissolved in dichloromethane (4 ml), and trifluoroacetic acid (0.5 ml) was added thereto, followed by stirring at room temperature for 40 minutes. After condensing the reaction mixture, the mixture was purified by thin layer chromatography (developed with ether/methanol=9/1) to obtain Compound 152 (7.5 mg, 31% yield).
IR (KBr) 3420, 2930, 1819, 1720, 1680, 1609, 1380, 1260, 1204, 977, 770 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3 +CD.sub.3 OD, 400 MHz) .delta. ppm; 8.99 (dd, J=16.6, 11.5 Hz, 1H), 7.42 (s, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.26 (t, J=11.5 Hz, 1H), 6.00 (d, J=16.6 Hz, 1H), 5.75 (br d, J=9.5 Hz, 1H), 5.71 (br d, J=9.5 Hz, 1H), 5.50 (q, J=6.8 Hz, 1H), 4.03 (d, J=17.6 Hz, 1H), 3.75 (br s, 2H), 3.27 (br, 2H), 2.54-1.45 (m, 4H), 2.31 (d, J=17.6 Hz, 1H), 2.13 (s, 3H), 1.90 (d, J=6.6 Hz, 3H), 1.74 (s, 3H), 1.61 (s, 3H)
FABMS m/z 709 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.33 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 709.1195, found 709.1184
EXAMPLE 141
Synthesis of Compound 153
According to the procedure as described in Example 45, Compound 153 (43 mg, 48% yield) was obtained from Compound 35 (70 mg, 0.11 mmol), p-methoxybenzyloxyacetic acid (66 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg, 0.34 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (14 mg, 0.11 mmol).
IR (KBr) 3400, 3294, 2938, 1820, 1720, 1680, 1647, 1608, 1513, 1443, 1378, 1250, 1110, 971, 815, 768, 730 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.17 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.41 (s, 1H), 7.20-7.15 (m, 2H), 6.82-6.75 (m, 2H), 6.61 (d, J=11.5 Hz, 1H), 6.32 (t, J=11.5 Hz, 1H), 6.05 (d, J=16.6 Hz, 1H), 5.77 (br s, 2H), 5.54 (q, J=6.6 Hz, 1H), 5.41 (br s, 1H), 4.50 (d, J=11.4 Hz, 1H), 4.48 (d, J=11.4 Hz, 1H), 4.03 (bs, 2H), 4.02 (d, J=17.8 Hz, 1H), 3.78 (s, 3H), 3.77 (br s, 2H), 2.46-1.45 (m, 4H), 2.27 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.82 (d, J=6.6 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H)
FABMS m/z 801 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.41 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 801.1821, found 801.1808
EXAMPLE 142
Synthesis of Compound 154
Compound 153 (40 mg, 0.050 mmol) obtained in Example 141 was dissolved in dichloromethane (3 ml), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (86 mg, 0.44 mmol) and water (0.2 ml) were added thereto, followed by stirring at room temperature for 24 hours. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=97/3) to obtain Compound 154 (20 mg, 59% yield).
IR (KBr) 3420, 2932, 1816, 1720, 1680, 1648, 1609, 1440, 1375, 1266, 1195, 1075, 976, 863, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, MHz) .delta. ppm; 9.19 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.43 (s, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.32 (t, J=11.5 Hz, 1H), 6.04 (d, J=16.6 Hz, 1H), 5.78 (br s, 2H), 5.58 (q, J=6.6 Hz, 1H), 5.39 (br s, 1H), 5.12 (d, J=5.6 Hz, 2H), 4.02 (d, J=17.6 Hz, 1H), 3.78 (br s, 2H), 2.50-1.45 (m, 4H), 2.31 (d, J=5.6 Hz, 1H), 2.29 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.88 (d, J=6.6 Hz, 3H), 1.80 (s, 3H), 1.71 (s, 3H)
FABMS m/z 681 (M+H).sup.+
HRFABMS calcd for C.sub.29 H.sub.33 N.sub.2 O.sub.11 S.sub.3 (M+H).sup.+ 681.1246, found 681.1230
EXAMPLE 143
Synthesis of Compound 155
According to the procedure as described in Example 28, Compound 155 (11 mg, 30% yield) was obtained from Compound 35 (30 mg, 0.048 mmol), dichloromethane (2.0 ml), N,N-diisopropylethylamine (0.084 ml, 0.48 mmol) and 2-(2-methoxyethoxy)ethoxymethyl chloride (81 mg, 0.48 mmol).
IR (KBr) 3420, 2930, 1818, 1705, 1685, 1644, 1608, 1451, 1261, 1207, 1093, 1022, 970, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.48 (ddd, J=16.6, 11.5, 1.0 Hz, 1H), 7.40 (s, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.35 (t, J=11.5 Hz, 1H), 6.01 (d, J=16.6 Hz, 1H), 5.81 (br d, J=9.3 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.50 (br s, 1H), 4.83 (dd, J=9.3, 1.2 Hz, 1H), 4.71 (d, J=6.8 Hz, 1H), 4.69 (d, J=6.8 Hz, 1H), 4.03 (d, J=17.6 Hz, 1H), 3.78 (br s, 2H), 3.70-3.48 (m, 8H), 3.36 (s, 3H), 2.45-1.42 (m, 4H), 2.28 (d, J=17.6 Hz, 1H), 2.15 (s, 3H), 1.88 (d, J=6.6 Hz, 3H), 1.75 (d, J=1.2 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 755 (M+H).sup.+
HRFABMS calcd for C.sub.33 H.sub.43 N.sub.2 O.sub.12 S.sub.3 (M+H).sup.+ 755.1978, found 755.1984
EXAMPLE 144
Synthesis of Compound 156
According to the procedure as described in Example 45, Compound 156 (32 mg, 47% yield) was obtained from Compound 35 (54 mg, 0.086 mmol), N-Boc-glycine (60 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (66 mg, 0.34 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (3.1 mg, 0.025 mmol).
IR (KBr) 3420, 2936, 1820, 1755, 1708, 1694, 1647, 1610, 1448, 1368, 1259, 1161, 977, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.23 (dd, J=16.6, 11.5, 1H), 7.43 (s, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.32 (t, J=11.5 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.77 (br d, J=9.5 Hz, 1H), 5.72 (d, J=9.5 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 5.42 (br s, 1H), 4.96 (br, 1H), 4.03 (d, J=17.5 Hz, 1H), 3.96 (br dd, J=18.5, 6.6 Hz, 1H), 3.83 (dd, J=18.5, 5.1 Hz, 1H), 3.78 (br s, 2H), 2.50-2.22 (m, 3H), 2.29 (d, J=17.5 Hz, 1H), 2.14 (s, 3H), 1.91 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.71 (s, 3H), 1.55-1.42 (m, 1H), 1.40 (s, 9H)
FABMS m/z 780 (M+H).sup.+
HRFABMS calcd for C.sub.34 H.sub.42 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 780.1930, found 780.1926
EXAMPLE 145
Synthesis of Compound 157
According to the procedure as described in Example 45, Compound 157 (36 mg, 54% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), N-Cbz-glycine (84 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg, 0.40 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (3 mg, 0.025 mmol).
IR (KBr) 3400, 2940, 1821, 1722, 1692, 1650, 1610, 1527, 1453, 1371, 1265, 1207, 1178, 1055, 981, 770 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.19 (dd, J=16.5, 11.2 Hz, 1H), 7.41 (s, 1H), 7.39-7.25 (m, 5H), 6.61 (d, J=11.4 Hz, 1H), 6.31 (dd, J=11.4, 11.2 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.81-5.70 (m, 2H), 5.57 (q, J=6.6 Hz, 1H), 5.41 (br s, 1H), 5.21 (br s, 1H), 5.07 (br s, 2H), 4.02 (d, J=17.7 Hz, 1H), 4.07-3.85 (m, 2H), 3.78 (br s, 2H), 2.50-2.01 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.91 (d, J=6.6 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H), 1.55-1.47 (m, 1H)
FABMS m/z 814 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.40 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 814.1774, found 814.1766
EXAMPLE 146
Synthesis of Compound 158
According to the procedure as described in Example 45, Compound 158 (25 mg, 60% yield) was obtained from Compound 35 (30 mg, 0.047 mmol), Fmoc-glycine (19 mg, 0.094 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18 mg, 0.094 mmol), dichloromethane (3.5 ml) and 4-dimethylaminopyridine (1.0 mg, 0.008 mmol).
IR (KBr) 3406, 2930, 1819, 1725, 1685, 1609, 1518, 1450, 1390, 1374, 1261, 1204, 1182, 1104, 1051, 979, 760, 740 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.19 (dd, J=16.6, 11.7 Hz, 1H), 7.75 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.2 Hz, 2H), 7.41 (s, 1H), 7.38 (dd, J=7.5, 7.2 Hz, 2H), 7.30 (dd, J=7.5, 7.2 Hz, 2H), 6.61 (d, J=11.5 Hz, 1H), 6.31 (dd, J=11.7, 11.5 Hz, 1H), 6.03 (d, J=16.6 Hz, 1H), 5.77 (s, 2H), 5.58 (q, J=6.6 Hz, 1H), 5.40 (br s, 1H), 5.23 (br, 1H), 4.35 (d, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 1H), 4.04 (dd, J=18.5, 5.8 Hz, 1H), 4.02 (d, J=17.5 Hz, 1H), 3.92 (dd, J=18.5, 4.7 Hz, 1H), 3.78 (s, 2H), 2.58-1.50 (m, 4H), 2.29 (d, J=17.5 Hz, 1H), 2.14 (s, 3H), 1.91 (d, J=6.6 Hz, 3H), 1.80 (s, 3H), 1.71 (s, 3H)
FABMS m/z 902 (M+H).sup.+
HRFABMS calcd for C.sub.44 H.sub.44 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 902.2087, found 902.2072
EXAMPLE 147
Synthesis of Compound 159
According to the procedure as described in Example 45, Compound 159 (16 mg, 35% yield) was obtained from Compound 35 (40 mg, 0.064 mmol), N-formylglycine (67 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol), dichloromethane (8 ml) and 4-dimethylaminopyridine (4.6 mg, 0.038 mmol).
IR (KBr) 3400, 2986, 2932, 1818, 1750, 1677, 1610, 1516, 1443, 1376, 1266, 1206, 1186, 1108, 1094, 976, 859, 807, 768, 731, 669 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.19 (ddd, J=16.6, 11.2, 1.0 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H), 7.45 (s, 1H), 6.65 (d, J=11.5 Hz, 1H), 6.33 (dd, J=11.5, 11.2 Hz, 1H), 6.08 (br, 1H), 6.04 (d, J=16.6 Hz, 1H), 5.79 (br d, J=9.5 Hz, 1H), 5.77 (dd, J=9.5, 1.0 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 5.41 (br s, 1H), 4.16 (dd, J=18.5, 5.6, 1.0 Hz, 1H), 4.02 (d, J=17.8 Hz, 1H), 4.00 (ddd, J=18.5, 4.6, 1.0 Hz, 1H), 3.79 (br s, 2H), 2.50-2.25 (m, 3H), 2.32 (d, J=17.8 Hz, 1H), 2.16 (s, 3H), 1.93 (s, J=6.6 Hz, 3H), 1.81 (d, J=1.0 Hz, 3H), 1.72 (s, 3H), 1.61-1.50 (m, 1H)
FABMS m/z 708 (M+H).sup.+
HRFABMS calcd for C.sub.30 H.sub.34 N.sub.3 O.sub.11 S.sub.3 (M+H).sup.+ 708.1355, found 708.1373
EXAMPLE 148
Synthesis of Compound 160
According to the procedure as described in Example 45, Compound 160 (22 mg, 32% yield) was obtained from Compound 35 (59 mg, 0.1095 mmol), N-acetylglycine (166 mg, 1.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (273 mg, 1.4 mmol), dichloromethane (12 ml) and 4-dimethylaminopyridine (10 mg, 0.085 mmol).
IR (KBr) 3394, 2932, 1820, 1720, 1678, 1609, 1534, 1447, 1376, 1266, 1206, 1108, 1035, 978, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.21 (ddd, J=1608, 11.5, 1.0 Hz, 1H), 7.43 (s, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.32 (t, J=11.5 Hz, 1H), 6.02 (dd, J=1.0, 16.8 Hz, 1H), 5.91 (m, 1H), 5.79 (br d, J=9.5 Hz, 1H), 5.74 (dd, J=9.5, 1.0 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.43 (br s, 1H), 4.08 (dd, J=18.5, 5.4 Hz, 1H), 4.02 (d, J=17.6 Hz, 1H), 3.93 (dd, J=18.5, 4.7 Hz, 1H), 3.77 (br s, 2H), 2.48-1.50 (m, 4H), 2.29 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.98 (s, 3H), 1.90 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 722 (M+H).sup.+
HRFABMS calcd for C.sub.31 H.sub.36 N.sub.3 O.sub.11 S.sub.3 (M+H).sup.+ 722.1512, found 722.1508
EXAMPLE 149
Synthesis of Compound 161
According to the procedure as described in Example 45, Compound 161 (46 mg, 72% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), N-Boc-sarcosine (46 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg, 0.24 mmol), dichloromethane (3 ml) and 4-dimethylaminopyridine (10 mg, 0.080 mmol).
IR (KBr) 3420, 2932, 1820, 1720, 1680, 1657, 1612, 1452, 1367, 1260, 1140, 977, 879, 769, 731 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.20-9.06 (m, 1H), 7.41 (s, 1H), 6.61 (d, J=11.5 Hz, 1H), 6.03 (br d, J=16.6 Hz, 1H), 5.80-5.70 (m, 2H), 5.57 (q, J=6.6 Hz, 1H), 5.44, 5.41 (br s, 1H), 4.20-3.75 (m, 3H), 3.77 (br s, 2H), 2.86, 2.84 (br s, 3H), 2.45-1.50 (m, 5H), 2.14 (s, 3H), 1.93 (d, J=6.6 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H), 1.43, 1.37 (s, 9H)
FABMS m/z 794 (M+H).sup.+
HRFABMS calcd for C.sub.35 H.sub.44 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 794.2087, found 794.2097
EXAMPLE 150
Synthesis of Compound 162
According to the procedure as described in Example 45, Compound 162 (49 mg, 73% yield) was obtained from Compound 35 (51 mg, 0.081 mmol), N-Cbz-sarcosine (189 mg, 0.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg, 0.81 mmol), dichloromethane (6 ml) and 4-dimethylaminopyridine (6 mg, 0. 048 mmol).
IR (KBr) 3420, 2934, 1819, 1750, 1705, 1690, 1609, 1451, 1400, 1364, 1263, 1206, 1149, 1115, 977, 769, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; major isomer 9.14 (dd, J=16.7, 11.3 Hz, 1H), 7.41 (s, 1H), 7.38-7.22 (m, 5H), 6.61 (d, J=11.6 Hz, 1H), 6.32 (dd, J=11.6, 11.3 Hz, 1H), 6.04 (d, J=16.7 Hz, 1H), 5.77 (br s, 2H), 5.57 (q, J=6.7 Hz, 1H), 5.43 (br s, 1H), 5.09 (s, 2H), 4.17 (d, J=17.7 Hz, 1H), 4.02 (d, J=17.7 Hz, 1H), 3.90 (d, J=17.7 Hz, 1H), 3.77 (br s, 2H), 2.94 (s, 3H), 2.46-1.95 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.93 (d, J=6.6 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H), 1.62-1.48 (m, 1H); minor isomer 9.06 (dd, J=16.5, 11.3 Hz, 1H), 7.41 (s, 1H), 7.38-7.22 (m, 5H), 6.58 (d, J=11.6 Hz, 1H), 6.23 (dd, J=11.6, 11.3 Hz, 1H), 5.97 (d, J=16.5 Hz, 1H), 5.72 (s, 2H), 5.54 (q, J=6.7 Hz, 1H), 5.40 (br s, 1H), 5.07 (br s, 2H), 4.01 (d, J=17.7 Hz, 1H), 3.98 (d, J=17.7 Hz, 1H), 3.94 (d, J=17.7 Hz, 1H), 3.77 (br s, 2H), 2.95 (s, 3H), 2.46-1.95 (m, 3H), 2.28 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.87 (d, J=6.6 Hz, 3H), 1.74 (s, 3H), 1.70 (s, 3H), 1.62-1.48 (m, 1H)
FABMS m/z 828 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.42 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 828.1930, found 828.1939
Anal calcd for C.sub.38 H.sub.41 N.sub.3 O.sub.12 S.sub.3.0.5H.sub.2 O: C, 54.54; H, 5.06; N, 5.02; found: C, 54.67; H, 5.13; N, 4.94
EXAMPLE 151
Synthesis of Compound 163
According to the procedure as described in Example 45, Compound 163 (25 mg, 53% yield) was obtained from Compound 35 (35 mg, 0.056 mmol), N-Cbz-L-alanine (38 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.17 mmol), dichloromethane (5 ml) and 4-dimethylaminopyridine (1.4 mg, 0.011 mmol).
IR (KBr) 3400, 2984, 2932, 1820, 1712, 1690, 1610, 1524, 1454, 1374, 1264, 1208, 1159, 1113, 1070, 977, 770, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.06 (br dd, J=17.1, 11.0 Hz, 1H), 7.39 (s, 1H), 7.37-7.25 (m, 5H), 6.59 (d, J=11.6 Hz, 1H), 6.30 (br dd, J=11.6, 11.0 Hz, 1H), 6.01 (d, J=17.1 Hz, 1H), 5.76 (br d, J=9.2 Hz, 1H), 5.64 (d, J=9.2 Hz, 1H), 5.55 (q, J=6.7 Hz, 1H), 5.42 (br, 1H), 5.29 (br, 1H), 5.04 (br d, J=12.2 Hz, 1H), 5.00 (br d, J=12.2 Hz, 1H), 4.36 (m, 1H), 4.01 (d, J=17.7 Hz, 1H), 3.79 (d, J=15.3 Hz, 1H), 3.76 (d, J=15.3 Hz, 1H), 2.46-2.20 (m, 3H), 2.32 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.93 (d, J=6.7 Hz, 3H), 1.77 (br s, 3H), 1.70 (s, 3H), 1.68-1.60 (m, 1H), 1.37 (d, J=7.0 Hz, 3H)
FABMS m/z 828 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.42 N.sub.3 O.sub.12 S.sub.3 (M+H).sup.+ 828.1930, found 828.1932
EXAMPLE 152
Synthesis of Compound 164
According to the procedure as described in Example 45, tert-butyldimethylsilyl ether compound of Compound 164 (90 mg, 86% yield) was obtained from Compound 35 (69 mg, 0.11 mmol), N-Cbz-O-tert-butyldimethylsilyl-L-serine (473 mg, 1.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (257 mg, 1.33 mmol), tetrahydrofuran (14 ml) and 4-dimethylaminopyridine (9.5 mg, 0.077 mmol).
The obtained tert-butyldimethylsilyl ether compound (90 mg, 0.094 mmol) was dissolved in methanol (5 ml), and 3N hydrochloric acid (0.2 ml) was added thereto, followed by stirring for 1 hour. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 164 (12 mg, 15% yield).
IR (KBr) 3430, 2934, 1818, 1719, 1706, 1682, 1609, 1521, 1453, 1375, 1341, 1267, 1209, 1155, 1059, 979, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 8.76 (br dd, J=16.6, 11.5 Hz, 1H), 7.38 (s, 1H), 7.40-7.26 (m, 5H), 6.60 (d, J=11.7 Hz, 1H), 6.27 (dd, J=11.7, 11.5 Hz, 1H), 6.06 (d, J=16.6 Hz, 1H), 5.84 (br d, J=8.5 Hz, 1H), 5.73 (br d, J=8.5 Hz, 1H), 5.71 (br, 1H), 5.47 (br q, J=6.6 Hz, 1H), 5.37 (br s, 1H), 5.15-5.00 (m, 2H), 4.46-3.98 (m, 1H), 3.98-3.80 (m, 2H), 3.96 (d, J=17.8 Hz, 1H), 3.77 (br s, 2H), 2.45-1.50 (m, 4H), 2.30 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.97 (d, J=6.6 Hz, 3H), 1.77 (br s, 3H), 1.74 (s, 3H)
FABMS m/z 844 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.42 N.sub.3 O.sub.13 S.sub.3 (M+H).sup.+ 844.1880, found 844.1872
EXAMPLE 153
Synthesis of Compound 165
According to the procedure as described in Example 45, Compound 165 (18 mg, 22% yield) was obtained from Compound 35 (61 mg, 0.097 mmol), N-Boc-glycylglycine (208 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (280 mg, 1.46 mmol), dichloromethane (6 ml) and 4-dimethylaminopyridine (18 mg, 0.15 mmol).
IR (KBr) 3400, 2984, 2938, 1819, 1773, 1703, 1685, 1610, 1534, 1369, 1267, 1169, 1109, 979, 770 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.21 (dd, J=16.6, 11.7 Hz, 1H), 7.44 (s, 1H), 6.63 (d, J=11.4 Hz, 1H), 6.55 (br dd, J=5.2, 4.9 Hz, 1H), 6.32 (dd, J=11.7, 11.4 Hz, 1H), 6.02 (dd, J=16.6, 0.8 Hz, 1H), 5.80 (br d, J=9.3 Hz, 1H), 5.76 (dd, J=9.3, 0.8 Hz, 1H), 5.57 (q, J=6.6 Hz, 1H), 5.46 (br s, 1H), 5.06 (br, 1H), 4.11 (dd, J=18.4, 11.4 Hz, 1H), 4.04 (d, J=17.8 Hz, 1H), 3.95 (dd, J=18.4, 4.9 Hz, 1H), 3.85-3.70 (m, 4H), 2.49-2.25 (m, 3H), 2.30 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.92 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.62-1.50 (m, 1H), 1.44 (s, 9H)
FABMS m/z 837 (M+H).sup.+
HRFABMS calcd for C.sub.36 H.sub.45 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 837.2145, found 837.2169
EXAMPLE 154
Synthesis of Compound 166
According to the procedure as described in Example 45, Compound 166 (2.3 mg, 29% yield) was obtained from Compound 35 (5.6 mg, 0.0090 mmol), N-Cbz-glycylglycine (24 mg, 0.090 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18 mg, 0.090 mmol), dichloromethane (3 ml) and 4-dimethylaminopyridine (1 mg, 0.090 mmol).
IR (KBr) 3370, 2928, 1818, 1721, 1710, 1684, 1675, 1609, 1527, 1451, 1375, 1264, 1176, 1092, 977, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.19 (dd, J=16.5, 11.6 Hz, 1H), 7.42 (s, 1H), 7.38-7.20 (m, 5H), 6.63 (d, J=11.3 Hz, 1H), 6.44 (br, 1H), 6.32 (dd, J=11.6, 11.3 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.81 (d, J=9.5 Hz, 1H), 5.79 (d, J=9.5 Hz, 1H), 5.56 (q, J=6.7 Hz, 1H), 5.44 (br s, 1H), 5.33 (br, 1H), 5.12 (br s, 2H), 4.16-3.84 (m, 4H), 4.02 (d, J=17.7 Hz, 1H), 3.79 (d, J=15.3 Hz, 1H), 3.75 (d, J=15.3 Hz, 1H), 2.47-2.26 (m, 3H), 2.30 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.90 (d, J=6.7 Hz, 3H), 1.80 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.62-1.52 (m, 1H)
FABMS m/z 871 (M+H).sup.+
HRFABMS calcd for C.sub.39 H.sub.43 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 871.1989, found 871.2014
EXAMPLE 155
Synthesis of Compound 167
According to the procedure as described in Example 45, Compound 167 (47 mg, 62% yield) was obtained from Compound 35 (59 mg, 0.090 mmol), N-benzoylglycylglycine (337 mg, 1.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (272 mg, 1.42 mmol), dichloromethane (15 ml) and 4-dimethylaminopyridine (10 mg, 0.08 mmol).
IR (KBr) 3400, 2936, 1816, 1685, 1656, 1609, 1529, 1488, 1447, 1374, 1268, 1202, 1108, 978, 769, 714 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.17 (ddd, J=16.8, 11.5, 0.6 Hz, 1H), 7.84-7.76 (m, 2H), 7.54-7.40 (m, 3H), 7.42 (s, 1H), 7.06 (br t, J=5.2 Hz, 1H), 6.77 (br t, J=5.2 Hz, 1H), 6.62 (d, J=11.3 Hz, 1H), 6.31 (dd, J=11.5, 11.3 Hz, 1H), 6.00 (d, J=16.8 Hz, 1H), 5.80 (br s, 2H), 5.55 (q, J=6.7 Hz, 1H), 5.53 (br s, 1H), 4.20-3.92 (m, 4H), 4.04 (d, J=17.7 Hz, 1H), 3.80-3.70 (m, 2H), 2.48-2.28 (m, 3H), 2.31 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.92 (d, J=6.7 Hz, 3H), 1.78 (d, J=0.6 Hz, 3H), 1.67 (s, 3H), 1.65-1.55 (m, 1H)
FABMS m/z 841 (M+H).sup.+
HRFABMS calcd for C.sub.38 H.sub.41 N.sub.4 O.sub.12 S.sub.3 (M+H).sup.+ 841.1883, found 841.1862
EXAMPLE 156
Synthesis of Compound 168
According to the procedure as described in Example 45, Compound 168 (27 mg, 30% yield) was obtained from Compound 35 (62 mg, 0.10 mmol), N-Cbz-L-alanylglycine (418 mg, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (287 mg, 1.5 mmol), tetrahydrofuran (10 ml) and 4-dimethylaminopyridine (11 mg, 0.090 mmol).
IR (KBr) 3400, 2982, 3942, 1818, 1717, 1686, 1677, 1609, 1521, 1452, 1376, 1262, 1205, 1130, 1000, 790, 718 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.19 (dd, J=16.4, 11.5 Hz, 1H), 7.43 (s, 1H), 7.38-7.26 (m, 5H), 6.63 (d, J=11.3 Hz, 1H), 6.53 (br, 1H), 6.32 (dd, J=11.5, 11.3 Hz, 1H), 6.02 (d, J=16.4 Hz, 1H), 5.79 (br d, J=9.8 Hz, 1H), 5.76 (d, J=9.8 Hz, 1H), 5.56 (q, J=6.7 Hz, 1H), 5.41 (br s, 1H), 5.23 (br, 1H), 5.11 (d, J=12.2 Hz, 1H), 5.09 (d, J=12.2 Hz, 1H), 4.28-4.20 (m, 1H), 4.11 (dd, J=18.3, 5.5 Hz, 1H), 4.02 (d, J=17.7 Hz, 1H), 3.89 (br d, J=18.3 Hz, 1H), 3.77 (s, 2H), 2.47-2.26 (m, 3H), 2.29 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.90 (d, J=6.7 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.60-1.50 (m, 1H), 1.36 (d, J=7.3 Hz, 3H)
FABMS m/z 885 (M+H).sup.+
HRFABMS calcd for C.sub.40 H.sub.45 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 885.2145, found 885.2125
EXAMPLE 157
Synthesis of Compound 169
According to the procedure as described in Example 45, Compound 169 (39 mg, 40% yield) was obtained from Compound 35 (70 mg, 0.11 mmol), N-Cbz-.beta.-alanylglycine (316 mg, 1.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (216 mg, 1.12 mmol), tetrahydrofuran (14 ml) and 4-dimethylaminopyridine (8.2 mg, 0.06 mmol).
IR (KBr) 3356, 2940, 1820, 1707, 1669, 1610, 1522, 1452, 1376, 1263, 1206, 1182, 1111, 979, 769, 735, 697 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.18 (dd, J=16.4, 11.3 Hz, 1H), 7.42 (s, 1H), 7.35-7.25 (m, 5H), 6.62 (d, J=11.5 Hz, 1H), 6.31 (dd, J=11.5, 11.3 Hz, 1H), 6.09 (m, 1H), 6.02 (d, J=16.4 Hz, 1H), 5.79 (br d, J=10.0 Hz, 1H), 5.77 (d, J=10.0 Hz, 1H), 5.55 (q, J=6.6 Hz, 1H), 5.42 (br s, 1H), 5.39 (m, 1H), 5.07 (br s, 2H), 4.09 (dd, J=18.3, 5.6 Hz, 1H), 4.02 (d, J=17.6 Hz, 1H), 3.90 (dd, J=18.3, 4.9 Hz, 1H), 3.79 (d, J=15.0 Hz, 1H), 3.75 (d, J=15.0 Hz, 1H), 3.52-3.40 (m, 2H), 2.50-2.25 (m, 5H), 2.30 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.90 (d, J=6.6 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 1.60-1.48 (m, 1H)
FABMS m/z 885 (M+H).sup.+
HRFABMS calcd for C.sub.40 H.sub.45 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 885.2145, found 885.2164
EXAMPLE 158
Synthesis of Compound 170
According to the procedure as described in Example 45, Compound 170 (14 mg, 21% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), N-Boc-.beta.-alanylglycine (198 mg, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (5.9 mg, 0.048 mmol).
IR (KBr) 3400, 2982, 2936, 1819, 1702, 1673, 1610, 1542, 1511, 1450, 1390, 1367, 1267, 1205, 1172, 1107, 978, 769 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.19, (dd, J=16.6, 11.5 Hz, 1H), 7.43 (s, 1H), 6.63 (d, J=11.5 Hz, 1H), 6.32 (t, J=11.5 Hz, 1H), 6.12 (br, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.79 (d, J=9.5 Hz, 1H), 5.75 (d, J=9.5 Hz, 1H), 5.57 (q, J=6.8 Hz, 1H), 5.44 (br s, 1H), 5.10 (br s, 1H), 4.09 (dd, J=18.6, 5.6 Hz, 1H), 4.02 (d, J=17.8 Hz, 1H), 3.93 (dd, J=18.6, 4.8 Hz, 1H), 3.78 (br s, 2H), 3.45-3.30 (m, 2H), 2.50-1.45 (m, 6H), 2.30 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.92 (d, J=6.8 Hz, 3H), 1.79 (s, 3H), 1.71 (s, 3H), 1.43 (s, 9H)
FABMS m/z 851 (M+H).sup.+
HRFABMS calcd for C.sub.37 H.sub.47 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 851.2302, found 851.2302
EXAMPLE 159
Synthesis of Compound 171
According to the procedure as described in Example 45, Compound 171 (16 mg, 16% yield) was obtained from Compound 35 (70 mg, 0.11 mmol), N-Cbz-.gamma.-aminobutyrylglycine (498 mg, 1.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (325 mg, 1.7 mmol), tetrahydrofuran (15 ml) and 4-dimethylaminopyridine (12 mg, 0.10 mmol).
IR (KBr) 3380, 2942, 1819, 1703, 1691, 1678, 1610, 1528, 1454, 1376, 1264, 1207, 1179, 1114, 979, 770, 739, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.20 (dd, J=16.6, 11.2 Hz, 1H), 7.42 (s, 1H), 7.38-7.27 (m, 5H), 6.62 (d, J=11.5 Hz, 1H), 6.39 (br, 1H), 6.31 (dd, J=11.5, 11.2 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.79 (d, J=9.5 Hz, 1H), 5.75 (d, J=9.5 Hz, 1H), 5.57 (q, J=6.7 Hz, 1H), 5.46 (br s, 1H), 5.08 (br s, 2H), 4.99 (br s, 1H), 4.07 (dd, J=18.1, 5.4 Hz, 1H), 4.02 (d, J=17.8 Hz, 1H), 3.92 (dd, J=18.1, 5.0 Hz, 1H), 3.77 (br s, 2H), 3.28-3.20 (m, 4H), 2.40-1.50 (m, 6H), 2.29 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.91 (d, J=6.7 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H)
FABMS m/z 899 (M+H).sup.+
HRFABMS calcd for C.sub.41 H.sub.47 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 899.2302, found 899.2315
EXAMPLE 160
Synthesis of Compound 172
According to the procedure as described in Example 45, Compound 172 (43 mg, 60% yield) was obtained from Compound 35 (51 mg, 0.081 mmol), N-Cbz-sarcosylglycine (229 mg, 0.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg, 0.81 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (5.9 mg, 0.048 mmol).
IR (KBr) 3400, 3090, 2938, 1817, 1700, 1687, 1671, 1610, 1530, 1453, 1402, 1366, 1263, 1207, 1152, 1111, 1030, 978, 862, 808, 769, 734, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.20 (br dd, J=16.5, 11.2 Hz, 1H), 7.43 (s, 1H), 7.40-7.25 (m, 5H), 6.63 (d, J=11.5 Hz, 1H), 6.47 (br, 1H), 6.32 (dd, J=11.5, 11.2 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 5.78 (br d, J=9.3 Hz, 1H), 5.74 (d, J=9.3 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 5.43 (br s, 1H), 5.14 (s, 2H), 4.12-3.88 (m, 2H), 4.03 (d, J=17.6 Hz, 1H), 3.96 (d, 16.6 Hz, 1H), 3.91 (d, J=16.6 Hz, 1H), 3.78 (s, 2H), 3.00 (s, 3H), 2.50-2.26 (m, 3H), 2.29 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.91 (d, J=6.6 Hz, 3H), 1.70 (d, J=1.0 Hz, 3H), 1.71 (s, 3H), 1.57-1.45 (m, 1H)
FABMS m/z 885 (M+H).sup.+
HRFABMS calcd for C.sub.40 H.sub.45 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 885.2145, found 885.2135
Anal calcd for C.sub.40 H.sub.44 N.sub.4 O.sub.13 S.sub.3.1.0H.sub.2 O: C, 53.20; H, 5.13; N, 6.20; found: C, 53.38; H, 5.20; N, 6.07
EXAMPLE 161
Synthesis of Compound 173
According to the procedure as described in Example 45, Compound 173 (37 mg, 36% yield) was obtained from Compound 35 (70 mg, 0.11 mmol), N-Cbz-leucylglycine (364 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg, 1.1 mmol), tetrahydrofuran (14 ml) and 4-dimethylaminopyridine (8.3 mg, 0.06 mmol).
IR (KBr) 3400, 2960, 2932, 1819, 1715, 1680, 1610, 1516, 1452, 1375, 1264, 1208, 1110, 1039, 981, 768 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.21 (dd, J=16.6, 11.2 Hz, 1H), 7.43 (s, 1H), 7.36-7.26 (m, 5H), 6.63 (d, J=11.5 Hz, 1H), 6.52 (br, 1H), 6.32 (dd, J=11.5, 11.2 Hz, 1H), 6.02 (d, J=16.6 Hz, 1H), 5.80 (br d, J=9.5 Hz, 1H), 5.77 (d, J=9.5 Hz, 1H), 5.54 (q, J=6.7 Hz, 1H), 5.42 (br s, 1H), 5.13 (br, 1H), 5.10 (br s, 2H), 4.20 (br, 1H), 4.10 (dd, J=18.3, 5.8 Hz, 1H), 4.02 (d, J=18.0 Hz, 1H), 3.90 (br d, J=18.3 Hz, 1H), 3.77 (br s, 2H), 2.47-1.43 (m, 7H), 2.29 (d, J=18.0 Hz, 1H), 2.14 (s, 3H), 1.89 (d, J=6.7 Hz, 3H), 1.79 (d, J=1.0 Hz, 3H), 1.70 (s, 3H), 0.91 (d, J=6.3 Hz, 6H)
FABMS m/z 927 (M+H).sup.+
HRFABMS calcd for C.sub.43 H.sub.51 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 927.2414, found 927.2614
EXAMPLE 162
Synthesis of Compound 174
According to the procedure as described in Example 45, tert-butyldimethylsilyl ether compound of Compound 174 (90 mg, 68% yield) was obtained from Compound 35 (84 mg, 0.13 mmol), N-Cbz-O-tert-butyldimethylsilyl-L-serylglycine (712 mg, 1.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (334 mg, 1.74 mmol), tetrahydrofuran (14 ml) and 4-dimethylaminopyridine (13 mg, 0.11 mmol).
The obtained tert-butyldimethylsilyl ether compound (85 mg, 0.084 mmol) was dissolved in methanol (5.0 ml), and 3N hydrochloric acid (0.5 ml) was added thereto, followed by stirring for 30 minutes. After subjecting the mixture to the usual post-treatment, the mixture was purified by thin layer chromatography (developed with chloroform/methanol=95/5) to obtain Compound 174 (13 mg, 17% yield).
IR (KBr) 3400, 2934, 1818, 1717, 1677, 1608, 1526, 1448, 1375, 1265, 1205, 1105, 975 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.11 (dd, J=16.4, 11.3 Hz, 1H), 7.42 (s, 1H), 7.38-7.28 (m, 5H), 6.95 (br, 1H), 6.63 (d, J=11.7 Hz, 1H), 6.31 (dd, J=11.7, 11.5 Hz, 1H), 6.02 (d, J=16.4 Hz, 1H), 5.78 (br s, 2H), 5.76 (br, 1H), 5.55 (q, J=6.8 Hz, 1H), 5.37 (br s, 1H), 5.12 (br s, 2H), 4,30-3.63 (m, 7H), 4.01 (d, J=17.8 Hz, 1H), 2.47-1.50 (m, 4H), 2.30 (d, J=17.8 Hz, 1H), 2.14 (s, 3H), 1.92 (d, J=6.8 Hz, 3H), 1.78 (s, 3H), 1.70 (s, 3H)
FABMS m/z 901 (M+H).sup.+
HRFABMS calcd for C.sub.40 H.sub.45 N.sub.4 O.sub.14 S.sub.3 (M+H).sup.+ 901.2094, found 901.2068
EXAMPLE 163
Synthesis of Compound 175
According to the procedure as described in Example 45, Compound 175 (55 mg, 66% yield) was obtained from Compound 35 (58 mg, 0.093 mmol), N-Cbz-.beta.-alanylsarcosine (330 mg, 1.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (180 mg, 0.93 mmol), tetrahydrofuran (17 ml) and 4-dimethylaminopyridine (6.8 mg, 0.056 mmol).
IR (KBr) 3400, 2934, 1818, 1708, 1689, 1656, 1511, 1452, 1403, 1372, 1264, 1206, 1115, 978, 769, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 9.11 (dd, J=16.5, 11.6 Hz, 1H), 7.41 (s, 1H), 7.36-7.20 (m, 5H), 6.61 (d, J=11.6 Hz, 1H), 6.31 (t, J=11.6 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.77 (br s, 2H), 5.55 (q, J=6.7 Hz, 1H), 5.52-5.40 (m, 2H), 5.07 (br s, 2H), 4.28 (d, J=17.1 Hz, 1H), 4.02 (d, J=17.7 Hz, 1H), 3.91 (d, J=17.1 Hz, 1H), 3.77 (br s, 2H), 3.50-3.40 (m, 2H), 2.97 (s, 3H), 2.62-2.10 (m, 6H), 2.29 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.93 (d, J=6.7 Hz, 3H), 1.78 (s, 3H), 1.70 (s, 3H)
FABMS m/z 899 (M+H).sup.+
HRFABMS calcd for C.sub.41 H.sub.47 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 899.2302, found 899.0309
EXAMPLE 164
Synthesis of Compound 176
According to the procedure as described in Example 45, Compound 176 (34 mg, 48% yield) was obtained from Compound 35 (50 mg, 0.080 mmol), N-Cbz-glycyl-.beta.-alanine (272 mg, 0.97 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg, 0.97 mmol), tetrahydrofuran (9 ml) and 4-dimethylaminopyridine (6.9 mg, 0.056 mmol).
IR (KBr) 3400, 2938, 1820, 1720, 1678, 1610, 1531, 1454, 1374, 1261, 1208, 1170, 1090, 979, 769, 699 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta. ppm; 8.99 (d, J=16.5, 11.8 Hz, 1H), 7.39 (s, 1H), 7.38-7.29 (m, 5H), 6.66 (br t, J=8.2 Hz, 1H), 6.60 (d, J=11.6 Hz, 1H), 6.27 (dd, J=11.8, 11.6 Hz, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.76 (s, 2H), 5.52 (q, J=6.7 Hz, 1H), 5.42 (br s, 1H), 5.41 (br, 1H), 5.12 (s, 2H), 4.00 (d, J=17.7 Hz, 1H), 3.83 (d, J=8.2 Hz, 2H), 3.77 (s, 2H), 3.59-3.46 (m, 2H), 2.54 (t, J=5.8 Hz, 2H), 2.46-2.24 (m, 3H), 2.28 (d, J=17.7 Hz, 1H), 2.14 (s, 3H), 1.93 (s, 3H), 1.77 (s, 3H), 1.72 (s, 3H), 1.65-1.55 (m, 1H)
FABMS m/z 885 (M+H).sup.+
HRFABMS calcd for C.sub.40 H.sub.45 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 885.2145, found 885.2133
EXAMPLE 165
Synthesis of Compound 177
According to the procedure as described in Example 45, Compound 177 (60 mg, 61% yield) was obtained from Compound 35 (71 mg, 0.11 mmol), N-Cbz-.beta.-alanyl-.beta.-alanine (503 mg, 1.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (327 mg, 1.7 mmol), tetrahydrofuran (17 ml) and 4-dimethylaminopyridine (12 mg, 0.10 mmol).
IR (KBr) 3382, 2942, 1818, 1710, 1690, 1678, 1648, 1610, 1531, 1453, 1373, 1264, 1208, 1168, 1094, 977, 769, 698 cm.sup.-1
.sup.1 H NMR (CDCl.sub.3, 400 MHz) .delta. ppm; 9.01 (dd, J=16.6, 11.2 Hz, 1H), 7.38 (s, 1H), 7.38-7.25 (m, 5H), 6.60 (d, J=11.5 Hz, 1H), 6.33 (br, 1H), 6.27 (dd, J=11.5, 11.2 Hz, 1H), 6.03 (d, J=16.6 Hz, 1H), 5.76 (s, 2H), 5.52 (q, J=6.6 Hz, 1H), 5.43 (br, 1H), 5.42 (br s, 1H), 5.09 (br s, 2H), 4.00 (d, J=17.6 Hz, 1H), 3.77 (br s, 2H), 3.55-3.40 (m, 4H), 2.55-1.55 (m, 8H), 2.27 (d, J=17.6 Hz, 1H), 2.14 (s, 3H), 1.92 (d, J=6.6 Hz, 3H), 1.77 (s, 3H), 1.72 (s, 3H)
FABMS m/z 899 (M+H).sup.+
HRFABMS calcd for C.sub.41 H.sub.47 N.sub.4 O.sub.13 S.sub.3 (M+H).sup.+ 899.2302, found 899.2291
INDUSTRIAL APPLICABILITY
The present invention provides DC107 derivatives having an antibacterial activity and an antitumor activity or pharmacologically acceptable slats thereof.
Claims
What is claimed is:
1. A compound represented by formula (I): ##STR80## wherein R.sup.1 represents hydrogen, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, a lower alkoxyalkoxyalkoxyalkyl group, an aralkyl group, a tetrahydropyranyl group, ##STR81## {wherein Q.sup.1 represents CH.sub.2, O, S, SO, SO.sub.2 or N--Q.sup.3 (wherein Q.sup.3 represents a substituted or unsubstituted aryl group or a lower alkoxycarbonyl group), and Q.sup.2 represents a lower alkyl group}, or COR.sup.4 {wherein R.sup.4 represents an alkyl group, an alicyclic alkyl group, an aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a lower alkoxy group, an alicyclic alkoxy group, a 9-fluorenylmethoxy group, an aralkyloxy group, a substituted or unsubstituted aryloxy group, (CH.sub.2).sub.m R.sup.4A (wherein m represents an integer of from 1 to 6, R.sup.4A represents hydroxy, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyloxy group, or NR.sup.4B COR.sup.4C {wherein R.sup.4B represents hydrogen or a lower alkyl group, and R.sup.4C represents hydrogen, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group, a 9-fluorenylmethoxy group, (CH.sub.2).sub.n NHCOR.sup.4D (wherein n represents an integer of from 1 to 6, R.sup.4D represents an alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group or a 9-fluorenylmethyloxy group) or CHR.sup.4E NHCOR.sup.4F (wherein R.sup.4E represents a lower alkyl group or a hydroxy lower alkyl group, and R.sup.4F has the same meaning as R.sup.4D)}) or CHR.sup.4G NHCOR.sup.4H (wherein R.sup.4G has the same meaning as R.sup.4E, and R.sup.4H has the same meaning as R.sup.4C)}; R.sup.2 represents hydrogen or COR.sup.5 (wherein R.sup.5 represents a lower alkyl group, an aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group); R.sup.3 represents a lower alkyl group, a lower alkenyl group, a substituted or unsubstituted aralkyl group, in which aryl may be substituted, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a substituted or unsubstituted aryloxyalkyl group, a lower alkoxycarbonylalkyl group, a lower alkanoyloxyalkyl group, an alicyclic alkanoyloxyalkyl group, or ##STR82## or R.sup.3 bonds to Y to represent a single bond; Y bonds to R.sup.3 to represent a single bond or bonds to Z to represent a single bond; Z represents hydrogen or bonds to Y to represent a single bond; W represents oxygen or NR.sup.6 (wherein R.sup.6 represents a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, an aralkyloxy group, a substituted or unsubstituted arylsulfonylamino group or a lower alkoxycarbonylamino group), with the proviso that when R.sup.1, R.sup.2 and Z each represent hydrogen and R.sup.3 bonds to Y to represent a single bond, then W cannot represent oxygen or a pharmacologically acceptable salt thereof.
2. The compound or the pharmacologically acceptable salt thereof according to claim 1, wherein Y bonds to Z to represent a single bond.
3. The compound or the pharmacologically acceptable salt thereof according to claim 1, wherein Y bonds to R.sup.3 to represent a single bond.
4. The compound or the pharmacologically acceptable salt thereof according to claim 1, wherein W is oxygen.
5. The compound or the pharmacologically acceptable salt thereof according to claim 1, wherein W is NR.sup.6 (wherein R.sup.6 represents hydroxy, a lower alkoxy group, a lower alkenyloxy group, an aralkyloxy group, a substituted or unsubstituted arylsulfonylamino group or a lower alkoxycarbonylamino group.
6. The compound or the pharmacologically acceptable salt thereof according to claim 2, wherein W is oxygen.
7. The compound or the pharmacologically acceptable salt thereof according to claim 6, wherein R.sup.1 is a tetrahydropyranyl group or ##STR83## {wherein Q.sup.1 represents CH.sub.2, O, S, SO, SO.sub.2 or N--Q.sup.13 (wherein Q.sup.3 represents a substituted or unsubstituted aryl group or a lower alkoxycarbonyl group) and Q.sup.2 represents a lower alkyl group}.
8. The compound or the pharmacologically acceptable salt thereof according to claim 6 wherein R.sup.1 is CO(CH.sub.2).sub.m R.sup.4A, wherein m represents an integer of from 1 to 6; R.sup.4A represents hydroxy, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyloxy group, or NR.sup.4B COR.sup.4C {wherein R.sup.4B represents hydrogen or a lower alkyl group; and R.sup.4C represents hydrogen, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group, a 9-fluorenylmethoxy group, (CH.sub.2).sub.n NHCOR.sup.4D (wherein n represents an integer of from 1 to 6, R.sup.4D represents an alkyl group, a lower alkoxy group or a 9-fluorenylmethoxy group) or CHR.sup.4E NHCOR.sup.4F (wherein R.sup.4E represents a lower alkyl group or a hydroxy lower alkyl group, and R.sup.4F has the same meaning as R.sup.4D)}, or COCHR.sup.4G NHCOR.sup.4H (wherein R.sup.4G has the same meaning as R.sup.4E, and R.sup.4H has the same meaning as R.sup.4C).
9. The compound or the pharmacologically acceptable salt thereof according to claim 7, wherein R.sup.3 is ##STR84##
10. An antibacterial agent comprising a compound or the pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
11. An antitumor agent comprising a compound or the pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I): ##STR85## or a pharmacologically acceptable salt thereof, wherein R.sup.1 represents hydrogen, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, a lower alkoxyalkoxyalkoxyalkyl group, an aralkyl group, a tetrahydropyranyl group, ##STR86## {wherein Q.sup.1 represents CH.sub.2, O, S, SO, SO.sub.2 or N--Q.sup.3 (wherein Q.sup.3 represents a substituted or unsubstituted aryl group or a lower alkoxycarbonyl group), and Q.sup.2 represents a lower alkyl group}, or COR.sup.4 {wherein R.sup.4 represents an alkyl group, an alicyclic alkyl group, an aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a lower alkoxy group, an alicyclic alkoxy group, a 9-fluorenylmethoxy group, an aralkyloxy group, a substituted or unsubstituted aryloxy group, (CH.sub.2).sub.m R.sup.4A (wherein m represents an integer of from 1 to 6, R.sup.4A represents hydroxy, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aralkyloxy group, or NR.sup.4B COR.sup.4C {wherein R.sup.4B represents hydrogen or a lower alkyl group, and R.sup.4C represents hydrogen, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group, a 9-fluorenylmethoxy group, (CH.sub.2).sub.n NHCOR.sup.4D (wherein n represents an integer of from 1 to 6, R.sup.4D represents an alkyl group, a lower alkoxy group, an aralkyloxy group, an aryl group, an aryloxy group or a 9-fluorenylmethyloxy group) or CHR.sup.4E NHCOR.sup.4F (wherein R.sup.4E represents a lower alkyl group or a hydroxy lower alkyl group, and R.sup.4F has the same meaning as R.sup.4D)}) or CHR.sup.4G NHCOR.sup.4H (wherein R.sup.4G has the same meaning as R.sup.4E, and R.sup.4H has the same meaning as R.sup.4C)}; R.sup.2 represents hydrogen or COR.sup.5 (wherein R.sup.5 represents a lower alkyl group, an aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group); R.sup.3 represents a lower alkyl group, a lower alkenyl group, a substituted or unsubstituted aralkyl group, in which aryl may be substituted, a lower alkoxyalkyl group, an aralkyloxyalkyl group, a substituted or unsubstituted aryloxyalkyl group, a lower alkoxycarbonylalkyl group, a lower alkanoyloxyalkyl group, an alicyclic alkanoyloxyalkyl group, or ##STR87## or R.sup.3 bonds to Y to represent a single bond; Y bonds to R.sup.3 to represent a single bond or bonds to Z to represent a single bond; Z represents hydrogen or bonds to Y to represent a single bond; W represents oxygen or NR.sup.6 (wherein R.sup.6 represents a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, an aralkyloxy group, a substituted or unsubstituted arylsulfonylamino group or a lower alkoxycarbonylamino group), with the proviso that when R.sup.1, R.sup.2 and Z each represent hydrogen and R.sup.3 bonds to Y to represent a single bond, then W cannot represent oxygen, and a pharmacologically acceptable carrier therefor.
13. A method for treating a patient exhibiting symptoms of bacterial activity comprising: administering an effective antibacterial amount of a compound or a pharmacologically acceptable salt thereof, as defined in claim 1.
14. A method for treating a patient exhibiting symptoms of tumor activity comprising: administering an effective antitumor amount of a compound or a pharmacologically acceptable salt thereof, as defined in claim 1.
Patent Citations (2)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US4999196 | 1991-03-01 | Nakano et al. | |
| EPX300294 | 1989-01-01 |
Non-Patent Literature (2)
- Chemical Abstracts, vol. 112, No. 11 (Mar. 12, 1990) 96887z.
- Hara et al., J. Antibiot., vol. 42, No. 12 (1989) 1768-74.