PGD2 receptor antagonistic pharmaceutical compositions

[0001] This application is the national phase of International Application No. PCT/JP01/09435, filed Oct. 26, 2001, published in a non-English language.

[0002] This invention relates to a bicyclic amide derivative, an antagonist against PGD₂ receptor, and a pharmaceutical composition comprising the same.

[0003] As a pharmaceutical composition comprising an antagonist against PGD₂ receptor, a compound of the formula:

 
wherein Y is bicyclic ring and R is phenyl etc., was described in WO 97/00853 (International publication date: Jan. 1, 1997).

[0004] On the other hand, it was disclosed that 3-oxa-derivatives were prepared as metabolically stable TXA₂/PGH₂ receptor antagonists in Bioorganic & Medicinal Chemistry Letters, Vol. 2, No. 9, pp. 1069-1072, 1992. The active value of the compound was only described but the metabolic stability has not been described in the literature.

 
wherein, Z is p-fluorophenyl; Rω is benzenesulfonamino and the like.

[0005] Furthermore, it was reported in PROSTAGLANDINS, 1986, 31, 95 that ILOPROST, PGI₂ mimetics was stabilized metabolically by converting to the 3-oxa-derivative. But, remaining activity of each compound was only compared under a presence of the metabolic enzyme of a rat and the metabolic stability did not mentioned.

[0006] The present inventors have carried out the structure modification research on α chain of a pharmaceutical composition comprising an antagonist against PGD₂ receptor described in WO97/00853, found out a metabolically stable antagonist against PGD₂ receptor and have completed the present invention.

[0007] The present invention provides:

• [0008] (1) a compound represented by the formula (I):
  
   
  wherein
  
   
• [0009] R¹ is optionally substituted heteroaryl;
• [0010] R² is hydrogen or alkyl;
• [0011] R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴;
• [0012] R⁴ is hydrogen or alkyl;
• [0013] X¹ is —O— or —S—,
  a prodrug, a pharmaceutically acceptable salt or a solvate thereof,
• [0014] (2) a compound as described in (1), wherein
  
   
• [0015]  a prodrug, a pharmaceutically acceptable salt or a solvate thereof,
• [0016] (3) a compound as described in (1) or (2), wherein R¹ is optionally substituted thienyl, optionally substituted benzothienyl, optionally substituted furyl, optionally substituted benzofuryl, optionally substituted pyrrolyl, optionally substituted thienopyrrolyl or optionally substituted indolyl, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,
• [0017] (4) a compound as described in (1) or (2), wherein R¹ is heteroaryl which may be substituted with a group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂— or —CH₂—C(═O)— and Z² is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,
• [0018] (5) a compound as described in any one of (1) to (4), wherein R³ is —CH₂—CH₂—CH₂——CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,
• [0019] (6) a compound as described in (5), wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,
• [0020] (7) a pharmaceutical composition containing a compound, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof as described in any one of (1) to (6),
• [0021] (8) a pharmaceutical composition having an antagonistic activity against PGD₂ receptor as described in (7),
• [0022] (9) a pharmaceutical composition as described in (7), which is used for the treatment of nasal,
• [0023] (10) a pharmaceutical composition as described in (7), which is used for the treatment of allergic conjunctivitis,
• [0024] (11) a pharmaceutical composition as described in (7), which is used for the treatment of allergic rhinitis,
• [0025] (12) a method for treating nasal blockage, allergic conjunctivitis or allergic rhinitis, which comprises administrating a composition as described in (7), and
• [0026] (13) use of the compound as described in any one of (1) to (6) for the preparation of a pharmaceutical composition for treating nasal blockage, allergic conjunctivitis or allergic rhinitis.

[0027] The terms used herein is explained below. Each term used herein is defined to have meanings below in either case of a single or a joint use with other terms.

[0028] The term “heteroaryl” includes a 5- to 7-membered aromatic heterocycle containing one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic heterocycle as fused with one or more carbocycle or other aromatic heterocycle, which has a bond at any substitutable. Any one of aromatic heterocycle and aromatic carbocycle may have a bond.

[0029] Examples of “heteroaryl” include pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazolyl (e.g., 3-pyrazolyl, 4pyrazolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), carbazolyl (e.g., 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), furyl (e.g., 2-furyl, 3-furyl), benzofuryl (e.g., 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl), thienyl (e.g., 2-thienyl, 3-thienyl), benzothienyl (e.g., benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), dibenzothienyl (e.g., 2-dibenzothienyl, 3-dibenzothienyl), dibenzofuryl (e.g., 2-dibenzofuryl, 3-dibenzofuryl), naphthothienyl (e.g., naphtho[2,3-b]thiophen-2-yl, naphtho[2,3-b]thiophen-3-yl, naphtho[1.2-b]thiophen-2-yl, naphtho[1.2-b]thiophen-3-yl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), imidazothiazolyl (e.g., imidazo[2.1-b]thiazol-2-yl, imidazo[2.1-b]thiazol-3-yl), benzoisoxazolyl (e.g., benzo[d]isoxazol-3-yl), benzothiazolyl (e.g., benzo[d]thiazol-2-yl), thienopyrrolyl (e.g., thieno[2,3-b]pyrrole-2-yl, thieno[2,3-b]pyrrole-3-yl, thieno[2,3-b]pyrrole-5-yl, thieno[2,3-c]pyrrole-2-yl, thieno[2,3-c]pyrrole-4-yl, thieno[3,2-b]pyrrole-2-yl, thieno[3,2-b]pyrrole-3-yl, thieno[3,2-b]pyrrole-5-yl), and the like.

[0030] Thienyl, benzothienyl, furyl, benzofuryl, pyrrolyl, are indolyl preferred.

[0031] The term of “aromatic carbocycle or other aromatic heterocycle” which may fuse the above “heteroaryl” includes 5- to 7-membered aromatic cycle which may contains one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic ring as fused with one or more other aromatic rings.

[0032] The above “heteroaryl” may be fused 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle. Examples of cycloalkane include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Examples of non-aromatic heterocycle include pyrrolidine, piperazine, oxorane, 1,3-dioxorane, 1,4-dioxane, thiorane, or the like. The above “cycloalkane” and “non-aromatic heterocycle” may be fused with other aromatic carbocycle such as benzene or aromatic heterocycle such as thiophene or furan. Examples of heteroaryl fused with 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle are illustrated below.

 

[0033] Examples of the substituent on “optionally substituted heteroaryl” include a group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂—, or —CH₂—C(═O)—, and Z² is alkyl, haloalkyl, alkenyl, alkynyl, or optionally substituted amino; carboxy; halogen (F, Cl, Br, I); hydroxyalkyl; hydroxy; nitro; cyano; mercapto; thioformyl; thioacetyl; thiocarboxy; dithiocarboxy; thiocarbamoyl; sulfino; sulfo; sulfamoyl; sulfoamino and the like. A group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂NH—C(═O)—O—, —CH₂—NH—SO₂—, or —CH₂—C(═O)—, and Z² is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; and nitro are preferred. Further, A group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —NH—C(═O)—, or —C(═O)—, and Z² is alkyl or optionally substituted amino; halogen; and hydroxy are preferred. One to three of the above substituents may be at any suitable position on the above heteroaryl.

[0034] “Alkyl” includes a straight or branched C1 to C8 alkyl group or a C3 to C8 cycloalkyl group. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A straight or branched C1 to C3 alkyl group is preferred.

[0035] “Haloalkyl” includes the above alkyl substituted with one to three halogen(s). A straight or branched C1 to C3 haloalkyl is preferred. Trifluoromethyl, 2,2,2-trifluoroethyl and the like are exemplified.

[0036] “Alkenyl” includes the above alkyl having one to three double bond(s). A straight or branched C2 to C3 alkenyl is preferred. Vinyl, allyl, 1-propenyl, isopropenyl and the like are exemplified.

[0037] “Alkynyl” includes the above alkyl having one to three triple bond(s). A straight C2 to C3 alkynyl is preferred. Ethynyl and the like are preferred.

[0038] Examples of the substituent of “optionally substituted amino” include alkyl, alkyloxy, alkylsulfonyl, hydroxy, and the like. It may be mono- or di-substituted with these substituents.

[0039] “Hydroxy alkyl” includes the above alkyl substituted with one to three hydroxy. A straight or branched C1 to C3 hydroxyalkyl is preferred. Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and the like are exemplified.

[0040] “Halogen” includes fluoro, chloro, bromo, and iodo.

[0041] A compound of the present invention has the following [2.2.1] and [3.1.1] bicyclic skeleton.

 

[0042] A compound of the present invention can be any of the following stereo isomers of [2.2.1] and [3.1.1] bicyclic skeleton.

[0043] In a case of

 

[0044] In a case of

 

[0045] In a case of

 

[0046] In these stereo isomers, preferable is a compound having the skeleton of the formula:

 

[0047] The present invention includes all stereo isomers of them and the optional mixtures thereof. Namely, the bond binding to the bicyclic ring is in R configuration or S configuration, and all of the stereo isomers (diastereomer, epimer, enantiomer and the like), racemates, and optional mixture thereof are included in the present invention.

[0048] Moreover, the α chain of the compound of the present invention can be in Z configuration or E configuration, thus a compound having any of the configurations and the mixture thereof are included in the present invention.

[0049] Further, as the α chain (R³) of the compound of the present invention, —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ and —CH₂—CH₂—CH₂—CH₂—COOR⁴ (R⁴ is hydrogen or alkyl; X¹ is —O— or —S—) are exemplified. Especially, —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ and —CH₂—CH₂—CH₂—CH₂—COOR⁴ (R⁴ is hydrogen; X¹ is —O— or —S—) are preferred. Further, —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ and —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴ (R⁴ is hydrogen; X¹ is —O—or —S—) are preferred.

[0050] This invention includes not only a compound represented by the formula (I), but also a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

[0051] A prodrug of a compound of the formula (I) is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition. Method for the selection and process of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985.

[0052] When the compound of the formula (I) has a carboxyl group, an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide derivative prepared by reacting a basal acid compound with a suitable amine is exemplified as a prodrug. A particularly preferred ester derivative as an prodrug is an optionally substituted alkyl ester derivative (e.g., methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester), an arylalkyl ester derivative (e.g., benzyl ester, phenethyl ester, benzhydryl ester), or the like. A particularly preferred amide derivative as a prodrug is alkyl amide derivative (e.g., N-methyl amide, N-ethyl amide, N-(n-propyl)amide, N-isopropyl amide, N-(n-butyl)amide, N-isobutyl amide, N-(tert-butyl)amide), aryl alkyl amide (e.g., N-benzyl amide, N-phenethyl amide, benzhydryl amide), or the like.

[0053] When the compound of the formula (I) has a hydroxy group, an acyloxy derivative prepared by reacting with a suitable acyl halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred acyloxy derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyloxy (e.g., —OCOC₂H₅, —OCO(tert-Bu), —OCOC₁₅H₃₁, —OCOCH₂CH₂COONa, —OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂—), optionally substituted arylcarbonyloxy (e.g., —OCO(m-COONa-Ph) or the like.

[0054] When the compound of the formula (I) has an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred amide derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyl (e.g., —NHCO(CH₂)₂₀CH₃, —NHCOCH(NH₂)CH₃) or the like.

[0055] Examples of a salt of the compound of the formula (I) or its prodrug include alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline-earth metal salts such as calcium salts, salts with organic bases such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylene methylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthorathene, 2-aminoanthorathene, dehydroabiethylamine, N-methylmorpholine, pyridine), basic amino acid salts such as arginine salts or lysine salts.

[0056] A solvate means a solvate with an organic solvent, a hydrate and the like of the compound of the formula (I), its prodrug or its pharmaceutically acceptable salt, for example, monohydrate, dihydrate or the like.

[0057] “A pharmaceutical composition having an antagonistic activity against PGD₂ receptor” means a pharmaceutical composition comprising at least one compound of the formula (I) having an antagonistic activity against a PGD₂ receptor. In addition to a compound of the formula (I), the other active agents (e.g. antiinflammatory agents, antiallergy agents and the like) and pharmaceutically acceptable admixtures (e.g., binding agent, filler and the like) may be included.

[0058] A PGD₂ antagonist is useful in the improvement of conditions due to excessive production of PGD₂, particularly as a composition for treating diseases in which mast cell dysfunction is involved, for example, systemic mastocytosis and disorder of systemic mast cell activation as well as for nasal blockage, allergic conjunctivitis, allergic rhinitis, airway contraction, asthma, urticaria, ischemic reperfusion injury, inflammation, and atopic dermatitis.

[0059] This invention includes a method for treating a condition due to excessive production of PGD₂ such as nasal blockage, allergic conjunctivitis, allergic rhinitis, and the like, which comprises administrating a compound represented by the formula (I). In addition, this invention includes use of the compound represented by the formula (I) for the preparation of a pharmaceutical composition for treating a condition due to excessive production of PGD₂ such as nasal blockage, allergic conjunctivitis or allergic rhinitis.

[0060] The compound represented by the formula (I) can be prepared in accordance with the following method.

 

• [0061] R¹ is optionally substituted heteroaryl;
• [0062] R² is hydrogen or alkyl;
• [0063] R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴;
• [0064] R⁴ is hydrogen or alkyl; and
• [0065] X¹ is —O— or —S—.

[0066] As shown in the above process, the compound of the formula (I) can be prepared by reacting a carboxylic acid of the formula (M-2) or its reactive derivative with an amino compound of the formula (M-1).

[0067] The reactive derivatives of carboxylic acid of the formula (M-2) mean the corresponding acid halides (e.g., chloride, bromide, iodide), anhydrides (e.g., mixed anhydride with formic acid or acetic acid), active esters (e.g., N-hydroxysuccinimide ester), and the like, and include acylating agents used for the usual acylation of amino group.

[0068] For example, an acid halide is obtained by reacting the compound (M-2) with a thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), and the like, in accordance with known methods as described in the literatures.

[0069] The reaction can be conducted under a condition generally used for the acylation of amino group. For example, in the case of condensation with the acid halide, the reaction is carried out in a solvent such as an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane), benzene solvent (e.g., benzene, toluene, xylene), halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform) as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, or the like, if necessary, in the presence of a base (e.g., organic base such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine; inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, or the like) under cooling, at room temperature, or under heating, preferably at a temperature ranging from −20° C. to ice-cooling temperature, or from room temperature to a refluxing temperature of the reaction system, during several min to several hr, preferably for 0.5 hr to 24 hr, more preferably for 1 hr to 12 hr.

[0070] When R⁴ is alkyl, a free form may be used without converting the carboxy group (M-2) into the reactive derivatives and the reaction may be conducted in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-methylaminopropyl)carbodiimide, N,N′-carbonyldiimidazole, or the like) usually used in the condensation reaction of amine and carboxylic acid.

[0071] When the substituent of “optionally substituted aryl” or “optionally substituted heteroaryl” of the compound of the formula (M-2) is substituted with a hydroxy group, an amino group or the like, such a compound can be used after protection by acetyl group or the like in accordance with the well known method.

[0072] In the reaction of the other reactive derivatives or free acid (M-2) with the amine (M-1), the reaction conditions are determined according to the property of each reactive derivative or free acid, in accordance with a known method. The reaction product can be purified in accordance with a conventional purification, such as the extraction with a solvent, chromatography, recrystallization, and the like.

 
wherein Q is a protective group of an amino group; R², X¹ and R⁴ are as defined above.

[0073] The compounds represented by formula (M-1) can be prepared from the aldehyde derivative (Q is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like) represented by a general formula (M-3a) or (M-3b) by one or more reaction(s) of a ylide compound under a Wittig reaction condition (Org. Reaction, 1965, 14, 270) in combination with other reactions.

[0074] For example, the aldehyde (M-3a) is reacted with phosphonium salt derived from 6-bromo-3-oxahexanoic acid described in WO97/40104 under a well known Wittig reaction condition to give a compound (M-4). The compound (M-4) is hydrogenated in the presence of palladium, platinum and the like to give a starting material (M-1a, X¹=O), wherein R³ is —CH₂CH₂CH₂CH₂OCH₂COOR⁴. Furthermore, after Wittig reaction using methoxymethyltriphenyl-phosphonium salt, followed by a hydrolysis with hydrochloric acid, formic acid, acetic acid and the like can furnish an aldehyde (M-3b). Under Wittig reaction condition using a stable ylide such as methyl (triphenylphophoranidene)acetate and the like or Honer-Emmons reaction condition using methyl dimethylphosphonoacetate, the above aldehyde can be converted into α,β-unsaturated carboxylic acid derivative represented by the formula (M-5). An alcohol derivative (M-6a, X¹=O) which is obtained by reduction of compound (M-5) is reacted with halogenated acetic acid or its ester derivative in accordance with well known methods to give a starting compound (M-1b, X¹=O) wherein R³ is —CH₂CH═CHCH₂OCH₂COOR⁴. Further, after an alcohol derivative (M-6a, X¹=O) is converted into a thiol derivative (X¹=S) in accordance with well known methods, the obtained compound is reacted with halogenated acetic acid derivative as shown the above to give a starting compound (M-1b, X¹=S) wherein R³ is —CH₂CH═CHCH₂SCH₂COOR⁴. Also, after an alcohol derivative (M-6a, X¹=O) is converted into a halogenated derivative in accordance with well known methods, the obtained compound is reacted with a glycolic acid or a thioglycollic acid in the presence of a base to give the above compound (M-1b, X¹=S). The double bonds in the R³ can be reduced by hydrogenation in the presence of catalyst such as palladium, platinum, and the like at the suitable stage to give a corresponding saturated derivative (M-1a, X¹=O or S) at ease.

[0075] The aldehyde (M-3b) is converted into a compound represented by the formula (M-7) by Wittig reaction using 2-(1,3-dioxolane-2-yl)ethyltriphenylphosphonium salt. A hydrogenation of the compound (M-7) and an acidic hydrolysis of acetal are carried out to give the aldehyde (M-3c) as shown in the above. Under Wittig reaction condition using a stable ylide such as methyl (triphenylphophoranidene)acetate and the like or Honer-Emmons reaction condition using methyl dimethylphosphonoacetate, the above aldehyde (M-3c) can be converted into a starting compound (M-1c) wherein R³ corresponds to —CH₂CH₂CH₂CH₂CH═CHCOOR⁴.

[0076] Amidation with a starting carboxylic acid (M-2) can be accomplished after a deprotection of an amino protecting group Q in a way of conversion to α-chain, if necessary.

[0077] In case of the introduction of a substituent(s) into the “optionally substituted aryl” or “optionally substituted heteroaryl”, the change of the functional group can be performed before or after reacting a carboxylic acid or its reactive derivative thereof (M-2) with the amine (M-1). For example, the compound having an aromatic heterocycle substituted with a nitro group can be prepared through the nitration of the compound with a nitrating acid. Moreover, the compound having an aromatic heterocycle substituted with an amino group can be prepared through the reduction of the above-obtained compound with tin in the presence of hydrochloride. Moreover, the compound having an aromatic heterocycle substituted with a hydroxy group can be prepared through the diazonization of the above-obtained compound and the hydrolysis with alkali. On the other hand, the compound having an aromatic heterocycle substituted with an alkoxy group can be prepared through the reaction of the diazonium derivative with alcohol. The compound having an aromatic heterocycle substituted with halogen can be prepared through Sandmeyer reaction, the reaction of the diazonium derivative with a copper salt (e.g., CuCl₂, CuBr₂). The compound having an aromatic heterocycle substituted with halogen can be also prepared through the direct reaction of the compound having an aromatic heterocycle with chlorine and the like. Using the above-mentioned methods appropriately, halogen can be introduced into a desired position(s). The group of alkyl, alkenyl or acyl group can be directly introduced into an aromatic heterocycle through Friedel Crafts reaction with alkylating agent, an alkenylating agent, or an acylating agent, respectively, in the presence of anhydrous aluminum chloride and the like.

[0078] When using the compound (I) of the present invention in treatment, it can be formulated into ordinary formulations for oral and parenteral administration. A pharmaceutical composition containing the compound (I) of the present invention can be in the form for oral and parenteral administration. Specifically, it can be formulated into formulations for oral administration such as tablets, capsules, granules, powders, syrup, and the like; or those for parenteral administration such as injectable solution or suspension for intravenous, intramuscular, or subcutaneous injection, inhalant, eye drops, nasal drops, suppositories, or percutaneous formulations such as ointment.

[0079] In preparing the formulations, carriers, excipients, solvents, and bases known to one having ordinary skill in the art may be used. In case of tablets, they are prepared by compressing or formulating an active ingredient together with auxiliary components. Examples of usable auxiliary components include pharmaceutically acceptable excipients such as binders (e.g., cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., starch sodium glycolate) or lubricants (e.g., magnesium stearate). Tablets may be coated appropriately. In case of liquid formulations such as syrups, solutions, or suspensions, they may contain suspending agents (e.g., methyl cellulose), emulsifiers (e.g., lecithin), preservatives, and the like. In case of injectable formulations, it may be in the form of solution, suspension, or oily or aqueous emulsion, which may contain suspension-stabilizing agents or dispersing agent, and the like. In case of an inhalant, it is formulated into a liquid formulation applicable to an inhaler. In case of eye drops, it is formulated into a solution or a suspension.

[0080] Especially, in case of a nasal drug for treating nasal blockage, it can be used as a solution or suspension prepared by a conventional formulating method, or administered as a powder formulated using a powdering agent (e.g., hydroxypropyl cellulose, carbopole) into the nasal cavity. Alternatively, it can be used as an aerosol filled into a special container together with a solvent of low boiling point.

[0081] In a case using as an eyewash drug for treating allergic conjunctivitis, it can be used as a solution or suspension of the compound or can be used by solving or suspending the compound before use. A stabilizing agent, solubilizing agent, suspending agent, emulsifier, buffer, preservatives and the like can be included. In a case using as an eyewash drug, aseptic treatment is preferable.

[0082] Although an appropriate dosage of the compound (I) varies depending on the administration route, age, body weight, sex, or conditions of the patient, and the kind of drug(s) used together, if any, and should be determined by the physician in the end, in the case of oral administration, the daily dosage can generally be between 0.01-100 mg, preferably 0.01-10 mg, more preferably 0.01-1 mg, per kg body weight. In case of parenteral administration, the daily dosage can generally be between 0.001-100 mg, preferably 0.001-1 mg, more preferably 0.001-0.1 mg, per kg body weight. The daily dosage can be administered in 1-4 divisions.

[0083] The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope.

[0084]

 

Process 1

[0085] To a solution of compound (1) (10.11 g, 39.9 mmol) in toluene (100 ml) was added triphenylphosphoranylidene acetic acid methyl ester (14.68 g, 43.9 mmol) and the resulting mixture was stirred for 17 h at room temperature. Hexane (100 ml) was added to the mixture and the insoluble residue was filtered off. The filtration was concentrated to give 16.56 g of residue. 16.12 g of the residue was dissolved in THF(160 ml), 2N lithium hydroxide aq. (40 ml) was added to the solution and the resulting mixture was stirred for 5 h at 60° C. After THF was concentrated in vacuo, the residue was diluted with water (100 ml). The water layer was washed with toluene twice and acidified with hydrochloric acid (pH=1) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and concentrated. To a solution of the residue in methanol was added 10% palladium-carbon (360 mg) and the resulting mixture was stirred for 3 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated and the residues was dissolved in THF (120 ml). To the mixture were added triethylamine (6.2 ml, 44.5 mmol) and ethyl chloroformate (4.3 ml, 44.5 mmol ) at ice-cooling, and the resulting mixture was stirred for 30 min at ice-cooling. The insoluble salt was filtered off and sodium borohydride (3.06 g, 80.9 mmol) was added to the filtration. To the mixture was added methanol (40 ml) dropwise over 30 min and the mixture was stirred for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine respectively and dried. The residue was crystallized from hexane-ethyl acetate (90:10) to give compound (2) (8.77 g; yield 80%). mp. 90-92° C.

Process 2

[0086] To a solution of the compound (2) (1.68 g, 5.94 mmol) in toluene (17 ml) were added t-butyl bromoacetate (1.32 ml, 68.91 mmol), sodium hydrogensulfate (201 mg, 0.6 mmol) and 50% sodium hydroxide aq. (1.7 ml) and the resulting mixture was vigorously stirred for 22 h at room temperature. Toluene layer was separated, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=7:1) to give compound (3) (1.60 g; yield 68%).

Process 3

[0087] To a solution of the compound (3) (10.42 g, 26.2 mmol) in methanol (50 ml) was added 4N dioxane solution of hydrogen chloride (65.5 ml, 262 mmol) and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was concentrated in vacuo to give crystalline residue. The residue was washed with hexane-ether to give compound (4) (6.88 g; yield 90%).

Process 4

[0088] To a solution of compound (4) (642 mg, 2.20 mmol) in THF (8 ml) were added thiophene-3-carboxylic acid (256 mg, 2.00 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and triethylamine (0.34 ml, 2.40 mmol) at ice-cooling. Further, 3-ethyl-3-(3-dimethylaminopropyl)carbodiimide (370 mg, 2.40 mmol) was added to the mixture at ice-cooling. The reaction mixture was stirred for 16 h at room temperature and diluted with ethyl acetate. The resulting mixture was washed with dilute hydrochloric acid and sodium hydrogencarbonate respectively, dried, concentrated, and chromatographed on silica gel (toluene-hexane=3:1) to give compound (5) (627 mg; yield 86%). m.p. 68-70° C.

Process 5

[0089] To a solution of compound (5) (620 mg, 1.70 mmol) in methanol (2 ml)-THF (1 ml) was added 4N sodium hydroxide aq.(1.0 ml, 4.0 mmol) and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid. and extracted with ethyl acetate. The organic layer was washed with water and brine respectively, dried and concentrated. The residue was crystallized from methanol-water (5:7) to give compound (Ic-4) (461 mg; yield 77%). m.p. 104-105° C.

[0090]

 

Process 1

[0091] To a solution of compound (2) (2.28 g, 8.05 mmol) in dichloromethane (20 ml) were added triphenylphosphine (2.32 g, 8.85 mmol) and N-bromosuccinimide (1.58 g, 8.85 mmol) at ice-cooling and the resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was diluted with toluene, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=9:1) to give compound (6) (2.70 g; yield 97%).

Process 2

[0092] To a solution of sodium methoxide (842 mg, 15.6 mmol) in methanol (20 ml) was added methyl thioglycolate (1.40 ml, 15.6 mmol) and the resulting mixture was stirred for 15 min at room temperature. To the mixture was added a THF (20 ml) solution of compound (6) (2.70 g, 7.80 mmol) and the resulting mixture was stirred for 15 h. The reaction was diluted with ethyl acetate, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=78:22) to give compound (7) (2.84 g; yield 98%).

Process 3

[0093] 4N Ethyl acetate solution of hydrogen chloride (15 ml) was added to compound (7) (2.84 g, 7.64 mmol) and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo to give the residue. The residue was crystallized from hexane-ether to give compound (8) (2.16 g; yield 92%).

Process 4

[0094] To a solution of compound (8) (246 mg, 0.80 mmol) in THF (6 ml) were added benzothiophene-7-carboxylic acid (150 mg, 0.80 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol), triethylamine (0.12 ml, 0.96 mmol) at ice-cooling. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (149 mg, 0.96 mmol) was added to the mixture at ice-cooling. The reaction mixture was stirred for 16 h at room temperature and diluted with ethyl acetate. The resulting mixture was washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=3:1) to give compound (9) (324 mg; yield 94%).

Process 5

[0095] To a solution of compound (9) (315 mg, 0.73 mmol) in THF (3.6 ml)-methanol (7.3 ml) was added 1N sodium hydroxide aq.(1.82 ml, 1.82 mmol) and the resulting mixture was stirred for 48 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine respectively to give compound (Ie-34) (301 mg; yield 99%).

[0096]

 

Process 1

[0097] A solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (3.0 ml, 14.3 mmol) and 18-crown-6 (5.64 g, 21.3 mmol) in THF (100 ml) was cooled at −55° C. and bis(trimethylsilyl)amide potassium (0.5M toluene solution, 28.5 ml, 14.3 mmol) was added dropwise to the mixture. The resulting mixture was stirred for 15 min. To the mixture was added a solution of compound (10) (2.0 g, 7.11 mmol) in THF (20 ml) was added dropwise over 15 min and the mixture was stirred for 1 h at the same temperature. The reaction mixture was allowed to warm to 0° C., diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=4:1) to give compound (11) (2.16 g; yield 90%).

Process 2

[0098] A solution of compound (11) (1.37 g, 4.05 mmol) in dichloromethane (10 ml)-hexane (10 ml) was cooled to −60° C. and diisopropylaluminum hydride (0.95M hexane solution, 10.7 ml, 10.2 mmol) was added dropwise to the solution. The mixture was stirred for 30 min at the same temperature and methanol (0.6 ml) was added. The resulting mixture was allowed to warm to room temperature and 2N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium hydrogencarbonate aq. and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=2:1) to give compound (12) (1.14 g; yield 91%). m.p. 67-69° C.

Process 3

[0099] To a solution of compound (12) (1.03 g, 3.31 mmol) in toluene (10 ml) were added t-butyl bromoacetate (0.70 ml, 4.30 mmol), tetrabutylammonium hydrogensulfate (170 mg, 0.5 mmol), and 50% sodium hydroxide (1.5 ml) and the resulting mixture was vigorously stirred for 18 h at room temperature. The reaction mixture was extracted with toluene, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=4:1) to give compound (13) (1.32 g; yield 94%).

Process 4

[0100] To a solution of compound (13) (1.3 g, 3.07 mmol) in toluene (3 ml) was added trifluoroacetic acid (3.5 ml, 46 mmol) and the resulting mixture was stirred for 3.5 h at 65° C. The reaction mixture was concentrated in vacuo and methanol (30 ml) and concentrated sulphuric acid (0.33 ml) were added to the mixture. The resulting mixture was stirred for 1 h at reflux. The reaction mixture was concentrated and the residue was dissolved in toluene. To the mixture was added triethylamine (4.3 ml, 30 mmol) and sodium hydrogencarbonate aq. respectively. The toluene layer was separated, washed with water and brine respectively, dried, and concentrated to give compound (14) (697 mg; yield 81%).

Process 5

[0101] To a solution of compound (14) (141 mg, 0.50 mmol) in THF (4 ml) were added 5-fluorobenzothiophene-3-carboxylic acid (98 mg, 0.50 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) at ice-cooling. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (93 mg, 0.6 mmol) was added at the same temperature. The reaction mixture was stirred for 16 h at room temperature, diluted with ethyl acetate, washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=83:17) to give compound (15) (93 mg; yield 40%).

Process 6

[0102] To a solution of compound (15) (93 mg, 0.20 mmol) in THF (1 ml)-methanol (2 ml) was added 1N sodium hydroxide aq.(0.5 ml, 0.5 mmol) and the resulting mixture was stirred for 18 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine respectively to give compound (IIb-28) (82 mg; yield 91%).

[0103]

 

Process 1

[0104] A suspension of 2-(1,3-dioxorane-2-yl)ethyltriphenylphosphonium bromide (13.28 g, 30.0 mmol) in THF (60 ml) was cooled to −30° C. and potassium t-butoxide (6.73 g, 60.0 mmol) was added. The mixture was stirred for 1 h at −30° C. to 0° C. and allowed to cool to −25° C. To the mixture was added a solution of compound (10) (5.62 g, 20.0 mmol) in THF (40 ml) dropwise over 15 min. The reaction mixture was allowed to warm to 0° C., stirred for additional 1.5 h, diluted with water. The water layer was extracted with ethyl acetate and the extract is washed with water and brine, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=85:15) to give compound (16) (6.27 g; yield 86%).

Process 2

[0105] A solution of compound (16) (4.10 g, 11.2 mmol) in methanol (41 ml) was stirred for 2 h in the presence of 10% palladium-carbon (0.21 g) under hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a residue (4.12 g; yield 100%). To a solution of the crude compound (3.68 g, 10.0 mmol) in acetone-water (4:1, 50 ml) was added pyridinium p-toluenesulfonate (503 mg, 2.0 mmol) and the mixture was heated for 6 h at reflux. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, concentrated. A solution of the residue in toluene (35 ml) was added methyl (triphenylphosphoranylidene)acetate (2.93 g, 8.76 mmol) and the resulting mixture was stirred for 18 h at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=85:15) to give compound (17) (2.71 g; yield 71%).

Process 3

[0106] To a solution of compound (17) (2.35 g, 6.19 mmol) in dichloromethane (38 ml) was added trifluoroacetic acid (3.82 ml, 49.5 mmol) and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in toluene (50 ml) and water (10 ml). The water layer was alkalinized with 2N sodium hydroxide (pH=10). Toluene layer was separated, washed with water and brine, dried, and concentrated to give compound (18) (1.70 g, yield 98%).

Process 4

[0107] To a solution of compound (18) (280 mg, 1.0 mmol) in THF (5 ml) were added 5-acetoxybenzofuran-3-carboxylic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (13 mg, 0.1 mmol). Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (200 mg, 1.3 mmol) was added at ice-cooling. After the reaction mixture was stirred for 16 h at room temperature, the mixture was diluted with toluene, washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=3:1) to give compound (19) (422 mg; yield 88%). m.p. 119-120° C.

Process 5

[0108] To a solution of compound (19) (422 mg, 0.88 mmol) in THF (5.6 ml) was added 1N lithium hydroxide aq. (3.0 ml, 3.0 mmol) and the resulting mixture was stirred for 20 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine respectively, dried, and concentrated. The residue was crystallized from hexane-ethyl acetate to give compound (IIa-52) (327 mg; yield 87%). m.p. 159-160° C.

[0109] The structure and physical property of the compound prepared in accordance with the above examples are shown below. Each sign such as Ia, Ib, IIe, and IIf used in the following Tables means the partial structure represented below:

 

[0110]

TABLE 1
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-1	Ib-1	Ic-1	Id-1	Ie-1	If-1
	Ia-2	Ib-2	Ic-2	Id-2	Ie-2	If-2
	Ia-3	Ib-3	Ic-3	Id-3	Ie-3	If-3
	Ia-4	Ib-4	Ic-4	Id-4	Ie-4	If-4
	Ia-5	Ia-5	Ic-5	Id-5	Ie-5	If-5
	Ia-6	Ib-6	Ic-6	Id-6	Ie-6	If-6
	Ia-7	Ib-7	Ic-7	Id-7	Ie-7	If-7
	Ia-8	Ib-8	Ic-8	Id-8	Ie-8	If-8
	Ia-9	Ib-9	Ic-9	Id-9	Ie-9	If-9
	Ia-10	Ib-10	Ic-10	Id-10	Ie-10	If-10

 

[0111]

TABLE 2
R1	Ia	Ib	Ic	Id	Ie	If
	Ia- 11	Ib-11	Ic-11	Id-11	Ie-11	If-11
	Ia- 12	Ib-12	Ic-12	Id-12	Ie-12	If-12
	Ia- 13	Ib-13	Ic-13	Id-13	Ie-13	If-13
	Ia- 14	Ib-14	Ic-14	Id-14	Ie-14	If-14
	Ia- 15	Ia-15	Ic-15	Id-15	Ie-15	If-15
	Ia- 16	Ib-16	Ic-16	Id-16	Ie-16	If-16
	Ia- 17	Ib-17	Ic-17	Id-17	Ie-17	If-17
	Ia- 18	Ib-18	Ic-18	Id-18	Ie-18	If-18
	Ia- 19	Ib-19	Ic-19	Id-19	Ie-19	If-19
	Ia- 20	Ib-20	Ic-20	Id-20	Ie-20	Ief-20

 

[0112]

TABLE 3
R1	Ia	Ib	Ic	Id	Ie	If
	Ia- 21	Ib-21	Ic-21	Id-21	Ie-21	If-21
	Ia- 22	Ib-22	Ic-22	Id-22	Ie-22	If-22
	Ia- 23	Ib-23	Ic-23	Id-23	Ie-23	If-23
	Ia- 24	Ib-24	Ic-24	Id-24	Ie-24	If-24
	Ia- 25	Ia-25	Ic-25	Id-25	Ie-25	If-25
	Ia- 26	Ib-26	Ic-26	Id-26	Ie-26	If-26
	Ia- 27	Ib-27	Ic-27	Id-27	Ie-27	If-27
	Ia- 28	Ib-28	Ic-28	Id-28	Ie-28	If-28
	Ia- 29	Ib-29	Ic-29	Id-29	Ie-29	If-29
	Ia- 30	Ib-30	Ic-30	Id-30	Ie-30	If-30

 

[0113]

TABLE 4
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-31	Ib-31	Ic-31	Id-31	Ie-31	If-31
	Ia-32	Ib-32	Ic-32	Id-32	Ie-32	If-32
	Ia-33	Ib-33	Ic-33	Id-33	Ie-33	If-33
	Ia-34	Ib-34	Ic-34	Id-34	Ie-34	If-34
	Ia-35	Ia-35	Ic-35	Id-35	Ie-35	If-35
	Ia-36	Ib-36	Ic-36	Id-36	Ie-36	If-36
	Ia-37	Ib-37	Ic-37	Id-37	Ie-37	If-37
	Ia-38	Ib-38	Ic-38	Id-38	Ie-38	If-38
	Ia-39	Ib-39	Ic-39	Id-39	Ie-39	If-39
	Ia-40	Ib-40	Ic-40	Id-40	Ie-40	If-40

 

[0114]

TABLE 5
R1	Ia	Ib	Ic	Id	Ie	If
	Ia- 41	Ib-41	Ic-41	Id-41	Ie-41	If-41
	Ia- 42	Ib-42	Ic-42	Id-42	Ie-42	If-42
	Ia- 43	Ib-43	Ic-43	Id-43	Ie-43	If-43
	Ia- 44	Ib-44	Ic-44	Id-44	Ie-44	If-44
	Ia- 45	Ia-45	Ic-45	Id-45	Ie-45	If-45
	Ia- 46	Ib-46	Ic-46	Id-46	Ie-46	If-46
	Ia- 47	Ib-47	Ic-47	Id-47	Ie-47	If-47
	Ia- 48	Ib-48	Ic-48	Id-48	Ie-48	If-48
	Ia- 49	Ib-49	Ic-49	Id-49	Ie-49	If-49
	Ia- 50	Ib-50	Ic-50	Id-50	Ie-50	If-50

 

[0115]

TABLE 6
R1	Ia	Ib	Ic	Id	Ie	If
	Ia- 51	Ib-51	Ic-51	Id-51	Ie-51	If-51
	Ia- 52	Ib-52	Ic-52	Id-52	Ie-52	If-52
	Ia- 53	Ib-53	Ic-53	Id-53	Ie-53	If-53
	Ia- 54	Ib-54	Ic-54	Id-54	Ie-54	If-54
	Ia- 55	Ia-55	Ic-55	Id-55	Ie-55	If-55
	Ia- 56	Ib-56	Ic-56	Id-56	Ie-56	If-56
	Ia- 57	Ib-57	Ic-57	Id-57	Ie-57	If-57
	Ia- 58	Ib-58	Ic-58	Id-58	Ie-58	If-58
	Ia- 59	Ib-59	Ic-59	Id-59	Ie-59	If-59
	Ia- 60	Ib-60	Ic-60	Id-60	Ie-60	If-60

 

[0116]

TABLE 7
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-61	Ib-61	Ic-61	Id-61	Ie-61	If-61
	Ia-62	Ib-62	Ic-62	Id-62	Ie-62	If-62
	Ia-63	Ib-63	Ic-63	Id-63	Ie-63	If-63
	Ia-64	Ib-64	Ic-64	Id-64	Ie-64	If-64
	Ia-65	Ia-65	Ic-65	Id-65	Ie-65	If-65
	Ia-66	Ib-66	Ic-66	Id-66	Ie-66	If-66
	Ia-67	Ib-67	Ic-67	Id-67	Ie-67	If-67
	Ia-68	Ib-68	Ic-68	Id-68	Ie-68	If-68
	Ia-69	Ib-69	Ic-69	Id-69	Ie-69	If-69
	Ia-70	Ib-70	Ic-70	Id-70	Ie-70	If-70

 

[0117]

TABLE 8
R1	Ia	Ib	Ic	Id	Ie	If
	Ia- 71	Ib-71	Ic-71	Id-71	Ie-71	If-71
	Ia- 72	Ib-72	Ic-72	Id-72	Ie-72	If-72
	Ia- 73	Ib-73	Ic-73	Id-73	Ie-73	If-73
	Ia- 74	Ib-74	Ic-74	Id-74	Ie-74	If-74
	Ia- 75	Ia-75	Ic-75	Id-75	Ie-75	If-75
	Ia- 76	Ib-76	Ic-76	Id-76	Ie-76	If-76
	Ia- 77	Ib-77	Ic-77	Id-77	Ie-77	If-77
	Ia- 78	Ib-78	Ic-78	Id-78	Ie-78	If-78
	Ia- 79	Ib-79	Ic-79	Id-79	Ie-79	If-79
	Ia- 80	Ib-80	Ic-80	Id-80	Ie-80	If-80

 

[0118]

TABLE 9
R1	Ia	Ib	Ic	Id	Ie	If
	Ia- 81	Ib- 81	Ic- 81	Id- 81	Ie- 81	If-81
	Ia- 82	Ib- 82	Ic- 82	Id- 82	Ie- 82	If-82
	Ia- 83	Ib- 83	Ic- 83	Id- 83	Ie- 83	If-83
	Ia- 84	Ib- 84	Ic- 84	Id- 84	Ie- 84	If-84
	Ia- 85	Ib- 85	Ic- 85	Id- 85	Ie- 85	If-85
	Ia- 86	Ib- 86	Ic- 86	Id- 86	Ie- 86	If-86
	Ia- 87	Ib- 87	Ic- 87	Id- 87	Ie- 87	If-87
	Ia- 88	Ib- 88	Ic- 88	Id- 88	Ie- 88	If-88
	Ia- 89	Ib- 89	Ic- 89	Id- 89	Ie- 89	If-89
	Ia- 90	Ib- 90	Ic -90	Id- 90	Ie- 90	If-90

 

[0119]

TABLE 10
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-91	Ib-91	Ic-91	Id-91	Ie-91	If-91
	Ia-92	Ib-92	Ic-92	Id-92	Ie-92	If-92
	Ia-93	Ib-93	Ic-93	Id-93	Ie-93	If-93
	Ia-94	Ib-94	Ic-94	Id-94	Ie-94	If-94
	Ia-95	Ib-95	Ic-95	Id-95	Ie-95	If-95
	Ia-96	Ib-96	Ic-96	Id-96	Ie-96	If-96
	Ia-97	Ib-97	Ic-97	Id-97	Ie-97	If-97
	Ia-98	Ib-98	Ic-98	Id-98	Ie-98	If-98
	Ia-99	Ib-99	Ic-99	Id-99	Ie-99	If-99
	Ia-100	Ib-100	Ic-100	Id-100	Ie-100	If-100

 

[0120]

TABLE 11
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-101	Ib-101	Ic-101	Id-101	Ie-101	If-101
	Ia-102	Ib-102	Ic-102	Id-102	Ie-102	If-102
	Ia-103	Ib-103	Ic-103	Id-103	Ie-103	If-103
	Ia-104	Ib-104	Ic-104	Id-104	Ie-104	If-104
	Ia-105	Ib-105	Ic-105	Id-105	Ie-105	If-105
	Ia-106	Ib-106	Ic-106	Id-106	Ie-106	If-106
	Ia-107	Ib-107	Ic-107	Id-107	Ie-107	If-107
	Ia-108	Ib-108	Ic-108	Id-108	Ie-108	If-108
	Ia-109	Ib-109	Ic-109	Id-109	Ie-109	If-109
	Ia-110	Ib-110	Ic-110	Id-110	Ie-110	If-110

 

[0121]

TABLE 12
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-111	Ib-111	Ic-111	Id-111	Ie-111	If-111
	Ia-112	Ib-112	Ic-112	Id-112	Ie-112	If-112
	Ia-113	Ib-113	Ic-113	Id-113	Ie-113	If-113
	Ia-114	Ib-114	Ic-114	Id-114	Ie-114	If-114
	Ia-115	Ib-115	Ic-115	Id-115	Ie-115	If-115
	Ia-116	Ib-116	Ic-116	Id-116	Ie-116	If-116
	Ia-117	Ib-117	Ic-117	Id-117	Ie-117	If-117
	Ia-118	Ib-118	Ic-118	Id-118	Ie-118	If-118
	Ia-119	Ib-119	Ic-119	Id-119	Ie-119	If-119
	Ia-120	Ib-120	Ic-120	Id-120	Ie-120	If-120

 

[0122]

TABLE 13
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-121	Ib-121	Ic-121	Id-121	Ie-121	If-121
	Ia-122	Ib-122	Ic-122	Id-122	Ie-122	If-122
	Ia-123	Ib-123	Ic-123	Id-123	Ie-123	If-123
	Ia-124	Ib-124	Ic-124	Id-124	Ie-124	If-124
	Ia-125	Ib-125	Ic-125	Id-125	Ie-125	If-125
	Ia-126	Ib-126	Ic-126	Id-126	Ie-126	If-126
	Ia-127	Ib-127	Ic-127	Id-127	Ie-127	If-127
	Ia-128	Ib-128	Ic-128	Id-128	Ie-128	If-128
	Ia-129	Ib-129	Ic-129	Id-129	Ie-129	If-129
	Ia-130	Ib-130	Ic-130	Id-130	Ie-130	If-130

 

[0123]

TABLE 14
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-131	I-131b	Ic-131	Id-131	Ie-131	If-131
	Ia-132	I-132b	Ic-132	Id-132	Ie-132	If-132
	Ia-133	I-133b	Ic-133	Id-133	Ie-133	If-133
	Ia-134	I-134b	Ic-134	Id-134	Ie-134	If-134
	Ia-135	I-135b	Ic-135	Id-135	Ie-135	If-135
	Ia-136	I-136b	Ic-136	Id-136	Ie-136	If-136
	Ia-137	I-137b	Ic-137	Id-137	Ie-137	If-137
	Ia-138	I-138b	Ic-138	Id-138	Ie-138	If-138
	Ia-139	I-139b	Ic-139	Id-139	Ie-139	If-139
	Ia-140	I-140b	Ic-140	Id-140	Ie-140	If-140

 

[0124]

TABLE 15
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-141	Ib-141	Ic-141	Id-141	Ie-141	If-141
	Ia-142	Ib-142	Ic-142	Id-142	Ie-142	If-142
	Ia-143	Ib-143	Ic-143	Id-143	Ie-143	If-143
	Ia-144	Ib-144	Ic-144	Id-144	Ie-144	If-144
	Ia-145	Ib-145	Ic-145	Id-145	Ie-145	If-145
	Ia-146	Ib-146	Ic-146	Id-146	Ie-146	If-146
	Ia-147	Ib-147	Ic-147	Id-147	Ie-147	If-147
	Ia-148	Ib-148	Ic-148	Id-148	Ie-148	If-148
	Ia-149	Ib-149	Ic-149	Id-149	Ie-149	If-149
	Ia-150	Ib-150	Ic-150	Id-150	Ie-150	If-150

 

[0125]

TABLE 16
R1	Ia	Ib	Ic	Id	Ie	If
	Ia-151	Ib-151	Ic-151	Id-151	Ie-151	If-151
	Ia-152	Ib-152	Ic-152	Id-152	Ie-152	If-152
	Ia-153	Ib-153	Ic-153	Id-153	Ie-153	If-153
	Ia-154	Ib-154	Ic-154	Id-154	Ie-154	If-154
	Ia-155	Ib-155	Ic-155	Id-155	Ie-155	If-155
	Ia-156	Ib-156	Ic-156	Id-156	Ie-156	If-156
	Ia-157	Ib-157	Ic-157	Id-157	Ie-157	If-157
	Ia-158	Ib-158	Ic-158	Id-158	Ie-158	If-158
	Ia-159	Ib-159	Ic-159	Id-159	Ie-159	If-159
	Ia-160	Ib-160	Ic-160	Id-160	Ie-160	If-160

 

[0126]

TABLE 17
R1	Ia	Ib	Ic	Id	Ic	If
	Ia-161	Ib-161	Ic-161	Id-161	Ic-161	If-161
	Ia-162	Ib-162	Ic-162	Id-162	Ic-162	If-162
	Ia-163	Ib-163	Ic-163	Id-163	Ic-163	If-163
	Ia-164	Ib-164	Ic-164	Id-164	Ic-164	If-164
	Ia-165	Ib-165	Ic-165	Id-165	Ic-165	If-165
	Ia-166	Ib-166	Ic-166	Id-166	Ic-166	If-166

 

[0127]

TABLE 18
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-1	IIb-1	IIc-1	IId-1	IIe-1	IIf-1
	IIa-2	IIb-2	IIc-2	IId-2	IIe-2	IIf-2
	IIa-3	IIb-3	IIc-3	IId-3	IIe-3	IIf-3
	IIa-4	IIb-4	IIc-4	IId-4	IIe-4	IIf-4
	IIa-5	IIb-5	IIc-5	IId-5	IIe-5	IIf-5
	IIa-6	IIb-6	IIc-6	IId-6	IIe-6	IIf-6
	IIa-7	IIb-7	IIc-7	IId-7	IIe-7	IIf-7
	IIa-8	IIb-8	IIc-8	IId-8	IIe-8	IIf-8
	IIa-9	IIb-9	IIc-9	IId-9	IIe-9	IIf-9
	IIa- 10	IIb- 10	IIc- 10	IId- 10	IIe- 10	IIf- 10

 

[0128]

TABLE 19
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-11	IIb-11	IIc-11	IId-11	IIe-11	IIf-11
	IIa-12	IIb-12	IIc-12	IId-12	IIe-12	IIf-12
	IIa-13	IIb-13	IIc-13	IId-13	IIe-13	IIf-13
	IIa-14	IIb-14	IIc-14	IId-14	IIe-14	IIf-14
	IIa-15	IIb-15	IIc-15	IId-15	IIe-15	IIf-15
	IIa-16	IIb-16	IIc-16	IId-16	IIe-16	IIf-16
	IIa-17	IIb-17	IIc-17	IId-17	IIe-17	IIf-17
	IIa-18	IIb-18	IIc-18	IId-18	IIe-18	IIf-18
	IIa-19	IIb-19	IIc-19	IId-19	IIe-19	IIf-19
	IIa-20	IIb-20	IIc-20	IId-20	IIe-20	IIf-20

 

[0129]

TABLE 20
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-21	IIb-21	IIc-21	IId-21	IIe-21	IIf-21
	IIa-22	IIb-22	IIc-22	IId-22	IIe-22	IIf-22
	IIa-23	IIb-23	IIc-23	IId-23	IIe-23	IIf-23
	IIa-24	IIb-24	IIc-24	IId-24	IIe-24	IIf-24
	IIa-25	IIb-25	IIc-25	IId-25	IIe-25	IIf-25
	IIa-26	IIb-26	IIc-26	IId-26	IIe-26	IIf-26
	IIa-27	IIb-27	IIc-27	IId-27	IIe-27	IIf-27
	IIa-28	IIb-28	IIc-28	IId-28	IIe-28	IIf-28
	IIa-29	IIb-29	IIc-29	IId-29	IIe-29	IIf-29
	IIa-30	IIb-30	IIc-30	IId-30	IIe-30	IIf-30

 

[0130]

TABLE 21
R1	IIA	IIb	IIc	IId	IIe	IIf
	IIa-31	IIb-31	IIc-31	IId-31	IIe-31	IIf-31
	IIa-32	IIb-32	IIc-32	IId-32	IIe-32	IIf-32
	IIa-33	IIb-33	IIc-33	IId-33	IIe-33	IIf-33
	IIa-34	IIb-34	IIc-34	IId-34	IIe-34	IIf-34
	IIa-35	IIb-35	IIc-35	IId-35	IIe-35	IIf-35
	IIa-36	IIb-36	IIc-36	IId-36	IIe-36	IIf-36
	IIa-37	IIb-37	IIc-37	IId-37	IIe-37	IIf-37
	IIa-38	IIb-38	IIc-38	IId-38	IIe-38	IIf-38
	IIa-39	IIb-39	IIc-39	IId-39	IIe-39	IIf-39
	IIa-40	IIb-40	IIc-40	IId-40	IIe-40	IIf-40

 

[0131]

TABLE 22
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-41	IIb-41	IIc-41	IId-41	IIe-41	IIf-41
	IIa-42	IIb-42	IIc-42	IId-42	IIe-42	IIf-42
	IIa-43	IIb-43	IIc-43	IId-43	IIe-43	IIf-43
	IIa-44	IIb-44	IIc-44	IId-44	IIe-44	IIf-44
	IIa-45	IIb-45	IIc-45	IId-45	IIe-45	IIf-45
	IIa-46	IIb-46	IIc-46	IId-46	IIe-46	IIf-46
	IIa-47	IIb-47	IIc-47	IId-47	IIe-47	IIf-47
	IIa-48	IIb-48	IIc-48	IId-48	IIe-48	IIf-48
	IIa-49	IIb-49	IIc-49	IId-49	IIe-49	IIf-49
	IIa-50	IIb-50	IIc-50	IId-50	IIe-50	IIf-50

 

[0132]

TABLE 23
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-51	IIb-51	IIc-51	IId-51	IIe-51	IIf-51
	IIa-52	IIb-52	IIc-52	IId-52	IIe-52	IIf-52
	IIa-53	IIb-53	IIc-53	IId-53	IIe-53	IIf-53
	IIa-54	IIb-54	IIc-54	IId-54	IIe-54	IIf-54
	IIa-55	IIb-55	IIc-55	IId-55	IIe-55	IIf-55
	IIa-56	IIb-56	IIc-56	IId-56	IIe-56	IIf-56
	IIa-57	IIb-57	IIc-57	IId-57	IIe-57	IIf-57
	IIa-58	IIb-58	IIc-58	IId-58	IIe-58	IIf-58
	IIa-59	IIb-59	IIc-59	IId-59	IIe-59	IIf-59
	IIa-60	IIb-60	IIc-60	IIe-60	IIe-60	IIf-60

 

[0133]

TABLE 24
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-61	IIb-61	IIc-61	IId-61	IIe-61	IIf-61
	IIa-62	IIb-62	IIc-62	IId-62	IIe-62	IIf-62
	IIa-63	IIb-63	IIc-63	IId-63	IIe-63	IIf-63
	IIa-64	IIb-64	IIc-64	IId-64	IIe-64	IIf-64
	IIa-65	IIb-65	IIc-65	IId-65	IIe-65	IIf-65
	IIa-66	IIb-66	IIc-66	IId-66	IIe-66	IIf-66
	IIa-67	IIb-67	IIc-67	IId-67	IIe-67	IIf-67
	IIa-68	IIb-68	IIc-68	IId-68	IIe-68	IIf-68
	IIa-69	IIb-69	IIc-69	IId-69	IIe-69	IIf-69
	IIa-70	IIb-70	IIc-70	IId-70	IIe-70	IIf-70

 

[0134]

TABLE 25
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-71	IIb-71	IIc-71	IId-71	IIe-71	IIf-71
	IIa-72	IIb-72	IIc-72	IId-72	IIe-72	IIf-72
	IIa-73	IIb-73	IIc-73	IId-73	IIe-73	IIf-73
	IIa-74	IIb-74	IIc-74	IId-74	IIe-74	IIf-74
	IIa-75	IIb-75	IIc-75	IId-75	IIe-75	IIf-75
	IIa-76	IIb-76	IIc-76	IId-76	IIe-76	IIf-76
	IIa-77	IIb-77	IIc-77	IId-77	IIe-77	IIf-77
	IIa-78	IIb-78	IIc-78	IId-78	IIe-78	IIf-78
	IIa-79	IIb-79	IIc-79	IId-79	IIe-79	IIf-79
	IIa-80	IIb-80	IIc-80	IId-80	IIe-80	IIf-80

 

[0135]

TABLE 26
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-81	IIb-81	IIc-81	IId-81	IIe-81	IIf-81
	IIa-82	IIb-82	IIc-82	IId-82	IIe-82	IIf-82
	IIa-83	IIb-83	IIc-83	IId-83	IIe-83	IIf-83
	IIa-84	IIb-84	IIc-84	IId-84	IIe-84	IIf-84
	IIa-85	IIb-85	IIc-85	IId-85	IIe-85	IIf-85
	IIa-86	IIb-86	IIc-86	IId-86	IIe-86	IIf-86
	IIa-87	IIb-87	IIc-87	IId-87	IIe-87	IIf-87
	IIa-88	IIb-88	IIc-88	IId-88	IIe-88	IIf-88
	IIa-89	IIb-89	IIc-89	IId-89	IIe-89	IIf-89
	IIa-90	IIb-90	IIc-90	IId-90	IIe-90	IIf-90

 

[0136]

TABLE 27
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-91	IIb-91	IIc-91	IId-91	IIe-91	IIf-91
	IIa-92	IIb-92	IIc-92	IId-92	IIe-92	IIf-92
	IIa-93	IIb-93	IIc-93	IId-93	IIe-93	IIf-93
	IIa-94	IIb-94	IIc-94	IId-94	IIe-94	IIf-94
	IIa-95	IIb-95	IIc-95	IId-95	IIe-95	IIf-95
	IIa-96	IIb-96	IIc-96	IId-96	IIe-96	IIf-96
	IIa-97	IIb-97	IIc-97	IId-97	IIe-97	IIf-97
	IIa-98	IIb-98	IIc-98	IId-98	IIe-98	IIf-98
	IIa-99	IIb-99	IIc-99	IId-99	IIe-99	IIf-99
	IIa-100	IIb-100	IIc-100	IId-100	IIe-100	IIf-100

 

[0137]

TABLE 28
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-101	IIb-101	IIc-101	IId-101	IIe-101	IIf-101
	IIa-102	IIb-102	IIc-102	IId-102	IIe-102	IIf-102
	IIa-103	IIb-103	IIc-103	IId-103	IIe-103	IIf-103
	IIa-104	IIb-104	IIc-104	IId-104	IIe-104	IIf-104
	IIa-105	IIb-105	IIc-105	IId-105	IIe-105	IIf-105
	IIa-106	IIb-106	IIc-106	IId-106	IIe-106	IIf-106
	IIa-107	IIb-107	IIc-107	IId-107	IIe-107	IIf-107
	IIa-108	IIb-108	IIc-108	IId-108	IIe-108	IIf-108
	IIa-109	IIb-109	IIc-109	IId-109	IIe-109	IIf-109
	IIa-110	IIb-110	IIc-110	IId-110	IIe-110	IIf-110

 

[0138]

TABLE 29
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-111	IIb-111	IIc-111	IId-111	IIe-111	IIf-111
	IIa-112	IIb-112	IIc-112	IId-112	IIe-112	IIf-112
	IIa-113	IIb-113	IIc-113	IId-113	IIe-113	IIf-113
	IIa-114	IIb-114	IIc-114	IId-114	IIe-114	IIf-114
	IIa-115	IIb-115	IIc-115	IId-115	IIe-115	IIf-115
	IIa-116	IIb-116	IIc-116	IId-116	IIe-116	IIf-116
	IIa-117	IIb-117	IIc-117	IId-117	IIe-117	IIf-117
	IIa-118	IIb-118	IIc-118	IId-118	IIe-118	IIf-118
	IIa-119	IIb-119	IIc-119	IId-119	IIe-119	IIf-119
	IIa-120	IIb-120	IIc-120	IId-120	IIe-120	IIf-120

 

[0139]

TABLE 30
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-121	IIb-121	IIc-121	IId-121	IIe-121	IIf-121
	IIa-122	IIb-122	IIc-122	IId-122	IIe-122	IIf-122
	IIa-123	IIb-123	IIc-123	IId-123	IIe-123	IIf-123
	IIa-124	IIb-124	IIc-124	IId-124	IIe-124	IIf-124
	IIa-125	IIb-125	IIc-125	IId-125	IIe-125	IIf-125
	IIa-126	IIb-126	IIc-126	IId-126	IIe-126	IIf-126
	IIa-127	IIb-127	IIc-127	IId-127	IIe-127	IIf-127
	IIa-128	IIb-128	IIc-128	IId-128	IIe-128	IIf-128
	IIa-129	IIb-129	IIc-129	IId-129	IIe-129	IIf-129
	IIa-130	IIb-130	IIc-130	IId-130	IIe-130	IIf-130

 

[0140]

TABLE 31
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-131	IIb-131	IIc-131	IId-131	IIe-131	IIf-131
	IIa-132	IIb-132	IIc-132	IId-132	IIe-132	IIf-132
	IIa-133	IIb-133	IIc-133	IId-133	IIe-133	IIf-133
	IIa-134	IIb-134	IIc-134	IId-134	IIe-134	IIf-134
	IIa-135	IIb-135	IIc-135	IId-135	IIe-135	IIf-135
	IIa-136	IIb-136	IIc-136	IId-136	IIe-136	IIf-136
	IIa-137	IIb-137	IIc-137	IId-137	IIe-137	IIf-137
	IIa-138	IIb-138	IIc-138	IId-138	IIe-138	IIf-138
	IIa-139	IIb-139	IIc-139	IId-139	IIe-139	IIf-139
	IIa-140	IIb-140	IIc-140	IId-140	IIe-140	IIf-140

 

[0141]

TABLE 32
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-141	IIb-141	IIc-141	IId-141	IIe-141	IIf-141
	IIa-142	IIb-142	IIc-142	IId-142	IIe-142	IIf-142
	IIa-143	IIb-143	IIc-143	IId-143	IIe-143	IIf-143
	IIa-144	IIb-144	IIc-144	IId-144	IIe-144	IIf-144
	IIa-145	IIb-145	IIc-145	IId-145	IIe-145	IIf-145
	IIa-146	IIb-146	IIc-146	IId-146	IIe-146	IIf-146
	IIa-147	IIb-147	IIc-147	IId-147	IIe-147	IIf-147
	IIa-148	IIb-148	IIc-148	IId-148	IIe-148	IIf-148
	IIa-149	IIb-149	IIc-149	IId-149	IIe-149	IIf-149
	IIa-150	IIb-150	IIc-150	IId-150	IIe-150	IIf-150

 

[0142]

TABLE 33
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-151	IIb-151	IIc-151	IId-151	IIe-151	IIf-151
	IIa-152	IIb-152	IIc-152	IId-152	IIe-152	IIf-152
	IIa-153	IIb-153	IIc-153	IId-153	IIe-153	IIf-153
	IIa-154	IIb-154	IIc-154	IId-154	IIe-154	IIf-154
	IIa-155	IIb-155	IIc-155	IId-155	IIe-155	IIf-155
	IIa-156	IIb-156	IIc-156	IId-156	IIe-156	IIf-156
	IIa-157	IIb-157	IIc-157	IId-157	IIe-157	IIf-157
	IIa-158	IIb-158	IIc-158	IId-158	IIe-158	IIf-158
	IIa-159	IIb-159	IIc-159	IId-159	IIe-159	IIf-159
	IIa-160	IIb-160	IIc-160	IId-160	IIe-160	IIf-160

 

[0143]

TABLE 34
R1	IIa	IIb	IIc	IId	IIe	IIf
	IIa-161	IIb-161	IIc-161	IId-161	IIe-161	IIf-161
	IIa-162	IIb-162	IIc-162	IId-162	IIe-162	IIf-162
	IIa-163	IIb-163	IIc-163	IId-163	IIe-163	IIf-163
	IIa-164	IIb-164	IIc-164	IId-164	IIe-164	IIf-164
	IIa-165	IIb-165	IIc-165	IId-165	IIe-165	IIf-165
	IIa-166	IIb-166	IIc-166	IId-166	IIe-166	IIf-166

 

[0144]

TABLE 35
Compound No.	Physical property
Ia-04	mp 175-178° C.; 1H-NMR (CDCl3—CD3OD) δ 1.04 (1H, m), 1.25-1.49
	(10H, m), 1.57-1.66 (2H, m), 2.00 (1H, m), 2.15-2.22 (2H, m), 2.51
	(1H, m), 3.82 (1H, m), 5.77 (1H, dt, J = 15.9, 1.5 Hz), 6.41 (1H, d,
	J = 7.8 Hz), 6.95 (1H, dt, J = 15.9, 7.1 Hz), 7.34 (1H, dd, J = 3.0,
	4.8 Hz), 7.41 (1H, dd, J = 1.5, 4.8 Hz), 7.90 (1H, dd, J = 1.5, 3.0
	Hz); IR (Nujol) 3363, 3105, 2627, 1697, 1618, 1554, 1248 cm−1;
	[α]D25 + 44.3 ± 0.8° (c = 1.011, MeOH); Anal. (C19H25NO3S) Calcd. (%):
	C, 65.68; H, 7.25; N, 4.03; S, 9.23 Found (%): C, 65.58; H, 7.18; N,
	4.03; S, 9.18
Ia-17	mp 155-157° C.; 1H-NMR (CDCl3—CD3OD) δ 1.04 (1H, m), 1.22-1.53
	(10H, m), 1.60-1.71 (2H, m), 2.02 (1H, m), 2.17-2.23 (2H, m), 2.58
	(1H, m), 3.92 (1H, m), 5.78 (1H, dt, J = 15.6, 1.5 Hz), 6.33 (1H, d,
	J = 7.5 Hz), 6.97 (1H, dt, J = 15.6, 6.9 Hz), 7.38-7.49 (2H, m),
	7.86-7.89 (3H, m), 8.30 (1H, dd, J = 0.9, 6.9 Hz); IR (Nujol) 3276,
	2671, 1693, 1622, 1529, 1421, 1377, 1298, 1277, 1254 cm−1; [α]D25 +
	38.5 ± 0.8° (c = 1.018, MeOH); Anal. (C23H27NO3S.0.2H2O) Calcd.
	(%): C, 68.87; H, 6.88; N, 3.49; S, 7.99 Found (%): C, 68.93; H,
	7.01; N, 3.55; S, 7.87
Ia-20	mp 129-131° C.; 1H-NMR (CDCl3) δ 1.01 (1H, m), 1.26-1.52 (10H,
	m), 1.60-1.66 (2H, m), 2.02 (1H, m), 2.18-2.25 (2H, m), 2.49 (3H,
	s), 2.58 (1H, m), 3.95 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.06 (1H,
	d, J = 7.8 Hz), 7.04 (1H, dt, J = 15.6, 7.1 Hz), 7.23 (1H, dd, J = 1.2,
	8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.80 (1H, s), 8.14 (1H, s); IR
	(Nujol) 3269, 3078, 2677, 1697, 1649, 1624, 1539, 1437, 1377,
	1298, 1281 cm−1; [α]D25 + 32.0 ± 0.7° (c = 1.005, MeOH); Anal.
	(C24H29NO3S) Calcd. (%): C, 70.04; H, 7.10; N, 3.40; S, 7.79 Found
	(%): C, 69.83; H, 7.10; N, 3.43; S, 7.64
Ia-28	mp 138-140° C.; 1H-NMR (CDCl3) δ 1.02 (1H, m), 1.21-1.52 (10H,
	m), 1.59-1.70 (2H, m), 2.01 (1H, m), 2.17-2.24 (2H, m), 2.56 (1H,
	m), 3.92 (1H, m), 5.79 (1H, dt, J = 15.6, 1.5 Hz), 6.14 (1H, d, J =
	8.1 Hz), 7.03 (1H, dt, J = 15.6, 7.1 Hz), 7.16 (1H, td, J = 8.6, 2.7
	Hz), 7.77 (1H, dd, J = 4.8, 8.6 Hz), 7.91 (1H, s), 8.07 (1H, dd, J =
	2.7, 10.2 Hz); IR (Nujol) 3276, 2671, 1695, 1624, 1533, 1442, 1433,
	1296, 1277, 1246, 1200 cm−1; [α]D25 + 35.6 ± 0.8° (c = 1.014, MeOH);
	Anal. (C23H26FNO3S.0.2H2O) Calcd. (%): C, 65.91; H, 6.35; F, 4.53;
	N, 3.34; S, 7.65 Found (%): C, 65.99; H, 6.38; F, 4.42; N, 3.39; S,
	7.57
Ia-34	mp 172-173° C.; 1H-NMR (CDCl3—CD3OD) δ 1.08 (1H, m), 1.29-1.55
	(10H, m), 1.60-1.69 (2H, m), 2.03 (1H, m), 2.14-2.21 (2H, m), 2.60
	(1H, m), 3.96 (1H, m), 5.76 (1H, dt, J = 15.6, 1.5 Hz), 6.57 (1H, d, J =
	7.5 Hz), 6.97 (1H, dt, J = 15.6, 7.1 Hz), 7.38 (1H, d, J = 5.7 Hz),
	7.42 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 5.7 Hz), 7.65 (1H, d, J =
	6.9 Hz), 7.95 (1H, d, J = 7.8 Hz); IR (Nujol) 3302, 2698, 1739,
	1693, 1657, 1622, 1581, 1568, 1547, 1205 cm−1; [α]D25 + 35.0 ± 0.7°
	(c = 1.013, MeOH); Anal. (C23H27NO3S.0.2H2O) Calcd. (%): C,
	68.87; H, 6.88; N, 3.49; S, 7.99 Found (%): C, 68.92; H, 7.05; N,
	3.44; S, 7.67

 

[0145]

TABLE 36
Compound No.	Physical property
Ia-49	1H-NMR (CDCl3) δ 1.02 (1H, m), 1.29-1.74 (12H, m), 2.02 (1H, m),
	2.17-2.24 (2H, m), 2.56 (1H, m), 3.44 (3H, s), 3.96 (1H, m), 4.79
	(2H, s), 5.79 (1H, dt, J = 15.6, 1.2 Hz), 5.98 (1H, d, J = 7.8 Hz),
	7.01 (1H, dt, J = 15.6, 7.2 Hz), 7.33-7.40 (2H, m), 7.77 (1H, dd, J =
	7.2, 2.4 Hz), 8.14 (1H, s); IR (CHCl3) 3442, 2682, 1695, 1652,
	1573, 1508, 1425, 1284, 1205, 1120 cm−1; [α]D25.0 + 31.0 ± 0.7°
	(c = 1.009, MeOH); Anal. (C25H31NO5.0.5H2O) Calcd. (%): C, 69.10;
	H, 7.42; N, 3.22 Found (%): C, 68.83; H, 7.48; N, 3.30
Ia-51	1H-NMR (CDCl3—CD3OD) δ 1.03 (1H, m), 1.20-1.51 (9H, m), 1.59-
	1.71 (3H, m), 2.01 (1H, d, J = 3.6 Hz), 2.15-2.22 (2H, m), 2.56 (1H,
	s), 3.90 (1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.90 (1H, dd, J = 2.1, 8.4
	Hz), 6.96 (1H, dt, J = 15.6, 6.9 Hz), 6.99 (1H, d, J = 2.1 Hz), 7.58
	(1H, d, J = 8.4 Hz), 8.01 (1H, s); IR (KBr) 3350, 3141, 1695, 1628,
	1560, 1523, 1493, 1441, 1367, 1279, 1225, 1136, 1124 cm−1;
	[α]D27 + 26.6 ± 0.7° (c = 1.008, MeOH); Anal. (C23H27NO5.0.3H2O)
	Calcd. (%): C, 68.57; H, 6.91; N, 3.48 Found (%): C, 68.47; H, 6.91;
	N, 3.66
Ia-52	1H-NMR (CDCl3—CD3OD) δ 1.02 (1H, m), 1.22-1.48 (9H, m), 1.57-
	1.60 (3H, m), 1.98 (1H, d, J = 3.3 Hz), 2.11-2.18 (2H, m), 2.53 (1H,
	s), 3.89 (1H, m), 5.75 (1H, dd, J = 1.5, 15.3 Hz), 6.31 (1H, d, J = 7.8
	Hz), 6.90 (1H, dd, J = 2.4, 8.7 Hz), 6.96 (1H, dt, J = 15.3, 6.9 Hz),
	7.33 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.07 (1H, s); IR
	(KBr) 3347, 1695, 1635, 1558, 1524, 1462, 1309, 1271, 1192, 1173,
	1134 cm−1; [α]D25 + 20.1 ± 0.6° (c = 1.013, MeOH); Anal.
	(C23H27NO5.0.4H2O) Calcd. (%): C, 68.27; H, 6.92; N, 3.46 Found
	(%): C, 68.12; H, 7.00; N, 3.59
Ia-54	1H-NMR (CDCl3) δ 1.05 (1H, m), 1.23-1.72 (10H, m), 2.02 (1H, m),
	2.18-2.25 (2H, m), 2.55 (1H, m), 3.94 (1H, m), 5.79 (1H, dt, J =
	15.6, 1.5 Hz), 5.91 (1H, d, J = 8.1 Hz), 7.03 (1H, dt, J = 15.6, 6.9
	Hz), 7.09-7.16 (1H, m), 7.25 (1H, dd, J = 9.0, 1.8 Hz), 7.84 (1H, dd,
	J = 9.0, 5.4 Hz), 8.06 (1H, s); IR (CHCl3) 3442, 2680, 1695, 1652,
	1563, 1506, 1257, 1224, 1218, 1133, cm−1; [α]D25.0 + 25.4 ± 0.7°
	(c = 1.005, MeOH); Anal. (C23H28FNO4.0.1H2O) Calcd. (%): C, 68.85;
	H, 6.58; F, 4.73; N, 3.49 Found (%): C, 68.65; H, 6.43; F, 4.59; N,
	3.60
Ia-56	1H-NMR (CDCl3) δ 1.12 (1H, m), 1.29-1.53 (9H, m), 1.60-1.74 (3H,
	m), 2.04 (1H, d, J = 3.6 Hz), 2.16-2.22 (2H, m), 2.57 (1H, s), 4.03
	(1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J = 2.1 Hz), 7.02
	(1H, dt, J = 15.3, 7.2 Hz), 7.36 (1H, t, J = 7.5 Hz), 7.57 (1H, d, J =
	7.8 Hz), 7.74 (1H, dd, J = 1.2, 7.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 8.11
	(1H, dd, J = 1.2, 7.5 Hz); IR (CHCl3) 3435, 2679, 1695, 1653, 1595,
	1547, 1533, 1475, 1458, 1421, 1306, 1286, 1167, 1120 cm−1;
	[α]D25.5 + 47.7 ± 0.9° (c = 1.003, MeOH); Anal. (C23H27NO40.1H2O)
	Calcd. (%): C, 72.08; H, 7.15; N, 3.65 Found (%): C, 72.01; H, 7.11;
	N, 3.72

 

[0146]

TABLE 37
Compound No.	Physical property
Ia-65	1H-NMR (CDCl3) δ 1.02 (1H, m), 1.27-1.71 (12H, m), 2.01 (1H, d, J =
	3.9 Hz), 2.16-2.23 (2H, m), 2.48 (1H, br s), 3.92 (1H, m), 5.81
	(1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 1.5
	Hz), 6.98 (1H, dt, J = 5.4 and 0.6 Hz), 7.03 (1H, dt, J = 15.6 and
	6.9 Hz), 10.49 (1H, s); IR (CHCl3) 3446, 3215, 1726, 1693, 1643,
	1541, 1504, 1477, 1462, 1402, 1373, 1303, 1248 cm−1; [α]D26 + 67.8 ±
	1.1° (c = 1.002, MeOH) Anal. (C21H26N2O3S.0.25CH3COOEt)
	Calcd. (%): C, 63.43; H, 6.77; N, 6.72; S, 7.69 Found (%): C, 63.66;
	H, 6.60; N, 6.93; S, 7.60
Ia-66	1H-NMR (CDCl3) δ 1.02 (1H, m), 1.27-1.70 (12H, m), 2.01 (1H, d, J =
	3.6 Hz), 2.15-2.22 (2H, m), 2.51 (1H, br s), 3.92 (1H, m), 5.80
	(1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 2.1
	Hz), 6.88 (1H, d, J = 5.4 Hz), 6.95 (1H, d, J = 5.4 Hz), 7.03 (1H,
	dt, J = 15.6 and 6.9 Hz), 11.07 (1H, s); IR (CHCl3) 3444, 3191,
	2677, 1693, 1639, 1543, 1518, 1475, 1458, 1421, 1396, 1378, 1296,
	1279, 1255 cm−1; [α]D26 + 55.3 ± 1.0° (c = 1.001, MeOH) Anal.
	(C21H26N2O3S.0.3H2O) Calcd. (%): C, 64.36; H, 6.84; N, 7.15; S,
	8.18 Found (%): C, 64.22; H, 6.48; N, 7.13; S, 8.22
Ia-95	mp 113-114° C.; 1H-NMR (CDCl3—DMSO—d6) δ 1.12 (1H, m), 1.26
	(3H, t, J = 6.9 Hz), 1.27-1.64 (12H, m), 2.01 (1H, m), 2.15-2.22 (2H,
	m), 2.57 (1H, br s), 3.90 (1H, m), 4.14 (2H, q, J = 6.9 Hz), 4.48 (2H,
	br s), 5.57 (1H, br s), 5.77 (1H, d, J = 15.6 Hz), 6.68 (1H, br s), 6.92
	(1H, dd, J = 15.6, 7.2 Hz), 7.38 (1H, br d, J = 8.1 Hz), 7.81 (1H, d,
	J = 8.1 Hz), 7.95 (1H, s), 8.33 (1H, br s); IR (CHCl3) 3446, 1703,
	1653, 1514, 1435, 1300, 1223, 1134 cm−1; [α]D23 + 5.5 ± 0.5° (c = 1.008,
	MeOH) Anal. (C27H34N2O5S.0.3H2O) Calcd. (%): C, 64.34; H,
	6.92; N, 5.56; S, 6.36 Found (%): C, 64.27; H, 6.69; N, 5.54; S, 6.37
Ic-04	mp 105-107° C.; 1H-NMR (CDCl3) δ 1.02 (1H, m), 1.20-1.70 (12H,
	m), 2.00 (1H, m), 2.49 (1H, br s), 3.47-3.58 (2H, m), 3.91 (1H, m),
	4.04 (2H, s), 6.07 (1H, d, J = 7.2 Hz), 7.34 (1H, dd, J = 3.0, 5.1 Hz),
	7.37 (1H, dd, J = 1.5, 5.1 Hz), 7.88 (1H, dd, J = 1.5, 3.0 Hz); IR
	(Nujol) 3354, 3093, 2553, 1730, 1612, 1556, 1240, 1138 cm−1; [α]D25 +
	46.6 ± 0.9° (c = 1.009, MeOH); Anal. (C18H25NO4S) Calcd. (%): C,
	61.51; H, 7.17; N, 3.99; S, 9.12 Found (%): C, 61.45; H, 7.32; N,
	4.06; S, 9.10
Ic-17	mp 149-151° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.72 (12H,
	m), 2.02 (1H, m), 2.57 (1H, br s), 3.47-3.58 (2H, m), 3.98 (1H, m),
	4.03 (2H, s), 6.14 (1H, d, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.44
	(1H, dt, J = 1.2, 7.5 Hz), 7.46 (1H, dt, J = 1.2, 7.5 Hz), 7.87 (1H,
	dd, J = 1.2, 7.5 Hz), 7.88 (1H, s), 8.29 (1H, dd, J = 1.2, 7.5 Hz); IR
	(Nujol) 3296, 2528, 1726, 1604, 1558, 1240, 1228, 1140 cm−1; [α]D25 +
	38.1 ± 0.8° (c = 1.013, MeOH); Anal. (C22H27NO4S) Calcd. (%): C,
	65.18; H, 6.78; N, 3.49; S, 7.99 Found (%): C, 65.62; H, 7.06; N,
	3.51; S, 7.78

 

[0147]

TABLE 38
Compound No.	Physical property
Ic-19	mp 145-147° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.33 (2H, m),
	1.40-1.71 (10H, m), 2.01 (1H, m), 2.48 (3H, s), 2.6 (1H, br s),
	3.47-3.58 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.8
	Hz), 7.28 (1H, m), 7.65 (1H, m), 7.78 (1H, s), 8.15 (1H, d, J = 8.4
	Hz); IR (Nujol) 3288, 2521, 1724, 1601, 1560, 1225, 1138 cm−1;
	[α]D25 + 36.8 ± 0.8° (c = 1.008, MeOH) Anal. (C23H29NO4S) Calcd.
	(%): C, 66.48; H, 7.03; N, 3.37; S, 7.72 Found (%): C, 66.33; H,
	7.03; N, 3.30; S, 7.43
Ic-20	mp 135-136° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.72 (12H,
	m), 2.02 (1H, m), 2.49 (3H, s), 2.57 (1H, br s), 3.48-3.59 (2H, m),
	3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.5 Hz), 7.23 (1H, dd, J =
	1.5, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.83 (1H, s), 8.12 (1H, d, J =
	1.5 Hz); IR (Nujol) 3384, 3361, 2546, 1736, 1718, 1616, 1533, 1225,
	1140 cm−1; [α]D25 + 32.4 ± 0.7° (c = 1.003, MeOH); Anal. (C23H29NO4S)
	Calcd. (%): C, 66.48; H, 7.03; N, 3.37; S, 7.72 Found (%): C, 66.31;
	H, 7.32; N, 3.34; S, 7.60
Ic-22	mp 76-79° C.; 1H-NMR (CDCl3—CD3OD) δ 1.07 (1H, m), 1.20-1.32
	(2H, m), 1.34-1.70 (10H, m), 2.00 (1H, m), 2.57 (1H, br s), 3.44-
	3.55 (2H, m), 3.88 (1H, m), 4.00 (2H, s), 6.43 (1H, d, J = 7.8 Hz),
	6.97 (1H, dd, J = 2.4 and 8.7 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.65
	(1H, s), 8.06 (1H, d, J = 8.7 Hz); IR (CHCl3) 3599, 3437, 1780,
	1649, 1603, 1516, 1124 cm−1; [α]D25 + 36.4 ± 0.8° (c = 1.013, MeOH)
	Anal. (C22H27NO5S.0.6H2O) Calcd. (%): C, 61.69; H, 6.64; N, 3.27;
	S, 7.49 Found (%): C, 61.58; H, 6.37; N, 3.54; S, 7.48
Ic-23	mp 149-151° C.; 1H-NMR (CDCl3) δ 1.08 (1H, m), 1.21-1.86 (12H,
	m), 1.99 (1H, m), 2.22 (2H, br s), 2.56 (1H, m), 3.53 (2H, t, J = 6.0
	Hz), 3.92 (1H, m), 4.03 (2H, s), 6.31 (1H, d, J = 7.2 Hz), 7.00 (1H,
	dd, J = 2.1, 8.7 Hz), 7.67 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 2.4
	Hz), 7.83 (1H, s); IR (Nujol) 3313, 3104, 2636, 1743, 1626, 1599,
	1552, 1439, 1248, 1190, 1153, 1124 cm−1; [α]D26 + 33.6 ± 0.7°
	(c = 1.002%, MeOH); Anal. (C22H27NO5S) Calcd. (%): C, 63.29; H,
	6.52; N, 3.35; S, 7.68 Found (%): C, 62.99; H, 6.66; N, 3.39; S, 7.57
Ic-28	mp 149-151° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.72 (12H,
	m), 2.03 (1H, m), 2.56 (1H, br s), 3.48-3.60 (2H, m), 3.95 (1H, m),
	4.04 (2H, s), 6.11 (1H, d, J = 8.1 Hz), 7.16 (1H, dt, J = 2.4, 8.7 Hz),
	7.78 (1H, dd, J = 4.8, 8.7 Hz), 7.92 (1H, s), 8.05 (1H, dd, J = 2.4, 9.9
	Hz); IR (Nujol) 3384, 3361, 2546, 1736, 1718, 1616, 1533, 1225,
	1140 cm−1; [α]D25 + 35.6 ± 0.8° (c = 1.014, MeOH); Anal.
	(C22H26FNO4S) Calcd. (%): C, 62.99; H, 6.25; F, 4.53; N, 3.34; S,
	7.64 Found (%): C, 62.84; H, 6.51; F, 4.44; N, 3.41; S, 7.40
Ic-34	mp 154-157° C.; 1H-NMR (CDCl3) δ 1.09 (1H, m), 1.24-1.72 (12H,
	m), 2.04 (1H, m), 2.59 (1H, br s), 3.47-3.58 (2H, m), 4.02 (1H, m),
	4.02 (2H, s), 6.42 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43
	(1H, d, J = 7.5 Hz), 7.59 (1H, d, J = 5.4 Hz), 7.61 (1H, d, J = 7.5
	Hz), 7.96 (1H, dd, J = 0.9, 7.5 Hz); IR (Nujol) 3288, 2540, 1726,
	1614, 1577, 1554, 1319, 1244, 1225, 1138 cm−1; [α]D25 + 39.8 ± 0.8°
	(c = 1.017, MeOH); Anal. (C22H27NO4S) Calcd. (%): C, 65.81; H,
	6.78; N, 3.49; S, 7.99 Found % C, 65.53; H, 6.94; N, 3.52; S, 7.76

 

[0148]

TABLE 39
Compound No.	Physical property
Ic-39	1H-NMR (CDCl3) δ 1.10 (1H, m), 1.25-1.71 (12H, m), 2.03 (1H, m),
	2.58 (1H, br s), 3.49-3.56 (2H, m), 3.98 (3H, s), 4.02 (2H, s), 4.03
	(1H, m), 6.40 (1H, d, J = 8.4 Hz), 6.42 (2H, s), 7.42 (1H, t, J = 7.5
	Hz), 7.66 (1H, d, J = 7.5 Hz), 7.93 (1H, d, J = 7.5 Hz); IR (CHCl3)
	3451, 1780, 1732, 1649, 1508, 1373, 1220, 1151 cm−1; [α]D24 +
	37.0 ± 0.8° (c = 1.008, MeOH); Anal. (C23H29NO5S.0.3H2O) Calcd.
	(%): C, 63.22; H, 6.83; N, 3.21; S, 7.34 Found (%): C, 63.26; H,
	6.78; N, 3.23; S, 7.17
Ic-49	1H-NMR (CDCl3) δ 1.06 (1H, m), 1.29-1.36 (2H, m), 1.36-1.74 (10H,
	m), 2.03 (1H, m), 2.53 (1H, m), 3.45 (3H, s), 3.52 (2H, dt, J = 6.3,
	1.5 Hz), 4.00 (1H, m), 4.02 (2H, s), 4.79 (2H, s), 6.07 (1H, d, J = 7.8
	Hz), 7.33-7.40 (2H, m), 7.77 (1H, dd, J = 6.9, 2.1 Hz), 8.16 (1H, s);
	IR (CHCl3) 3440, 2829, 1652, 1573, 1509, 1226, 1205, 1124 cm−1;
	[α]D25.0 + 33.3 ± 0.7° (c = 1.016, MeOH); Anal. (C24H31NO6) Calcd. (%):
	C, 67.11; H, 7.27; N, 3.26 Found (%): C, 66.82; H, 7.39; N, 3.32
Ic-51	1H-NMR (CDCl3—CD3OD) δ 1.08 (1H, m), 1.25-1.28 (2H, m), 1.37-
	1.62 (10H, m), 1.99 (1H, d, J = 3.3 Hz), 2.54 (1H, s), 3.45-3.49 (2H,
	m), 3.87 (1H, m), 4.00 (2H, s), 6.44 (1H, d, J = 7.8 Hz), 6.88 (1H,
	dd, J = 2.1, 8.7 Hz), 6.97 (1H, d, J = 2.1 Hz), 7.60 (1H, d, J = 8.7
	Hz), 8.02 (1H, s); IR (KBr) 3365, 3140, 1734, 1628, 1560, 1527,
	1493, 1440, 1363, 1279, 1220, 1136, 1124 cm−1; [α]D27 + 29.1 ± 0.7°
	(c = 1.016, MeOH); Anal. (C22H27NO6.0.5H2O) Calcd. (%): C, 64.38;
	H, 6.88; N, 3.41 Found (%): C, 64.39; H, 6.95; N, 3.66
Ic-52	1H-NMR (CDCl3—CD3OD) δ 1.07 (1H, m), 1.24-1.30 (3H, m), 1.45-
	1.49 (5H, m), 1.59-1.65 (4H, m), 2.00 (1H, d, J = 3.3 Hz), 2.59 (1H,
	s), 3.52 (2H, t, J = 6.0 Hz), 3.89 (1H, m), 4.00 (1H, d, J = 16.5 Hz),
	4.06 (1H, d, J = 16.5 Hz), 6.14 (1H, d, J = 8.1 Hz), 6.90 (1H, dd, J =
	2.1, 9.0 Hz), 7.34 (1H, d, J = 2.1 Hz), 7.36 (1H, d, J = 9.0 Hz), 8.06
	(1H, s); IR (CHCl3) 3438, 3267, 1730, 1647, 1620, 1558, 1514,
	1468, 1169, 1134 cm−1; [α]D27 + 25.0 ± 0.7° (c = 1.003, MeOH); Anal.
	(C22H27NO6.0.3H2O) Calcd. (%): C, 64.95; H, 6.84; N, 3.44 Found
	(%): C, 64.84; H, 6.96; N, 3.62
Ic-54	1H-NMR (CDCl3) δ 1.04 (1H, m), 1.25-1.32 (2H, m), 1.43-1.68 (10H,
	m), 2.03 (1H, m), 2.53 (1H, m), 3.53 (2H, t, J = 6.6 Hz), 3.96 (1H,
	m), 4.04 (2H, s), 6.04 (1H, d, J = 8.1 Hz), 7.09-7.16 (1H, m), 7.25
	(1H, dd, J = 8.4, 2.4 Hz), 7.84 (1H, dd, J = 8.4, 5.7 Hz), 8.10 (1H,
	s); IR (CHCl3) 3440, 2875, 1656, 1563, 1506, 1224, 1216, 1205
	cm−1; [α]D26.0 + 27.6 ± 0.7° (c = 1.018, MeOH); Anal.
	(C22H26FNO5.0.6H2O) Calcd. (%): C, 63.79; H, 6.62; F, 4.59; N, 3.38
	Found (%): C, 63.48; H, 6.49; F, 4.47; N, 3.59
Ic-65	mp 148-149° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.27-1.30 (2H, m),
	1.41-1.52 (6H, m), 1.59-1.71 (4H, m), 2.01 (1H, d, J = 3.3 Hz), 2.45
	(1H, s), 3.53 (2H, dt, J = 1.5, 6.3 Hz), 3.94 (1H, m), 4.07 (2H, s),
	6.13 (1H, d, J = 8.1 Hz), 6.78 (1H, d, J = 1.5 Hz), 6.98 (1H, d, J =
	5.1 Hz), 7.23 (1H, d, J = 8.1 Hz), 10.27 (1H, s); IR (KBr) 3367,
	3292, 3111, 2758, 2636, 2544, 1712, 1601, 1574, 1510, 1458, 1325,
	1250, 1225, 1138 cm−1; [α]D25 + 66.6 ± 1.1° (c = 1.008, MeOH); Anal.
	(C20H26N2O4S.0.1H2O) Calcd. (%): C, 61.23; H, 6.68; N, 7.14; S,
	8.17 Found (%): C, 61.20; H, 6.79; N, 7.25; S, 8.25

 

[0149]

TABLE 40
Compound No.	Physical property
Ic-66	mp 143-144° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.24-1.30 (2H, m),
	1.38-1.52 (6H, m), 1.59-1.67 (4H, m), 2.01 (1H, d, J = 3.0 Hz), 2.48
	(1H, s), 3.52 (2H, t, J = 6.3 Hz), 3.94 (1H, m), 4.07 (2H, s), 6.12
	(1H, d, J = 8.4 Hz), 6.73 (1H, d, J = 1.8 Hz), 6.88 (1H, d, J = 5.4
	Hz), 6.93 (1H, d, J = 5.4 Hz), 10.80 (1H, s); IR (KBr) 3348, 3105,
	2754, 2648, 2551, 1738, 1587, 1556, 1520, 1437, 1425, 1223, 1146
	cm−1; [α]D25 + 50.5 ± 0.9° (c = 1.014, MeOH); Anal.
	(C20H26N2O4S.0.1H2O) Calcd. (%): C, 61.23; H, 6.68; N, 7.14; S,
	8.17 Found (%): C, 61.13; H, 6.79; N, 7.17; S, 8.07
Ic-81	1H-NMR (CDCl3—CD3OD) δ 1.06 (1H, m), 1.20-1.28 (2H, m), 1.34-
	1.49 (6H, m), 1.55-1.63 (4H, m), 1.95 (1H, d, J = 3.6 Hz), 2.42 (3H,
	s), 2.56 (1H, brs), 3.48 (2H, t, J = 6.5 Hz), 3.84 (1H, br s), 4.01 (2H,
	s), 6.37 (1H, d, J = 7.5 Hz), 6.71 (1H, d, J = 2.1 Hz), 7.16 (1H, d, J =
	2.1 Hz), 8.10 (1H, s); IR (KBr) 3361, 3134, 1734, 1635, 1560,
	1529, 1458, 1415, 1362, 1288, 1198, 1165, 1136 cm−1; [α]D24 +
	28.1 ± 0.7° (c = 1.012, MeOH) Anal. (C23H29NO6.0.5H2O) Calcd.
	(%): C, 65.08; H, 7.12; N, 3.30 Found (%): C, 65.14; H, 7.06; N, 3.43
Ic-84	mp 133-135° C.; 1H-NMR (CDCl3) δ 1.09 (1H, m), 1.22-1.70 (12H,
	m), 2.01 (1H, d, J = 3.3 Hz), 2.55 (1H, br s), 3.50-3.68 (2H, m),
	3.96-4.09 (3H, m), 4.21-4.35 (2H, m), 6.11 (1H, m), 7.64 (1H, dd, J =
	1.8, 8.7 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.85 (1H, br s), 8.18 (1H, br
	s); IR (Nujol) 3323, 2924, 1736, 1599, 1562, 1514, 1448, 1281,
	1217, 1142 cm−1; [α]D24 + 21.7 ± 0.6° (c = 1.017%, MeOH); Anal.
	(C25H32N2O6S) Calcd. (%): C, 61.45; H, 6.60; N, 5.73; S, 6.56 Found
	(%): C, 61.26; H, 6.41; N, 5.70; S, 6.48
Ic-86	1H-NMR (CDCl3) δ 1.16-1.69 (13H, m), 1.92 (1H, br s), 2.39 (1H, br
	s), 3.41 (2H, t, J = 5.4 Hz), 3.68 (1H, m), 3.92 (2H, s), 5.83 (2H, s),
	7.65 (1H, dd, J = 2.1, 8.7 Hz), 7.83 (1H, d, J = 8.7 Hz), 8.23 (1H, d,
	J = 8.4 Hz), 8.25 (1H, s), 8.27 (1H, d, J = 2.1 Hz), 8.77 (1H, s),
	12.53 (1H, br s); IR (Nujol) 3332, 2924, 1724, 1680, 1631, 1572,
	1529, 1444, 1375, 1350, 1244, 1128 cm−1; [α]D24 + 23.6 ± 0.6°
	(c = 1.014%, MeOH); Anal. (C23H29N3O5S.0.4H2O) Calcd. (%): C,
	59.18; H, 6.43; N, 9.00; S, 6.87 Found (%): C, 59.33; H, 6.48; N,
	8.87; S, 6.48
Ic-95	mp 118-120° C.; 1H-NMR (CDCl3—DMSO—d6) δ 1.16 (1H, m), 1.26
	(3H, t, J = 7.2 Hz), 1.27-1.66 (12H, m), 2.01 (1H, m), 2.59 (1H, m),
	3.52 (2H, m), 3.90 (1H, m), 4.00 (2H, s), 4.14 (2H, q, J = 7.2 Hz),
	4.48 (2H, br s), 5.62 (1H, br s), 6.68 (1H, br s), 7.38 (1H, br d, J =
	8.7 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.96 (1H, s), 8.31 (1H, br s); IR
	(CHCl3) 3442, 1724, 1655, 1516, 1477, 1435, 1225, 1217, 1132,
	1059 cm−1; [α]D23 + 25.9 ± 0.7° (c = 1.012, MeOH) Anal.
	(C26H34N2O6S.0.2H2O) Calcd. (%): C, 61.69; H, 6.85; N, 5.53; S,
	6.33 Found (%): C, 61.71; H, 6.73; N, 5.48; S, 6.32

 

[0150]

TABLE 41
Compound No.	Physical property
Ic-99	1H-NMR (d6—DMSO) δ 1.19-1.68 (13H, m), 1.93 (1H, br s), 2.43 (1H,
	br s), 3.41 (2H, t, J = 6.6 Hz), 3.49 (2H, s), 3.71 (1H, m), 3.92 (2H,
	s), 7.38 (1H, br s), 7.87 (1H, dd, J = 1.8, 8.7 Hz), 8.07 (1H, br s),
	8.09 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 6.6 Hz), 8.39 (1H, s), 8.85
	(1H, d, J = 1.2 Hz); IR (Nujol) 3340, 3251, 2927, 1741, 1655, 1624,
	1539, 1458, 1377, 1244, 1134 cm−1; [α]D25 + 24.2 ± 0.6° (c = 1.009%,
	MeOH); Anal. (C23H28N2O5S.0.5H2O) Calcd. (%): C, 60.91; H, 6.44;
	N, 6.18; S, 7.07 Found (%): C, 60.89; H, 6.57; N, 5.80; S, 6.91
Ic-115	mp 133-135° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.21-1.34 (2H, m),
	1.40-1.72 (10H, m), 2.02 (1H, m), 2.47 (3H, s), 2.53 (3H, s), 2.57
	(1H, br s), 3.48-3.59 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H,
	d, J = 7.5 Hz), 7.05 (1H, s), 7.84 (1H, s), 7.94 (1H, s); IR (Nujol)
	3344, 2540, 1730, 1614, 1539, 1219, 1142 cm−1; [α]D25 + 34.7 ± 0.7°
	(c = 1.012, MeOH) Anal. (C23H29NO4S) Calcd. (%): C, 67.10; H,
	7.27; N, 3.26; S, 7.64 Found (%): C, 66.81; H, 7.50; N, 3.18; S, 7.32
Ic-128	1H-NMR (CDCl3) δ 1.05 (1H, m), 1.19-1.68 (12H, m), 1.99 (1H, br
	s), 2.57 (1H, br s), 3.48 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 3.95 (1H,
	m), 3.99 (2H, s), 4.85 (2H, br s), 6.27 (1H, d, J = 8.1 Hz), 7.47 (1H,
	d, J = 9.9 Hz), 7.76 (1H, s), 8.07 (1H, d, J = 8.4 Hz); IR (CHCl3)
	3435, 3192, 2954, 1730, 1637, 1520, 1435, 1275 cm−1; [α]D26 +
	29.9 ± 0.7° (c = 1.011%, MeOH); Anal. (C22H26NO5SF.0.4H2O) Calcd.
	(%): C, 59.20; H, 6.14; N, 3.14; S, 7.18; F, 4.26 Found (%): C, 59.16;
	H, 5.90; N, 3.05; S, 7.09; F, 4.14
Ic-129	mp 135-137° C.; 1H-NMR (CDCl3) δ 1.05 (1H, m), 1.22-1.69 (12H,
	m), 2.04 (1H, br s), 2.56 (1H, br s), 3.54 (2H, dt, J = 1.5, 6.6 Hz),
	3.96 (1H, m), 3.98 (3H, s), 4.03 (2H, s), 6.12 (1H, d, J = 6.9 Hz),
	7.52 (1H, d, J = 10.5 Hz), 7.77 (1H, s), 8.04 (1H, d, J = 8.4 Hz); IR
	(Nujol) 3334, 2924, 1745, 1618, 1535, 1498, 1462, 1415, 1281, 1259
	cm−1; [α]D24 + 23.6 ± 0.6° (c = 1.014%, MeOH); Anal. (C23H28NO5SF)
	Calcd. (%): C, 61.45; H, 6.28; N, 3.12; S, 7.13; F, 4.23 Found (%):
	C, 61.17; H, 6.33; N, 3.03; S, 7.04; F, 4.03
Ic-135	1H-NMR (CDCl3—DMSO—d6) δ 1.17 (1H, m), 1.26-1.66 (12H, m), 2.00
	(1H, m), 2.56 (1H, m), 3.53 (2H, t, J = 6.3 Hz), 3.86 (1H, m), 4.01
	(2H, s), 6.62 (1H, br d, J = 8.1 Hz), 7.40 (2H, br s), 7.96 (1H, s),
	8.17 (1H, s); IR (nujol) 1726, 1633, 1556, 1303, 1252, 1176, 1130
	cm−1; [α]D24 + 19.5 ± 0.6° (c = 1.009, MeOH)
Ic-140	mp 96-98° C.; 1H-NMR (DMSO—d6) δ 1.18-1.31 (8H, m), 1.49-1.56
	(5H, m), 1.94 (1H, m), 2.38 (1H, br s), 3.40 (2H, t, J = 6.5 Hz), 3.47
	(2H, s), 3.68 (1H, m), 3.93 (2H, s), 6.88 (1H, br s), 7.26 (1H, dd, J =
	1.5 and 8.7 Hz), 7.50 (1H, br s), 7.54 (1H, d, J = 8.7 Hz), 7.94 (1H,
	d, J = 1.5 Hz), 8.12 (1H, d, J = 6.6 Hz), 8.59 (1H, s); IR (Nujol)
	3386, 3276, 3195, 3064, 2549, 1747, 1697, 1666, 1624, 1560, 1128
	cm−1; [α]D25 + 22.0 ± 0.6° (c = 1.006, MeOH) Anal.
	(C24H30N2O6.0.8H2O) Calcd. (%): C, 63.09; H, 6.97; N, 6.13 Found
	(%): C, 63.18; H, 6.98; N, 5.94

 

[0151]

TABLE 42
Compound No.	Physical property
Ic-142	1H-NMR (CDCl3—CD3OD) δ 1.19 (1H, m), 1.26-1.31 (2H, m), 1.39-
	1.64 (10H, m), 1.98 (1H, m), 2.55 (1H, br s), 3.50 (2H, t, J = 6.3
	Hz), 3.86 (1H, m), 4.01 (2H, s), 6.44 (1H, br s), 6.88 (1H, d, J = 7.2
	Hz), 7.29 (1H, br s), 7.50 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 1.8
	and 8.4 Hz), 8.22 (1H, s), 8.45 (1H, d, J = 1.8 Hz); IR (CHCl3) 3026,
	3014, 2875, 1728, 1662, 1587, 1562, 1510, 1126 cm−1; [α]D25 +
	19.6 ± 0.6° (c = 1.008, MeOH) Anal. (C23H28N2O6.0.5H2O) Calcd.
	(%): C, 63.14; H, 6.68; N, 6.40 Found (%): C, 63.02; H, 6.49; N, 6.35
Ie-34	1H-NMR (CDCl3) δ 1.08 (1H, m), 1.23-1.71 (12H, m), 2.03 (1H, d, J =
	3.3 Hz), 2.60 (1H, br s), 2.63 (2H, t, J = 6.9 Hz), 3.18 (2H, br s),
	4.03 (1H, m), 6.45 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.42
	(1H, t, J = 7.5 Hz), 7.58 (1H, d, J = 5.4 Hz), 7.63 (1H, d, J = 6.9
	Hz), 7.96 (1H, d, J = 7.8 Hz); IR (CHCl3) 3452, 2954, 1711, 1649,
	1520, 1495, 1458, 1300, 1284 cm−1; [α]D26 + 38.1 ± 1.6° (c = 0.502%,
	MeOH); Anal. (C22H27NO3S2.0.3H2O) Calcd. (%): C, 62.47; H, 6.58;
	N, 3.31; S, 15.16 Found (%): C, 62.53; H, 6.63; N, 3.38; S, 15.16
Ie-49	1H-NMR (CDCl3) δ 1.07 (1H, m), 1.29-1.68 (12H, m), 2.01 (1H, m),
	2.55 (1H, m), 2.64 (2H, t, J = 7.5 Hz), 3.18 (2H, s), 3.44 (3H, s),
	3.99 (1H, m), 4.78 (2H, s), 6.12 (1H, d, J = 7.2 Hz), 7.33-7.40 (2H,
	m), 7.79 (1H, dd, J = 6.9, 1.8 Hz), 8.17 (1H, s); IR (CHCl3) 3440,
	2670, 1710, 1650, 1573, 1562, 1509, 1425, 1297, 1238, 1224 cm−1;
	[α]D24.0 + 33.2 ± 0.7° (c = 1.019, MeOH); Anal. (C24H31NO5S.0.2H2O)
	Calcd. (%): C, 64.18; H, 7.05; N, 3.12 Found (%): C, 64.11; H, 7.11;
	N, 3.24
IIa-22	1H-NMR (CDCl3) 60.94 (1H, d, J = 10.2 Hz), 1.11 (3H, s), 1.23 (3H,
	s), 1.34-1.54 (6H, m), 1.65-1.89 (2H, m), 2.00 (1H, m), 2.13-2.39
	(5H, m), 4.32 (1H, m), 5.75 (1H, dt, J = 15.9, 1.2 Hz), 6.22 (1H, d, J =
	8.7 Hz), 6.98 (1H, dd, J = 2.1, 9.0 Hz), 6.99 (1H, td, J = 7.2, 15.9
	Hz), 7.26 (1H, d, J = 2.1 Hz), 7.58 (1H, s), 8.08 (1H, d, J = 9.0 Hz);
	IR (KBr) 3300, 1695, 1603, 1522, 1468, 1417, 1236 cm−1; [α]D26 +
	31.3 ± 0.7° (c = 1.000, MeOH); Anal. (C25H31NO4S.0.4H2O) Calcd.
	(%): C, 66.91; H, 7.14; N, 3.12; S, 7.14 Found (%): C, 66.81; H,
	7.05; N, 3.13; S, 7.07
IIa-23	mp 189-192° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13
	(3H, s), 1.25 (3H, s), 1.28-2.39 (14H, m), 4.31 (1H, m), 5.78 (1H, d,
	J = 15.6 Hz), 6.19 (1H, d, J = 9.6 Hz), 6.99 (1H, m), 7.01 (1H, dd, J =
	8.7, 2.7 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.67 (1H, s), 7.89 (1H, d, J =
	2.7 Hz); IR (Nujol) 3199, 2683, 1684, 1635, 1599, 1525, 1437,
	1304, 1286, 1225 cm−1; [α]D26.0 + 26.8 ± 0.7° (c = 1.011, MeOH); Anal.
	(C25H31NO4S.0.3H2O) Calcd. (%): C, 68.00; H, 7.08; N, 3.17; S, 7.26
	Found (%): C, 68.09; H, 6.94; N, 3.16; S, 7.18

 

[0152]

TABLE 43
Compound No.	Physical property
IIa-24	1H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.15 (3H, s), 1.27 (3H,
	s), 1.32-1.60 (6H, m), 1.66-1.90 (2H, m), 2.04 (1H, m), 2.17-2.43
	(5H, m), 4.29 (1H, m), 5.79 (1H, d, J = 15.6 Hz), 6.49 (1H, d, J = 9.0
	Hz), 6.93 (1H, dd, J = 2.7, 5.7 Hz), 7.02 (1H, td, J = 6.9, 15.6 Hz),
	7.31 (1H, d, J = 2.7 Hz), 7.32 (1H, t, J = 5.7 Hz), 7.65 (1H, s), 12.09
	(1H, s); IR (CHCl3) 3521, 3454, 2686, 1695, 1651, 1624, 1585,
	1562, 1522, 1456, 1271 cm−1; [α]D27 + 29.4 ± 0.7° (c = 1.004, MeOH);
	Anal. (C25H31NO4S.0.4H2O) Calcd. (%): C, 66.91; H, 7.14; N, 3.12;
	S, 7.14 Found (%): C, 66.97; H, 7.01; N, 3.23; S, 7.17
IIa-28	mp 172-174° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.13
	(3H, s), 1.25 (3H, s), 1.30-2.42 (14H, m), 4.31 (1H, m), 5.79 (1H, dt,
	J = 15.6, 1.5 Hz), 6.08 (1H, d, J = 9.3 Hz), 7.03 (1H, dt, J = 15.6, 7.2
	Hz), 7.17 (1H, dt, J = 8.7, 2.7 Hz), 7.80 (1H, dd, J = 8.7, 5.1 Hz),
	7.83 (1H, s), 8.07 (1H, dd, J = 10.2, 2.7 Hz); IR (Nujol) 3374, 2719,
	1698, 1650, 1627, 1525, 1442, 1431 cm−1; [α]D24.0 + 28.2 ± 0.7°
	(c = 1.012, MeOH); Anal. (C30H37NO4S.1.1H2O) Calcd. (%): Calcd.
	(%): C, 67.57; H, 6.50; N, 3.15; S, 7.22 Found (%): C, 67.35; H,
	6.76; N, 3.26; S, 7.12
IIa-34	mp 141-142° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 9.9 Hz), 1.16
	(3H, s), 1.24 (3H, s), 1.29-2.42 (14H, m), 4.39 (1H, m), 5.77 (1H, d,
	J = 15.6 Hz), 6.43 (1H, d, J = 8.7 Hz), 7.01 (1H, dt, J = 15.6, 3.6
	Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.54 (1H, d, J =
	7.5 Hz), 7.59 (1H, d, J = 5.4 Hz), 7.96 (1H, d, J = 7.5 Hz); IR
	(Nujol) 3380, 2686, 1699, 1619, 1581, 1461, 1234, 1200 cm−1;
	[α]D25.0 + 48.8 ± 0.9° (c = 1.009, MeOH); Anal. (C25H31NO3S) Calcd.
	(%): C, 70.55; H, 7.34; N, 3.29; S, 7.53 Found (%): C, 70.35; H,
	7.33; N, 3.31; S, 7.44
IIa-51	mp 211-213° C.; 1H-NMR (CDCl3—CD3OD) δ 0.94 (1H, d, J = 9.9 Hz),
	1.15 (3H, s), 1.24 (3H, s), 1.36-1.55 (6H, m), 1.70 (1H, m), 1.83
	(1H, m), 2.02 (1H, m), 2.15-2.38 (5H, m), 4.29 (1H, m), 5.74 (1H, d,
	J = 15.6 Hz), 6.90 (1H, dd, J = 2.1, 8.7 Hz), 6.90 (1H, dt, J = 15.6,
	6.9 Hz), 7.00 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.99 (1H,
	s); IR (KBr) 3425, 3255, 2600, 1938, 1685, 1626, 1605, 1579, 1522,
	1442, 1265, 1146, 1128, 1107 cm−1; [α]D27 + 23.9 ± 0.6° (c = 1.004,
	MeOH); Anal. (C25H31NO5.0.1H2O) CaLcd. (%): C, 70.27; H, 7.36; N,
	3.28 Found (%): C, 70.13; H, 7.34; N, 3.47
IIa-52	mp 159-160° C.; 1H-NMR (CDCl3) δ 0.92 (1H, d, J = 9.9 Hz), 1.11
	(3H, s), 1.21 (3H, s), 1.36-1.50 (6H, m), 1.63 (1H, m), 1.79 (1H, m),
	1.98 (1H, s), 2.10-2.20 (4H, m), 2.30 (1H, s), 4.30 (1H, s), 5.69 (1H,
	d, J = 15.6 Hz), 6.20 (1H, d, J = 9.0 Hz), 6.91 (1H, dd, J = 2.4, 9.0
	Hz), 6.94 (1H, dt, J = 15.6, 6.9 Hz), 7.33 (1H, d, J = 9.0 Hz), 7.56
	(1H, d, J = 2.4 Hz), 7.98 (1H, s); IR (KBr) 3255, 2688, 1684, 1643,
	1560, 1522, 1306, 1288, 1269, 1219, 1192, 1167, 1134 cm−1; [α]D25 +
	21.8 ± 0.6° (c = 1.020, MeOH); Anal. (C25H31NO5) Calcd. (%): C,
	70.57; H, 7.34; N, 3.29 Found (%): C, 70.41; H, 7.16; N, 3.34

 

[0153]

TABLE 44
Compound No.	Physical property
IIa-54	1H-NMR (CDCl3) δ 0.95 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,
	s), 1.32-1.57 (6H, m), 1.69-1.88 (2H, m), 2.02 (1H, m), 2.16-2.24
	(4H, m), 2.35 (1H, m), 4.32 (1H, m), 5.78 (1H, dt, J = 15.3, 1.5 Hz),
	6.02 (1H, d, J = 9.0 Hz), 7.02 (1H, dt, J = 15.3, 6.9 Hz), 7.09-7.15
	(1H, m), 7.26 (1H, dd, J = 8.7, 2.1 Hz), 7.82 (1H, dd, J = 8.7, 5.4
	Hz), 8.05 (1H, s); IR (CHCl3) 3446, 2680, 1695, 1652, 1257, 1220,
	1214 cm−1; [α]D25.0 + 23.3 ± 0.6° (c = 1.008, MeOH); Anal.
	(C25H30FNO4.0.4H2O) Calcd. (%): C, 69.07; H, 7.14; F, 4.37; N, 3.22
	Found (%): C, 68.82; H, 6.89; F, 4.49; N, 3.34
IIa-66	1H-NMR (CDCl3) δ 0.95 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,
	s), 1.40-1.55 (6H, m), 1.70-1.85 (2H, m), 2.00 (1H, br s), 2.12-2.37
	(5H, m), 4.30 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.17 (1H, d, J = 9.0
	Hz), 6.68 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 5.4 Hz), 6.94 (1H, d,
	J = 5.4 Hz), 7.03 (1H, dt, J = 15.6 and 6.9 Hz), 11.22 (1H, s); IR
	(CHCl3) 3448, 3188, 1693, 1637, 1543, 1518, 1471, 1421, 1396,
	1385, 1257, 1232 cm−1; [α]D26 + 18.2 ± 0.6° (c = 1.005, MeOH) Anal.
	(C23H30N2O3S.0.2H2O) Calcd. (%): C, 66.06; H, 7.33; N, 6.70; S,
	7.66 Found (%): C, 66.19; H, 7.06; N, 6.83; S, 7.35
IIa-81	mp 167-168° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13
	(3H, s), 1.23 (3H, s), 1.33-1.54 (6H, m), 1.64 (1H, m), 1.80 (1H, m),
	1.99 (1H, br s), 2.12-2.38 (5H, m), 2.44 (3H, s), 4.31 (1H, m), 5.71
	(1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 9.6 Hz), 6.72 (1H, d, J = 2.1
	Hz), 6.97 (1H, dt, J = 15.6 and 6.9 Hz), 7.30 (1H, d, J = 2.1 Hz),
	7.97 (1H, s); IR (KBr) 3276, 2686, 1693, 1643, 1610, 1562, 1518,
	1460, 1417, 1385, 1367, 1284, 1200, 1136 cm−1; [α]D24 + 23.0 ± 0.6°
	(c = 1.020, MeOH) Anal. (C26H33NO5.0.2HO) Calcd. (%): C, 70.47;
	H, 7.60; N, 3.16 Found (%): C, 70.50; H, 7.47; N, 3.35
IIa-94	1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.25 (3H,
	s), 1.42-1.56 (6H, m), 1.70-1.88 (2H, m), 2.00 (1H, m), 2.03 (3H, s),
	2.18-2.38 (5H, m), 4.31 (1H, m), 4.55 (2H, m), 5.78 (1H, d, J = 15.6
	Hz), 6.18-6.23 (2H, m), 6.98 (1H, dt, J = 15.6, 6.9 Hz), 7.34 (1H,
	dd, J = 1.8, 8.4 Hz), 7.77 (1H, s), 7.79 (1H, d, J = 8.4 Hz), 8.31 (1H,
	br s); IR (CHCl3) 3446, 1695, 1655, 1514, 1471, 1435, 1369, 1222,
	1215 cm−1; [α]D24 + 23.4 ± 0.6° (c = 1.006, MeOH) Anal.
	(C28H36N2O4S.0.4H2O) Calcd. (%): C, 66.74; H, 7.36; N, 5.56; S,
	6.36 Found (%): C, 66.79; H, 7.23; N, 5.51; S, 6.39
IIa-99	mp 130-133° C.; 0.85 (1H, d, J = 9.6 Hz), 1.12 and 1.19 (3H, s),
	1.25-2.38 (12H, m), 3.99 (1H, m), 5.72 (1H, d, J = 15.6 Hz), 6.79
	(1H, dt, J = 6.6, 15.6 Hz), 7.38 (1H, s), 7.87 (1H, dd, J = 1.8, 8.7
	Hz), 8.05-8.13 (3H, m), 8.31 (1H, s), 8.82 (1H, d, J = 1.2 Hz); IR
	(Nujol) 3375, 3178, 2918, 1703, 1653, 1626, 1527, 1460, 1398, 1255
	cm−1; [α]D25 + 27.9 ± 0.7° (c = 1.011%, MeOH); Anal.
	(C26H32N2O4S.0.7AcOEt) Calcd. (%): C, 65.23; H, 7.15; N, 5.28; S,
	6.05 Found (%): C, 64.99; H, 6.91; N, 5.52; S, 6.18

 

[0154]

TABLE 45
Compound No.	Physical property
IIb-28	1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.26 (3H,
	s), 1.59 (1H, ddd, J = 2.7, 5.7, 13.5 Hz), 1.95-2.57 (7H, m), 4.06-
	4.27 (4H, m), 4.33 (1H, m), 5.60-5.80 (2H, m), 6.18 (1H, d, J = 9.0
	Hz), 7.17 (1H, dt, J = 3.0, 9.0 Hz), 7.79 (1H, dd, J = 4.8, 8.7 Hz),
	7.89 (1H, s), 8.04 (1H, dd, J = 2.7, 9.9 Hz); IR (CHCl3) 3442, 3022,
	1734, 1651, 1603, 1564, 1516, 1496, 1471, 1433, 1244, 1119 cm−1;
	[α]D25 + 43.8 ± 1.4° (c = 1.003%, MeOH); Anal. (C24H28NO4SF.0.4H2O)
	Calcd. (%): C, 63.67; H, 6.41; F, 4.20; N, 3.09; S, 7.08 Found (%): C,
	63.73; H, 6.35; F, 4.11; N, 3.20; S, 7.07
IIc-04	mp 132-134° C.; 1H-NMR (CDCl3) δ 0.94 (1H, d, J = 9.9 Hz), 1.13
	(3H, s), 1.23 (3H, s), 1.40-1.86 (8H, m), 2.00 (1H, m), 2.13 (1H, m),
	2.18-2.37 (2H, m), 3.53 (2H, t, J = 6.0 Hz), 4.04 (2H, s), 4.28 (1H,
	m), 6.14 (1H, d, J = 9.0 Hz), 7.31-7.36 (2H, m), 7.85 (1H, m); IR
	(Nujol) 3373, 3105, 2528, 1736, 1601, 1556, 1215, 1138 cm−1; [α]D25 +
	22.7 ± 0.6° (c = 1.004, MeOH); Anal. (C20H29NO4S) Calcd. (%): C,
	63.30; H, 7.70; N, 3.69; S, 8.45 Found (%): C, 63.10; H, 7.73; N,
	3.74; S, 8.34
IIc-17	mp 125-126° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.2 Hz), 1.13
	(3H, s), 1.25 (3H, s), 1.40-1.93 (8H, m), 2.02 (1H, m), 2.17-2.41
	(3H, m), 3.53 (2H, t, J = 6.3 Hz), 4.02 (2H, s), 4.36 (1H, m), 6.21
	(1H, d, J = 9.0 Hz), 7.37-7.49 (2H, m), 7.84 (1H, s), 7.87 (1H, m),
	8.30 (1H, m); IR (Nujol) 3282, 2540, 1724, 1604, 1554, 1246, 1228,
	1130, 1109 cm−1; [α]D25 + 29.6 ± 0.7° (c = 1.013, MeOH); Anal.
	(C24H31NO4S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.46 Found
	(%): C, 66.88; H, 7.10; N, 3.30; S, 7.25
IIc-19	1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.24 (3H,
	s), 1.40-1.92 (8H, m), 2.01 (1H, m), 2.17-2.40 (3H, m), 2.48 (3H, s),
	3.47-3.58 (2H, m), 3.97 (1H, m), 4.02 (2H, s), 4.34 (1H, m), 6.21
	(1H, d, J = 9.3 Hz), 7.28 (1H, m), 7.65 (1H, m), 7.75 (1H, s), 8.16
	(1H, d, J = 8.4 Hz); IR (CHCl3) 3442, 2567, 1780, 1732, 1649, 1514,
	1242, 1134 cm−1; [α]D25 + 28.7 ± 0.8° (c = 1.003, MeOH) Anal.
	(C25H33NO4S.0.4H2O) Calcd. (%): C, 66.61; H, 7.56; N, 3.11; S, 7.11
	Found (%): C, 66.67; H, 7.37; N, 3.03; S, 6.88
IIc-20	mp 87-90° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.14
	(3H, s), 1.26 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41
	(3H, m), 2.49 (3H, s), 3.54 (2H, t, J = 6.0 Hz), 4.02 (2H, s), 4.35
	(1H, m), 6.20 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 0.6, 8.4 Hz), 7.74
	(1H, d, J = 8.4 Hz), 7.80 (1H, s), 8.11 (1H, d, J = 0.6 Hz); IR (Nujol)
	3411, 3357, 1736, 1604, 1531, 1219, 1134 cm−1; [α]D25 + 27.4 ± 0.7°
	(c = 1.013, MeOH); Anal. (C25H33NO4S.0.3H2O) Calcd. (%): C, 66.87;
	H, 7.54; N, 3.12; S, 7.14 Found (%): C, 66.90; H, 7.50; N, 3.23; S,
	7.05

 

[0155]

TABLE 46
Compound No.	Physical property
IIc-21	mp 183-185° C.; 1H-NMR (d6—DMSO) δ 0.84 (1H, d, J = 9.6 Hz), 1.11
	(3H, s), 1.18 (3H, s), 1.22-1.60 (7H, m), 1.93 (1H, m), 2.10-2.34
	(6H, m), 3.41 (2H, t, J = 6.3 Hz), 3.92 (2H, s), 3.97 (1H, m), 6.79
	(1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.77 (1H, d, J = 7.8
	Hz), 7.97 (1H, d, J = 6.9 Hz), 8.18 (1H, s), 10.39 (1H, br), 12.53
	(1H, br); IR (Nujol) 3425, 3303, 3093, 2598, 1729, 1604, 1574,
	1522, 1469, 1282, 1230, 1122 cm−1; [α]D27 + 32.1 ± 0.7° (c = 1.000,
	MeOH); Anal. (C24H31NO5S.0.4H2O) Calcd. (%): C, 63.66; H, 7.08;
	N, 3.09; S, 7.08 Found (%): C, 63.79; H, 7.14; N, 3.15; S, 7.06
IIc-22	1H-NMR (CDCl3) δ 0.93 (1H, d, J = 10.2 Hz), 1.10 (3H, s), 1.23 (3H,
	s), 1.38-1.92 (8H, m), 1.99 (1H, m), 2.16-2.38 (3H, m), 3.46 (2H, t,
	J = 6.3 Hz), 3.95 (2H, s), 4.32 (1H, m), 6.32 (1H, d, J = 9.0 Hz),
	6.96 (1H, dd, J = 2.1, 9.0 Hz), 7.24 (1H, t, J = 2.1 Hz), 7.51 (1H, s),
	8.04 (1H, d, J = 9.0 Hz); IR (KBr) 3359, 1734, 1603, 1523, 1469,
	1236, 1128 cm−1; [α]D26 + 26.8 ± 0.7° (c = 1.015, MeOH); Anal.
	(C24H31NO5S.0.4H2O) Calcd. (%): C, 63.66; H, 7.08; N, 3.09; S, 7.08
	Found (%): C, 63.64; H, 7.13; N, 3.07; S, 6.99
IIc-23	1H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.12 (3H, s), 1.24 (3H,
	s), 1.38-2.40 (12H, m), 3.47 (2H, t, J = 6.6 Hz), 3.97 (2H, s), 4.33
	(1H, m), 5.36 (2H, br s), 6.28 (1H, d, J = 9.0 Hz), 7.00 (1H, dd, J =
	2.1, 8.7 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.71 (1H, s), 7.98 (1H, d, J =
	2.1 Hz); IR (CHCl3) 3438, 3238, 1730, 1637, 1601, 1518, 1436,
	1124 cm−1; [α]D24 + 23.7 ± 0.6° (c = 1.004, MeOH); Anal.
	(C24H31NO5S.0.5H2O) Calcd. (%): C, 63.41; H, 7.10; N, 3.08; S, 7.05
	Found (%): C, 63.40; H, 6.98; N, 3.25; S, 7.09
IIc-24	1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.5 Hz), 1.16 (3H, s), 1.20 (3H,
	s), 1.40-1.92 (8H, m), 2.04 (1H, m), 2.18-2.42 (3H, m), 3.55 (2H, t,
	J = 6.3 Hz), 4.04 (2H, s), 4.30 (1H, m), 6.55 (1H, d, J = 8.7 Hz),
	6.93 (1H, dd, J = 2.4, 6.6 Hz), 7.32 (1H, d, J = 2.4 Hz), 7.33 (1H, d,
	J = 6.6 Hz), 7.67 (1H, s), 12.10 (1H, s); IR (CHCl3) 3508, 3450,
	2684, 1780, 1732, 1624, 1585, 1562, 1523, 1456, 1269 cm−1; [α]D27 +
	28.4 ± 0.7° (c = 1.000, MeOH); Anal. (C24H31NO5S.0.5H2O) Calcd.
	(%): C, 63.41; H, 7.10; N, 3.08; S, 7.05 Found (%): C, 63.48; H,
	6.98; N, 3.16; S, 6.98
IIc-27	1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.25 (3H,
	s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.17-2.41 (3H, m), 3.53 (2H, t,
	J = 6.6 Hz), 4.03 (2H, s), 4.32 (1H, m), 6.18 (1H, d, J = 8.7 Hz),
	7.21 (1H, dt, J = 2.4, 9.0 Hz), 7.53 (1H, dd, J = 2.4, 8.4 Hz), 8.33
	(1H, dd, J = 5.1, 9.0 Hz); IR (CHCl3) 3508, 3442, 1780, 1732, 1651,
	1603, 1516, 1468, 1244, 1122 cm−1; [α]D25 + 29.2 ± 0.7° (c = 1.006,
	MeOH); Anal. (C24H30FNO4S.0.3H2O) Calcd. (%): C, 63.64; H, 6.81;
	F, 4.19; N, 3.09; S, 7.08 Found (%): C, 63.65; H, 6.76; F, 4.10; N,
	3.14; S, 7.16

 

[0156]

TABLE 47
Compound No.	Physical property
IIc-28	mp 144-146° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.13
	(3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.17-2.41
	(3H, m), 3.52-3.57 (2H, m), 4.03 (2H, s), 4.33 (1H, m), 6.16 (1H, d,
	J = 8.4 Hz), 7.17 (1H, dt, J = 2.7, 8.7 Hz), 7.78 (1H, dd, J = 5.1, 8.7
	Hz), 8.06 (1H, dd, J = 2.7, 9.9 Hz); IR (Nujol) 3286, 2538, 1722,
	1608, 1552, 1244, 1136 cm−1; [α]D25 + 27.3 ± 0.7° (c = 1.009, MeOH);
	Anal. (C24H30FNO4S) Calcd. (%): C, 64.41; H, 6.76; F, 4.24; N, 3.13;
	S, 7.16 Found (%): C, 64.23; H, 6.84; F, 4.16; N, 3.19; S, 7.12
IIc-34	mp 95-96° C.; 1H-NMR (CDCl3) δ 0.97 (1H, d, J = 10.5 Hz), 1.17
	(3H, s), 1.24 (3H, s), 1.40-1.96 (8H, m), 2.02 (1H, m), 2.18-2.41
	(3H, m), 3.47-3.58 (2H, m), 4.01 (2H, s), 4.40 (1H, m), 6.50 (1H, d,
	J = 8.7 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.55
	(1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 5.7 Hz), 7.96 (1H, dd, J = 1.2,
	7.8 Hz); IR (Nujol) 3265, 2544, 1728, 1608, 1577, 1550, 1319,
	1240, 1225, 1128, 1111 cm−1; [α]D25 + 45.6 ± 0.9° (c = 1.006, MeOH);
	Anal. (C24H31NO4S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.46
	Found (%): C, 66.88; H, 7.14; N, 3.34; S, 7.43
IIc-39	1H-NMR (CDCl3) δ 0.99 (1H, d, J = 10.2 Hz), 1.17 (3H, s), 1.24 (3H,
	s), 1.44-1.94 (8H, m), 2.02 (1H, m), 2.18-2.40 (3H, m), 3.53 (2H, t,
	d = 6.3 Hz), 3.98 (3H, s), 4.01 (2H, s), 4.40 (1H, m), 6.43 (1H, s),
	6.49 (1H, d, J = 8.7 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.58 (1H, dd, J =
	0.9, 7.5 Hz), 7.93 (1H, dd, J = 0.9, 7.5 Hz); IR (CHCl3) 3455, 1780,
	1732, 1649, 1508, 1373, 1205, 1151 cm−1; [α]D24 + 41.7 ± 0.8°
	(c = 1.007, MeOH); Anal. (C25H33NO5S.0.2H2O) Calcd. (%): C, 64.82;
	H, 7.27; N, 3.02; S, 6.92 Found (%): C, 64.85; H, 7.30; N, 3.10; S,
	6.64
IIc-41	1H-NMR (CDCl3) δ 0.98 (1H, d, J = 9.9 Hz), 1.19 (3H, s), 1.25 (3H,
	s), 1.46-1.96 (8H, m), 2.03 (1H, m), 2.22-2.41 (3H, m), 3.53 (2H, t,
	J = 6.3 Hz), 4.00 (2H, s), 4.43 (1H, m), 6.53 (1H, d, J = 9.3 Hz),
	7.44-7.56 (3H, m), 7.66 (1H, d, J = 6.3 Hz), 7.91 (1H, m), 8.18 (1H,
	m), 8.30 (1H, d, J = 7.5 Hz); IR (CHCl3) 3454, 1780, 1731, 1649,
	1512, 1444, 1217, 1122 cm−1; [α]D25 + 45.4 ± 0.8° (c = 1.013, MeOH);
	Anal. (C28H33NO4S.0.3H2O) Calcd. (%): C, 69.34; H, 6.98; N, 2.89;
	S, 6.61 Found (%): C, 69.21; H, 7.01; N, 3.04; S, 6.59
IIc-49	1H-NMR (CDCl3) δ 0.97 (1H, d, J = 9.9 Hz), 1.17 (3H, s), 1.25 (3H,
	s), 1.49-2.39 (12H, m), 3.45 (2H, s), 3.51 (2H, t, J = 6.3 Hz), 4.00
	(3H, s), 4.37 (1H, m), 4.79 (2H, s), 6.20 (1H, d, J = 9.3 Hz), 7.32-
	7.40 (2H, m), 7.74 (1H, dd, J = 7.2, 1.5 Hz), 8.16 (1H, s); IR
	(CHCl3) 3444, 2829, 1733, 1650, 1573, 1508, 1471, 1425, 1384,
	1367, 1214 cm−1; [α]D24.0 + 24.8 ± 0.6° (c = 1.020, MeOH); Anal.
	(C26H35NO6.0.5H2O) Calcd. (%): C, 66.93; H, 7.78; N, 3.00 Found
	(%): C, 66.85; H, 7.78; N, 3.10

 

[0157]

TABLE 48
Compound No.	Physical property
IIc-51	1H-NMR (CDCl3) δ 0.93 (1H, d, J = 9.9 Hz), 1.14 (3H, s), 1.23 (3H,
	s), 1.41-1.90 (8H, m), 2.00 (1H, m), 2.17-2.38 (3H, m), 3.49 (2H, t,
	J = 6.3 Hz), 3.99 (2H, s), 4.29 (1H, m), 6.27 (1H, d, J = 9.0 Hz), 6.89
	(1H, dd, J = 2.1, 8.7 Hz), 6.99 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J =
	8.7 Hz), 8.00 (1H, s); IR (KBr) 3475, 1734, 1626, 1560, 1518, 1493,
	1471, 1441, 1385, 1367, 1265, 1221, 1122 cm−1; [α]D27 + 22.3 ± 0.6°
	(c = 1.000, MeOH); Anal. (C24H31NO6.0.5H2O) Calcd. (%): C, 65.74;
	H, 7.35; N, 3.19 Found (%): C, 65.79; H, 7.43; N, 3.36
IIc-52	1H-NMR (CDCl3) δ 0.98 (1H, d, J = 10.5 Hz), 1.13 (3H, s), 1.24 (3H,
	s), 1.48-1.90 (8H, m), 2.01 (1H, m), 2.18-2.40 (3H, m), 3.49 (2H, t,
	J = 6.5 Hz), 3.95 (1H, d, J = 16.5 Hz), 4.02 (1H, d, J = 16.5 Hz),
	4.32 (1H, m), 6.12 (1H, d, J = 9.0 Hz), 6.91 (1H, dd, J = 2.7, 9.0 Hz),
	7.36 (1H, d, J = 9.0 Hz), 7.52 (1H, d, J = 9.0 Hz), 7.98 (1H, s); IR
	(CHCl3) 3442, 3265, 1730, 1643, 1620, 1558, 1514, 1468, 1385,
	1367, 1190, 1167, 1136 cm−1; [α]D27 + 21.6 ± 0.6° (c = 1.006, MeOH);
	Anal. (C24H31NO60.5H2O) Calcd. (%): C, 65.74; H, 7.35; N, 3.19
	Found (%): C, 65.80; H, 7.46; N, 3.34
IIc-56	1H-NMR (CDCl3) δ 0.99 (1H, d, J = 10.2 Hz), 1.25 (6H, s), 1.47-1.79
	(7H, m), 1.92-2.05 (2H, m), 2.19 (1H, m), 2.25-2.39 (2H, m), 3.51
	(2H, t, J = 6.3 Hz), 3.96 (1H, d, J = 16.2 Hz), 4.00 (1H, d, J = 16.2
	Hz), 4.46 (1H, m), 6.89 (1H, d, J = 2.1 Hz), 7.37 (1H, t, J = 7.8 Hz),
	7.69 (1H, d, J = 2.1 Hz), 7.74 (1H, dd, J = 1.2, 7.8 Hz), 7.88 (1H, d,
	J = 9.3 Hz), 8.13 (1H, dd, J = 1.2, 7.8 Hz); IR (CHCl3) 3435, 2665,
	2573, 2474, 1780, 1732, 1651, 1606, 1595, 1547, 1535, 1473, 1421,
	1367, 1352, 1325, 1296, 1167, 1120 cm−1; [α]D25.5 + 14.7 ± 0.5°
	(c = 1.007, MeOH); Anal. (C24H31NO5.0.3H2O) Calcd. (%): C, 68.81;
	H, 7.60; N, 3.34 Found (%): C, 68.71; H, 7.60; N, 3.44
IIc-65	mp 191-192° C.; 1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.5 Hz), 1.15
	(3H, s), 1.25 (3H, s), 1.46-1.88 (8H, m), 2.01 (1H, m), 2.11 (1H, m),
	2.21-2.37 (2H, m), 3.51-3.58 (2H, m), 4.07 (2H, s), 4.30 (1H, m),
	6.21 (1H, d, J = 9.3 Hz), 6.68 (1H, d, J = 1.2 Hz), 6.99 (1H, d, J =
	5.4 Hz), 7.23 (1H, dd, J = 0.6, 5.4 Hz), 11.27 (1H, s) ; IR (KBr)
	3433, 3276, 2663, 2534, 1736, 1591, 1541, 1508, 1473, 1458, 1244,
	1228, 1211, 1151 cm−1; [α]D25 + 18.0 ± 06° (c = 1.008, MeOH); Anal.
	(C22H30N2O4S.0.1H2O) Calcd. (%): C, 62.86; H, 7.24; N, 6.66; S,
	7.63 Found (%): C, 62.81; H, 7.30; N, 6.80; S, 7.47
IIc-66	1H-NMR (CDCl3) δ 0.96 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H,
	s), 1.46-1.88 (8H, m), 2.01 (1H, m), 2.14 (1H, m), 2.21-2.37 (2H,
	m), 3.53 (2H, t, J = 6.6 Hz), 4.07 (2H, s), 4.29 (1H, m), 6.20 (1H, d,
	J = 9.3 Hz), 6.64 (1H, d, J = 2.1 Hz), 6.86 (1H, d, J = 5.4 Hz), 6.92
	(1H, d, J = 5.4 Hz), 11.06 (1H, s); IR (CHCl3) 3448, 3209, 1726,
	1631, 1543, 1518, 1126 cm−1; [α]D25 + 14.4 ± 0.5° (c = 1.007, MeOH);
	Anal. (C22H30N2O4S.0.4H2O) Calcd. (%): C, 62.06; H, 7.29; N, 6.58;
	S, 7.53 Found (%): C, 62.02; H, 7.31; N, 6.67; S, 7.56