N-Monosubstituted cyclopentenylamines, a process for their preparation and their use as medicaments

Abstract: The invention relates to a substituted-amine compound of the following formula: pharmaceutical acceptable salts of it, processes for preparing it, pharmaceutical compositions comprising it and its use for the manufacture of medicaments.

Description: This invention relates to a novel substituted-amine compound and a pharmaceutically acceptable salt thereof. More particularly, it relates to a novel substituted-amine compound and a pharmaceutically acceptable salt thereof which have anticholinergic activity and sodium channel blocking activity, and are useful for the prevention and/or treatment of dysuria such as pollakiuria and urinary incontinence in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis and chronic prostatitis; and for the prevention and/or treatment of spasm and/or hyperkinesia in case of gastric ulcer, duodenal ulcer, gastroxynsis, esophagospasm, gastritis, enteritis, irritable colon syndrome, enteralgia, cholecystitis, cholangitis, pylorospasm, pancreatitis, pain in case of pancreatitis, biliary dyskinesia, aftereffect after cholecystectomy, urinary calculus, cystitis, dysmenorrhea, hidrosis, spasm of urinary tract; and for the prevention and/or treatment of arrhythmia and congestive heart failure; and useful as local anesthetic; and which as expected to be useful for the prevention and/or treatment of asthma, Parkinson disease and angina pectoris; to a process for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the prevention and/or treatment of aforesaid diseases in human being or animals. One object of this invention is to provide a novel substituted-amine compound and a pharmaceutically acceptable salt thereof which are useful for the prevention and/or treatment of aforesaid diseases. Another object of this invention is to provide a process for the preparation of said substituted-amine compound or a salt thereof. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said substituted-amine compound or a pharmaceutically acceptable salt thereof, which is useful as an agent for the prevention and/or treatment of aforesaid diseases. US-A 3,376,312 describes 4,4-diphenyl-cyclohexylamines and derivatives thereof as therapeutic agents particularly for effecting spasmolytic or cholinolytic activities. The compound 4,4-diphenylcyclohexyl-t-butylamine is mentioned. AT 273,065 describes a process for the preparation of new acid addition salts of 4,4-diphenyl-cyclohexylamines. The compounds can be used in pharmaceutical compositions and effect spasmolytic and cholinolytic activities. Acta Pharmaceutica Suecia vol. 12, 1975, p.149 - 172 reports about phenylcycloalkylamines as antidepressant agents. US-A 4,141,993 describes compounds of the diphenylcyclopentylamine type and methods for their preparation. DE-A 22 27 844 describes 4,4-diphenylcyclohexylamines as antidepressive agents. The compound (+)-4,4-diphenyl-cyclohex-2-enylamin is mentioned. DE-A 17 93 611 discloses 4,4-diphenylcyclohexylamines, their acid addition salts and their quarternary ammonium salts. US-A 3,479,352 discloses trichloromethyl-tertiary-amino substituted cycloalkenes and their preparation by reacting cyclic dieneamines with trichloroacetic acid in an aromatic hydrocarbon medium. The object substituted-amine compound (I) of the present invention is shown by the following formula (I) : wherein a group of the formula : is cyclopentenyl, R 1 and R 2 are each hydrogen, C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino; C 2 -C 6 alkynyl which may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; or cyclo(C 3 -C 6 )alkyl which may have 1 to 3 C 1 -C 6 alkyl, R 4 is hydrogen, in which R 3 and R 4 may be linked together to form 1-piperazinyl or morpholino, each of which may have 1 to 3 C 1 -C 6 alkanoyl, and R 5 and R 6 are each hydrogen or hydroxy, with proviso that (i) R 3 is t-butyl, when R 1 , R 2 , R 5 and R 6 are each hydrogen. The object substituted-amine compound (I) of the present invention can be prepared by the processes as illustrated in the following reaction schemes. wherein a group of the formula : R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each as defined above, a group of the formula : is cyclopentyl, and X is a leaving group. Among the starting compounds, some of the compound (II) are novel and can be prepared by the following reaction schemes. wherein R 1 / aand R 2 / a are each C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 8 is acyloxy, R 9 is halogen, X is as defined above, a group of the formula : is as defined above. Some of the starting compound (IV) are novel and can be prepared according to the methods disclosed in Preparations mentioned later in the present specification or the similar manners thereto. As for the object substituted-amine compound (I), it is to be noted that the compound (I) can include the stereo isomers due to the asymmetric carbon atom(s). Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic mono or di salts and include an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate] and a salt with an amino acid [e.g. arginine salt, aspartic acid salt and glutamic acid salt]. In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows : The term "C 1 -C 6 " is intended to mean 1 to 6 carbon atom(s). Suitable "cyclo(C 3 -C 6 )alkyl" may include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Said "cyclo(C 3 -C 6 )alkyl" may have 1 to 3 C 1 -C 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl). Suitable "C 1 -C 6 alkyl" may include the straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl, in which the preferred one may be (C 1 -C 4 )alkyl and the more preferred one may be methyl, ethyl, isopropyl, butyl and t-butyl. Said "C 1 -C 6 alkyl" may have 1 to 3 suitable substituent(s) such as hydroxy; phenyl; and N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino, in which suitable "C 1 -C 6 alkyl" moiety can be referred to aforesaid "C 1 -C 6 alkyl", and suitable "phenyl(C 1 -C 6 )alkyl" moiety can be referred to the ones as exemplified below for "phenyl(C 1 -C 6 )alkyl"; and the concrete examples of said "N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 ) alkylamino" may be N-methyl-N-benzylamino, N-ethyl-N-benzylamino and N-propyl-N-phenethylamino, in which the preferred one may be N-(C 1 -C 4 )alkyl-N-phenyl(C 1 -C 4 )alkylamino and the more preferred one may be N-methyl-N-benzylamino. Suitable "C 2 -C 6 alkynyl" may include straight or branched ones such as ethynyl, 2-propynyl, 1-propynyl, 2-butynyl, 2-methyl-3-butynyl, 3-pentynyl, 1,1-dimethyl-2-butynyl and 5-hexynyl, in which the preferred one may be (C 4 -C 6 )alkynyl and the more preferred one may be 1,1-dimethyl-2-butynyl. Said "C 2 -C 6 alkynyl" may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; in which suitable "C 1 -C 6 alkyl" moiety can be referred to aforesaid "C 1 -C 6 alkyl"; and the concrete examples of said N,N-di(C 1 -C 6 )alkylamino may be N,N-dimethylamino, N-methyl-N-ethylamino, N,N-diethylamino, N,N-dipropylamino, N-isopropyl-N-butylamino, N,N-dipentylamino and N,N-dihexylamino, in which the preferred one may be N,N-di(C 1 -C 4 )alkylamino and the more preferred one may be N,N-diethylamino. Said "phenyl" may have 1 to 3 suitable substituent(s) such as aforesaid C 1 -C 6 alkyl. Suitable "phenyl(C 1 -C 6 )alkyl" may include mono-(or di- or tri-)phenyl(C 1 -C 6 )alkyl such as benzyl, phenethyl, benzhydryl and trityl; in which the preferred one may be phenyl(C 1 -C 4 )alkyl, and the more preferred one may be benzyl. 1-Piperazinyl and morpholino which are formed in case R 3 and R 4 are linked together may have 1 to 3 C 1 -C 6 alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, pentanoyl and hexanoyl). Suitable "a leaving group" may include halogen (e.g. chloro, fluoro, bromo, iodo); and acyloxy such as C 1 -C 6 alkanoyloxy (e.g. acetoxy, propionyloxy, butyryloxy, pentanoyloxy and hexanoyloxy) and sulfonyloxy (e.g. mesyloxy, ethylsulfonyloxy and tosyloxy). In the object substituted-amine compound (I), one of very preferred compound can be shown by the following formula (I-1) : wherein R 1 , R 2 , R 3 and R 4 are each as defined above, in which the preferred R 1 and R 2 may be each phenyl which may have 1 to 3 C 1 -C 6 alkyl, and the more preferred ones may be each phenyl; and the preferred R 3 may be ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl-(C 1 -C 6 )alkylamino, the more preferred one may be ethyl or t-butyl and the most preferred one may be t-butyl. Another very preferred compound among the object substituted-amine compound (I) can be shown by the following formula (I-2) : As to the foregoing, it is to be noted that in the above some very preferred compounds of the object substituted-amine compound (I) are only exemplified, and so the scope of the object substituted-amine compound (I) of the present invention is never limited at all to said very preferred ones exemplified above. The processes for preparing the object compound (I) of the present invention are explained in detail in the following. Process 1 The object compound (I) or a salt thereof can be prepared by reacting the compound (II) with the compound (III) or a salt thereof. Suitable salt of the compound (III) can be referred to the ones as exemplified for the compound (I). The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate and alkali metal bicarbonate, and organic base such as trialkylamine. The reaction temperature is not critical, and the reaction is usually carried out at room temperature, under warming or under heating. The present reaction is preferably carried out in the presence of alkali metal halide [e.g. sodium iodide and potassium iodide] or alkali metal thiocyanate [e.g. sodium thiocyanate and potassium thiocyanate]. In this reaction, the compound (II) may be converted from the corresponding alcohol compound by the conventional method (e.g. reaction with methanesulfonyl chloride) during the reaction. As for this process, the following point is to be noted. The leaving group X is located at the allyl position of the double bond as illustrated by the following formula : there may be the case the compound (III) reacts at position 3 ○ instead of position 1 ○, and this case is also included within the scope of the present invention. Process 2 The object compound (I) or a salt thereof can be prepared by reacting the compound (IV) with the compound (III) or a salt thereof and then subjecting the resultant intermediate compound to reduction. This reaction can be carried out without isolation of the intermediate compound. i) The reaction of the compound (IV) with the compound (III) or a salt thereof is usually carried out in a conventional solvent such as alcohol (e.g. methanol and ethanol), methylene chloride, chloroform, or any other solvent which does not adversely influence the reaction. The reaction temperature is not critical and the reaction can be carried out under cooling, at room temperature, under warming to heating. ii) The reduction can be carried out by the reaction with a reducing agent, for example, metal hydride compound such as alkali metal aluminum hydride (e.g. lithium aluminum hydride), di(C 1 -C 6 )alkylaluminum hydride (e.g. diisobutylaluminum hydride) and alkali metal borohydride (e.g. sodium borohydride). The reaction is usually carried out in a solvent such as diethyl ether, chloroform, methylene chloride, tetrahydrofuran, benzene, toluene, alcohol (e.g. methanol and ethanol) or any other solvent which does not adversely influence the reaction. The reaction temperature is not critical and the reaction can be carried out under cooling, at room temperature or under warming. Process 3 The object compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of diol. The suitable salts of the compounds (Ia) and (Ib) can be referred to the ones as exemplified for the compound (I). The elimination reaction of this process can be carried out by reacting the compound (Ia) or a salt thereof with aldehyde compound (e.g. benzaldehyde), tri(C 1 -C 6 )alkyl orthoformate (e.g. trimethyl orthoformate), and then a base such as lower alkyl lithium (e.g. methyl lithium and n-butyl lithium), lithium di(C 1 -C 6 )alkylamide (e.g. lithium diisopropylamide), alkali metal hydroxide (e.g. sodium hydroxide); or an acid such as lower alkanoic acid (e.g. acetic acid and propionic acid) and sulfonic acid (e.g. p-toluenesulfonic acid). This reaction is usually carried out in a solvent such as n-hexane, diethyl ether, tetrahydrofuran, methylene chloride, toluene, xylene, or any other solvent which does not adversely influence the reaction. The reaction temperature is not critical and the reaction can be carried out at room temperature, under warming to heating. The process for the preparation of some of the starting compound (II) is explained in detail as follows. Process A step 1 The compound (VI) can be prepared by subjecting the compound (V) to reduction. The reduction of this step can be carried out according to a similar manner to that as explained in Process 2. step 2 The compound (IIa) can be prepared by subjecting the compound (VI) to acylation. The acylation of this step can be carried out by reacting the compound (VI) with an acid corresponding to acyl group to be introduced or its reactive derivative or a salt thereof. The reaction can be carried out in a conventional manner in this field of the art, for example, by the method disclosed in Preparation of the present specification. step 3 The compound (IIb) can be prepared by subjecting the compound (VI) to halogenation. The halogenation of this step can be carried out by reacting the compound (VI) with carbon tetrahalide (e.g. carbon tetrachloride and carbon tetrabromide) or thionyl halide (e.g. thionyl chloride). The reaction can be carried out in a conventional manner in this field of the art, for example, by the method disclosed in Preparation of the present specification. The object compound (I) and a pharmaceutically acceptable salt thereof of this invention have anticholinergic activity and sodium channel blocking activity and are useful for the treatment of dysuria or other diseases as mentioned before in human being and animals. In the object compound (I) and a pharmaceutically acceptable salt thereof, side effect such as mydriasis is alleviated. In order to illustrate the usefulness of the object compound (I) and a pharmaceutically acceptable salt thereof, the pharmacological test data of the representative compound of this invention are shown in the following. Test on Inhibition of Urinary Bladder Contractions Induced by Water Filling in Rats [I] Test Method Male Sprague-Dawly rats, weighing 240-450 g, were anesthetized with urethane 1.0 g/kg s.c. The bladder was exposed through a midline incision in the abdomen for the recording of pressure within the bladder as follows; a balloon attached to one end of a stainless steel tube (O.E., 1.2 mm, 5 cm in length) was inserted into the bladder through a small incision in the bladder dome. The other end of the tube was connected to a pressure-transducer. The ureters were ligated and cut, and the proximal cut end was cannulated with polyethylene tubing and the urine was led outside. Hyperactive urinary bladder (hyperactive contractions of the detrusor muscle) was induced by water filling of the bladder. Therefore, the balloon in the bladder was filled with water of a volume which caused a resting pressure of about 13.33 hPa (10 mmHg). Systemic blood pressure and heart rate were monitored from the common carotid artery. When the contractile responses to water filling became constant, test compounds were administered intravenously. [II] Test compound (-)-N-t-Butyl-4,4-diphenyl-2-cyclopentenylamine methanesulfonate [III] Test Result ED 30 = 0.18 (mg/kg) Test on Na channel blocking activity [I] Test Method : Male Japanese white rabbits weighing 2.0-3.0 kg were used to evaluate the local anesthetic effect of test compound on the corneal blink reflex. Corneal reflexes were elicited by pressing a flexible monofilament (rabbit whisker) against the cornea. 1.0% Test compound solution in saline was applied to one eye (50 µl drops) and the contralateral eye received as a control. Corneal blink responses were scored at 5, and 15 minutes after test compound application. Local anesthetic activities were expressed as an inhibition percent of blink responses. [II] Test Compound (-)-N-t-Butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride [III] Test Result Inhibition % 5 minutes 100 15 minutes 100 The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation or intravesical administration. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carrier for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The object compound (I) or a pharmaceutical acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases. For applying the composition to human being or animal, it is preferable to apply it by intravenous, intramuscular, pulmonary, or oral administration, or insufflation. While the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 20 mg of the object compound (I) per kg weight of human being or animal, in the case of intramuscular administration, a daily dose of 0.1 - 20 mg of the object compound (I) per kg weight of human being or animal, in case of oral administration, a daily dose of 0.5 - 50 mg of the object compound (I) per kg weight of human being or animal is generally given for treating or preventing the aforesaid diseases. The following Preparations and Examples are given for the purpose of illustrating this invention in more detail. Preparation 1 To a solution of 5,5-diphenyl-2-cyclopenten-1-one (1.0 g) and cerium trichloride 7 hydrate (1.59 g) in methanol (10 ml) and methylene chloride (4 ml) was added dropwise a solution of sodium borohydride (0.16 g) in ethanol (6 ml) at 0°C to 3°C. To the reaction mixture, cerium trichloride 7 hydrate (0.80 g) and sodium borohydride (0.08 g) were added 4 times an hour. After the reaction finished, cold water (30 ml) was added, and the mixture was extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give 5,5-diphenyl-2-cyclopenten-1-ol (0.83 g). IR (Neat) : 3350, 3420 cm -1 , NMR (CDCl 3 , δ) : 1.28 (1H, broad s), 2.82-3.00 (1H, m), 3.40-3.55 (1H, m), 5.45 (1H, s), 5.88-5.98 (1H, m), 6.08-6.20 (1H, m), 7.10-7.40 (10H, m) Example 1 To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.20 g) in N,N-dimethylformamide (1 ml) were added methanesulfonyl chloride (0.35 ml) and triethylamine (0.60 ml) at 5 to 10°C. After being stirred for 1 hour, t-butylamine (1.78 ml) was added to the reaction mixture at 5 to 12°C. The reaction mixture was stirred for 3 days at room temperature. To the reaction mixture were added water and ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.11 g). NMR (CDCl 3 , δ) : 0.80-1.40 (1H, broad m), 1.12 (9H, s), 2.04 (1H, dd, J=7.6Hz and 13.0Hz), 3.09 (1H, dd, J=6.8Hz and 13.0Hz), 3.94-4.10 (1H, m), 5.85 (1H, dd, J=1.7Hz and 5.6Hz), 6.21 (1H, dd, J=2.0Hz and 5.6Hz), 7.09-7.38 (10H, m) Example 2 N-t-Butyl-4,4-diphenyl-2-cyclopentenylamine methanesulfonate was obtained according to a conventional manner from the corresponding free amine compound of Example 1. mp : 204-206°C IR (Nujol) : 1600, 1490 cm -1 NMR (DMSO-d 6 , δ) : 1.42 (9H, s), 2.50 (3H, s), 2.79 (1H, dd, J=13.1Hz and 8.9Hz), 3.23 (1H, dd, J=13.1Hz and 6.7Hz), 4.18-4.34 (1H, m), 6.22 (1H, dd, J=5.7Hz and 1.2Hz), 6.36 (1H, dd, J=5.7Hz and 2.1Hz), 7.08-7.35 (10H, m), 8.67 (2H, broad s) Example 3 A mixture of (±)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (17.22 g) and (-)-di-p-toluoyl-L-tartaric acid (11.69 g) in ethanol (30 ml) was refluxed and the resulting solution was allowed to stand at room temperature. After kept standing for 8 hours, the resulting precipitates were collected and recrystallized repeatedly with ethanol to give (+)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine 1/2[(-)-di-p-toluoyl-L-tartrate] (4.15 g). The resultant salt was added to 10% aqueous solution of sodium hydroxide and extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (20:1) as an eluent to give (+)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (1.58 g). [α] 30 / D= +172.24° (C=1.39, MeOH) IR (Film) : 3310, 3050, 1595 cm -1 NMR (CDCl 3 , δ) : 0.60-1.60 (1H, broad m), 1.13 (9H, s), 2.04 (1H, dd, J=13.0Hz and 7.7Hz), 3.09 (1H, dd, J=13.0Hz and 6.8Hz), 4.04 (1H, dddd, J=7.7Hz, 6.8Hz, 2.0Hz and 1.7Hz), 5.86 (1H, dd, J=5.5Hz and 1.7Hz), 6.21 (1H, dd, J=5.5Hz and 2.0Hz), 7.09-7.47 (10H, m) Example 4 The previously obtained mother liquor of (+)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine·1/2 [(-)-di-p-toluoyl-L-tartrate] was converted to the corresponding amine (9.44 g) by treatment of aqueous solution of sodium hydroxide. To the amine thus obtained (9.44 g) were added (+)-di-p-toluoyl-D-tartaric acid (6.50 g) and ethanol (25 ml) and the mixture was heated under reflux until a clear solution was obtained. After being allowed to stand at room temperature overnight, the resulting precipitates were collected by filtration and recrystallized repeatedly with ethanol to give (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine·1/2[(+)-di-p-toluoyl-D-tartrate] (6.90 g). IR (Nujol) : 1720, 1635 cm -1 NMR (DMSO-d 6 , δ) : 1.18 (18H, s), 2.24 (2H, dd, J=13.2Hz and 8.4Hz), 2.35 (6H, s), 3.19 (2H, dd, J=13.2Hz and 6.9Hz), 4.18 (2H, broad t, J=7.4Hz), 5.58 (2H, s), 5.92 (2H, d, J=5.5Hz), 6.37 (2H, d, J=5.5Hz), 7.07-7.38 (24H, m), 7.84 (4H, d, J=8.1Hz) Example 5 (-)-N-t-Butyl-4,4-diphenyl-2-cyclopentenylamine·1/2-[(+)-di-p-toluoyl-D-tartrate] (6.36 g) was added to 10% aqueous solution of sodium hydroxide and extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (3.54 g). IR (Film) : 3310, 3050, 1595 cm -1 NMR (CDCl 3 , δ) : 0.60-1.60 (1H, broad m), 1.13 (9H, s), 2.04 (1H, dd, J=13.0Hz and 7.7Hz), 3.09 (1H, dd, J=13.0Hz and 6.8Hz), 4.03 (1H, dddd, J=7.7Hz, 6.8Hz, 2.0Hz and 1.7Hz), 5.85 (1H, dd, J=5.5Hz and 1.7Hz), 6.21 (1H, dd, J=5.5Hz and 2.0Hz), 7.09-7.47 (10H, m) Example 6 To a solution of (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (3.54 g) in ethyl acetate (20 ml) was added a solution of methanesulfonic acid (1.16 g) in ethyl acetate (1 ml). The solvent was evaporated in vacuo and diethyl ether was added. After kept standing for 4 hours, the resulting precipitate was collected by filtration to give (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine methanesulfonate (3.90 g). [α] 28 / D = -155.64° (C=1.05, MeOH) mp : 150-151°C IR (Nujol) : 3400, 1600 cm -1 NMR (CDCl 3 , δ) : 1.43 (9H, s), 2.51 (3H, s), 2.79 (1H, dd, J=13.1Hz and 8.9Hz), 3.24 (1H, dd, J=13.1Hz and 6.7Hz), 4.28 (1H, broad t, J=8.1Hz), 6.22 (1H, d, J=5.7Hz), 6.36 (1H, dd, J=5.7Hz and 2.1Hz), 7.08-7.35 (10H, m), 8.31-8.87 (2H, broad m) Example 7 (+)-7-t-Butyl-4,4-diphenyl-2-cyclopentenylamine methanesulfonate was obtained according to a similar manner to that of Example 6 . [α] 29 / D = +155.84° (C=0.817, MeOH) mp : 153-154°C IR (Nujol) : 3400, 1600 cm -1 NMR (CDCl 3 , δ) : 1.42 (9H, s), 2.51 (3H, s), 2.79 (1H, dd, J=13.1Hz and 8.9Hz), 3.24 (1H, dd, J=13.1Hz and 6.7Hz), 4.28 (1H, broad t, J=8.1Hz), 6.22 (1H, d, J=5.7Hz), 6.37 (1H, dd, J=5.7Hz and 2.0Hz), 7.08-7.35 (10H, m), 8.08-9.27 (2H, broad m) Example 8 To a solution of (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (8.82 g) in diethyl ether (50 ml) was added water (15 ml) and conc. hydrochloric acid (5 ml) at 0 - 10°C and stirred for 30 minutes. The resulting precipitate was collected by filtration and washed with diethyl ether to give (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (9.70 g). [α] 26 / D = -189.4° (C=1.073, CH 3 OH) mp : 259-261°C (dec.) IR (Nujol) : 2730, 2690, 2640, 2610, 2475, 2440 cm -1 NMR (CDCl 3 , δ) : 1.47 (9H, s), 3.10 (1H, dd, J=8.5 and 13.1Hz), 3.17 (1H, dd, J=7.4 and 13.1Hz), 4.23 (1H, broad s), 6.16 (1H, dd, J=5.7 and 2.3Hz), 6.41 (1H, dd, J=5,7 and 1.4Hz), 7.04-7.41 (10H, m), 9.64 (1H, broad s), 9.75 (1H, broad s) Preparation 2 To a suspension of 5,5-diphenyl-2-cyclopenten-1-one (5.0 g) in toluene (25 ml) was added dropwise diisobutylaluminum hydride (15 ml, 1.5 M solution in toluene) for 10 minutes at -78°C to -50°C. After 30 minutes, ethyl acetate (5 ml) was added to the resultant yellow solution. The solution was acidified to pH 1 with 6N hydrochloric acid (20 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent and further purified by bulb to bulb distillation to give 5,5-diphenyl-2-cyclopenten-1-ol (2.46 g). bp : 200°C/0.533 hPa (0.4 mmHg) The physical data of this compound were identified with those of the compound of Preparation 1 . Preparation 3 To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.70 g) in pyridine (5 ml) were added acetic anhydride (0.84 ml) and catalytic amount of 4-dimethylaminopyridine at room temperature. After being stirred for 30 minutes, the pH of the reaction mixture was adjusted to 1.0 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 5,5-diphenyl-2-cyclopentenyl acetate (0.82 g). IR (Neat) : 1720 cm -1 NMR (CDCl 3 , δ) : 1.68 (3H, s), 2.80-3.00 (1H, m), 3.48-3.70 (1H, m), 6.00-6.10 (1H, m), 6.14-6.26 (1H, m), 6.49 (1H, s), 7.10-7.35 (10H, m) Preparation 4 To a mixture of 5,5-diphenyl-2-cyclopentenyl acetate (0.30 g) and sodium azide (84 mg) in a solution of tetrahydrofuran (3 ml) and water (1.5 ml) was added tetrakis(triphenylphosphine)palladium(O) (62 mg) at room temperature under an argon atmosphere. After being stirred for 14.5 hours, ethyl acetate was added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate as an eluent to give 4,4-diphenyl-2-cyclopentenyl azide (0.16 g). IR (Neat) : 2100 cm -1 NMR (CDCl 3 , δ) : 2.45 (1H, dd, J=6Hz and 14Hz), 3.05 (1H, dd, J=14Hz and 8Hz), 4.42-4.70 (1H, m), 5.90 (1H, dd, J=2Hz and 6Hz), 6.42 (1H, dd, J=1Hz and 6Hz), 6.95-7.30 (10H, m) Preparation 5 To a mixture of 2,2-diphenylacetonitrile (135.77 g), 2-propynyl chloride (52.35 g) and tetrabutylammonium hydrogen sulfate (0.51 g) was added dropwise 50% aqueous solution of sodium hydroxide (100 ml) at room temperature. After being stirred for 6 hours, the mixture was poured into water and extracted with diethyl ether. The extract was washed successively with diluted hydrochloric acid and brine, and evaporated in vacuo. The residue was distilled in vacuo to give 2,2-diphenyl-2-(2-propynyl)acetonitrile. bp : 138-142°C/0.4 hPa (0.3 mmHg) IR (Film) : 3290, 3060, 2240, 1600 cm -1 NMR (CDCl 3 , δ) : 2.13 (1H, t, J=2.6Hz), 3.25 (2H, d, J=2.6Hz), 7.22-7.53 (10H, m) Preparation 6 A mixture of 2,2-diphenyl-2-(2-propynyl)acetonitrile (1.38 g) and lithium aluminum hydride (0.21 g) in tetrahydrofuran (15 ml) was refluxed for 2 hours. The reaction mixture was poured into cold water, acidified with hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and benzene (1:1) as an eluent to give 2,2-diphenyl-2-(2-propynyl)acetaldehyde (0.46 g). IR (Film) : 3280, 3050, 1715, 1595 cm -1 NMR (CDCl 3 , δ) : 1.92 (1H, t, J=2.7Hz), 3.15 (2H, d, J=2.7Hz), 7.16-7.54 (10H, m), 9.85 (1H, s) Preparation 7 A solution of 2,2-diphenyl-2-(2-propynyl)acetaldehyde (83.0 g) in acetic acid (83 ml) was added dropwise to a solution of mercuric acetate (3.1 g) and sulfuric acid (18.3 g) in a mixture of acetic acid (300 ml) and water (75 ml) over a period of 2 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and aqueous solution of sodium bicarbonate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g). IR (Film) : 3060, 1720, 1600 cm -1 NMR (CDCl 3 , δ) : 2.05 (3H, s), 3.59 (2H, s), 7.14-7.45 (10H, m), 10.02 (1H, s) Preparation 8 To a solution of 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g) in a mixture of tetrahydrofuran (55 ml) and methanol (30 ml) was added 10% aqueous solution of potassium hydroxide (15 ml) at room temperature. The solution was stirred for 2 hours and evaporated in vacuo. To the residue was added brine and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 4,4-diphenyl-2-cyclopenten-1-one (39.76 g). IR (Film) : 3080, 1700, 1665, 1580 cm -1 NMR (CDCl 3 , δ) : 3.12 (2H, s), 6.25 (1H, d, J=5.6Hz), 7.06-7.49 (10H, m), 7.99 (1H, d, J=5.6Hz) Preparation 9 To a solution of 4,4-diphenyl-2-cyclopenten-1-one (0.30 g) in toluene (3 ml) was added a 1 M solution of diisobutylaluminum hydride in n-hexane (2.0 ml) at -5°C to 4°C. After being stirred for 20 minutes, ethyl acetate (3 ml) and 10% hydrochloric acid (2 ml) was added to the solution successively, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give 4,4-diphenyl-2-cyclopenten-1-ol (0.29 g). IR (Neat) : 3320 cm -1 NMR (CDCl 3 , δ) : 2.41 (1H, dd, J=4.7Hz and 13.8Hz), 3.00 (1H, dd, J=6.9Hz and 13.8Hz), 4.90-5.10 (1H, m), 5.98 (1H, dd, J=2.0Hz and 5.5Hz), 6.38 (1H, dd, J=1.2Hz and 5.5Hz), 7.1-7.38 (10H, m) Preparation 10 A mixture of 2,2-bis(p-tolyl)acetic acid (8.52 g), allyl alcohol (6.6 ml) and p-toluenesulfonic acid monohydrate (0.34 g) in toluene (25 ml) was refluxed for 20 hours with continuous removal of water with Dean-Stark apparatus. After being cooled, the mixture was poured into 1N sodium hydroxide aqueous solution and extracted with ethyl acetate. The extract was washed with 1N sodium hydroxide aqueous solution, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give allyl 2,2-bis(p-tolyl)acetate (8.09 g). IR (Film) : 1730, 770, 750 cm -1 NMR (CDCl 3 , δ) : 2.31 (6H, s), 4.60-4.70 (2H, m), 4.98 (1H, s), 5.15-5.30(2H, m), 5.80-6.00 (1H, m), 6.95-7.36 (8H, m) Preparation 11 A solution of allyl 2,2-bis(p-tolyl)acetate (8.00 g) in toluene (40 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (1.6 g) in toluene (30 ml) at 130°C under nitrogen atmosphere, and the mixture was refluxed for 6 hours. After being cooled, the mixture was poured into cooled 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 2,2-bis(p-tolyl)-4-pentenoic acid (4.41 g). It was used for the next reaction without further purification. NMR (CDCl 3 , δ) : 2.32 (6H, s), 3.12 (2H, d, J=6.9Hz), 4.89 (1H, s), 4.96 (1H, d, J=5.1Hz), 5.45-5.70 (1H, m), 6.90-7.25 (8H, m) Preparation 12 To a solution of 2,2-bis(p-tolyl)-4-pentenoic acid (8.17 g) in N,N-dimethylformamide (1.0 ml) and methylene chloride (45 ml) was added thionyl chloride (3.2 ml), and the solution was stirred at room temperature for 1 day. The solution was evaporated in vacuo and the residue was dissolved in methylene chloride (50 ml). The solution was added dropwise to a suspension of aluminum chloride (4.66 g) in methylene chloride (50 ml) with dry ice-acetone bath cooling under nitrogen atmosphere, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into cooled 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water, 1N sodium hydroxide, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1 ∼ 5:1) as an eluent to give 5,5-bis(p-tolyl)-2-cyclopenten-1-one (2.30 g). mp : 61-63°C IR (Nujol) : 1690, 810, 780, 760, 720 cm -1 NMR (CDCl 3 , δ) : 2.31 (6H, s), 3.47 (2H, t, J=2.5Hz), 6.20-6.35 (1H, m), 7.10 (8H, s), 7.75-7.90 (1H, m) The following compounds ( Preparations 13 and 14 ) were obtained according to a similar manner to that of Preparation 9 . Preparation 13 5,5-Bis(p-tolyl)-2-cyclopenten-1-ol IR (Film) : 3350, 3430, 810, 790, 760, 740, 720 cm -1 NMR (CDCl 3 , δ) : 1.22 (1H, d, J=9.5Hz), 2.29 (3H, s), 2.32 (3H, s), 2.80-2.95 (1H, m), 3.30-3.46 (1H, m), 5.32-5.50 (1H, m), 5.85-5.95 (1H, m), 6.05-6.15 (1H, m), 7.00-7.35 (8H, m) Preparation 14 4,4-Dimethyl-2-cyclopenten-1-ol bp : 41-43°C/10.66 hPa (8 mmHg) IR (Neat) : 3320, 1035 cm -1 NMR (CDCl 3 , δ) : 1.05 (3H, s), 1.16 (3H, s), 1.53 (1H, dd, J=4.1Hz and 13.5Hz), 1.54 (1H, br s), 2.11 (1H, dd, J=7.3Hz and 13.5Hz), 4.84-4.95 (1H, m), 5.65 (1H, dd, J=2.0Hz and 5.5Hz), 5.76 (1H, dd, J=1.0Hz and 5.5Hz) Preparation 15 A mixture of 4,4-diphenyl-2-cyclopenten-1-ol (0.30 g), and triphenylphosphine (0.43 g) in carbon tetrachloride (3 ml) was refluxed for 8 hours and cooled. To the mixture was added n-hexane (5 ml), and the mixture was stirred for 10 minutes at room temperature. The insoluble material was filtered off and the filtrate was condensed under reduced pressure. The residue was dissolved in methylene chloride, and to the solution was added silica gel (1 g). After being stirred for 10 minutes, silica gel was filtered off and the filtrate was evaporated in vacuo to give 4,4-diphenyl-2-cyclopentenyl chloride (0.30 g). IR (Neat) : 1595, 1490, 1445 cm -1 NMR (CDCl 3 , δ) : 2.87 (1H, dd, J=4.7Hz and 14.6Hz), 3.22 (1H, dd, J=7.3Hz and 14.6Hz), 5.05-5.20 (1H, m), 5.98 (1H, dd, J=2.1Hz and 5.5Hz), 6.39 (1H, dd, J=1.2Hz and 5.5Hz), 7.10-7.40 (10H, m) Preparation 16 A mixture of 2,2-dicyclopropylacetaldehyde (9.68 g), allyl alcohol (10.6 ml), toluene (9.7 ml) and p-toluenesulfonic acid (0.05 g) was heated under a 20 cm packed distillation topped by a Dean-Stark trap for 6 days. During this period, 0.9 ml of aqueous layer separated. Distillation of the reaction mixture gave, after removal of toluene and a small forerun, 2,2-dicyclopropyl-4-pentenal (4.90 g). bp : 43-47°C/0.266 hPa (0.2 mmHg) IR (Neat) : 1720 cm -1 NMR (CDCl 3 , δ) : 0.40-0.58 (8H, m), 0.68-0.85 (2H, m), 2.12-2.30 (2H, m), 5.00-5.18 (2H, m), 5.75-6.00 (1H, m), 9.47 (1H, s) Preparation 17 A suspension of cuprous chloride (2.25 g), and palladium dichloride (0.81 g) in N,N-dimethylformamide (12 ml) and water (2.2 ml) was stirred at room temperature for 1 hour while oxygen was bubbling through the suspension. To this mixture, a solution of 2,2-dicyclopropyl-4-pentenal (3.74 g) in N,N-dimethylformamide (10 ml) was added at 22°C to 35°C and the suspension was stirred for 4 hours at room temperature with bubbling of oxygen through the suspension. After diluting the suspension with water (110 ml), the aqueous layer was extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by distillation under reduced pressure to give 4-oxo-2,2-dicyclopropylpentanal (1.98 g). bp : 80-83°C/0.666 hPa (0.5 mmHg) IR (Neat) : 1720 cm -1 NMR (CDCl 3 , δ) : 0.24-0.60 (8H, m), 0.80-1.00 (2H, m), 2.15 (3H, s), 2.69 (2H, s), 9.61 (1H, s) Preparation 18 To a mixture of 5% aqueous solution of potassium hydroxide (4.7 ml) and tetrahydrofuran (4.7 ml) was added a solution of 4-oxo-2,2-dicyclopropylpentanal (1.88 g) in diethyl ether (9.4 ml). The mixture was heated at 38°C to 45°C for 3 hours and cooled. The aqueous layer was saturated with sodium chloride. The mixture was extracted with diethyl ether and the extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by distillation under reduced pressure to give 4,4-dicyclopropyl-2-cyclopenten-1-one (1.55 g). bp : 101-105°C/6.66 hPa (5 mmHg) IR (Neat) : 1710 cm -1 NMR (CDCl 3 , δ) : 0.10-0.54 (8H, m), 0.92-1.12 (2H, m), 2.04 (2H, s), 6.07 (1H, d, J=5.7Hz), 7.20 (1H, d, J=5.7Hz) Preparation 19 To a solution of 4,4-dicyclopropyl-2-cyclopenten-1-one (1.88 g) in diethyl ether (20 ml) was added diisobutylaluminum hydride (0.94N in n-hexane, 14 ml) at -70°C to -64°C under nitrogen atmosphere. After being stirred for 20 minutes, ethyl acetate (6 ml) was added thereto and the solution was acidified with dil. hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 4,4-dicyclopropyl-2-cyclopenten-1-ol (0.53 g). Since this compound was not so stable, it was used in the next reaction without purification. Example 9 To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.30 g) in acetone were added methanesulfonyl chloride (0.12 ml) and triethylamine (0.21 ml) at 1°C to 3°C. After being stirred for 15 minutes sodium iodide (0.23 g) was added thereto and the mixture was stirred for 10 minutes. To the mixture was added t-butylamine (2.67 ml) at -1°C to 2°C and the mixture was stirred at room temperature overnight. Cold water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate. To the solution was added 3N hydrochloric acid (1 ml) with cooling in an ice bath, and the mixture was stirred for 30 minutes. The resulting precipitates were collected by filtration, washed with water, ethyl acetate successively and dried to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (0.31 g). mp : 265-267°C (dec.) IR (Nujol) : 2730, 2690, 2530, 2490, 2430 cm -1 NMR (DMSO-d 6 , δ) : 1.37 (9H, s), 2.51 (1H, dd, J=8.1Hz and 13.3Hz), 3.34 (1H, dd, J=7.2Hz and 13.3Hz), 4.44 (1H, br m), 6.16 (1H, d, J=5.6Hz), 6.72 (1H, d, J=5.6Hz), 7.10-7.38 (10H, m), 8.89 (1H, br s), 9.52 (1H, br s) The following compounds ( Preparations 20 to 26 and Examples 10 to 14 ) were obtained according to a similar manner to that of Example 9 . Preparation 20 N-Methyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 168-169°C IR (Nujol) : 2680, 2430, 1600, 770, 750, 700 cm -1 NMR (DMSO-d 6 , δ) : 2.30 (1H, dd, J=8.2Hz and 13.4Hz), 2.56 (3H, s), 3.24 (1H, dd, J=7.0Hz and 13.4Hz), 4.20-4.35 (1H, m), 6.06 (1H, dd, J=5.7Hz and 1.5Hz), 6.78 (1H, dd, J=5.7Hz and 1.9Hz), 7.10-7.45 (10H, m), 9.21 (2H, broad s) Example 10 N-Ethyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 209-210°C (recrystallized from isopropyl alcohol-ethyl acetate) IR (Nujol) : 2680, 2450, 1595, 790, 770, 750, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.22 (3H, t, J=7.2Hz), 2.33 (1H, dd, J=13.3Hz and 8.3Hz), 3.00 (2H, qd, J=7.2Hz and 1.8Hz), 3.25 (1H, dd, J=13.3Hz and 7.0Hz), 4.25-4.35 (1H, m), 6.07 (1H, dd, J=5.7Hz and 1.4Hz), 6.76 (1H, dd, J=5.7Hz and 1.9Hz), 7.12-7.46 (10H, m), 9.25 (1H, broad s) Preparation 21 N-Butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 158.5-159°C (recrystallized from a mixture of n-hexane, ethyl acetate, and acetone) IR (Nujol) : 2770, 2710, 2660, 2610, 2580, 2550, 2480, 2440, 1600 cm -1 NMR (DMSO-d 6 , δ) : 0.88 (3H, t, J=7.5Hz), 1.33 (2H, sextet, J=7.5Hz), 1.61 (2H, quintet, J=7.5Hz), 2.35 (1H, dd, J=8.5Hz and 13.5Hz), 2.90 (2H, m), 3.26 (1H, dd, J=7.0Hz and 13.5Hz), 4.32 (1H, m), 6.09 (1H, d, J=5.5Hz), 6.76 (1H, dd, J=2.0Hz and 5.5Hz), 7.1-7.4 (10H, m), 9.25 (2H, br s) Preparation 22 N,N-Dimethyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 189-190°C (recrystallized from isopropyl alcohol-acetone) IR (Nujol) : 2550, 2430, 780, 760, 700 cm -1 NMR (DMSO-d 6 , δ) : 2.44 (1H, dd, J=13.6Hz and 8.1Hz), 2.74 (6H, s), 3.20 (1H, dd, J=13.6Hz and 7.1Hz), 4.40-4.55 (1H, m), 6.14 (1H, dd, J=1.6Hz and 5.8Hz), 6.85 (1H, dd, J=2.0Hz and 5.8Hz), 7.20-7.40 (10H, m), 10.73 (1H, broad s) Preparation 23 N,N-Diethyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 186-187°C (recrystallized from isopropyl alcohol-ethyl acetate) IR (Nujol) : 2520, 2470, 1600, 790, 750, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.23 (6H, t, J=7.12Hz), 2.35-2.47 (1H, m), 3.02-3.30 (5H, m), 4.53-4.72 (1H, m), 6.13 (1H, d, J=5.8Hz), 6.89 (1H, d, J=5.8Hz), 7.18-7.52 (10H, m), 10.03 (1H, broad s) Preparation 24 N-Benzyl-N-methyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 162-165°C IR (Nujol) : 3050, 2500, 780, 760, 750, 700 cm -1 NMR (DMSO-d 6 , δ) : 2.35-2.70 (1H, m), 3.10-3.45 (1H, m), 3.34 (3H, s), 4.10-4.30 (1H, m), 4.40-4.70 (2H, m), 6.15-6.30 (1H, m), 6.75-7.00 (1H, m), 7.10-7.40 (10H, m), 7.40-7.55 (3H, m), 7.55-7.70 (2H, m), 10.80-11.20 (1H, m) Preparation 25 N-Benzyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 201-204°C (recrystallized from methanol-isopropyl alcohol-ethyl acetate) IR (Nujol) : 1600, 1580, 760, 700 cm -1 NMR (DMSO-d 6 , δ) : 2.45 (1H, dd, J=13.2Hz and 8.6Hz), 3.28 (1H, dd, J=13.2Hz and 6.8Hz), 4.21 (2H, broad s), 4.30-4.50 (1H, m), 6.15 (1H, d, J=5.7Hz), 6.77 (1H, dd, J=5.7Hz and 1.7Hz), 7.10-7.35 (10H, m), 7.35-7.55 (3H, m), 7.55-7.80 (2H, m), 9.82 (2H, broad s) Preparation 26 N-(1,1-Dimethyl-2-hydroxyethyl)-4,4-diphenyl-2-cyclopentenylamine methanesulfonate mp : 176-177°C IR (Nujol) : 3400, 1600 cm -1 NMR (CDCl 3 , δ) : 1.39 (6H, s), 2.60 (3H, s), 2.77 (1H, dd, J=13.3Hz and 8.5Hz), 3.23 (1H, dd, J=13.3Hz and 6.9Hz), 3.62 (2H, s), 4.35 (1H, br s), 6.19 (1H, dd, J=5.7Hz and 1.0Hz), 6.43 (1H, dd, J=5.7Hz and 2.0Hz), 7.12-7.36 (10H, m), 8.17-8.56 (2H, m) Example 11 [N-[1,1-Dimethyl-2-(N-methylbenzylamino)ethyl]-4,4-diphenyl-2-cyclopentenylamine dihydrochloride mp : 196-197°C (dec.) (recrystallized from ethanol-ethyl acetate) IR (Nujol) : 2750, 2600, 2500, 1600, 1580, 790, 750, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.40 (3H, s), 1.59 (3H, s), 2.45-2.70 (1H, m), 2.89 (3H, s), 2.82 (1H, dd, J=6.9Hz and 13.2Hz), 3.35-3.90 (2H, m), 4.20-4.60 (1H, m), 4.45 (2H, s), 6.11 (1H, d, J=5.3Hz), 6.74 (1H, d, J=5.5Hz), 6.95-7.85 (15H, m), 9.64 (1H, broad s), 10.23 (1H, broad s), 11.03 (1H, broad s) Example 12 N- (1-Ethylcyclohexan-1-yl)-4,4-diphenyl-2-cyclopentenylamine hydrochloride mp : 228-234°C (dec.) (recrystallized from methanol-ethanol-ethyl acetate) IR (Nujol) : 1580, 780, 770, 700 cm -1 NMR (DMSO-d 6 , δ) : 0.89 (3H, t, J=7.4Hz), 1.00-2.10 (12H, m), 2.58 (1H, dd, J=13.4Hz and 8.2Hz), 3.28 (1H, dd, J=13.4Hz and 6.1Hz), 4.42 (1H, broad s), 6.14 (1H, broad d, J=5.7Hz), 6.73 (1H, broad d, J=3.9Hz), 7.10-7.50 (10H, m), 8.55-8.80 (1H, m), 8.90-9.20 (1H, m) Example 13 4-(4,4-Diphenyl-2-cyclopentenyl)morpholine hydrochloride mp : 285-288°C (dec.) (recrystallized from methanol) IR (Nujol) : 2520, 2440, 790, 760, 700 cm -1 NMR (DMSO-d 6 , δ) : 3.00-3.82 (8H, m), 3.90-4.08 (2H, m), 4.48-4.60 (1H, m), 6.19-6.30 (1H, m), 6.84-6.95 (1H, m), 7.15-7.42 (10H, m), 10.50-10.72 (1H, broad s) Example 14 N-t-Butyl-4,4-bis(p-tolyl)-2-cyclopentenylamine hydrochloride mp : 265-267°C (recrystallized from ethanol-isopropyl alcohol) IR (Nujol) : 2760, 2630, 820, 800, 720 cm -1 NMR (DMSO-d 6 , δ) : 1.36 (9H, s), 2.25 (3H, s), 2.26 (3H, s), 2.46 (1H, dd, J=7.9Hz and 13.4Hz), 3.26 (1H, dd, J=7.1Hz and 13.4Hz), 4.39 (1H, broad s), 6.10 (1H, dd, J=1.3Hz and 5.7Hz), 6.65 (1H, dd, J=1.8Hz and 5.7Hz), 7.09 (4H, s), 7.12 (4H, s), 8.82 (2H, broad s), 9.38 (1H, broad s) Example 15 To a solution of 4,4-dicyclopropyl-2-cyclopenten-1-ol (0.52 g) in acetone (5 ml) were added methanesulfonyl chloride (0.27 ml) and triethylamine (0.49 ml) with ice bath cooling. After being stirred for 10 minutes, sodium iodide (0.52 g) was added thereto, and the mixture was stirred for 10 minutes. To the mixture was added t-butylamine (6.4 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and then cold water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was dissolved in ethyl acetate, and hydrogen chloride in ethanol (8.9N, 0.5 ml) was added thereto, and evaporated in vacuo. The residue was crystallized from diethyl ether to give N-t-butyl-4,4-dicyclopropyl-2-cyclopentenylamine hydrochloride (0.51 g). These crystals were recrystallized from a mixture of isopropyl alcohol and ethyl acetate to give pure one (0.41 g). mp : 202.5-203.5°C IR (Nujol) : 2750, 2625, 2500, 2455, 2430, 1580 cm -1 NMR (CDCl 3 , δ) : -0.10-0.15 (2H, m), 0.15-0.64 (6H, m), 0.64-0.85 (1H, m), 0.96-1.15 (1H, m), 1.50 (9H, s), 2.19 (1H, dd, J=7.6Hz and 12.9Hz), 2.27 (1H, dd, J=8.0Hz and 12.9Hz), 4.08-4.28 (1H, m), 5.41 (1H, dd, J=2.2Hz and 5.8Hz), 6.22 (1H, dd, J=1.5Hz and 5.8Hz), 9.37 (2H, broad s) Example 16 A mixture of 4,4-diphenyl-2-cyclopenten-1-ol (0.30 g) and carbon tetrabromide (0.55 g) in diisopropyl ether (3 ml) was refluxed for 30 minutes. After being cooled, n-hexane (10 ml) and diisopropyl ether (2 ml) was added thereto and the insoluble material was filtered off. The filtrate was evaporated in vacuo below 30°C. To the residue acetone (4 ml) and t-butylamine (2 ml) were added and refluxed for 30 minutes, and cooled. The mixture was condensed under reduced pressure and was purified by column chromatography on silica-gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.26 g). The physical data were identified with those of the compound of Example 1 . Example 17 N-t-Butyl-4,4-dimethyl-2-cyclopentenylamine hydrochloride was obtained according to a similar manner to that of Example 16 . mp : 194°C (dec.) (recrystallized from a mixture of diethyl ether and chloroform) IR (Nujol) : 3400, 2760, 2690, 2640, 2470 cm -1 NMR (CDCl 3 , δ) : 1.05 (3H, s), 1.26 (3H, s), 1.51 (9H, s), 2.17 (1H, dd, J=8.0Hz and 13.3Hz), 2.37 (1H, dd, J=7.3Hz and 13.3Hz), 4.26-4.45 (1H, m), 5.78 (1H, dd, J=2.1Hz and 5.6Hz), 6.03 (1H, dd, J=1.7Hz and 5.6Hz), 9.35 (2H, br s) Example 18 A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.20 g), t-butylamine (2 ml) and a catalytic amount of sodium iodide in acetone (4 ml) was refluxed for 15 hours and cooled. The mixture was evaporated in vacuo and water was added thereto extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.15 g). The physical data of this compound were identified with those of the compound of Example 1 . Example 19 A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.30 g), t-butylamine (1.24 ml), a catalytic amount of sodium iodide and 18-crown-6 in methylene chloride (3 ml) was refluxed for 47 hours and cooled. The solvent was removed off in vacuo, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. To the residue were added ethyl acetate (5 ml) and 3N hydrochloric acid (2 ml) with cooling in an ice bath, and the mixture was stirred for 3 hours. The precipitate was collected by filtration, washed with ethyl acetate, water, ethyl acetate successively and dried to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (0.28 g). The physical data of this compound were identified with those of the compound of Example 9 . Example 20 A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.26 g) and sodium iodide (0.15 g) in acetone (5 ml) was refluxed for 90 minutes. The insoluble material was filtered off. To the filtrate were added t-butylamine (1.5 ml) and acetone (5 ml). The solution was refluxed for 2 hours and cooled. The solvent was removed off in vacuo and water was added thereto, extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.25 g). The physical data of this compound were identified with those of the compound of Example 1 . Preparation 27 To a solution of 4,4-diphenyl-2-cyclopentenyl azide (0.30 g) in acetone (3 ml) was added triphenylphosphine (0.33 g) at room temperature and refluxed for 21 hours. After being cooled, the solvent was removed under reduced pressure and a solution of sodium borohydride (0.22 g), in methanol (3 ml) was added thereto. After being stirred for 20 minutes, brine and ethyl acetate were added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-isopropyl-4,4-diphenyl-2-cyclopentenylamine (0.26 g). NMR (CDCl 3 , δ) : 1.07 (3H, d, J=6.20Hz), 1.09 (3H, d, J=6.20Hz), 1.90 (1H, br s), 2.15 (1H, dd, J=7.05Hz and 13.14Hz), 1.85-3.14 (2H, m), 4.00-4.15 (1H, m), 5.60 (1H, dd, J=5.61Hz and 1.74Hz), 6.28 (1H, dd, J=5.61Hz and 1.84Hz), 7.10-7.40 (10H, m) To a solution of the free amine compound obtained above (0.26 g) in chloroform was added methanesulfonic acid (92 mg) in methanol and evaporated in vacuo. The residue was triturated with a mixture of diethyl ether and ethyl acetate to give its methanesulfonate (0.26 g). mp : 148-150°C IR (Nujol) : 1610, 1490 cm -1 NMR (CDCl 3 , δ) : 1.38 (3H, d, J=6.2Hz), 1.39 (3H, d, J=6.2Hz), 2.52 (3H, s), 2.64 (1H, dd, J=8.7Hz) and 13.0Hz), 3.19 (1H, dd, J=6.7Hz and 13.0Hz), 3.20-3.50 (1H, m), 4.35 (1H, br s), 6.12 (1H, d, J=5.7Hz), 6.42 (1H, d, J=5.7Hz), 7.10-7.40 (10H, m), 8.75 (2H, br s) Example 21 A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.60 g), 4-diethylamino-1,1-dimethyl-2-butynylamine (0.79 g) and a catalytic amount of sodium iodide in acetone (5 ml) was refluxed for 8 hours. After being cooled, the solvent was removed off under reduced pressure and the residue was purified with column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-[4-diethylamino-1,1-dimethyl-2-butynyl]-4,4-diphenyl-2-cyclopentenylamine (0.54 g). The free amine obtained above was dissolved in chloroform, and to the solution was added hydrogen chloride in methanol (0.18 g/ml, 1 ml). The solution was evaporated in vacuo and triturated with a mixture of ethanol and isopropyl alcohol to give its hydrochloride (0.45 g). mp : 225°C (dec.) (recrystallized from ethanol) IR (Nujol) : 2725, 2300 cm -1 NMR (D 2 O, δ) : 1.26 (6H, t, J=7.3Hz), 1.77 (6H, s), 2.57 (1H, dd, J=8.2Hz and 13.4Hz), 3.23 (4H, q, J=7.3Hz), 3.47 (1H, dd, J=7.0Hz and 13.4Hz), 4.17 (2H, s), 4.60-4.80 (1H, m), 6.15 (1H, dd, J=1.2Hz and 5.7Hz), 6.85 (1H, dd, J=1.8Hz and 5.7Hz), 7.24-7.50 (10H, m) Example 22 To a solution of 2-cyclopenten-1-one (2.0 g) in diethyl ether (20 ml) was added diisobutylaluminum hydride (0.94 M in n-hexane, 28.5 ml) at -70°C to -60°C under nitrogen atmosphere. After being stirred for 1 hour, ethyl acetate (11.9 ml) was added thereto, and the solution was acidified with dil. hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was removed off by distillation. The residue was dissolved in acetone (50 ml). To the solution were added methanesulfonyl chloride (1.88 ml) and triethylamine (3.39 ml) with ice bath cooling. After being stirred for 10 minutes, sodium iodide (3.63 g) was added thereto, and the mixture was stirred for 10 minutes. To the mixture was added t-butylamine (49 ml), and the mixture was stirred at room temperature overnight. The solvent was removed off by distillation, and then cold water was added thereto, and the mixture was extracted with ethyl acetate. To the extract was added hydrogen chloride in ethanol (8.9N, 3 ml), and condensed under reduced pressure. The residue was crystallized from a mixture of diethyl ether and isopropyl alcohol to give t-butylamine hydrochloride (0.40 g). The resultant salt was removed off by filtration, and the filtrate was evaporated in vacuo. The residue was crystallized from a mixture of diethyl ether and ethyl acetate to give N-t-butyl-2-cyclopentenylamine hydrochloride (0.74 g). These crystals were recrystallized from a mixture of isopropyl alcohol and ethyl acetate to give pure compound (0.26 g). mp : 178-180°C (dec.) IR (Nujol) : 2770, 2650, 2500, 2440 cm -1 NMR (CDCl 3 , δ) : 1.52 (9H, s), 2.20-2.64 (3H, m), 2.64-2.90 (1H, m), 4.24 (1H, br s), 6.00-6.18 (2H, m), 9.24 (2H, br s) Example 23 To a solution of 4,4-diphenyl-2-cyclopenten-1-one (0.40 g), t-butylamine (0.75 g) in methylene chloride (9 ml) was added dropwise a solution of titanium tetrachloride (0.50 g) in methylene chloride (5 ml) at -70°C to -60°C. After being stirred for 2 hours, sodium borohydride (0.35 g) and methanol (6 ml) were added successively at 0°C. After being stirred for 0.5 hour, the precipitate was filtered off using celite and the filtrate was condensed under reduced pressure. To the residue, 1N sodium hydroxide aqueous solution was added and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.13 g) and N-t-butyl-3,3-diphenylcyclopentylamine (0.19 g) respectively. N-t-Butyl-4,4-diphenyl-2-cyclopentenylamine NMR (CDCl 3 , δ) : 0.80-1.40 (1H, br m), 1.12 (9H, s), 2.04 (1H, dd, J=7.6Hz and 13.0Hz), 3.09 (1H, dd, J=6.8Hz and 13.0Hz), 3.94-4.10 (1H, m), 5.85 (1H, dd, J=1.7Hz and 5.6Hz), 6.21 (1H, dd, J=2.0Hz and 5.6Hz), 7.09-7.38 (10H, m) N-t-Butyl-3,3-diphenylcyclopentylamine NMR (CDCL 3 , δ) : 1.03 (9H, s), 1.49-1.72 (1H, m), 1.93-2.63 (5H, m), 2.74-2.89 (1H, m), 3.14-3.37 (1H, m), 7.02-7.14 (10H, m) The following compounds ( Preparations 28 to 35 and Examples 24 to 33 ) were obtained according.to a similar manner to that of Example 23 . Preparation 28 N-Methyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2680, 2430, 1600, 770, 750, 700 cm -1 Example 24 N-Ethyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2680, 2450, 1595, 790, 770, 750, 700 cm -1 Preparation 29 N-Butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2770, 2710, 2660, 2610, 2580, 2550, 2480, 2440, 1600 cm -1 Preparation 30 N,N-Dimethyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2550, 2430, 780, 760, 700 cm -1 Preparation 31 N,N-Diethyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2520, 2470, 1600, 790, 750, 700 cm -1 Preparation 32 N-Benzyl-N-methyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 3050, 2500, 780, 760, 750, 700 cm -1 Preparation 33 N-Benzyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 1600, 1580, 760, 700 cm -1 Preparation 34 N-(1,1-Dimethyl-2-hydroxyethyl)-4,4-diphenyl-2-cyclopentenylamine methanesulfonate IR (Nujol) : 3400, 1600 cm -1 Example 25 N-[1,1-Dimethyl-2-(N-methylbenzylamino)ethyl]-4,4-diphenyl-2-cyclopentenylamine dihydrochloride IR (Nujol) : 2750, 2600, 2500, 1600, 1580, 790, 750, 700 cm -1 Example 26 N-(1-Ethylcyclohexan-1-yl)-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 1580, 780, 770, 700 cm -1 Example 27 4-(4,4-Diphenyl-2-cyclopentenyl)morpholine hydrochloride IR (Nujol) : 2520, 2440, 790, 760, 700 cm -1 Example 28 N-t-Butyl-4,4-bis(p-tolyl)-2-cyclopentenylamine hydrochloride IR (Nujol) : 2760, 2630, 820, 800, 720 cm -1 Example 29 N-t-Butyl-4,4-dicyclopropyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2750, 2625, 2500, 2455, 2430, 1580 cm -1 Example 30 N-t-Butyl-4,4-dimethyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 3400, 2760, 2690, 2640, 2470 cm -1 Preparation 35 N-Isopropyl-4,4-diphenyl-2-cyclopentenylamine methanesulfonate IR (Nujol) : 1610, 1490 cm -1 Example 31 N-[4-Diethylamino-1,1-dimethyl-2-butynyl]-4,4-diphenyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2725, 2300 cm -1 Example 32 N-t-Butyl-2-cyclopentenylamine hydrochloride IR (Nujol) : 2770, 2650, 2500, 2440 cm -1 Example 33 1-(4,4-Diphenyl-2-cyclopentenyl)piperazine dihydrochloride IR (Nujol) : 1590, 770, 750, 700 cm -1 Example 34 1-(4,4-Diphenyl-2-cyclopentenyl)piperazine dihydrochloride was obtained by reacting 5,5-diphenyl-2-cyclopenten-1-ol and 1-formylpiperazine according to a similar manner to that of Example 9 to give 1-(4,4-diphenyl-2-cyclopentenyl)-4-formylpiperazine, then eliminating formyl group thereof in a conventional manner. mp : 244°C (dec.) IR (Nujol) : 1590, 770, 750, 700 cm -1 NMR (CD 3 OD, δ) : 2.58 (1H, dd, J=13.9Hz and 7.7Hz), 3.39 (1H, dd, J=13.9Hz and 7.5Hz), 3.63 (8H, broad s), 4.76 (1H, pseudo t, J=7.5Hz), 6.17 (1H, dd, J=5.7Hz and 1.6Hz), 6.87 (1H, dd, J=5.7Hz and 1.9Hz), 7.10-7.40 (10H, m) Preparation 36 To a suspension of 5,5-diphenyl-2-cyclopenten-1-ol (5.0 g), dimethyl D-tartrate (0.49 g), molecular sieves 4A (activated powder 0.5 g) in methylene chloride (50 ml) was added titanium(IV) isopropoxide (0.63 ml) under nitrogen atmosphere with cooling in a dry-ice acetone bath. After being stirred for 30 minutes, t-butyl hydroperoxide (3.0 M solution in 2,2,4-trimethylpentane, 3.57 ml) was added thereto. Then, the mixture was stored in a freezer for 4 days. The mixture was poured into ice and water (50 ml), and the resulting emulsion was filtered through celite pad. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give (+)-5,5-diphenyl-2-cyclopenten-1-ol (1.84 g, [α] 21.2 / D = +100.8°, C=1.19, CH 3 OH) and (-)-rel-(1R,2R,3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol* [(-) isomer rich mixture] (1.27 g, [α] 22.4 / D= -150.5°, C=0.6276, CH 2 Cl 2 ). Preparation 37 (+)-rel-(1R,2R,3S)-2,3-Epoxy-5,5-diphenylcyclopentan-1-ol [(+) isomer rich mixture; [α] 22 / D = +45.34° (C=0.743, CH 3 OH)] and (-)-5,5-diphenyl-2-cyclopenten-1-ol were obtained according to a similar manner to that of Preparation 36 . Preparation 38 The crude product, (-)-rel-(1R,2R,3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol [(-) isomer rich mixture], was purified as follows : The crude product (1.21 g) was recrystallized from ethyl acetate (3 ml) to give its racemate (0.48 g, mp 140-141°C). The filtrate was condensed under reduced pressure, and the residue was crystallized from diisopropyl ether (7 ml) to give pure (-)-isomer (0.52 g). mp : 92.5-94°C [α] 21.2 / D= -298.6° (C=0.66, CH 2 Cl 2 ) IR (Nujol) : 3420 cm -1 NMR (CDCl 3 , δ) : 1.61 (1H, d, J=12.3Hz), 2.42 (1H, d, J=15.1Hz), 3.47 (1H, d, J=15.1Hz), 3.66 (2H, pseudo s), 4.96 (1H, d, J=12.3Hz), 7.07-7.35 (10H, m) Preparation 39 The crude product, (+)-rel-(1R, 2R, 3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol was purified according to a similar manner to that of Preparation 38 . mp : 92-93°C [α] 22 / D= +268.17° (C=0.465, CH 2 Cl 2 ) IR (Nujol) : 3450, 3420, 770, 750, 700 cm -1 NMR (CDCl 3 , δ) : 1.61 (1H, d, J=12.3Hz), 2.42 (1H, d, J=15.1Hz), 3.47 (1H, d, J=15.1Hz), 3.66 (2H, pseudo s), 4.96 (1H, d, J=12.3Hz), 7.07-7.35 (10H, m) Preparation 40 (-)-rel-(1R,2R,3S)-2,3-Epoxy-5,5-diphenylcyclopentan-1-ol [(-) isomer rich mixture] obtained in Preparation 36 was recrystallized from ethyl acetate to give (±)-rel-(1R,2R,3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol (racemic mixture). mp : 163-137°C IR (Nujol) : 3420, 3050, 800, 770, 750, 740, 700 cm -1 Preparation 41 To a solution of (-)-rel-(1R,2R,3S)-2,3-epoxy-5,5-diphenylcyclopentan-1-ol (297 mg) in methylene chloride (3 ml) and isopropyl alcohol (1.2 ml) was added titanium(IV) isopropoxide (0.46 ml) with ice bath cooling. After being stirred for 30 minutes, t-butylamine (0.25 ml) was added thereto, and the mixture was stirred at room temperature overnight. The solution was evaporated in vacuo and the residue was dissolved in diethyl ether (3 ml). To the solution was added 3N hydrochloric acid (1.66 ml) in an ice bath, and the mixture was stirred for 3 hours. The resulting precipitates were collected by filtration, washed with diethyl ether (3 ml), and dried to give (-)-rel-(1R,25,3R)-3-t-butylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride (0.36 g). mp : 279-281°C (dec.) [α] 19.2 / D= -77.1° (C=0.31, MeOH) IR (Nujol) : 3420, 3350, 3160 cm -1 NMR (DMSO-d 6 , δ) : 1.36 (9H,s), 2.63 (1H, dd, J=14.0Hz and 7.7Hz), 3.12 (1H, dd, J=14.0Hz and 9.9Hz), 3.48-3.72 (1H, br s), 4.09-4.26 (1H, m), 4.68-4.84 (1H, m), 5.15 (1H, d, J=5.8Hz), 5.23 (1H, d, J=4.9Hz), 7.00-7.50 (10H, m), 8.78 (1H, br s), 9.17 (1H, br s) The following compounds ( Preparations 42 to 45 ) were obtained according to a similar manner to that of Preparation 41 . Preparation 42 (+)-rel-(1R,2S,3R)-3-t-Butylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride [α] 21 / D = +74.6° (C=0.335, MeOH) mp : 288°C IR (Nujol) : 3520, 3320, 1590, 770, 740, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.35 (9H, s), 2.52-2.70 (1H, m), 3.01-3.21 (1H, m), 3.50-3.72 (1H, m), 4.08-4.21 (1H, m), 4.77 (1H, t, J=4.8Hz), 5.15 (1H, d, J=5.8Hz), 5.21 (1H, d, J=4.8Hz), 7.00-7.52 (10H, m), 8.71 (1H, broad s), 9.05 (1H, broad s) Preparation 43 (±)-rel-(1R,2S,3R)-3-t-Butylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride mp : 278-279°C (dec.) IR (Nujol) : 3500, 3300, 3190, 1580, 770, 740, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.36 (9H, s), 2.63 (1H, dd, J=14.0Hz and 7.7Hz), 3.12 (1H, dd, J=14.0Hz and 9.9Hz), 3.61 (1H, broad s), 4.10-4.20 (1H, m), 4.70-4.80 (1H, m), 5.15 (1H, d, J=5.8Hz), 5.23 (1H, d, J=4.9Hz), 7.00-7.50 (10H, m), 8.78 (1H, broad s), 9.17 (1H, broad s) Preparation 44 (±)-rel-(1R,2S,3R)-3-Isopropylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride mp : 283-285°C (dec.) IR (Nujol) : 3500, 3300, 770, 750, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.28 (6H, d, J=5.1Hz), 2.35 (1H, dd, J=13.6Hz and 9.0Hz), 3.06 (1H, dd, J=13.6Hz and 9.0Hz), 3.25-3.65 (2H, m), 4.15-4.30 (1H, m), 4.71 (1H, pseudo t, J=5.7Hz), 5.09 (1H, d, J=6.3Hz), 5.16 (1H, d, J=4.8Hz), 7.02-7.58 (10H, m), 9.06 (2H, broad s) Preparation 45 (±)-rel-(1R,2S,3R)-3-Diethylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride mp : 243-245°C (dec.) IR (Nujol) : 3470, 3150, 800, 760, 750, 720, 710, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.08-1.35 (6H, m), 2.38 (1H, dd, J=13.2Hz and 10.0Hz), 2.94-3.10 (5H, m), 3.42-3.65 (1H, m), 4.28-4.42 (1H, m), 4.67 (1H, dd, J=6.7Hz and 5.8Hz), 5.18 (1H, d, J=6.7Hz), 5.26 (1H, d, J=4.8Hz), 7.02-7.50 (10H, m), 10.56 (1H, broad s) Example 35 To a suspension of (-)-rel-(1R,2S,3R)-3-t-butylamino-5,5-diphenylcyclopentane-1,2-diol hydrochloride (299 mg) and p-toluenesulfonic acid monohydrate (16 mg) in methylene chloride (6 ml) was added trimethyl orthoformate (0.45 ml), and the mixture was stirred at room temperature overnight. The solvent was removed off by evaporation. The residue was dissolved in xylene (9 ml), and refluxed for 3 hours. After being cooled, 2.5N sodium hydroxide solution (1.0 ml) was added thereto, and the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (130 mg). This amine was suspended in a mixture of isopropyl alcohol (0.4 ml) and water (0.2 ml). To the suspension was added conc. hydrochloric acid (0.065 ml) in an ice bath, and the mixture was stirred for 5 hours. The resulting precipitates were collected by filtration, washed with 30% aqueous isopropyl alcohol (0.4 ml), and dried to give (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (89 mg). The physical data of this compound were identified with those of the compound of Example 8 . Example 36 (+)-N-t-Butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride was obtained according to a similar manner to that of Example 35 . mp : 259-260°C (dec.) [α] 23 / D = +189.16° (C=0.60, MeOH) IR (Nujol) : 3400, 2750, 2700, 1600, 780, 770, 700 cm -1 NMR (DMSO-d 6 , δ) : 1.36 (9H, s), 2.34-2.47 (1H, m), 3.33-3.46 (1H, m), 4.44-4.61 (1H, m), 6.03 (1H, broad d, J=5.6Hz), 6.76 (1H, broad d, J=5.6Hz), 7.15-7.25 (10H, m), 8.50-8.68 (1H, m), 8.90-9.15 (1H, m)

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE A substituted-amine compound of the following formula : wherein a group of the formula : is cyclopentenyl, R 1 and R 2 are each hydrogen, C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino; C 2 -C 6 alkynyl which may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; or cyclo(C 3 -C 6 )alkyl which may have 1 to 3 C 1 -C 6 alkyl, R 4 is hydrogen, in which R 3 and R 4 may be linked together to form 1-piperazinyl or morpholino, each of which may have 1 to 3 C 1 -C 6 alkanoyl, and R 5 and R 6 are each hydrogen or hydroxy, with proviso that (i) R 3 is t-butyl, when R 1 , R 2 , R 5 and R 6 are each hydrogen, and a pharmaceutically acceptable salt thereof. A compound of claim 1, wherein R 5 and R 6 are each hydrogen. A compound of claim 2, wherein R 1 and R 2 are each phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino. A compound of claim 3, wherein R 1 and R 2 are each phenyl, and R 3 is ethyl or t-butyl. A compound of claim 4, which is (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine or its hydrochloride. A process for preparing a substituted-amine compound of the following formula : wherein a group of the formula : is cyclopentenyl, R 1 and R 2 are each hydrogen, C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino; C 2 -C 6 alkynyl which may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; or cyclo(C 3 -C 6 )alkyl which may have 1 to 3 C 1 -C 6 alkyl, R 4 is hydrogen, in which R 3 and R 4 may be linked together to form 1-piperazinyl or morpholino, each of which may have 1 to 3 C 1 -C 6 alkanoyl, and R 5 and R 6 are each hydrogen or hydroxy, with proviso that (i) R 3 is t-butyl, when R 1 , R 2 , R 5 and R 6 are each hydrogen, or a salt thereof, which comprises (i) reacting a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 5 and R 6 are each as defined above, and X is a leaving group, with a compound of the formula: wherein R 3 and R 4 are each as defined above, or a salt thereof, or (ii) reacting a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 5 and R 6 are each as defined above, with a compound of the formula : wherein R 3 and R 4 are each as defined above, or a salt thereof, and then subjecting the resultant intermediate compound to reduction, or (iii) subjecting a compound of the formula : wherein a group of the formula : is cyclopentyl, and R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof, to elimination reaction of diol, to give a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers and/or excipient. Use of the compound of claim 1 or a salt thereof for the manufacture of a medicament. Use of a compound of claims 1 to 5 or a salt thereof for the manufacture of a medicament for the prevention and/or treatment of dysuria, spasm, hyperkinesia, arrhythmia, and congestive heart failure in human beings or animals. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. Claims for the following Contracting State : GR A substituted-amine compound of the following formula : wherein a group of the formula : is cyclopentenyl, R 1 and R 2 are each hydrogen, C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino; C 2 -C 6 alkynyl which may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; or cyclo(C 3 -C 6 )alkyl which may have 1 to 3 C 1 -C 6 alkyl, R 4 is hydrogen, in which R 3 and R 4 may be linked together to form 1-piperazinyl or morpholino, each of which may have 1 to 3 C 1 -C 6 alkanoyl, and R 5 and R 6 are each hydrogen or hydroxy, with proviso that (i) R 3 is t-butyl, when R 1 , R 2 , R 5 and R 6 are each hydrogen, and a pharmaceutically acceptable salt thereof. A compound of claim 1, wherein R 5 and R 6 are each hydrogen. A compound of claim 2, wherein R 1 and R 2 are each phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino. A compound of claim 3, wherein R 1 and R 2 are each phenyl, and R 3 is ethyl or t-butyl. A compound of claim 4, which is (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine or its hydrochloride. A process for preparing a substituted-amine compound of the following formula : wherein a group of the formula : is cyclopentenyl, R 1 and R 2 are each hydrogen, C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino; C 2 -C 6 alkynyl which may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; or cyclo(C 3 -C 6 )alkyl which may have 1 to 3 C 1 -C 6 alkyl, R 4 is hydrogen, in which R 3 and R 4 may be linked together to form 1-piperazinyl or morpholino, each of which may have 1 to 3 C 1 -C 6 alkanoyl, and R 5 and R 6 are each hydrogen or hydroxy, with proviso that (i) R 3 is t-butyl, when R 1 , R 2 , R 5 and R 6 are each hydrogen, or a salt thereof, which comprises (i) reacting a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 5 and R 6 are each as defined above, and X is a leaving group, with a compound of the formula: wherein R 3 and R 4 are each as defined above, or a salt thereof, or (ii) reacting a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 5 and R 6 are each as defined above, with a compound of the formula : wherein R 3 and R 4 are each as defined above, or a salt thereof, and then subjecting the resultant intermediate compound to reduction, or (iii) subjecting a compound of the formula : wherein a group of the formula : is cyclopentyl, and R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof, to elimination reaction of diol, to give a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof. Use of the compound of claim 1 or a salt thereof for the manufacture of a medicament. Use of a compound of claims 1 to 5 or a salt thereof for the manufacture of a medicament for the prevention and/or treatment of dysuria, spasm, hyperkinesia, arrhythmia, and congestive heart failure in human beings or animals. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. Claims for the following Contracting State : ES A process for preparing a substituted-amine compound of the following formula (I) : wherein a group of the formula : is cyclopentenyl, R 1 and R 2 are each hydrogen, C 1 -C 6 alkyl, cyclo(C 3 -C 6 )alkyl or phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino; C 2 -C 6 alkynyl which may have 1 to 3 N,N-di(C 1 -C 6 )alkylamino; or cyclo(C 3 -C 6 )alkyl which may have 1 to 3 C 1 -C 6 alkyl, R 4 is hydrogen, in which R 3 and R 4 may be linked together to form 1-piperazinyl or morpholino, each of which may have 1 to 3 C 1 -C 6 alkanoyl, and R 5 and R 6 are each hydrogen or hydroxy, with proviso that (i) R 3 is t-butyl, when R 1 , R 2 , R 5 and R 6 are each hydrogen, or a salt thereof, which comprises (i) reacting a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 5 and R 6 are each as defined above, and X is a leaving group, with a compound of the formula: wherein R 3 and R 4 are each as defined above, or a salt thereof, or (ii) reacting a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 5 and R 6 are each as defined above, with a compound of the formula : wherein R 3 and R 4 are each as defined above, or a salt thereof, and then subjecting the resultant intermediate compound to reduction, or (iii) subjecting a compound of the formula : wherein a group of the formula : is cyclopentyl, and R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof, to elimination reaction of diol, to give a compound of the formula : wherein a group of the formula : R 1 , R 2 , R 3 and R 4 are each as defined above, or a salt thereof. A process of claim 1, wherein R 5 and R 6 are each hydrogen. A process of claim 2, wherein R 1 and R 2 are each phenyl which may have 1 to 3 C 1 -C 6 alkyl, R 3 is ethyl or t-butyl which may have one N-(C 1 -C 6 )alkyl-N-phenyl(C 1 -C 6 )alkylamino. A process of claim 3, wherein R 1 and R 2 are each phenyl, and R 3 is ethyl or t-butyl. A process of claim 4, which is (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine or its hydrochloride. Use of the compound of claim 1 or a salt thereof for the manufacture of a medicament. Use of a compound of claims 1 to 5 or a salt thereof for the manufacture of a medicament for the prevention and/or treatment of dysuria, spasm, hyperkinesia, arrhythmia, and congestive heart failure in human beings or animals. A compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

Inventors: OKUMURA KAZUO, SHIOKAWA YOUICHI, TAKE KAZUHIKO, TSUBAKI KAZUNORI, OKUMURA, KAZUO, SHIOKAWA, YOUICHI, TAKE, KAZUHIKO, TSUBAKI, KAZUNORI
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1991
Main classification: C07C211
IPC codes: A61P15, A61P25, C07C211, C07D295, C07C209, C07C215, A61P9, A61P21, A61P11, A61K31, C07C213, A61P13