US 5,231,105 AGrant
Ethylamine Derivatives and Antihypertensives Containing the Same
Issue Date:1993-07-27
•23 Claims
Abstract
An ethylamine derivative of formula (I): ##STR1## wherein A represents a carbon atom or a nitrogen atom; B represents a substituted or unsubstituted aralkyl or aryl group; C represents hydrogen, alkyl, aralkyl, or aryl, each of which may optionally be substituted or C may optionally be bonded to A to form an alkylene bridge which is optionally substituted, Q represents a substituted or unsubstituted aryl group, said group optionally being substituted by hetero atom(s) or substituent(s) optionally containing hetero atom(s); and X represents an alkylene bridge having from 2 to 20 carbon atoms and is optionally substituted with groups which include hetero atoms with the non-hetero atom substituents optionally containing hetero atoms.
Metadata
Assignee
- Ajinomoto Co., Inc.
Inventors
- Masataka Shoji
- Kozo Toyota
- Chikahiko Eguchi
- Ryota Yoshimoto
- Yosikatsu Koyama
- Hideki Domoto
- Akira Kamimura
Application Information
Application Number:US 3548805
Filing Date:1989-05-22
Priority Date:1987-06-02
Art Unit:122
Classifications
IPC:
C07D21170C07D21134A61K 51445
Field of Search:
546514203;204;208;212;213;214;215;216;225;230;232;233;237;240325;317;318;326;327;330;331
Patent Drawings
This patent does not have any drawings.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an ethylamine derivative, which exhibits antihypertensive properties.
2. Description of the Background
It is said that there are about 13,000,000 hypertension patients in Japan, and the frequency of hypertension is higher with advancement in age. In addition, the condition of hypertension is an important factor in cerebral apoplexy and cardiopathy which are the second and third highest causes of death, respectively. Accordingly, antihypertensive drugs are one of the most important classes of drugs in the treatment of gereatric diseases.
About 90% or more of hypertensive patients are believed to suffer from essential hypertension, the cause of which is not clear, and the remedy therefore is merely within the range of an expectant treatment for the disease. Accordingly, patients are required to continuously take an antihypertensive drug all of their lives, and so the antihypertensive drug should have high safety and a sure pharmaceutical activity against hypertensive and further must be durable.
Recently, the serotonin-antagonistic antihypertensives have been reported. However, these compounds are not always satisfactory from the viewpoint of their antihypertensive mechanism, as well as their durability. In addition, serotonin-antagonistic drugs have been reported to be effective against various diseases caused by serotonin, for example, thrombosis, ulcers and the like, but the effect of such drugs against such diseases is not so clear. On the other hand, from the viewpoint of the preparation of the said antihypertensives, not an insignificant number of compounds and synthetic intermediates for the antihypertensives are difficultly soluble in organic solvents or are produced by procedures which are complicated and troublesome. A need therefore continues to exist for antihypertensive drugs which can be conveniently prepared at low cost and which have excellent overall effective properties.
SUMMARY OF THE INVENTION
Briefly, one object of the present invention is to provide an antihypertensive drug which has several desirable features in its stated function and which is conveniently able to be produced industrially.
Accordingly, this object and other objects of the present invention as hereinafter will become more readily apparent can be attained by an ethylamine derivative of formula (I): ##STR2## wherein A represents a carbon atom or a nitrogen atom;
B represents a substituted or unsubstituted aralkyl or aryl group;
C represents hydrogen, alkyl, aralkyl, or aryl, each of which may optionally be substituted or
C may optionally be bonded to A to form an alkylene bridge which is optionally substituted,
Q represents a substituted or unsubstituted aryl group, said group optionally being substituted by hetero atom(s) or substituent(s) optionally containing hetero atom(s); and
X represents an alkylene bridge having from 2 to 20 carbon atoms and is optionally substituted with groups which include hetero atoms with the non-hetero atom substituents optionally containing hetero atoms.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the structure of the compound above, the radical Q includes the likes of ##STR3## in which E represents a nitrogen atom, substituted nitrogen, an oxygen atom or a sulfur atom;
Y, Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 may be same or different and each represents a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group, and a part of the organic groups may optionally be substituted by hetero atom(s) or substituent(s) optionally containing hetero atom(s); Y may optionally be bonded to X to form an alkylene bridge or an alkylene bridge having at least one oxygen, sulfur or nitrogen atom and optionally having substituent(s); and Z.sup.1 and Z.sup.2, Z.sup.2 and Z.sup.3, or Z.sup.3 and Z.sup.4 may optionally be bonded to each other to form an alkylene bridge or an alkylene bridge having at least one oxygen, sulfur or nitrogen atom and optionally having substituent(s).
In the structure of the present compound, radical B represents an aralkyl group or an aryl group having for 6 to 16 carbon atoms which is optionally substituted.
C represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms which is optionally substituted. C may be optionally bonded to A to form an alkylene bridge having 1 to 6 carbon atoms and is optionally substituted. Other suitable groups for radical C include hydrogen, methyl, ethyl, propyl, butyl, pentyl and hexyl. Further, C may be bonded to A as a methylene, ethylene or propylene group.
Structural examples of the unit A-B in the formula include: ##STR4##
In the formulas II to III above, Y, Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 may be same or different and each represents a hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, an aralkyl group having 6 to 12 carbon atoms or an aryl group having from 6 to 12 carbon atoms, each of which is optionally substituted, or the organic groups are each substituted by halogen atom(s) and/or at least one oxygen atom, sulfur atom, nitrogen atom or phosphorus atom. More preferably, Y, Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 may be same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a hydroxyamino group, a nitro group, or a cyano group, or an organic group selected from the group consisting of an alkyl group, an aralkyl group, an aryl group, an alkoxy group, an aralkyloxy group, an aryloxy group, an alkylamino group, an aralkylamino group, an arylamino group, an acylamino group, an acyloxy group and an aminosulfonyl group, each of which may be substituted.
Suitable examples of radical Q in formula I above include: o-nitrophenyl, o-aminophenyl, o-ethylcarbamoylphenyl, o-styrylcarbamoylphenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dihydroxyphenyl 3-trifluoromethylphenyl, pyrrolyl, N-methylpyrrolyl, 4-methoxyphenyl, 3-benzoylphenyl, phenyl, 3,4-dimethylphenyl, 2-methoxy-5 bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chlorophenyl, 3-iodophenyl, 3-phenoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3,5-dimethoxyphenyl, 3-benzyloxyphenyl, 3,4-dibenzyloxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-ethoxyphenyl, 2-methylnaphthyl, 2-bromophenyl, 2-bromo-4,5-dimethoxyphenyl, pentafluorophenyl, 2-chlorophenyl, 2,3,6-trichlorophenyl, 2,4-dichlorophenyl, 2-chloro-6 fluorophenyl, 2,6-dichlorophenyl, 2-6-dimethylphenyl, 2-iodophenyl, 2-nitro-4-trifluoromethylphenyl, 2-phenoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-benzyloxyphenyl, 2-ethoxyphenyl, 0-biphenyl, 2-trifluorophenyl, 2-methylphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-methylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4-cyanophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-ethoxyphenyl, 3-methoxy- 4-ethoxyphenyl, 4-(2-diethylaminoethoxy)phenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 3-ethoxy-4-hydroxyphenyl, p-biphenyl, 4-butoxyphenyl, 4-(2-methyl-2-butyl)phenyl, 4-isopropylphenyl, p-tolyl, 4-benzylphenyl, 4-ethylphenyl, 4-hydroxyphenyl, 2-cyano-4-methylphenyl, 3,4-methylenedioxyphenyl, 3-pyridyl, 2-nitrophenyl, 2-chloro-4-nitrophenyl, 3-nitrophenyl, 2-nitro-5-fluorophenyl, 4-nitrophenyl, 4-aminophenyl, 3,5-di(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,4-di(trifluoromethyl)phenyl, 3,5-difluorophenyl, 4-ethenylphenyl, 2,4,5-trimethylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-3-ethoxyphenyl, 4-(2-methylpropyl)phenyl, 4-methoxycarbonylphenyl, 3,4-diethoxyphenyl, 2-iodo-4,5-dimethoxyphenyl, 4-neopentanoylphenyl, 2-nitro -4,5-dimethoxyphenyl, 2-thiopheno, 2-furyl, 3-pyrrolyl, N-methyl-3-pyrrolyl, 3-thiopheno, 3-furyl and the like.
In the structure of formula I, group X preferably is ##STR5## in which n represents an integer from 0 to 9; Z.sup.4 and Z.sup.5 are the same or different and each represents a hydrogen atom, an alkyl group, an aralkyl group, each of which is optionally substituted; and the organic groups may be optionally substituted by hetero atom(s) or substituents optionally containing hetero atom(s).
More preferably, group X is: ##STR6## in which n represents a value from 0 to 9; Z.sup.5 and Z.sup.6 each represent an alkyl group having from 1 to 20 carbon atoms which is optionally substituted, and the organic groups may be optionally substituted by hetero atom(s) or substituent(s) optionally containing hetero atom(s).
The ethylamine derivative of the present invention may be in the form of a salt thereof.
Of course, when the salt of the same derivative is the active antihypertensive ingredient of a formulation, it is required to be in the form of a pharmaceutically acceptable salt of the derivative.
The ethylamine derivative of the present invention can be advantageously used as an antihypertensive in the treatment of hypertensive mammals and humans. The present compound can be perorally administered in the form of a preparation such as a tablet, a capsule or an elixir, or it may be parenterally administered in the form of a sterile solvent solution or suspension, for the purpose of blood pressure depression. The ethylamine derivative of the present invention can be administered to patients or animals which must be treated with an antihypertensive agent several times each in unit dosages of from 0.2 to 500 mg/patient or animal, and accordingly, the total dosage of the derivative may range from 1 to 2000 mg/patient or animal/day. It is a matter of course that the dosage required to achieve necessary and essential treatment may be varied in accordance with the condition of the disease, the weight of the patient or animal and other factors which are considered necessary by one skilled in the art.
The ethylamine derivative of the present invention can also be used together with any other antihypertensive agent. Suitable examples of the antihypertensive agents which can be used together with the derivative of the present invention include an .alpha..sub.1 -antagonist such as prazosin or the like; a calcium-antagonist such as nifedipine, nicardipine, diliagen, verapanil and the like; and a convertase inhibitor such as captopril emalopril, and the like.
A typical antihypertensive composition within the scope of the present invention contains from about 0.2 to about 500 mg of the derivative of the present invention or a physiologically acceptable salt thereof or a mixture thereof blended with a physiologically acceptable vehicle, carrier, extender, binder, antiseptic, stabilizer, flavoring agent or the like in a unit amount as required for a conventional pharmaceutical preparation. The amount of the active ingredient in the pharmaceutical composition or preparation should be such that an appropriate dosage falling within the indicated range can be obtained by the administration of the said composition or preparation.
Examples of pharmaceutical excipients which are combined with the present antihypertensive agent for the preparation of tablets, capsules and the like include binders such as tragacanth, gum arabic, corn starch or gelatin; a vehicle such as fine crystalline cellulose; an extender such as corn starch, pre-gelatinated starch, alginic acid, or the like; a sweetener such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, an oil from Gaulthenia adenothrix Maxim or cherry. When the unit preparation is in the form of a capsule, the composition may further contain a liquid carrier such as a fat or oil, in addition to the above-mentioned additive materials. Other ingredients may be employed which form coated pills or which vary the physical form of the unit preparation by a different method. For example, tablets can be coated with shellac, sugar or a combination thereof. A syrup or elixir can contain the active compound together with sucrose as a sweetener, methyl- or propyl-paraben as an antiseptic, a dye and cherry or orange aroma as a flavoring agent.
A sterile composition for injection can be prepared in a conventional manner, for example, by dissolving or suspending the active substance in a vehicle such as distilled water for injection, together with a natural vegetable oil such as sesame oil, coconut oil, peanut oil, cotton seed oil or the like or a synthetic fat vehicle such as ethyl oleate or the like. If desired, a buffer, an antiseptic, an antioxidant or the like can be incorporated into the composition.
Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein.
EXAMPLES
Example 1: Synthesis of 1-[2-(2-nitrobenzenesulfonyl)aminoethyl]-4-(4-fluorobenzoyl)piperidine
(a) Synthesis of (2-nitrobenzenesulfonyl)aminoethyl bromide
A 20 ml amount of a dichloroethane solution of 21.0 g (200 mmol) of triethylamine was added dropwise to 80 ml of a dichloroethane solution containing 22.1 g (100 mmol) of 2-nitrobenzenesulfonyl chloride and 20.4 g (100 mmol) of 2-bromoethylamine hydrobromide, while cooled with ice. After the completion of the dropwise addition, the mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was washed twice with 100 ml of 1N hydrochloric acid solution and then once with 100 ml of water, and then the organic layer was dried with anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure and the above-entitled compound was obtained in the form of crystals.
Yield: 29.5 g (95.4 mmol), 95%.
Thin Layer Chromatography: (TLC) (AcOEt:n --C.sub.6 H.sub.14 =1:4).
R.sub.f =0.70.
Mass Spectrum: MS (FAB, m/z) 309 (M+H.sup.+).
Nuclear Magnetic Resonance Spectrum (.sup.1 H-NMR): (TMS/CDCl.sub.3, .delta./ppm) 3.45.about.3.65 (4H, m), 6.75 (1H, z), 7.53.about.8.08 (4H, m).
(b) Synthesis of 1-[2-(2-nitrobenzenesulfonyl)aminoethyl]-4-(4-fluorobenzoyl)piperidine)
A mixture comprising 9.27 g (30 mmol) of (2-nitrobenzenesulfonyl)aminoethyl bromide, 7.31 g (30 mmol) of 4-fluorobenzoylpiperidine hydrochloride, 8.48 g (80 mmol) of sodium carbonate and 100 ml of methyl isobutyl ketone was stirred overnight in an oil bath.
After the reaction, 50 ml of water was added to the reaction mixture for washing, and then the organic layer was isolated and the solvent was evaporated under reduced pressure.
After purification by silica gel column chromatography (eluent: chloroform/methanol=5/1), the resulting product was converted into its hydrochloride with 4N hydrogen chloride/dioxane solution.
Yield: 10.5 g (22.2 mmol), 76%.
TLC (CHCl.sub.3 :MeOH=9:1).
R.sub.f =0.81.
MS (FAB, m/z) 436 (M+H.sup.+).
.sup.1 H-NMR (TMS/DMSO-d.sub.6, .delta./ppm) 1.80.about.2.05 (5H, m), 3.04.about.3.35 (6H, m), 3.56.about.3.65 (2H, m), 3.65.about.3.75 (1H, m), 7.90.about.7.96 (2H, m), 7.40 (2H, dd, J=8, 8Hz), 8.45 (1H, bs), 8.02.about.8.13 (4H, m).
Example 2 Synthesis of 1-[2-(2-aminobenzenesulfonyl)aminoethyl]-4-(4-fluorobenzoyl)piperidine
A suspension of 1-[2-(2-nitrobenzenesulfonyl)aminoethyl]-4-(4-fluorobenzoyl)piperidine (see Example 1) in 160 ml of acetic acid was heated at 90.degree. C. and then 8 g of iron (powder) was gradually added thereto over a period of 10 minutes. The reaction solution became black, and then the solution was stirred for a further 10 minutes. A white crystalline material precipitated from solution. After cooling, the reaction solution was filtered, and the residue was washed with methanol. The solvent was evaporated from the resulting filtrate, and 4N hydrogen chloride/dioxane solution was added to the residue. Thus the above-entitled compound was obtained in the form of a hydrochloride thereof.
Yield: 65.8 g (13.8 mmol), 91%.
TLC (CHCl.sub.3 ; MeOH=5:1).
R.sub.f =0.40.
MS (FAB, m/z) 406 (M+H.sup.+).
.sup.1 H-NMR (TMS/DMSO-d.sub.6, .delta./ppm) 1.84.about.2.01 (5H, m), 3.02.about.3.20 (6H, m), 3.48.about.3.55 (2H, m), 3.64.about.3.72 (1H, m), 4.72.about. (1H, bs), 6.63 (1H, dd, J=8, 8Hz), 6.84 (1H, dd, J=8Hz), 7.30 (1H, dd, J=8, 8Hz), 7.39 (2H, dd, J=6, 6Hz), 7.53 (1H, dd, J=8Hz), 7.98 (1H, bs), 8.08 (2H, dd, J=8, 6Hz).
Example 3: Synthesis of 1-[2-(2-ethoxycarbonylaminobenzenesulfonyl)aminoethyl]-4-(4-fluorobenzoyl) piperidine
Thirty ml of a chloroform solution containing 3.65 g (9.00 mmol) of 1-[2-(2-aminobenzenesulfonyl)aminoethyl]-4-(4-fluorobenzoyl)piperidine, 0.16 g (0.90 mmol) of 4-piperidinopyridine and 0.91 g (9.00 mmol) of triethylamine was stirred and 0.976 g (9.00 mmol) of ethyl chloroformate was dropwise added thereto. After the completion of the reaction, the reaction mixture was stirred for 3 hours and then extracted twice with 50 ml of 1N hydrochloric acid and then once with 50 ml of water in the stated order. Next, the resulting organic layer was dried with anhydrous magnesium sulfate.
The solvent was evaporated and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=20/1). The above-entitled compound was obtained as an oily product.
Yield: 3.18 g (6.67 mmol), 74.1%.
TLC (AcOEt:EtOH=20:1).
R.sub.f =0.87.
MS (D, m/l) 478 (M+H.sup.+).
.sup.1 H-NMR (TMS/DMSO-d.sub.6, .delta./ppm) 1.12 (3H, t, J=8Hz), 1.82.about.2.10 (5H, m), 3.12.about.3.27 (2H, m), 3.65.about.3.77 (4H, m), 4.10 (2H, q, J=8Hz), 4.23.about.4.30 (2H, m), 6.16 (1H, bs), 6.68 (1H, dd, J=8, 8Hz), 6.89 (1H, d, J=8Hz), 7.36 (1H, dd, J=8.8Hz), 7.40 (2H, dd, (J=8, 6Hz), 7.59 (1H, d, J=8Hz), 8.10 (2H, dd, J=8, 6Hz).
Example 4: Synthesis of 5,6-benzo-2,4-diaza-2-[2-[(4-fluorobenzoyl)piperidin-1-yl]ethyl]tetrahydro thiopyrane-1,1-dioxide
Twenty ml of a pyridine solution of 1.10 g (2.30 mmol) of 4-[2-(2-ethoxycarbonylaminobenzenesulfonyl)aminoethyl]-1-(4-fluorobenzoyl) piperidine (refer to Example 3) was heated at reflux for 15 hours. After the completion of the reaction, the solvent was evaporated, and dichloroethane-ether was added to the residue for crytallization. The resulting crystal was taken out by filtration, washed with ether and then dried under reduced pressure to obtain the above-entitled compound.
Yield: 0.31 g (0.72 mmol), 32%.
TLC (CHCl.sub.3 :MeOH=9:1).
R.sub.f =0.66.
MS (FD, m/z) 432 (M+H.sup.+).
.sup.1 H-NMR (TMS/CDCl.sub.3, .delta./ppm) 1.78.about.1.98 (5H, m), 2.38.about.2.52 (2H, m), 2.82.about.2.92 (2H, m), 3.05.about.3.14 (2H, m), 3.25 (1H, bs), 4.20 (2H, t, J=7Hz), 7.13 (2H, dd, J=8, 8Hz), 7.20 (1H, d, J=8Hz), 7.26 (1H, dd,J=8, 8Hz), 7.57 (1H, d, J=8, 8Hz), 7.80 (1H, d, J=8Hz), 7.94 (2H, dd, J=8, 8Hz).
Example 5 Synthesis of 2-[3,4-dimethoxyphenyl]-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-isopropylv aleronitrile hydrochloride
(a) Synthesis of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile
A three-necked flask equipped with an argon balloon and two dropping funnels was flushed with argon and 6.6 g (90.17 mmol) of sodium amide was placed therein. After flushing again with argon, 30 ml of 1,2-dimethoxyethane was added thereto. A 25 g (0.14 mmol) amount- of 3,4-dimethoxyphenylacetonitrile was placed in another flask, which was then added thereto. The solution was transferred into the above-mentioned dropping funnels with a cylinder. The 3,4-dimethoxyphenylacetonitrile solution was added dropwise to the sodium amide suspension with stirring while being cooled with ice. The ice cooling bath was removed and then the whole was stirred for another hour. Next, the ice cooling bath was again applied to the reaction solution and a 1,2-dimethoxyethane solution (17 ml) containing 17.4 ml (0.19 mmol) of isopropyl bromide was added dropwise thereto, and then the reaction solution was stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with ether and then washed with a 1N aqueous sodium hydroxide solution, water, an aqueous 5% citric acid solution and water in the stated order. The ether layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 29.11 g of an oily product. A small amount of ethanol was added thereto for crystallization, and the resulting crystalline material was recrystallized. (3,4-Dimethoxyphenyl)-2-isopropylacetonitrile was obtained accordingly.
Yield: 19.2 g (8.77 mmol), 63%)
(b) Synthesis of 5-chloro-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
A 0.32 g (8.2 mmol) amount of sodium amide was placed in a three-necked flask flushed with argon, and after further argon flushing, 5 ml of 1,2-dimethoxyethane was added thereto. A 1.49 g (6.8 mmol) amount of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile was placed in another flask, which was also flushed with argon. Then 10 ml of 1,2-dimethoxyethane was added thereto. This solution was added dropwise to the above-prepared sodium amide suspension via a cylinder. After a while, the reaction mixture became cloudy white. The mixture was drawn into a cylinder and added dropwise to 1,2-dimethoxyethane (50 ml) containing 2.5 ml (26.3 mmol) of 1-bromo-3-chloropropane which had been prepared in another argon flushed flask. This mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with chloroform and dried with anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure to obtain 2.12 g of a crude product. The non-reacted starting materials were found to still remain in the reaction mixture by TLC (SiO.sub.2 /CHCl.sub.3), but the reaction mixture was used in the next reaction as such without being further purified.
(c) Synthesis of 2-[3,4-dimethoxyphenyl]-5-[4-(4-fluorobenzoyl)1-piperidinyl]-2-isopropylva leronitrile
Fifty ml of toluene and 2.12 g of the above crude 5-chloro-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile were added to a mixture comprising 2.6 g (10.7 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride and 0.9 g (8.5 mmol) of anhydrous sodium carbonate, and the mixture was heated at reflux. The reaction was traced by TLC and the heating was stopped at a pertinent step. Water was added to the reaction mixture, which was then extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the crude product thus obtained was purified by silica gel column chromatography (CHCl.sub.3 /MeOH) to obtain the above-entitled compound.
Yield: 0.76 g (1.6 mmol). (0.2 g of the compound was converted into the hydrochloride).
TLC (CHCl.sub.3 :MeOH=9:1).
R.sub.f =0.52.
MS (FD, m/z) 466 (M.sup.+).
.sup.1 H-NMR (TMS/CDCl.sub.3, .delta./ppm) 0.80 (3H, d, J=7Hz), 1.20 (3H, d, J=7Hz), 1.9.about.3.5 (1.5H, m), 3.83 (3H, z), 3.88 (3H, z), 6.8-7.2 (5H, m), 7.8-8.1 (2H, m).
Example 6: Synthesis of 4-(4-fluorobenzoyl)-1-(4-phenylbutyl)piperidine hydrochloride
(a) Synthesis of 4-phenylbutyl chloride
A 2.2 ml (20 mmol) amount of thionyl chloride was added dropwise to a methylene chloride solution (30 ml) containing 3 g (20 mmol) of 4-phenyl-1-butanol and stirred overnight at room temperature. The reaction solution was washed with water, an aqueous 50% sodium hydrogen carbonate solution, water, 1N hydrochloric acid and water in that order, and then the solvent was dried with anhydrous magnesium sulfate. After distillation under reduced pressure, 3.62 g of a crude 4-phenylbutyl chloride was obtained. This material was used in the next reaction without being further purified.
(b) Synthesis of 4-(4-fluorobenzoyl)-1-(4-phenylbutyl)piperidine
A necessary amount of toluene, 1.8 g (12 mmol) of sodium iodide and 31 g of the crude phenylbutyl chloride were added to a mixture comprising 3 g (12.3 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride and 2.6 g (24.5 mmol) of anhydrous sodium carbonate. The resulting mixture was heated at reflux. After reaction overnight, the heating was stopped. Water was added to the reaction mixture, which was then extracted with chloroform. The resulting extract was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain the above-entitled compound.
Yield: 0.13 g (0.38 mmol), 3%.
TLC (CHCl.sub.3 :MeOH=5:1).
R.sub.f =0.72.
MS (FD, m/z) 339 (M.sup.+).
.sup.1 H-NMR (TMS/CDCl.sub.3, .delta./ppm) 1.4-2.2 (10H, m), 2.2-2.7 (4H, m), 2.8-3.2 (3H, m), 6.9-7.2 (7H, m), 7.7-8.0 (2H, m).
Example 7: Synthesis of 1-[3-(2-cinnamoylaminophenylthio)propyl]-4-(4-fluorobenzoyl)piperidine
(a) Synthesis of 1-chloro-3-(2-aminophenylthio)propane
Twenty ml of an isopropyl alcohol solution of 6.25 g (50.0 mmol) of 2-aminothiophenol was added to 20 ml of an isopropyl alcohol solution containing 2.97 g (55.0 mmol) of sodium methoxide under a stream of nitrogen and the mixture was blended. After stirring for 30 minutes, the reaction mixture was cooled to 0.degree. C. and successively 10 ml of a toluene solution of 1-bromo-3-chloropropane was added dropwise thereto. After completion of the addition, the mixture was stirred for 1 hour at room temperature and then heated under reflux for 1 hour for further reaction. Then 60 ml of 1N sodium hydroxide was added and the reaction mixture was extracted with 50 ml of ether. The solvent was evaporated to obtain a crude product of the above-entitled compound.
Yield: 9.52 g (47.2 mmol), 94%.
TLC (Et.sub.2 O).
R.sub.f =0.85.
.sup.1 H-NMR (TMS/CDCl.sub.3, .delta./ppm) 1.83 (2H, tt, J=8, 8Hz), 2.80 (2H, t, J=8Hz), 3.57 (2H, t, J=8Hz), 4.20 (2E, bs), 6.50 (1H, dd, J=6.8 Hz), 6.62 (1H, d, J=8Hz), 7.05 (1H, dd, J=8, 8=Hz), 7.26 (1H, d, J=6Hz).
(b) Synthesis of 1-chloro-3-(2-cinnamoylaminophenylthio]propane
A ten ml amount of a dichloromethane solution of 3.33 g (20.0 mmol) of cinnamoyl chloride was added dropwise to 20 ml of a dichloromethane solution containing 4.02 g (20.0 mmol) of triethylamine at room temperature. After completion of the dropwise addition, the mixture was stirred overnight. After washing twice with 30 ml of 1N hydrochloric acid and then once with water in that order, the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated and then the residue was recrystallized form dichloromethane-ether-hexane to obtain the above-entitled compound.
Yield 4.70 g (14.2 mmol), 71%.
TLC (Et.sub.2 O).
R.sub.f =0.88.
.sup.1 H-NMR (TMS/CDCl.sub.3, .delta./ppm) 2.0 (2H, tt, J=8, 8Hz), 2.88 (2H, t, J=8Hz), 3.57 (2H, t, J=8Hz), 6.50 (1H, d, J=18Hz), 6.85.about.7.55 (9H, m), 7.65 (1H, d, J=18Hz), 8.55 (1H, bs).
(c) Synthesis of 1-[3-(2-cinnamoylaminophenylthio)propyl]-4-(4-fluorobenzoyl)piperidine
Using 3.17 g (9.58 mmol) of 1-chloro-3-[2-(cinnamoylamino)phenylthio]propane, 2.33 g (9.58 mmol) of 4-(4-chlorobenzoyl)piperidine hydrochloride, 2.76 g (20.0 mmol) of potassium carbonate and 30 ml of isoamyl alcohol as starting materials, the same reaction as Example- 1 was conducted. The product obtained was purified by column chromatography (eluent: chloroform/methanol=40/1) to obtain the above-entitled compound.
Yield: 2.97 g (6.10 mmol), 64%.
TLC (CHCl.sub.3 :MeOH=9:1).
R.sub.f =0.51.
MS (FD, m/z) 502 (M.sup.+).
.sup.1 H-NMR (TMS/DMSO-d.sub.4, .delta./ppm) 1.30.about.2.02 (7H, m), 2.95.about.3.22 (3H, m), 7.10 (1H, d, J=8, 8Hz), 7.23 (1H, dd, J=8, 8Hz), 7.31 (1H, dd, J=8, 8Hz), 7.39 (1H, dd, J=9, 9Hz), 7.41 (2H, dd, J=8, 8Hz), 7.46 (1H, d, J=8Hz), 7.55 (1H, d, J=8Hz), 7.60 (2H, d, J=18Hz), 7.65 (2H, d, J=8Hz), 7.71 (1H, d, J=8Hz), 8.06 (2H, dd, J=8, 6Hz), 9.64 (1H, s).
Example 8: Synthesis of 1-[3-(2-aminophenylthio)1-propyl]-4-(4-fluorobenzoyl)piperidine
Using 3.73 g (18.5 mmol) of 1-chloro-3-(2-aminophenylthio)propane, 4.52 g (18.5 mmol) of 4-(4-fluorobenzoyl)-piperidine hydrochloride, 6.90 g (50.0 mmol) of potassium carbonate and 50 ml of butanol as starting materials, the same reaction as Example 1 was conducted. The product obtained was purified by silica gel chromatography (eluent: chloroform/methanol=40/1) to obtain the above-entitled compound.
Yield: 0.50 g (1.12 mmol) in the form of the dihydrochloride, 6%.
TLC (CHCl.sub.3 :MeOH=9:1).
R.sub.f =0.66.
MS (FD, m/z) 373 (M.sup.+).
.sup.1 H-NMR (TMS/DMSO-d.sub.6, .delta./ppm) 1.80.about.2.04 (7H, m), 2.99 (2H, t, J=7Hz), 3.02.about.3.12 (2H, m), 3.20 (2H, t, J=8Hz), 3.52 (2H, d, J=12Hz), 4.56 (2H, bs), 7.00.about.7.12 (1H, m), 7.21.about.7.32 (2H, m), 7.39 (2H, dd, J=10, 10Hz), 7.55 (1H, d, J=8Hz), 8.10 (2H, dd, J=8, 8Hz).
Example 9 Synthesis of 4-(4-fluorobenzoyl)-1-(5-phenylpentyl)piperidine hydrochloride
(a) Synthesis of 5-phenylpentyl bromide
A 1.8 g (6.7 mmol) amount of phosphorus tribromide was added to a chloroform solution (20 ml) of 3.3 g (20 mmol) of 5-phenyl-1-pentanol and the resulting solution was heated at reflux for 4 hours. When the reaction was traced by TLC, the starting materials were found to still remain in the reaction mixture, and so 0.2 g of phosphorus tribromide was further added and heated at reflux. Afterwards, the reaction solution was washed with water and dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. Thus, 4.30 g of a crude 5-phenylpentyl bromide was obtained.
(b) Synthesis of 4-(4-fluorobenzoyl)-1-(5-phenylpentyl)piperidine
Fifty ml of isopropyl alcohol and 2.26 g of the crude 5-phenylpentyl bromide were added to a mixture comprising 2.4 g (9.9 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride and 2.1 g (19.8 mmol) of anhydrous sodium carbonate, and the resulting mixture was heated under reflux. The reaction was continued overnight and then the heating was stopped. The reaction mixture was concentrated under reduced pressure, and water was added thereto. This was extracted with chloroform. The resulting extract was dried with anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain the above-entitled compound.
Yield: 2.18 g, 62%.
TLC (CHCl.sub.3 :MeOH=9:1).
R.sub.f =0.41.
MS (FD, m/z) 353 (M.sup.+).
The compounds described in Experiments 10 to 108 below were synthesized by the same procedure described above.
Example 10
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]valeronitrile L-(+)-tartarate
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.48.
MS(FD, m/z) 424(M.sup.+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.8-2.4(8H,m), 2.9-3.7(6H,m), 3.85(3H,s), 3.88(3H,s), 3.8-4.4(2H,m), 6.8-6.9(3H,m), 7.1-7.2(2H,m), 7.9-8.0(2H,m).
Example 11
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-isopropyl-2-(3,4,5-trimethoxyphenyl )valeronitrile L-(+)-tartarate
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.48.
MS(FD,m/z) 497(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.76(3H,bs), 1.0-1.2(1H,m), 1.16(3H,bs), 1.4-2.5(12H,m), 2.9-3.4(3H,m), 3.82(3H,s), 3.87(3H,s), 6.6-6.8(2H,m), 6.6-6.8(2H,m), 7.0-7.2(2H,m), 7.8-8.1(2H,m), 7.0-7.2(2H,m).
Example 12
2-(3,4-Dimethoxyphenyl)-2-dodecyl-5-[4-(4-fluorobenzoyl)-1-piperidinyl]vale ronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.70.
MS(FD,m/z) (M+).
H-NMR (TMS/CDCl.sub.3, .delta./ppm) 0.84(3H,t,J=8Hz), 1.2-1.5(22H,m), 1.8-2.1(8H,m), 2.9-3.1(4H,m), 3.4-3.5(2H,m), 3.6-3.8(1H,m), 3.76(3H,s), 3.79(3H,s), 6.9-7.0(3H,m), 7.40(2h,dd,J=8,8Hz), 8.07(2H,dd,J=10,8Hz).
Example 13
2-(3,4-Dimethoxyphenyl)-2-(3-[4-(4-fluorobenzoyl)-1-piperidinyl]-1-propyl)- 1,3-dithiane-1,1,3,3-tetraoxide
TLC(CHCl.sub.3 :MeOH=5:1).
R.sub.f =0.58.
MS(FD,m/z) 567(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 2.0-2.1(4H,m), 2.5-4.0(17H,m), 3.90(6H,s), 4.45(3H,t,J=10Hz), 6.91(1H,d,J=8Hz), 7.18(2H,dd,J=8,8Hz), 7.46(1H,dd,J=8,2Hz), 7.67(1H,d,J=2Hz), 7.93(2H,dd,J=10,8Hz).
Example 14
5-[4-(4-Dimethoxybenzoyl)-1-piperidinyl]-2-(3,4-dimethoxyphenyl)-2-isopropy lvaleronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.83.
MS(FD, m/z) 508(M+). H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,t,J=6Hz), 1.21(3H,t,J=6Hz), 2.0-3.8(16H,m), 3.89(3H,s), 3.93(3H,s), 3.96(6H,s), 6.86(1H,d,J=8Hz), 6.91(1H,d,J=8Hz), 6.94(1H,d,J=2Hz), 7.00(1H,dd,J=8,2Hz), 7.44(1H,d,J=2Hz), 7.49(1H,dd,J=8,2Hz).
Example 15
2-(3,4-Dichlorophenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-isopropylval eronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.88.
MS(FD,m/z) 474(M+).
H-NMR(TMS,CDCl.sub.3, .delta./ppm) 0.80(3H,d,J=8Hz), 1.22(3H,d,J=8Hz), 1.8-3.8(16H,m), 7.18(2H,dd,J=8,8Hz), 7.32(1H,dd,J=2,8Hz), 7.52(1H,d,J=8Hz), 7.58(1H,d,J=2Hz), 7.92(2H,dd,J=10,8Hz).
Example 16
5-[4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-2-isopropylvaler onitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.90.
MS(FD, m/z) 532(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.77(3H,d,J=8Hz), 1.18(3H,d,J=8Hz), 1.6-3.3(15H,m), 3.86(3H,s), 3.92(3H,s), 6.8-7.4(11H,m).
Example 17
2-(3-Benzoylphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-methyl-valeroni trile L-(+)-tartarate
TLC(CHCl.sub.3: MeOH=9:1).
Rf=0.56.
MS(FD, m/z) 482(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.4-1.6(1H,m), 1.6-1.9(5H,m), 1.77(3H,s), 2.0-2.2(4H,m), 2.37(2H, pseud t,J=7Hz), 2.8-3.0(2H,m), 3.3-3.6(2H,m), 4.45(1H,bs), 6.9-7.4(9H,m).
Example 18
2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl ]-2-isopropylvaleronitrile L-(+)-tartarate
TLC(CHCl.sub.3 :MeOH=9:1.
Rf=0.27.
MS(FD, m/z) 469(MH+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.78(3H,d,J=7Hz), 1.1-1.2(4H,m), 1.16(3H,d,J=7Hz), 1.2-1.4(1H,m), 1.4-1.6(2H,m), 1.6-1.9(4H,m), 2.0-2.1(2H,m), 2.19(2H,pseud t,J=8Hz), 2.6-2.9(2H,m), 3.86(3H,s), 3.87(3H,s), 4.26(1H,d,J=7Hz), 6.8-7.1(5H,m), 7.1-7.3(2H,m).
Example 19
1-(4-Phenylbutyl)-.alpha.-(4-fluorophenyl)-4-piperidinemethanol L-(+)-tartarate
TLC(CHCl.sub.3 :MeOH=9:1)
Rf=0.21.
MS(FD,m/z) 341(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.3-2.2(10H,m), 2.4-2.7(4H,m), 2.8-3.0(2H,m), 3.3-3.6(2H,m), 4.45(1H,bs), 6.9-7.4(9H,m).
Example 20
2,2-Diphenyl-5-[4-(4-fluorobenzoyl)-1-piperidinyl]valeronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.60.
MS(FD m/z) 440((M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.9-2.1(4H,m), 3.0-3.1(4H m), 3.2-3.3(2H,m), 3.7-3.8(1H,m), 7.18(2H,dd,J=8,8Hz), 7.2-7.5(10H,m), 7.92(2H,dd,J=10,8Hz).
Example 21
5-(4-[Bis(4-fluorophenyl)methylene]-1-piperidinyl)-2-(3,4-dimethoxyphenyl)- 2-isopropylvaleronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.54.
MS(FD,M/z) 544(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.78(3H,d,J=8Hz), 1.20(3H,d,J=8Hz), 1.6-3.6(15H,m), 3.87(3H,s), 3.94(3H,s), 6.8-7.1(11H,m).
Example 22
2-(3,4-Dimethoxyphenyl)-6-4-(4-fluorobenzoyl)-1-piperidinyl]-2-isopropylhex anenitrile hydrochloride
TLC(CHCl.sub.3: MeOH=9:1).
Rf=0.54.
MS (FD, m/z) 480((M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,d,J=7Hz), 0.9-1.1(1H,m), 1.18(3H,d,J=7Hz), 1.3-1.7(3H,m), 1.8-1.9(5H,m), 2.0-2.2(4H,m), 2.30(2H,pseud t), 2.9-3.0(2H,m), 3.20(1H,pseud hept), 3.89(3H,s), 3.90(3H,s), 6.8-6.9(3H,m), 7.0-7.2(2H,m), 7.9-8.0(2H,m).
Example 23
2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-[4(2,4,6-trimethylbenzoyl)-1-piperidi nyl]valeronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
RF=0.64.
MS (FD,m/z) 490(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.8-1.3(6H,m), 1.9-3.6(25H,m), 3.9-4.0(6H,m), 6.8-7.0(5H,m).
Example 24
2-Dodecyl-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-(3-methoxyphenyl)valeroni trile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.65.
MS (FD, m/z) 562(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.88(3H,t,J=8Hz), 1.2-3.8(37H,m), 3.88(3H,s), 6.8-7.0(3H,m), 7.27(2H,dd,J=8,8Hz), 7.32(1H,dd,J=8,8Hz), 7.92(2H,dd,J=10,8Hz).
Example 25
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-phenylvaleronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.54.
MS (FD, m/z) 364(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.6-1.8(2H,m), 1.8-1.9(4H,m), 1.9-2.0(2H,m), 2.0-2.2(2H,m), 2.41(2H,t,J=7Hz), 2.9-3.0(2H,m), 3.20(1H,m), 3.88(1H,t,J=7Hz), 7.1-7.2(2H,m), 7.3-7.4(5H,m), 7.9-8.0(2H,m).
Example 26
2-(3-Chloropropyl)-5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-phenylvaleronitr ile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.61.
MS (FD,m/z) 440(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.2-1.4(1H,m), 1.5-1.9 (4H,m), 1.9-2.2(7H,m), 2.31(2H,t,J=8Hz), 2.8-3.0(2H,m), 3.18(1H,m), 3.46(2H,t,J=6Hz), 7.0-7.2(2H,m), 7.3-7.5(5H,m), 7.9-8.0(2H,m).
Example 27
2-(3,4-Dimethoxyphenyl)-7-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-isopropylhe ptanenitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.54.
MS (FD,m/z) 494(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,d,J=7Hz), 1.03(1H,m), 1.19(3H,d,J=7Hz), 1.2-1.5(5H,m), 1.7-1.9(5H,m), 2.0-2.2(4H,m), 2.28(2H,t), 2.9-3.0(2H,m), 3.20(1H,pseud quin), 3.88(3H,s), 3.90(3H,s), 6.8-7.0(3H,m), 7.1-7.2(2H,m), 7.9-8.0(2H,m).
Example 28
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-phenylthiov aleronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.69.
MS (FD, m/z) 532(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 2.0-3.8(15H,m), 3.88(3H,S), 3.90(3H,s), 6.8-7.0(3H,m), 7.18(2H,dd,J=8,8Hz), 7.3-7.5(5H,m), 7.92(2H,dd,J=10,8Hz).
Example 29
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-isopropyl-2-(-1-naphthyl)valeronitr ile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.68.
MS (FD,m/z) 456(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.82(3H,bs), 1.35(3H,bs), 1.8-3.7(16H,m), 7.16(2H,dd,J=8,8Hz), 7.2-7.9(9H,m).
Example 30
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-isopropyl-2-(2-naphthyl)valeronitri le hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.65.
MS (FD,m/z) 456(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,d,J=6Hz), 1.28(3H,d,J=6Hz), 1.5-3.7(16H,m), 7.1-8.0(11H,m).
Example 31
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorophenyl)methylene-1-piperidinyl]-2-iso propylvaleronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.73.
MS (FD,m/z) 450(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,d,J=8Hz), 1.20(3H,d,J=8Hz), 1.5-3.6(15H,m), 3.9-4.0(6H,m), 6.4-6.5(1H,m), 6.8-7.2(7H,m).
Example 32
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-isopropyl-2-(3-trifluoromethylpheny l)valeronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.64.
MS (FD,m/z) 474(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,d,J=8Hz), 1.23(3H,d,J=8Hz), 1.7-1.8(1H,m), 2.0-3.4(14H,m), 3.7-3.8(1H,m), 7.18(2H,dd,J=8,8Hz), 7.6-7.7(3H,m), 7.92(2H,dd,J=10,8Hz).
Example 33
2-(3,4-Dimethoxyphenyl)-8-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-isopropyloc tanenitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.53.
MS (FD,m/z) 508(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.80(3H,d,J-7Hz), 0.9-1.1(1H,m), 1.19(3H,d,7Hz), 1.2-1.5(10H,m), 1.7-1.9(5H,m), 2.0-2.2(4H,m), 2.33(2H,pseud t), 2.9-3.0(2H,m), 3.2(1H,pseud quin), 3.89(3H,s), 3.90(3H,s), 6.8-7.0(3H,m), 7.1-7.2(2H,m), 7.9-8.0(2H,m).
Example 34
5,6-Dimethoxy-1-(3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl)-1-indanenitri le hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.74.
MS (FD,m/z) 450(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.8-3.5(18H,m), 3.7-3.8(1H,m), 3.88(3H,s), 3.92(3H,s), 6.78(1H,s), 6.85(1H,s), 7.19(2H,dd,J=8,8Hz), 7.94(2H,dd,J=10,8Hz).
Example 35
2-(3,4-Dihydroxyphenyl)-2-dodecyl-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-val eronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.57.
MS (FD,m/z) 565(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.88(3H,d,J=6Hz), 1.1-3.8(39H,m), 6.8-7.2(5H,m), 7.9-8.0(2H,m).
Example 36
2-(3,4-Dimethoxyphenyl)-2-dodecyl-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-p iperidinyl]valeronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.39.
MS (FD,m/z) 565(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.88(3H,d,J=6Hz), 1.1-1.3(22H,m), 1.8-3.6(16H,m), 3.8-3.9(6H,m), 4.41(1H,d,J=8Hz), 6.8-7.3(7H,m).
Example 37
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-(1-methylpyrrole-2-yl)valeronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.42.
MS (FD,m/z) 367(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.7-1.9(6H,m), 1.9-2.2(4H,m), 2 4-2.5(2H,m), 2.9-3.1(2H,m), 3.21(1H,hep), 3.65(3H,s), 3.97(1H,dd,J=7,9Hz), 6.06-6.09(1H,m), 6.10-6.13(1H,m), 6.59-6.61(1H m), 7.10-7.17(2H,m), 7.93-7.99(2H,m).
Example 38
2-Butyl-2-(3,4-dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]valero nitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.67.
MS (FD,m/z) 480(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.86(3H,d,J=8Hz), 1.0-3.8(21H,m), 3.88(3H,s), 3.96(3H,s), 6.87(1H,d,J=8Hz), 6.92(1H,s), 6.99(1H,d,J=8Hz), 7.18(2H,dd,J=8,8Hz), 7.92(2H,dd,J=10,8Hz).
Example 39
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-octylvalero nitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.70.
MS (FD,m/z) 536(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.86(3H,d,J=8Hz), 1.0-3.8(14H,m), 3.88(3H,s), 3.96(3H,s), 6.87(1H,d,J=8Hz), 6.92(1H,d,J=2Hz), 6.99(1H,dd,J=8,2Hz), 7.18(2H,dd,J=8,8Hz), 7.90(2H,dd,J=10,8Hz).
Example 40
5-[4-(4-Fluorobenzoyl)-1-piperidinyl-2-isopropyl-2-(1-methylpyrrole-2-yl)va leronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.54.
MS (FD,m/z) 409(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 1.00(3H,d,J=7Hz), 1.08(3H,d,J=7Hz), 1.4-1.5(1H,m), 1.5-1.7(1H,m), 1.7-1.9(4H,m), 1.9-2.1(4H,m), 2.24(1H,hept,J=7Hz), 2.3-2.4(2H,m), 2.8-2.9(2H,m), 3.18(1H,hep), 3.74(3H,s), 6.00-6.03(1H,m), 6.10-6.14(1H,m), 6.52-6.54(1H,m), 7.09-7.16(2H,m), 7.93-7.98(2H,m).
Example 41
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-hexadecylva leronitrile hydrochloride
TLC(CHCl.sub.3 :MeOH=9:1).
Rf=0.76.
MS (FD,m/z) 648(M+).
H-NMR(TMS/CDCl.sub.3, .delta./ppm) 0.88(3H,t,J=8Hz), 1.0-3.8(45H,m), 3.88(3H,s), 3.96(3H,s), 6.86(1H,d,J=8Hz), 6.92(1H,s), 6.99(1H,d,J=8Hz), 7.18(2H,dd,J=8,8Hz), 7.91(2H,dd,J=10,8Hz).
Example 42
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-methylvaler onitrile
Example 43
2-(3,4-Dimethoxyphenyl)-2-ethyl-5-[4-(4-fluorobenzoyl)-1-piperidinyl]valero nitrile
Example 44
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-propylvaler onitrile
Example 45
2-(3 4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-pentylvaleronit rile
Example 46
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-hexylvalero nitrile
Example 47
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-heptylvaler onitrile
Example 48
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-nonylvalero nitrile
Example 49
2-Decyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)valeronitrile
Example 50
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-undecylvale ronitrile
Example 51
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-tridecylval eronitrile
Example 52
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-tetradecylv aleronitrile
Example 53
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-pentadecylv aleronitrile
Example 54
2-Allyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]valero nitrile
Example 55
2-Cyclopropyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl] valeronitrile
Example 56
2-Cyclobutyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]v aleronitrile
Example 57
2-Cyclopentyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl] valeronitrile
Example 58
2-Cyclohexyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]v aleronitrile
Example 59
2-Cyclooctyl-2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]v aleronitrile
Example 60
2-(3,4-Dimethoxyphenyl)-3-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-(3-pentyl)v aleronitrile
Example 61
2-(3,4-Dimethoxyphenyl)-3-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-(4-heptyl)v aleronitrile
Example 62
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-phenylvaler onitrile
Example 63
2-Benzyl-2-(3,4-dimethoxyphenyl)-5-[4-fluorobenzoyl)-1-piperidinyl]valeroni trile
Example 64
2-(3,4-Dimethoxyphenyl)-3-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-(1-naphthyl )valeronitrile
Example 65
2-(3,4-Dimethoxyphenyl)-3-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-(2-naphthyl )valeronitrile
Example 66
2-(3,4-Dimethoxyphenyl)-3-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-dodecylprop ionitrile
Example 67
2-(3,4-Dimethoxyphenyl)-4-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-dodecylbuty ronitrile
Example 68
2-(3,4-Dimethoxyphenyl)-6-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-dodecylhexa nenitrile
Example 69
2-(3,4-Dimethoxyphenyl)-7-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-dodecylhept anenitrile
Example 70
2-(3,4-Dimethoxyphenyl)-8-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-dodecylocta nenitrile
Example 71
5-(4-[Bis(4-fluorophenyl)methylene]-1-piperidinyl)-2-(3,4-dimethoxyphenyl)- 2-dodecylvaleronitrile
Example 72
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzyl)-1-piperidinyl]-2-dodecylvaler onitrile
Example 73
5-(4-Benzyl-1-piperidinyl)-2-(3,4-dimethoxyphenyl)-2-dodecylvaleronitrile
Example 74
5-(4-Benzoyl-1-piperidinyl)-2-(3,4-dimethoxyphenyl)-2-dodecylvaleronitrile
Example 75
2-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorobenzoyl)-1-piperadinyl]-2-dodecylvale ronitrile
Example 76
5-[4-(5H-Dibenzo(a,d)cyclohepten-5-ylidene)-1-piperidinyl]-2-dodecylvaleron itrile
Example 77
5-[4-(4-Dimethoxybenzoyl)-1-piperidinyl]-2-(3,4-dimethoxyphenyl)-2-dodecylv aleronitrile
Example 78
5-[4-(3,4-Dichlorophenyl)-2-dodecyl-5-[4-(4-fluorobenzoyl)-1-piperidinyl]va leronitrile
Example 79
2-(3,4-Dimethoxyphenyl)-2-dodecyl-5-[4-(2,4,6-trimethylbenzoyl)-1-piperidin yl]valeronitrile
Example 80
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-dodecyl-2-(1-naphthyl)valeronitrile
Example 81
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-dodecyl-2-(2-naphthyl)valeronitrile
Example 82
2-(3,4-Dimethoxyphenyl)-2-dodecyl-5-[4-(4-fluorophenyl)methylene-1-piperidi nyl]valeronitrile
Example 83
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-dodecyl-2-(3-trifluoromethylphenyl) valeronitrile
Example 84
5-[4-(4-Fluorobenzoyl)-1-piperidinyl]-2-dodecyl-2-(1-methylpyrrole-2-yl)val eronitrile
Example 85
2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl ]-2-methylvaleronitrile
Example 86
2-(3,4-Dimethoxyphenyl)-2-ethyl-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl]valeronitrile
Example 87
2 (3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl] -2-propylvalerontrile
Example 88
2-Butyl-2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl]valeronitrile
Example 89
2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl ]-2-pentylvaleronitrile
Example 90
2-(3,4-Dimethoxyphenyl)-2-hexyl-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl]valeronitrile
Example 91
2-(3,4-Dimethoxyphenyl)-2-heptyl-5-[4-(.alpha.-hydroxy 4-fluorobenzyl)-1-piperidinyl]valeronitrile
Example 92
2-(3 4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl]-2- octylvaleronitrile
Example 93
2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl ]-2-nonylvaleronitrile
Example 94
2-Decyl-2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl]valeronitrile
Example 95
2-(3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl -2-undecylvaleronitrile
Example 96
2-( 3,4-Dimethoxyphenyl)-5-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl]te tradecylvaleronitrile
Example 97
2-(3,4-Dimethoxyphenyl)-2-dodecyl-4-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-p iperidinyl]butyronitrile
Example 98
2-(3,4-Dimethoxyphenyl)-2-dodecyl-6-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-p iperidinyl]hexanenitrile
Example 99
2-(3,4-Dimethoxyphenyl)-2-dodecyl-7-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-p iperidinyl]-heptanenitrile
Example 100
2-(3,4-Dimethoxyphenyl)-2-dodecyl-8-[4-(.alpha.-hydroxy-4-fluorobenzyl)-1-p iperidinyl]-octanenitrile
Example 101
5-(3-[4-(4-Fluorobenzoyl)-1-piperidinyl]propyl)-2,3-dihydro-3-hydroxy-2-phe nyl-1,5-benzothiazepine-4(5H)-on
Example 102
5-(3-[4-(4-Fluorobenzoyl)-1-piperidinyl]propyl)-2,3-dihydro-3-hydroxy-2-phe nyl-1,5-benzothiazepine-4(5H)-on acetate L-(+)-tartarate
Example 103
4-[4-(4-Fluorobenzoyl)-1-piperidinyl]-(3,4-dimethoxyphenyl)butyrophenone
Example 104
4-[4-(5H,Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-4'-fluorobutyrop henone
Example 105
2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-(4-phenyl-1-piperidinyl)valeronitrile
Example 106
2,2-Bis{3-[4-fluorobenzoyl)-1-piperidinyl]-1-propyl}-(3-methoxyphenyl)aceto nitrile
Example 107
2-(3-[N-((3,4-Dimethoxyphenyl)-N-methylamino]-1-propyl)-2-(3,4-dimethoxyphe nyl)-5-[4-(4-fluorobenzoyl)-1-piperidinyl]valeronitrile
Example 108
3-(2-[4-(4-Fluorobenzoyl)-1-piperidinyl]-1-ethyl]-5-(2-methoxy-1-ethyl)-2,6 -dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
Example 109
Evaluation of Serotonin-Antagonistic Activity
SD male rats (from 8th to 12th week-age, weight: about 300 g) were killed and the abdomen of each rat was cut to remove the aorta. The aorta was cut into 2.5 pieces and hung in a M gnus' tube kept at 37.degree..+-.1.degree. C. and containing 20 ml of a K.S. Linger solution, into which a mixed gas of 95% O.sub.2 +5% CO.sub.2 was introduced. These specimens were connected to an isotonic transducer and recorded under a load of 1 g. The concentration of serotonin was from 1.times.10.sup.-7 M to 1.times.10.sup.-4 M; and the concentration of the product to be tested was from 1.times.10.sup.-4 M to 1.times.10.sup.-3 M. From the serotinin dose-reaction curve, pA.sub.2 was calculated by Van Rossem et al's method. The affinity for the 5-HT.sub.2 receptor was evaluated by receptor binding assay used by the microsomal fraction of the bovine cortex. The results are summarized in Table 1.
Example 110
Evaluation of Blood Antihypertive Activity
Six male SHR rats which had been bred under sufficient acclimation and were ascertained to be hypertensive (spontaneous hypertensive rats, weight: 400-440 g) were used as test animals.
A 1 ml amount of a physiological salt solution containing the product to be tested (10 mg/kg) in 2.5% of Nicol and 2.5% of ethanol was intravenously injected into each rat once. The blood pressure of the test animal was measured by a closed (bloodless) blood pressure measuring method. The results are summarized in Table 2.
Evaluation of the Data
From the above results, it is understood that the ethylamine derivative of the present invention has both serotonine-antagonistic activity and antihypertensive activity and can therefore be used as an antihypertensive agent. Accordingly, it is believed that the present compound in use will provide excellent antihypertensive effects.
Unless otherwise indicated, developing conditions for TLC were under chloroform/methanol=9/1; mass spectrum (MS) was performed in FD mode (m/z) and nuclear magnetic resonance spectrum (NMR) was measured using tetramethylsilane as the internal standard and deuterium chloroform as the solvent.
Example 111
2-Decyl-2-(3,4-dimethoxyphenyl)-5-(4-(.alpha.-hydroxy-4-fluoro-benzyl)-1-pi peridinyl)valeronitrile hydrochloride
TLC Rf=0.29.
MS 566 (M+).
NMR 0.88 (3H, t), 1.1-1.3 (18H, m), 1.8-3.6 (16H, m), 3.8-3.9 (6H, m), 4.41 (1H, d), 6.8-7.3 (7H, m).
Example 112
2-(3,4-Dimethoxyphenyl)-5-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-tridecylvaleronitrile hydrochloride
TLC Rf=0.38.
MS 608 (M+).
NMR 0.88 (3H, t), 1.1-1.3 (24H, m), 1.8-3.6 (16H, m), 3.8-3.9 (6H, m), 4.41 (1H, d), 6.8-7.3 (7H, m).
Example 113
2-Decyl-2-(3,4-dimethoxyphenyl)-6-(4-(4-fluorobenzoyl)-1-piperidinyl)hexane nitrile hydrochloride
TLC Rf=0.71.
MS 578 (M+).
NMR 0.84 (3H, t), 1.2-1 5 (18H, m), 1.6-2.1 (10H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H,m), 3.77 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.41 (2H, dd), 8.03 (2H, dd).
Example 114
2-(3,4-Dimethoxyphenyl)-6-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-undecylhexa nenitrile hydrochloride
TLC Rf=0.71.
MS 592 (M+).
NMR 0.84 (3H, t), 1.2-1.5 (20H, m), 1.6-2.1 (10H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.77 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.43 (2H, dd), 7.99 (2H, dd).
Example 115
2-(3,4-Dimethoxyphenyl)-6-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-tridecylhex anenitrile hydrochloride
TLC Rf=0.72.
MS 620 (M+).
NMR 0.84 (3H, t), 1.2-1.5 (24H, m), 1.6-2.1 (10H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.44 (2H, dd), 8.01 (2H, dd).
Example 116
2-(3,4-Dimethoxyphenyl)-6-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-tetradecylh exanenitrile hydrochloride
TLC Rf=0.73.
MS 634 (M+).
NMR 0.84 (3H, t), 1.2-1.5 (24H, m), 1.6-2.1 (10H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.76 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.41 (2H, dd), 8.02 (2H, dd).
Example 117
2-Decyl-2-(3,4-dimethoxyphenyl)-6-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl)hexanenitrile hydrochloride
TLC Rf=0.39.
MS 580 (M+).
NMR 0.87 (3H, t), 1.1-1.3 (18H, m), 1.8-3.6 (18H, m), 3.8-3.6 (18H, m), 3.8-3.9 (6H, m), 4.41 (1H, d), 6.8-7.3 (7H, m).
Example 118
2-(3,4-Dimethoxyphenyl)-6-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-undecylhexanenitrile hydrochloride
TLC Rf=0.39.
MS 594 (M+).
NMR 0.87 (3H, t , 1.1-1.3 (20H, m), 1.8-3.6 (18H, m), 3.8-3.9 (6H, m), 4.41 (1H, d), 6.8-7.3 (7H, m).
Example 119
2-(3,4-Dimethoxyphenyl)-6-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-tridecylhexanenitrile hydrochloride
TLC Rf=0.40.
MS 622 (M+).
NMR (fee base) 0.87 (3H, t), 1.1-1.3 (24H, m), 1.8-3.6 (18H, m), 3.8-3.9 (6H, m), 4.44 (1H, d), 6.8-7.3 (7H, m).
Example 120
2-(3,4-Dimethoxyphenyl)-6-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-tetradecylhexanenitrile hydrochloride
TLC Rf=0.41.
MS 636 (M+).
NMR (free base) 0.87 (3H, t), 1.1-1.3 (26H, m), 1.8-3.6 (18H, m), 3.8-3.9 (6H, m), 4.43 (1H, d), 6.8-7.3 (7H, m).
Example 121
2-Decyl-2-(3,4-dimethoxyphenyl)-7-(4-(4-fluorobenzoyl)-1-piperidinyl)heptan enitrile hydrochloride
TLC Rf=0.69.
MS 592 (M+).
NMR (free base) 0.81 (3H, t), 1.2-1.5 (18H, m), 1.6-2.2 (12H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.77 (3H, s), 3.78 (3H, s), 6.9-7.0 (3H, m), 7.42 (2H, dd), 8.02 (2H, dd).
Example 122
2-(3,4-Dimethoxyphenyl)-7-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-undecylhept anenitrile hydrochloride
TLC Rf=0.69.
MS 606 (M+).
NMR (free base) 0.84 (3H, t), 1.2-1.5 (20H, m), 1.6-2.2 (12H m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m) 3.6-3.8 (1H, m), 3.77 (3H, s), 3.78 (3H, s) 6.9-7.0 (3H, m , 7.41 (2H, dd), 8.04 (2H, dd).
Example 123
2-(3,4-Dimethoxyphenyl)-7-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-tridecylhep tanenitrile hydrochloride
TLC Rf=0.74.
MS 634 (M+).
NMR (free base) 0.84 (3H, t), 1.2-1.5 (24H, m), 1.6-2.2 (12H, m), 2.9-3.2 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.77 (3H, s), 3.80 (3H, s), 6 9-7.0 (3H, m), 7.44 (2H, dd), 8.10 (2H, dd).
Example 124
2-(3,4-Dimethoxyphenyl)-7-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-tetradecylh eptanenitrile hydrochloride
TLC Rf=0.72.
MS 648 (M+).
NMR 0.85 (3H, t), 1.2-1.5 (26H, m), 1.6-2.2 (12H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.76 (3H, s), 3.81 (3H, s), 6.9-7.0 (3H, m), 7.44 (2H, dd), 8.10 (2H, dd).
Example 125
2-Decyl-2-(3,4-dimethoxyphenyl)-7-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl)heptanenitrile hydrochloride
TLC Rf=0.41.
MS 594 (M+).
NMR 0.87 (3H, t), 1.1-1.3 (18H, m), 1.8-3.6 (20H, m), 3.8-3.9 (6H, m), 4.39 (1H, d), 6.8-7.3 (7H, m).
Example 126
2-(3,4-Dimethoxyphenyl)-7-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-undecylheptanenitrile hydrochloride
TLC Rf=0.39.
MS 608 (M+).
NMR 0.89 (3H, t), 1.1-1.3 (20H, m), 1.8-3.6 (20H, m), 3.8-3.9 (6H, m), 4.44 (1H, d), 6.8-7.3 (7H, m).
Example 127
2-(3,4-Dimethoxyphenyl)-7-(4-(.alpha.-hydroxy-4-fluorobenzoyl)-1-piperidiny l)-2-tridecylheptanenitrile hydrochloride
TLC Rf=0.45.
MS 636 (M+).
NMR 0.85 (3H, t), 1.1-1.3 (24H, m), 1.8-3.6 (20H, m), 3.8-3.9 (6H, m), 4.40 (1H, d), 6.8-7.4 (7H, m).
Example 128
2-(3,4-Dimethoxyphenyl)-7-(4-(.alpha.-hydroxy-4-fluorobenzoyl)-1-piperidiny l)-2-tetradecylheptanenitrile hydrochloride
TLC Rf=0.46.
MS 650 (M+).
NMR 0.85 (3H, t), 1.1-1.3 (26H, m), 1.8-3.6 (20H, m), 3.8-3.9 (6H, m), 4.41 (3H, d), 6.8-7.3 (7H, m).
Example 129
2-Decyl-2-(3,4-dimethoxyphenyl)-8-(4-(4-fluorobenzoyl)-1-piperidinyl)octane nitrile hydrochloride
TLC Rf=0.71.
MS 606 (M+).
NMR 0.88 (3H, t), 1.2-1.5 (18H, m), 1.6-2.2 (14H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.78 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.44 (2H, dd), 8.03 (2H, dd).
Example 130
2-(3,4-Dimethoxyphenyl)-7-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-undecylic acid nitrile hydrochloride
TLC Rf=0.78.
MS 620 (M+).
NMR 0.87 (3H, t), 1.2 1.5 (20H, m), 1.6-2.2 (14H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.78 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.44 (2H, dd), 8.03 (2H, dd).
Example 131
2-(3,4-Dimethoxyphenyl)-8-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-tridecyloct anenitrile hydrochloride
TLC Rf=0.70.
MS 648 (M+).
NMR 0.84 (3H, t), 1.1-1.5 (24H, m), 1.6-2.2 (14H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.78 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.41 (2H, dd), 8.03 (2H, dd).
Example 132
2-(3,4-Dimethoxyphenyl)-8-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-tetradecylo ctanenitrile hydrochloride
TLC Rf=0.70.
MS 662 (M+).
NMR 0.84 (3H, t), 1.1-1.5 (24H, m), 1.6-2.2 (14H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.78 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.41 (2H, dd), 8.03 (2H, dd).
Example 133
2-Decyl-2-(3,4-dimethoxyphenyl)-8-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-pip eridinyl)octanenitrile hydrochloride
TLC Rf=0.41.
MS 608 (M+).
NMR 0.85 (3H, t), 1.1-1.3 (18H, m), 1.8-3.6 (22H, m), 3.8-3.9 (6H, m), 4.42 (1H, d), 6.8-7.3 (7H, m).
Example 134
2-(3,4-Dimethoxyphenyl)-8-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-undecyloctanenitrile hydrochloride
TLC Rf=0.45.
MS 622 (M+).
NMR 0.85 (3H, t), 1.1-1.3 (20H, m), 1.8-3.6 (22H, m), 3.8-3.9 (6H, m), 4.43 (1H, d), 6.8-7.3 (7H, m).
Example 135
2-(3,4-Dimethoxyphenyl)-8-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-tridecylnitrile hydrochloride
TLC Rf=0.44.
MS 650 (M+).
NMR 0.88 (3H, t), 1.1-1.3 (24H, m), 1.8-3.6 (22H, m), 3.8-3.9 (6H, m), 4.45 (1H, d), 6.8-7.3 (7H, m).
Example 136
2-(3,4-Dimethoxyphenyl)-8-(4-(.alpha.-hydroxy-4-fluorobenzyl)-1-piperidinyl )-2-tetradecylnitrile hydrochloride
TLC Rf=0.42.
MS 664 (M+).
NMR 0.88 (3H, t), 1.1-1.3 (26H, m), 1.8-3.6 (22H, m), 3.8-3.9 (6H,m), 4.41 (1H, d), 6.8-7.3 (7H, m).
Example 137
2-(3,4-Dimethoxyphenyl)-2-dodecyl-4-(4-(4-fluorobenzoyl)-1-piperidinyl)buta nenitrile hydrochloride
TLC Rf=0.71.
MS 578 (M+).
NMR 0.85 (3H, t), 1.2-1.5 (22H, m), 1.6-2.2 (6H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.78 (3H, s), 3.79 (3H, s), 6 9-7.0 (3H, m), 7.41 (2H, dd), 8.03 (2H, dd).
Example 138
2-(3,4-Dimethoxyphenyl)-2-dodecyl-4-(4-(4-fluorobenzoyl)-1-piperidinyl)buta nenitrile hydrochloride
TLC Rf=0.37.
MS 580 (M+).
NMR 0.87 (3H, t), 1.1-1.3 (22H, m), 1.8-3.6 (12H, m), 3.8-3.9 (6H, m), 4.44 (1H, d), 6.8-7.3 (7H, m).
Example 139
2-Dodecyl-2-(4-methoxyphenyl)-5-(4-(4-fluorobenzoyl)-1-piperidinyl)valeroni trile hydrochloride
TLC Rf=0.78.
MS 562 (M+).
NMR 0.83 (3H, t), 1.2-1.5 (22H, m), 1.6-2.2 (8H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.79 (3H, s), 7.0-8.0 (8H, m).
Example 140
2-Dodecyl-5-(4-(4-fluorobenzoyl)-1-piperidinyl)-2-phenyl-valeronitrile hydrochloride
TLC Rf=0.79.
MS 532 (M+).
NMR 0.83 (3H, t), 1.2-1.5 (22H, m), 1.6-2.2 (8H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 7.0-8.0 (9H, m).
Example 141
2-(3,4-Dimethoxyphenyl)-2-dodecyl-5-(4-(.alpha.-hydroxybenzyl)-1-piperidiny l)valeronitrile hydrochloride
TLC Rf=0.40.
MS 576 (M+).
NMR 0.88 (3H, t), 1.1-1.3 (22H, m), 1.8-3.6 (16H, m), 3.8-3.9 (6H, m), 4.42 (1H, d), 6.8-7.3 (8H, m).
Example 142
2-(4-(3,4-Dimethoxy-.alpha.-hydroxybenzyl)-1-piperidinyl)-2-(3,4-dimethoxyp henyl)-2-dodecylvaleronitrile hydrochloride
TLC Rf=0.18.
MS 636 (M+).
NMR 0.88 (3H, t), 1.1-3.6 (38H, m), 3.8-3.9 (12H, m), 4.3-4.4 (1H, m), 6.8-7.3 (6H, m).
Example 143
2-(3,4-Dimethoxyphenyl-2-dodecyl-5-(4-phenyl-4-hydroxy-1-piperidinyl)valero nitrile hydrochloride
TLC Rf=0.45.
MS 562 (M+).
NMR (free base) 0.88 (3H, t), 1.0-2.9 (36H, m), 3.87 (3H, s), 3.93 (3H, s), 6.8-7.0 (3H, m), 7.2-7.6 (5H, m).
Example 144
5-(4-Benzhydryl-1-piperazinyl)-2-(3,4-dimethoxyphenyl)-2-dodecylvaleronitri le hydrochloride
TLC Rf=0.47.
MS 637 (M+).
NMR (free base) 0.88 (3H, t), 1.0-2.5 (36H, m), 3.84 (3H, s), 3.86 (3H, s), 4.20 (1H, s), 6.8-7.4 (13H, m).
Example 145
2-(3,4-Dimethoxyphenyl)-2-dodecyl-5-(4-(2,4,6-trimethylbenzyl)-1-piperidiny l)valeronitrile hydrochloride
TLC Rf=0.88.
MS 616 (M+).
NMR 0.88 (3H, t), 1.1-1.5 (22H, m), 1.8-3.5 (15H, m), 2.16, 2.18 (6H, 2s), 2.26, 2.29 (3H, 2s), 3.89, 3.90 (3H, 2s), 3.94, 3.96 (3H, s), 6.8-7.3 (5H, m).
Example 146
2-(3,4-Dimethoxyphenyl)-5-(4-(4-fluorobenzyl)-1-piperazinyl)-2-dodecylvaler onitrile hydrochloride
TLC Rf=0.34.
MS 579 (M+).
NMR 0.88 (3H, t), 1.1-3.4 (38H, m), 6.8-8.0 (7H, m).
Example 147
5-(4-Benzyl-1-piperazinyl)-2-(3,4-dimethoxyphenyl)-2-dodecylvaleronitrile hydrochloride
TLC Rf=0.39.
MS 561 (M+).
NMR 0.84 (3H, t), 1.1-3.4 (38H, m), 6.8-7.4 (8H, m).
Example 148
4-(3,4-Dimethoxyphenyl)-1-(4-(4-fluorobenzoyl)-1-piperidinyl)hexadecanenitr ile hydrochloride
TLC Rf=0.79.
MS 567 (M+).
NMR (free base) 0.87 (3H, t), 1.1-3.9 (38H, m), 6.8-7.4 (8H, m).
Example 149
Methyl 2-(3,4-dimethoxyphenyl)-2-dodecyl-2-(3-(4-(4-fluorobenzoyl)-1-piperidinyl) -1-propyl)acetate hydrochloride
TLC Rf=0.61.
MS 625 (M+).
NMR (free base) 0.84 (3H, t), 1.2-1.5 (22H, m), 1.8-2.1 (8H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.61 (3H, s), 3.76 (3H, s), 3.79 (3H, s), 6.9-7.0 (3H, m), 7.40 (2H, dd), 8.07 (2H, dd).
Example 150
2-(3,4-Dimethoxyphenyl)-2-dodecyl-2(3-(4-(4-fluorobenzoyl)-1-piperidinyl)-1 -propyl)acetid acid hydrochloride
TLC Rf=0.24.
MS 612 (MH+).
NMR (D
MSO-d6) 0.84 (3H, t), 1.2-1.5 (22H, m), 1.8-2.1 (8H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.75 (3H, s), 3.78 (3H, s) 6.9-7.0 (3H, m), 7.32 (2H, dd), 8.12 (2H, dd).
Example 151
2-(3,4-Dimethoxyphenyl)-2-dodecyl-2-(3-(4-(4-fluorobenzoyl)-1-piperidinyl)- 1-propyl)acetamide hydrochloride
TLC Rf=0.44.
MS 610 (M+).
NMR 0.87 (3H, t), 1.2-1.5 (22H, m), 1.8-2.1 (8H, m), 2.9-3.1 (4H, m), 3.4-3.5 (2H, m), 3.6-3.8 (1H, m), 3.82 (3H, s), 3.88 (3H, s), 6.9-7.0 (3H, m), 7.41 (2H, dd), 8.01 (2H, dd).
Example 152
2-(3,4-Dimethoxyphenyl)-7-(4-(.alpha.-hydroxy-4-fluorobenzoyl)-1-piperidiny l)-2-tridecylheptanenitrile hydrochloride
TLC Rf=0.67.
MS 580 (M+).
NMR 0.82 (3H, t), 1.1-3.4 (34H, m), 3.58 (3H, s), 3.86 (3H, s , 3.88 (3H, s), 6.9-8.0 (7H, m).
Example 153
N-(3-(4-(4-Fluorobenzoyl)-1-propyl)-N-methyl 4-cyano-4-(3,4-dimethoxyphenyl)hexadecylamine hydrochloride
TLC Rf=0.32.
MS 582 (M+).
NMR 0.87 (3H, t), 1.1-3.4 (34H, m), 3.58 (3H, s), 3.86 (3H, s , 3.88 (3H, s), 4.25 (1H, d), 6.9-8.0 (7H, m).
Example 154
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-hexylpiperidine hydrochloride
A solution of 273 mg (1 mmol) of 4-(5H-dibenzo[a,d]cyclo-hepten-5-ylidene)-1-hexylpiperidine, 165 mg (1 mmol) of 1-bromohexane, 745 mg (5 mmols) of sodium iodide and 414 mg (3 mmols) of potassium carbonate in 20 ml of methyl isobutyl ketone was stirred and refluxed at 120.degree. C. overnight on an oil bath. After the reaction, the mixture was washed by adding 20 ml of water thereto. Then the organic phase was separated and the solvent was distilled off under reduced pressure. After purifying by silica gel column chromatography (eluent: methanol/chloroform, 1/100-1/50), the product was converted into the hydrochloride with an equimolar hydrogen chloride/dioxane solution.
Amount yielded 180 mg.
Yield 46%.
TLC Rf=0.68.
MS 357 (M+).
NMR 0.83 (3H, t), 1.2-1.4 (6H, m), 1.7-1.9 (2H, m), 2.31 (2H, dd), 2.53 (2H, d), 2.7-2.8 (2H, m), 3.14 (2H, dd), 3.38 (2H, dd), 3.38 (2H, d), 6.92 (2H, s), 7.2-7.4 (8H, m).
The procedures of the following examples were conducted in a manner similar to that of Example 154.
Example 155
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-octylpiperidine hydrochloride
Amount yielded 300 mg.
Yield 72%.
TLC Rf=0.71.
MS 385 (M+).
NMR 0.85 (3H, t), 1.2-1.4 (10H, m), 1.7-2.0 (2H, m), 2.30 (2H, dd), 2.53 (2H, d), 2.7-2.9 (2H, m), 3.13 (2H, dd), 3.38 (2H, d), 6.90 (2H, s), 7.1-7.4 (8H, m).
Example 156
1-Decyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrochloride
Amount yielded 300 mg.
Yield 67%.
TLC Rf=0.75.
MS 413 (M+).
NMR 0.85 (3H, t), 1.2-1.4 (14H, m), 1.7-1.9 (2H, m), 2.33 (2H, dd), 2.54 (2H, d), 2.7-2.8 (2H, m), 3.15 (2H, dd), 3.39 (2H, d), 6.92 (2H, s), 7.1-7.4 (8H, m).
Example 157
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-dodecylpiperidine hydrochloride
Amount yielded 1.10 g.
Yield 92%.
TLC Rf=0.78.
MS 441 (M+).
NMR 0.85 (3H, t), 1.1-1.5 (18H, m), 1.7-1.9 (2H, m), 2.32 (2H, dd), 2.54 (2H, d), 2.7-2.8 (2H, m), 3.12 (2H, dd), 3.36 (2H, d), 6.93 (2H, s), 7.1-7.4 (8H, m).
Example 158
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-tetradecylpiperidine hydrochloride
Amount yielded 1.20 g.
Yield 95%.
TLC Rf=0.78.
MS 469 (M+).
NMR 0.82 (3H, t), 1.1-1.5 (22H, m), 1.7-1.9 (2H, m), 2.33 (2H, dd), 2.55 (2H, d), 2.7-2.8 (2H, m), 3.15 (2H, dd), 3.40 (2H, d), 6.92 (2H, s), 7.1-7.4 (8H, m).
Example 159
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-hexadecylpiperidine hydrochloride
Amount yielded 1.18 g.
Yield 88%.
TLC Rf=0.80.
MS 497 (M+).
NMR 0.80 (3H, t), 1.1-1.6 (26H, m), 1.7-1.9 (2H, m), 2.33 (2H, dd), 2.58 (2H, d), 2.7-2.8 (2H, m), 3.20 (2H, dd), 3.40 (2H, d), 6.88 (2H, s), 7.1-7.4 (8H, m).
Example 160
1-Cyclohexylmethyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine hydrochloride
Amount yielded 520 mg.
Yield 51%.
TLC Rf=0.75.
MS 369 (M+).
NMR 0.8-2.1 (11H, m), 2.42 (2H, dd), 2.65 (2H, d), 2.78 (2H, d), 3.20 (2H, dd), 3.42 (2H, d), 6.91 (2H, s), 7.1-7.4 (8H, m).
Example 161
1-Cyclohexyl-2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)etha ne hydrochloride
Amount yielded 780 mg.
Yield 74%.
TLC Rf=0.75.
MS 383 (M+).
NMR 0.8-2.1 (13H, m), 2.45 (2H, dd), 2.67 (2H, d), 2.7-2.9 (2H, m), 3.0 (2H, dd), 3.48 (2H, d), 6.94 (2H, s), 7.1-7.4 (8H, m).
Example 162
1-Cyclohexyl-3-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)prop ane hydrochloride
Amount yielded 1.02 g.
Yield 94%.
TLC Rf=0.77.
MS 397 (M+).
NMR 0.8-2.1 (15H, m), 2.47 (2H, dd), 2.68 (2H, d), 2.7-2.9 (2H, m), 3.0 (2H, dd), 3.49 (2H, d), 6.94 (2H, s), 7.1-7.4 (8H, m).
Example 163
1-Cyclohexyl-4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)buta ne hydrochloride
Amount yielded 815 mg.
Yield 72%.
TLC Rf=0.78.
MS 411 (M+).
NMR 0.8-2.1 (17H, m), 2.28 (2H, dd), 2.52 (2H, d), 2.7-2.9 (2H, m), 3.08 (2H, dd), 3.35 (2H, d), 6.92 (2H, s), 7.1-7.4 (8H, m).
Example 164
1-Cyclohexyl-5-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)pent ane hydrochloride
Amount yielded 750 mg.
Yield 65%.
TLC Rf=0.80.
MS 411 (M+).
NMR 0.8-2.1 (19H, m), 2.25 (2H, dd), 2.68 (2H, d), 2.7-2.9 (2H, m), 3.12 (2H, dd), 3.38 (2H, d), 6.92 (2H, s), 7.1-7.4 (8H, m).
Example 165
1-Benzyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrochloride
Amount yielded 320 mg.
Yield 80%.
TLC Rf=0.42.
MS 363 (M+).
NMR 2.28 (2H, dd), 2.52 (2H, d), 3.14 (2H, dd), 3.31 (2H, d), 4.01 (2H, d), 6.90 (2H, s), 7.1-7.6 (13H, m).
Example 166
2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylethane hydrochloride
Amount yielded 310 mg.
Yield 75%.
TLC Rf=0.45.
MS 377 (M+).
NMR 2.28 (2H, dd), 2.51 (2H, d), 3.0-3.3 (6H, m), 3.47 (2H, d), 6.90 (2H, s), 7.1-7.4 (13H, m).
Example 167
3-(4-(5H-Dibenzo[a d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylpropane hydrochloride
Amount yielded 330 mg.
Yield 77%.
TLC Rf=0.50.
MS 391 (M+).
NMR 2.1-2.4 (4H, m), 2.51 (2H, d), 2.65 (2H, t), 2.7-2.9 (2H, m), 3.12 (2H, dd), 3.38 (2H, d), 6.90 (2H, s), 7.1-7.4 (13H, m).
Example 168
(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylbutane hydrochloride
Amount yielded 180 mg.
Yield 41%.
TLC Rf=0.50.
MS 405 (M+).
NMR 1.4-1.9 (4H, m), 2.28 (2H, dd), 2.52 (2H, d), 2.61 (2H, t), 2.7-2.8 (2H, m), 3.12 (2H, dd), 3.35 (2H, d), 6.90 (2H, s), 7.1-7.4 (13H, m).
Example 169
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylpentane hydrochloride
Amount yielded 110 mg.
Yield 24%.
TLC Rf=0.55.
MS 419 (M+).
NMR 1.2-1.9 (6H, m), 2.25 (2H, dd), 2.52 (2H, d), 2.60 (2H, t), 2.7-2.8 (2H, m), 3.08 (2H, dd), 3.35 (2H, d), 6.90 (2H, s), 7.1-7.4 (13H, m).
Example 170
6-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylhexane hydrochloride
Amount yielded 315 mg.
Yield 67%.
TLC Rf=0.56.
MS 433 (M+).
NMR 1.1-1.9 (8H, m), 2.26 (2H, dd), 2.56 (2H, d), 2.61 (2H, t), 2.7-2.8 (2H, m), 3.10 (2H, dd), 3.35 (2H, d), 6.91 (2H, s), 7.1-7.4 (13H, m).
Example 171
7-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylheptane hydrochloride
Amount yielded 267 mg.
Yield 55%.
TLC Rf=0.56.
MS 447 (M+).
NMR 1.1-1.9 (10H, m), 2.25 (2H, dd), 2.55 (2H, d), 2.65 (2H, t), 2.7-2.8 (2H, m), 3.07 (2H, dd), 3.32 (2H, d), 6.90 (2H, s), 7.1-7.4 (13H, m).
Example 172
2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenoxyethane hydrochloride
Amount yielded 1.95 g.
Yield 55%.
TLC Rf=0.56.
MS 393 (M+).
NMR (fee base) 2.1-2.5 (2H, m), 2.58 (2H, t), 2.6-2.7 (2H, m), 4.05 (2H, t), 6.89 (2H, d), 6.92 (2H, s), 7.1-7.4 (11H, m).
Example 173
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenoxypropane hydrochloride
Amount yielded 2.15 g.
Yield 48%.
TLC Rf=0.58.
MS 407 (M+).
NMR (free base) 1.97 (2H, tt), 2.1-2.5 (6H, m), 2.54 (2H, t), 2.6-2.7 (2H, m), 3.97 (2H, dd), 6.86 (2H, d), 6.90 (2H, s), 7.1-7.4 (11H, m).
Example 174
4-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenoxybutane hydrochloride
Amount yielded 1.18 g.
Yield 86%.
TLC Rf=0.61.
MS 421 (M+).
NMR (free base) 1.8-2.7 (14H, m), 3.96 (2H, t), 6.87 (2H, d), 6.90 (2H, s , 7.1-7.4 (11H, m).
Example 175
2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylthioetha ne hydrochloride
Amount yielded 0.97 g.
Yield 87%.
TLC Rf=0.55.
MS 409 (M+).
NMR (free base) 2.0-2.6 (10H, m), 2.78 (2H, t), 6.86 (2H, s), 7.1-7.4 (11H, m).
Example 176
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylthioprop ane hydrochloride
Amount yielded 0.85 g.
Yield 74%.
TLC Rf=0.62.
MS 423 (M+).
NMR (free base) 1.73 (2H, tt), 2.0-2.6 (10H, m), 2.80 (2H, t), 6.88 (2H, d), 7.1-7.4 (11H, m).
Example 177
4-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-phenylthiobuta ne hydrochloride
Amount yielded 0.85 g.
Yield 72%.
TLC Rf=0.62.
MS 437 (M+).
NMR (free base) 1.6-2.6 (14H, m), 2.80 (2H, t), 6.88 (2H, d), 7.1-7.4 (11H, m).
Example 178
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-(2-nitrobenzene-sulfonyl)amin oethyl)piperidine hydrochloride
TLC Rf=0.72.
MS 502 (M+).
Example 179
1-(2-(2-Aminobenzenesulfonyl)aminoethyl)-4-(5H-dibenzo[a,d]-cyclohepten-5-y lidene)piperidine hydrochloride
TLC Rf=0.51.
MS 472 (M+).
Example 180
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-(2-ethoxycarbonyl-benzenesulf onyl)aminoethyl)piperidine hydrochloride
TLC Rf=0.68.
MS 544 (M+).
Example 181
3-(2-((4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-ethyl)-2,4(1 H,3H)quinazolinedione hydrochloride
TLC Rf=0.85.
MS 462 (M+).
Example 182
5,6-Benzo-2,4-diazo(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidin yl)ethyl)tetrahydrothiopyran hydrochloride
TLC Rf=0.91.
MS 498 (M+).
Example 183
2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-(3,4-dimethoxy phenyl)ethane hydrochloride
TLC Rf=0.78.
MS 450 (M+).
Example 184
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-propyl-4-fluorop henylsulfoxide hydrochloride
TLC Rf=0.78.
MS 457 (M+).
Example 185
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-propyl-4 fluorophenylsulfone hydrochloride
TLC Rf=0.62.
MS 473 (M+).
Example 186
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-(2-aminophenylthio)-1-propyl) piperidine hydrochloride
TLC Rf=0.84.
MS 439 (M+).
Example 187
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(1-(2-benzoylamino)-ethyl)piperi dine hydrochloride
TLC Rf=0.84.
MS 420 (M+).
Example 188
4-(5H-Dibenzo[a d]cyclohepten-5-ylidene)-1-(1-(2-N-phenyl-carbamoylamino)ethyl)piperidine hydrochloride
TLC Rf=0.55.
MS 435 (M+).
Example 189
1-(3-(2-Cinnamoylaminophenylthio)-1-propyl)-4-(5H-dibenzo[a,d]-cyclohepten- 5-ylidene)piperidine hydrochloride
TLC Rf=0.66.
MS 568 (M+).
NMR (free base) 1.74 (2H, tt), 2.0-2.6 (8H, m), 2.80 (2H, t), 6.59 (1H, d), 6.88 (2H, s), 7.0-7.6 (16H, m), 7.75 (1H, d), 8.5 (1H, d), 8.68 (1H, bs).
Example 190
1-Cinnamyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrochloride
TLC Rf=0.84.
MS 389 (M+).
NMR (free base) 2.1-2.7 (8H, m), 3.15 (2H, d), 6.25 (1H, td), 6.47 (1H, d), 6.90 (2H, s), 7.1-7.4 (13H, m).
Example 191
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4,5-trimeth oxyphenyl)-2-isopropylvaleronitrile hydrochloride
TLC Rf=0.80.
MS 563 (M+).
Example 192
2-(3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-propyl)-2-p henyl-1,3-dithiane-1,1,3,3-tetroxide hydrochloride
TLC Rf=0.48.
MS 573 (M+).
Example 193
2-(3,4-Dimethoxyphenyl)-2-(3-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-pi peridinyl)-1-propyl)-1,3-dithiane-1,1,3,3-tetroxide hydrochloride
TLC Rf=0.48.
MS 573 (M+).
Example 194
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dichlorop henyl)-2-isopropylvaleronitrile hydrochloride
TLC Rf=0.94.
MS 540 (M+).
Example 195
2-(3-Benzoylphenyl)-5-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidin yl)-2-methylvaleronitrile hydrochloride
TLC Rf=0.88.
MS 548 (M+).
Example 196
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2,2-diphenylvale ronitrile hydrochloride
TLC Rf=0.74.
MS 506 (M+).
Example 197
4-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-3',4'-dimethoxyb utyrophenone hydrochloride
TLC Rf=0.61.
MS 479 (M+).
Example 198
6-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenylhexaneni trile hydrochloride
TLC Rf=0.86.
MS 430 (M+).
Example 199
6-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-ph enylhexanenitrile hydrochloride
TLC Rf=0.88.
MS 472 (M+).
Example 200
6-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-isopropylhexanenitrile hydrochloride
TLC Rf=0.81.
MS 546 (M+).
Example 201
7-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenylheptanen itrile hydrochloride
TLC Rf=0.84.
MS 444 (M+).
Example 202
7-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-ph enylheptanenitrile hydrochloride
TLC Rf=0.84.
MS 486 (M+).
Example 203
7-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-isopropylheptanenitrile hydrochloride
TLC Rf=0.86.
MS 560 (M+).
Example 204
2-(3-Chloropropyl)-5-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidiny l)-2-phenylvaleronitrile hydrochloride
TLC Rf=0.92.
MS 506 (M+).
Example 205
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenyl-2-pheny lthiovaleronitrile hydrochloride
TLC Rf=0.81.
MS 538 (M+).
Example 206
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-phenylthiovaleronitrile hydrochloride
TLC Rf=0.91.
MS 598 (M+).
Example 207
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(1-naphthyl)va leronitrile hydrochloride
TLC Rf=0.85.
MS 580 (M+).
Example 208
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(1-naphthyl)-2 isopropylvaleronitrile hydrochloride
TLC Rf=0.90.
MS 522 (M+).
Example 209
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(2-naphthyl)va leronitrile hydrochloride
TLC Rf=0.85.
MS 480 (M+).
Example 210
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(2-naphthyl)-2 -isopropylvaleronitrile hydrochloride
TLC Rf=0.87.
MS 522 (M+).
Example 211
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3-trifluorome thylphenyl)valeronitrile hydrochloride
TLC Rf=0.72.
MS 498 (M+).
Example 212
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-(3 -trifluoromethylphenyl)valeronitrile hydrochloride
TLC Rf=0.75.
MS 540 (M+).
Example 213
8-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenyloctaneni trile hydrochloride
TLC Rf=0.84.
MS 472 (M+).
Example 214
8-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-ph enyloctanenitrile hydrochloride
TLC Rf=0.88.
MS 514 (M+).
Example 215
8-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-isopropyloctanenitrile hydrochloride
TLC Rf=0.82.
MS 574 (M+).
Example 216
1-(3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-propyl)-1-i ndanenitrile hydrochloride
TLC Rf=0.90.
MS 456 (M+).
Example 217
1-(3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-propyl)-5,6 -dimethoxy-1-indanenitrile hydrochloride
TLC Rf=0.85.
MS 516 (M+).
Example 218
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(1-methylpyrro l-2-yl)valeronitrile hydrochloride
TLC Rf=0.61.
MS 433 (M+).
Example 219
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-(1 -methylpyrrol-2-yl)valeronitrile hydrochloride
TLC Rf=0.71.
MS 475 (M+).
Example 220
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-(p yrrol-2-yl)valeronitrile hydrochloride
TLC Rf=0.55.
MS 461 (M+).
Example 221
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3-.alpha.-hyd roxybenzyl)phenyl)-2-methylvaleronitrile hydrochloride
TLC Rf=0.51.
MS 550 (M+).
Example 222
2-(3-Benzoylphenyl)-6-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidin yl)-2-methylhexanenitrile hydrochloride
TLC Rf=0.88.
MS 562 (M+).
Example 223
6-{4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3-(.alpha.-hy droxybenzyl)phenyl-2-methylhexanenitrile hydrochloride
TLC Rf=0.52.
MS 564 (M+).
Example 224
2-(3-Benzoylphenyl)-7-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidin yl)-2-methylheptanenitrile hydrochloride
TLC Rf=0.91.
MS 576 (M+).
Example 225
7-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3-(.alpha.-hy droxybenzyl)phenyl-2-methylheptanenitrile hydrochloride
TLC Rf=0.52.
MS 578 (M+).
Example 226
2-(3-Benzoylphenyl)-8-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidin yl)-2-methyloctanenitrile hydrochloride
TLC Rf=0.90.
MS 590 (M+).
Example 227
8-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3-(.alpha.-hy droxybenzyl)phenyl-2-methyloctanenitrile hydrochloride
TLC Rf=0.61.
MS 592 (M+).
Example 228
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-methyl-2-pheny lvaleronitrile hydrochloride
TLC Rf=0.91.
MS 544 (M+).
Example 229
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-methylvaleronitrile hydrochloride
TLC Rf=0.85.
MS 504 (M+).
Example 230
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-ethyl-2-phenyl valeronitrile hydrochloride
TLC Rf=0.92.
MS 458 (M+).
Example 231
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-ethylvaleronitrile hydrochloride
TLC Rf=0.90.
MS 518 (M+).
Example 232
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-propyl-2-pheny lvaleronitrile hydrochloride
TLC Rf=0.93.
MS 472 (M+).
Example 233
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-propylvaleronitrile hydrochloride
TLC Rf=0.91.
MS 532 (M+).
Example 234
2-Butyl-5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenyl valeronitrile hydrochloride
TLC Rf=0.95.
MS 486 (M+).
Example 235
2Butyl-5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-di methoxyphenyl)valeronitrile hydrochloride
TLC Rf=0.90.
MS 546 (M+).
Example 236
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-pentyl-2-pheny lvaleronitrile hydrochloride
TLC Rf=0.95.
MS 500 (M+).
Example 237
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-pentylvaleronitrile hydrochloride
TLC Rf=0.92.
MS 560 (M+).
Example 238
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-hexyl-2-phenyl valeronitrile hydrochloride
TLC Rf=0.95.
MS 514 (M+).
Example 239
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-hexylvaleronitrile hydrochloride
TLC Rf=0.92.
MS 574 (M+).
Example 240
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-heptyl-2-pheny lvaleronitrile hydrochloride
TLC Rf=0.95.
MS 528 (M+).
Example 241
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-heptylvaleronitrile hydrochloride
TLC Rf=0.91.
MS 588 (M+).
Example 242
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-octyl-2-phenyl valeronitrile hydrochloride
TLC Rf=0.94.
MS 543 (M+).
Example 243
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy pheny)-2-octylvaleronitrile hydrochloride
TLC Rf=0.94.
MS 602 (M+).
Example 244
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-nonyl-2-phenyl valeronitrile hydrochloride
TLC Rf=0.95.
MS 556 (M+).
Example 245
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)-2-nonylvaleronitrile hydrochloride
TLC Rf=0.93.
MS 616 (M+).
Example 246
2-Decyl-5-(4-(5H Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenylvaleronitrile hydrochloride
TLC Rf=0.95.
MS 570 (M+).
Example 247
2-Decyl-5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-d imethoxyphenyl)valeronitrile hydrochloride
TLC Rf=0.94.
MS 630 (M+).
Example 248
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl}-acetophenone hydrochloride
TLC Rf=0.71.
MS 391 (M+).
Example 249
2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-phen ylethane hydrochloride
TLC Rf=0.36.
MS 393 (M+).
Example 250
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-propiophenone hydrochloride
TLC Rf=0.74.
MS 405 (M+).
Example 251
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-phen ylpropane hydrochloride
TLC Rf=0.35.
MS 407 (M+).
Example 252
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-butyrophenone hydrochloride
TLC. Rf=0.75.
MS 419 (M+).
Example 253
4-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-phen ylbutane hydrochloride
TLC Rf=0.39.
MS 421 (M+).
Example 254
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-valerophenone hydrochloride
TLC Rf=0.76.
MS 433 (M+).
Example 255
5-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-phenylp entane hydrochloride
TLC Rf=0.78.
MS 447 (M+).
Example 256
2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-4'-fluoroacetoph enone hydrochloride
TLC Rf=0.80.
MS 409 (M+).
Example 257
2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-(4-f luorophenyl)ethane hydrochloride
TLC Rf=0.44.
MS 411 (M+).
Example 258
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-4'-fluoropropiop henone hydrochloride
TLC Rf=0.80.
MS 423 (M+).
Example 259
3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-(4-f luorophenyl)propane hydrochloride
TLC Rf=0.44.
MS 425 (M+).
Example 260
4-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-(4-f luorophenyl)butane hydrochloride
TLC Rf=0.45.
MS 439 (M+).
Example 261
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-4'-fluorovalerop henone hydrochloride
TLC Rf=0.84.
MS 451 (M+).
Example 262
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-hydroxy-1-(4-f luorophenyl)pentane hydrochloride
TLC Rf=0.51.
MS 453 (M+).
Example 263
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-fluorobenzyl)-piperidine hydrochloride
TLC Rf=0.75.
MS 381 (M+).
Example 264
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-fluorobenzyl)-piperidine hydrochloride
TLC Rf=0.79.
MS 381 (M+).
Example 265
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-fluorobenzyl)-piperidine hydrochloride
TLC Rf=0.61.
MS 381 (M+).
Example 266
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-trifluoromethylbenzyl)piperid ine hydrochloride
TLC Rf=0.83.
MS 431 (M+).
Example 267
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-trifluoromethylbenzyl)piperid ine hydrochloride
TLC Rf=0.82.
MS 431 (M+).
Example 268
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine hydrochloride
TLC Rf=0.79.
MS 431 (M+).
Example 269
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-methoxybenzyl)piperidine hydrochloride
TLC Rf=0.61.
MS 393 (M+).
Example 270
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-methoxybenzyl)piperidine hydrochloride
TLC Rf=0.61.
MS 393 (M+).
Example 271
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-methoxybenzyl)piperidine hydrochloride
TLC Rf=0.52.
MS 393 (M+).
Example 272
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-pentafluorobenzyl-piperidine hydrochloride
TLC Rf=0.80.
MS 453 (M+).
Example 273
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-phenylvaleroni trile hydrochloride
TLC Rf=0.86.
MS 440 (M+).
Example 274
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-isopropyl-2-ph enylvaleronitrile hydrochloride
TLC Rf=0.82.
MS 488 (M+).
Example 275
5-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-2-(3,4-dimethoxy phenyl)valeronitrile hydrochloride
TLC Rf=0.75.
MS 500 (M+).
Example 276
2-(3-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-1-propyl)-2 (4-fluorophenyl)-1,3-dioxolane hydrochloride
TLC Rf=0.68.
MS 481 (M+).
Example 277
4-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)-4'-fluorobutyrop henone hydrochloride
TLC Rf=0.82.
MS 437 {M+).
Example 278
As test animals, four male rats (weighing 400 to 440 g) with spontaneous hypertension that were sufficiently adapted for feeding and hypertension was confirmed were used.
Physiological saline aqueous solution containing 2.5% Nicole of sample and 2.5% ethanol was intravenously administered at once in a dose of 1 ml/kg. Blood pressure after the administration was measured by the tail-cuff method.
The results are shown below
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Claims
What is new and desired to be secured by Letters Patent of the United States is:
1. An ethylamine compound of formula (I): ##STR7## wherein the moiety A-B is selected from the group consisting of ##STR8## Q is a member selected from the group consisting of o-nitrophenyl, o-aminophenyl, o-ethylcarbamoylphenyl, o-styrylcarbamoylphenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dihydroxyphenyl, 3-trifluoromethylphenyl, pyrrolyl, N-methylpyrrolyl, 4-methoxyphenyl, 3-benzoylphenyl, phenyl, 3,4-dimethylphenyl, 2-methoxy-5-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chlorophenyl, 3-iodophenyl, 3-phenoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3,5-dimethoxyphenyl, 3-benzyloxphenyl, 3,4-dibenzyloxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-ethoxyphenyl, 2-methylnaphthyl, 2-bromophenyl, 2-bromo-4,5-dimethoxyphenyl, pentafluorophenyl, 2-chlorophenyl, 2,3,6-trichlorophenyl, 2,4-dichlorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2-iodophenyl, 2-nitro-4-trifluoromethylphenyl, 2-phenoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-benzyloxyphenyl, 2-ethoxyphenyl, o-biphenyl, 2-trifluorophenyl, 2-methylphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-methylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4-cyanophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-ethoxyphenyl, 3-methoxy-4-ethoxyphenyl, 4-(2-diethylaminoethoxy)phenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 3-ethoxy-4-hydroxyphenyl, p-biphenyl, 4-butoxyphenyl, 4-(2'-methyl-2'-butyl)phenyl, 4-isopropylphenyl, p-tolyl, 4-benzylphenyl, 4-ethylphenyl, 4-hydroxyphenyl, 2-cyano-4-methylphenyl, 3,4-methylenedioxyphenyl, 3-pyridyl, 2-nitrophenyl, 2-chloro-4-nitrophenyl, 3-nitrophenyl, 2-nitro-5-fluorophenyl, 4-nitrophenyl, 4-aminophenyl, 3,5-di(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,4-di(trifluoromethyl)phenyl, 3,5-difluorophenyl, 4-ethenylphenyl, 2,4,5-trimethylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-3-ethoxyphenyl, 4-(2'-methylpropyl)phenyl, 4-methoxycarbonylphenyl, 3,4-diethoxyphenyl, 2-iodo-4,5-dimethoxyphenyl, 4-neopentanoylphenyl, 2-nitro-4,5-dimethoxyphenyl, 2-thiopheno, 2-furyl, 3-pyrrolyl, N-methyl-3-pyrrolyl, 3-thiopheno, 3-furyl, n-butyl, cyclohexyl, 3-(.alpha.-hydroxybenzyl)phenyl, 4-trifluoromethylphenyl and 3-methoxyphenyl; X is a member selected from the group consisting of ##STR9## --CO--(CH.sub.2).sub.m --, --CHOH--(CH.sub.2).sub.o --, --S(O).sub.k --(CH.sub.2).sub.l --, --(CH.sub.2).sub.p --, --O--(CH.sub.2).sub.q --, --SO.sub.2 --NH--, --CO--NH--, --NH--CO--NH--, ##STR10## wherein R is hydrogen, C.sub.1-15 alkyl, C.sub.3-8 cycloalkyl, 3-chloropropyl, phenyl, benzyl, phenylthio, 1-naphthyl or 2-naphthyl, R.sup.1 is --CN, --CONH.sub.2, --COOCH.sub.3, n is an integer of from 0 to 6, m is an integer of from 0 to 6, o is an integer of from 0 to 6, p is an integer of from 0 to 12, k is an integer of from 0 to 2, l is an integer of from 2 to 4, q is an integer of from 2 to 4, r is an integer of from 2 to 4, and s is an integer of from 2 to 4; or a physiologically acceptable salt thereof.
2. The ethylamine compound of claim 1, wherein A-B is: ##STR11##
3. The ethylamine compound of claim 1, having a formula selected from the group consisting of: ##STR12##
4. The ethylamine compound of claim 2; wherein X is ##STR13## --CO--(CH.sub.2).sub.m --, --S(O).sub.k --(CH.sub.2).sub.l --, --(CH.sub.2).sub.p --, --SO.sub.2 --NH-- and ##STR14## wherein R is hydrogen, C.sub.1-15 alkyl, C.sub.3-8 cycloalkyl, 3-chloropropyl, phenyl, benzyl, phenylthio, 1-naphthyl or 2-naphthyl, R.sup.1 is --CN, --CONH.sub.2 or --COOCH.sub.3, n is an integer of from 0 to 6, m is an integer of from 0 to 6, p is an integer of from 0 to 12, k is an integer of from 0 to 2, l is an integer of from 2 to 4, and s is an integer of from 2 to 4.
5. The ethylamine compound of claim 4, having a formula selected from the group consisting of: ##STR15##
6. The ethylamine compound of claim 2, wherein X is ##STR16## R is C.sub.1-15 alkyl or C.sub.3-8 cycloalkyl, R.sup.1 is --CN, and n is an integer of from 0 to 6.
7. The ethylamine compound of claim 4, having a formula selected from the group consisting of: ##STR17## compounds of the formula: ##STR18## wherein n is 2, 4, 5 or 6; compounds of the formula: ##STR19## wherein R is a C.sub.10, C.sub.13 or C.sub.14 alkyl group; compound of the formula: ##STR20## wherein R is a C.sub.10 or C.sub.13 alkyl group; compounds of the formula: ##STR21## wherein R is C.sub.1-7 alkyl, C.sub.9-15 alkyl, C.sub.3-6 cycloalkyl, C.sub.8 cycloalkyl, phenyl, benzyl, 1-naphthyl or 2-naphthyl; compounds of the formula: ##STR22## wherein n is 3 and R is C.sub.1-11 alkyl or C.sub.14 alkyl; or R is C.sub.12 alkyl and n is 2, 4, 5 or 6; and compounds of the formula: ##STR23## wherein Z is --(CHOH)--, n is 4-6 and R is C.sub.10-11 alkyl or C.sub.13-14 alkyl; Z is --(C.dbd.O)--, n is 4-6 and R is C.sub.10-11 alkyl or C.sub.13-14 alkyl; and Z is --(C.dbd.O)--, n is 2 and R is C.sub.10 alkyl or C.sub.12 alkyl.
8. An ethylamine compound of formula (I): ##STR24## wherein the moiety of A-B is selected from the group consisting of ##STR25## Q is a member selected from the group consisting of o-nitrophenyl, o-aminophenyl, o-ethylcarbamoylphenyl, o-styrylcarbamoylphenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dihydroxyphenyl, 3-trifluoromethylphenyl, pyrrolyl, N-methylpyrrolyl, 4-methoxyphenyl, 3-benzoylphenyl, phenyl, 3,4-dimethylphenyl, 2-methoxy-5-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chlorophenyl, 3-iodophenyl, 3-phenoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3,5-dimethoxyphenyl, 3-benzyloxphenyl, 3,4-dibenzyloxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-ethoxyphenyl, 2-methylnaphthyl, 2-bromophenyl, 2-bromo-4,5-dimethoxyphenyl, pentafluorophenyl, 2-chlorophenyl, 2,3,6-trichlorophenyl, 2,4-dichlorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2-iodophenyl, 2-nitro-4-trifluoromethylphenyl, 2-phenoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-benzyloxyphenyl, 2-ethoxyphenyl, o-biphenyl, 2-trifluorophenyl, 2-methylphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-methylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4-cyanophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-ethoxyphenyl, 3-methoxy-4-ethoxyphenyl, 4-(2-diethylaminoethoxy)phenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 3-ethoxy-4-hydroxyphenyl, p-biphenyl, 4-butoxyphenyl, 4-(2'-methyl-2'-butyl)phenyl, 4-isopropylphenyl, p-tolyl, 4-benzylphenyl, 4-ethylphenyl, 4-hydroxyphenyl, 2-cyano-4-methylphenyl, 3,4-methylenedioxyphenyl, 3-pyridyl, 2-nitrophenyl, 2-chloro-4-nitrophenyl, 3-nitrophenyl, 2-nitro-5-fluorophenyl, 4-nitrophenyl, 4-aminophenyl, 3,5-di(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,4-di(trifluoromethyl)phenyl, 3,5-difluorophenyl, 4-ethenylphenyl, 2,4,5-trimethylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-3-ethoxyphenyl, 4-(2'-methylpropyl)phenyl, 4-methoxycarbonylphenyl, 3,4-diethoxyphenyl, 2-iodo-4,5-dimethoxyphenyl, 4-neopentanoylphenyl, 2-nitro-4,5-dimethoxyphenyl, 2-thiopheno, 2-furyl, 3-pyrrolyl, N-methyl-3-pyrrolyl, 3-thiopheno, 3-furyl, cyclohexyl, 3-(.alpha.-hydroxybenzyl)phenyl, 4-trifluoromethylphenyl and 3-methoxyphenyl; X is a member selected from the group consisting of ##STR26## --S(O).sub.k --(CH.sub.2).sub.l --, --O--(CH.sub.2).sub.q --, --SO.sub.2 --NH--, --CO--NH--, --NH--CO--NH--, ##STR27## wherein R is hydrogen, C.sub.1-15 alkyl, C.sub.3-8 cycloalkyl, 3-chloropropyl, phenyl, benzyl, phenylthio, 1-naphthyl or 2-naphthyl, R.sup.1 is --CN, --CONH.sub.2, --COOCH.sub.3, n is an integer of from 0 to 6, k is an integer of from 0 to 2, l is an integer of from 2 to 4, q is an integer of from 2 to 4, r is an integer of from 2 to 4, and s is an integer of from 2 to 4; or a physiologically acceptable salt thereof.
9. The ethylamine compound of claim 8, having a formula selected from the group consisting of: ##STR28##
10. An ethylamine compound of formula (I): ##STR29## wherein the moiety A-B is ##STR30## Q is a member selected from the group consisting of o-nitrophenyl, o-aminophenyl, o-ethylcarbamoylphenyl, o-styrylcarbamoylphenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dihydroxyphenyl, 3-trifluoromethylphenyl, pyrrolyl, N-methylpyrrolyl, 4-methoxyphenyl, 3-benzoylphenyl, phenyl, 3,4-dimethylphenyl, 2-methoxy-5-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chlorophenyl, 3-iodophenyl, 3-phenoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3,5-dimethoxyphenyl, 3-benzyloxphenyl, 3,4-dibenzyloxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-ethoxyphenyl, 2-methylnaphthyl, 2-bromophenyl, 2-bromo-4,5-dimethoxyphenyl, pentafluorophenyl, 2-chlorophenyl, 2,3,6-trichlorophenyl, 2,4-dichlorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2-iodophenyl, 2-nitro-4-trifluoromethylphenyl, 2-phenoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-benzyloxyphenyl, 2-ethoxyphenyl, o-biphenyl, 2-trifluorophenyl, 2-methylphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-methylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4-cyanophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-ethoxyphenyl, 3-methoxy-4-ethoxyphenyl, 4-(2-diethylaminoethoxy)phenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 3-ethoxy-4-hydroxyphenyl, p-biphenyl, 4-butoxyphenyl, 4-(2'-methyl-2'-butyl)phenyl, 4-isopropylphenyl, p-tolyl, 4-benzylphenyl, 4-ethylphenyl, 4-hydroxyphenyl, 2-cyano-4-methylphenyl, 3,4-methylenedioxyphenyl, 3-pyridyl, 2-nitrophenyl, 2-chloro-4-nitrophenyl, 3-nitrophenyl, 2-nitro-5-fluorophenyl, 4-nitrophenyl, 4-aminophenyl, 3,5-di(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,4-di(trifluoromethyl)phenyl, 3,5-difluorophenyl, 4-ethenylphenyl, 2,4,5-trimethylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-3-ethoxyphenyl, 4-(2'-methylpropyl)phenyl, 4-methoxycarbonylphenyl, 3,4-diethoxyphenyl, 2-iodo-4,5-dimethoxyphenyl, 4-neopentanoylphenyl, 2-nitro-4,5-dimethoxyphenyl, 2-thiopheno, 2-furyl, 3-pyrrolyl, N-methyl-3-pyrrolyl, 3-thiopheno, 3-furyl, cyclohexyl, 3-(.alpha.-hydroxybenzyl)phenyl, 4-trifluoromethylphenyl and 3-methoxyphenyl; X is a member selected from the group consisting of ##STR31## --S(O).sub.k --(CH.sub.2).sub.l --, --SO.sub.2 --NH--, --CO--NH--, --NH--CO--NH--, ##STR32## wherein R is hydrogen, C.sub.1-15 alkyl, C.sub.3-8 cycloalkyl, 3-chloropropyl, phenyl, benzyl, phenylthio, 1-naphthyl or 2-naphthyl, R.sup.1 is --CN, --CONH.sub.2, --COOCH.sub.3, n is an integer of from 0 to 6, k is an integer of from 0 to 2, l is an integer of from 2 to 4, r is an integer of from 2 to 4, and s is an integer of from 2 to 4; or a physiologically acceptable salt thereof.
11. The ethylamine compound of claim 10, wherein Q is a member selected from the group consisting of o-nitrophenyl, o-aminophenyl, o-ethylcarbamoylphenyl, o-styrylcarbamoylphenyl, 1-naphthyl, 2-naphthyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dihydroxyphenyl, 3-trifluoromethylphenyl, pyrrolyl, N-methylpyrrolyl, 4-methoxyphenyl, 3-benzoylphenyl, phenyl, 3,4-dimethylphenyl, 2-methoxy-5-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chlorophenyl, 3-iodophenyl, 3-phenoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3,5-dimethoxyphenyl, 3-benzyloxphenyl, 3,4-dibenzyloxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-ethoxyphenyl, 2-methylnaphthyl, 2-bromophenyl, 2-bromo-4,5-dimethoxyphenyl, pentafluorophenyl, 2-chlorophenyl, 2,3,6-trichlorophenyl, 2,4-dichlorophenyl, 2-chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2-iodophenyl, 2-nitro-4-trifluoromethylphenyl, 2-phenoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-benzyloxyphenyl, 2-ethoxyphenyl, o-biphenyl, 2-trifluorophenyl, 2-methylphenyl, 2,3-dimethyl-4-methoxyphenyl, 3-methylphenyl, 3-methyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4-cyanophenyl, 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-ethoxyphenyl, 3-methoxy-4-ethoxyphenyl, 4-(2-diethylaminoethoxy)phenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 3-ethoxy-4-hydroxyphenyl, p-biphenyl, 4-butoxyphenyl, 4-benzylphenyl, 4-hydroxyphenyl, 2-cyano-4-methylphenyl, 3,4-methylenedioxyphenyl, 3-pyridyl, 2-nitrophenyl, 2-chloro-4-nitrophenyl, 3-nitrophenyl, 2-nitro-5-fluorophenyl, 4-nitrophenyl, 4-aminophenyl, 3,5-di(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,4-di(trifluoromethyl)phenyl, 3,5-difluorophenyl, 4-ethenylphenyl, 2,4,5-trimethylphenyl, 2-hydroxy-3-methoxyphenyl, 2-hydroxy-3-ethoxyphenyl, 4-methoxycarbonylphenyl, 3,4-diethoxyphenyl, 2-iodo-4,5-dimethoxyphenyl, 4-neopentanoylphenyl, 2-nitro-4,5-dimethoxyphenyl, 2-thiopheno, 2-furyl, 3-pyrrolyl, N-methyl-3-pyrrolyl, 3-thiopheno, 3-furyl, cyclohexyl, 3-(.alpha. -hydroxybenzyl)phenyl, 4-trifluoromethylphenyl and 3-methoxyphenyl.
12. The ethylamine compound of claim 11, having a formula selected from the group consisting of: ##STR33## wherein Q' is CH.sub.3 and n is 7, 9, 11, 13 or 15; Q' is cyclohexyl and n is 2-5; Q' is phenyl and n is 2-7; Q' is phenoxy and n is 2-4; Q' is phenylthio and n is 2-4; n is 2 and Q' is 3',4'-dimethoxyphenyl, ##STR34## or n is 3 and Q' is 4'-fluorophenylsulfoxyl, 4'-fluorophenylsulfonyl, 2'-aminophenylthio, or a substituent selected from the following: ##STR35##
13. The ethylamine compound of claim 11, wherein X is a member selected from the group consisting of ##STR36## --SO.sub.2 --NH--, --CO--NH--, --NH--CO--NH--, ##STR37##
14. The ethylamine compound of claim 13, wherein X is ##STR38## R is hydrogen or C.sub.1-15 alkyl, and R.sup.1 is --CN.
15. The ethylamine compound of claim 14, having a formula selected from the group consisting of: ##STR39## the formula: ##STR40## wherein n is 3 and Q' is selected from the following: ##STR41## n is 4 and Q' is selected from the following: ##STR42## n is 5 and Q' is selected from the following: ##STR43## n is 6 and Q' is selected from the following: ##STR44## and the formula: ##STR45## wherein X' is hydrogen or methoxy, and R is C.sub.1-10 alkyl.
16. The compound of formula (I) as claimed in claim 1, which is in the form of a physiologically acceptable salt.
17. 1-Cyclohexyl-4-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1-piperidinyl)-butane or a physiologically acceptable salt thereof.
18. An antihypertensive composition, comprising an amount of the ethylamine compound of claim 1 effective to treat hypertension and a pharmaceutically acceptable excipient.
19. The composition of claim 18, further comprising a member selected from the group consisting of a diuretic, a calcium antagonist, a .beta.-blocker, an .alpha.-blocker and a converting enzyme inhibitor.
20. An antihypertensive composition, comprising an amount of the ethylamine compound of claim 8 effective to treat hypertension and a pharmaceutically acceptable excipient.
21. The composition of claim 20, further comprising a member selected from the group consisting of a diuretic, a calcium antagonist, a .beta.-blocker, an .alpha.-blocker and a converting enzyme inhibitor.
22. An antihypertensive composition, comprising an amount of the ethylamine compound of claim 10 effective to treat hypertension and a pharmaceutically acceptable excipient.
23. The composition of claim 22, further comprising a member selected from the group consisting of a diuretic, a calcium antagonist, a .beta.-blocker, an .alpha.-blocker and a converting enzyme inhibitor.