1,4-Substituted piperidines as acetylchozinesterase inhibitors and their use for the treatment of Alzheimer's disease

Abstract: Cyclic amines are provided of the formula: wherein J is: (a) a group, substituted or unsubstituted, selected from the group consisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl and (7) furyl; (b) a monovalent group derived from a cyclic amide compound; (c) a lower alkyl or (d) a group of R²¹-CH=CH- in which R²¹ is hydrogen or a lower alkoxycarbonyl; K is phenyl, an arylalkyl or cynnamyl; B is -(CHR22)r-, R22 being H or methyl, -CO-(CHR22)r-, =(CH-CH=CH)b-, =CH-(CH2)c- or =(CH-CH)d=; and the ring including T and Q is piperidine. The compound is useful for the preparation of pharmaceutical compositions and for medicaments effective against senile dementia.

Description: The invention relates to a cyclic amine compound, a therapeutical composition and medical treatment of senile dementia. ( Statement of Prior Arts ) With a rapid increase in the population of aged people, the establishment of the therapy for senile dementia, such as Alzheimer senile dementia, is eagerly desired. Various attempts have been made to treat the senile dementia with a drug. So far, however, there has been no drug which is very useful for the treatment of these diseases. Studies on the development of therapeutic agents for these diseases have been made from various aspects. Particularly, since Alzheimer senile dementia is accompanied by the lowering in cholinergic hypofunction, the development of the therapeutic agent from the aspect of an acetylcholine precursor and an acetylcholinesterase inhibitor was proposed and is in fact attempted. Representative examples of the anti-cholinesterase inhibitor include physostigmine and tetrahydroaminoacridine. However, these drugs have drawbacks such as an unsatisfactory effect and the occurrence of unfavorable side effects. At the present time, there are no decisive therapeutic agents. EP-A-0 229 391, having respective priority and filing dates of 27 December 1985 and 24 December 1986, discloses various piperidine derivatives which are useful for preventing dementia. In view of the above situation, the present inventors have made extensive and intensive studies on various compounds for many years with a view to developing a drug which has a persistent activity and a high safety. As a result, the present Inventors have found that a piperidine derivative represented by the following general formula (XXV) can attain the desired object. Specifically, the compound of the present invention represented by the following general formula (XXV) has great advantages of having strong and highly selective antiacetylcholinesterase activity, increasing the amount of acetylcholine present in the brain, exhibiting an excellent effect on a model with respect to disturbance of memory, and having a persistent activity and a high safety when compared with physostigmine which is a conventional popular drug in the art, which renders the compound of the present invention very valuable. The compound of the present invention was found based on the acetylcholinesterase inhibitory action and, therefore, is effective for treatment and prevention of various diseases which are thought to be derived from the deficiency of acetylcholine as a neurotransmitter in vivo. Examples of such diseases include various kinds of dementia including Alzheimer senile dementia and further include Huntington's chorea, Pick's disease, and ataxia. Therefore, the objects of the present invention are to provide a novel piperidine derivative effective as a pharmaceutical, particularly for treatment and prevention of central nervous system diseases, and to provide a pharmaceutical comprising the same as an effective ingredient. (Summary of the Invention) The invention provides a cyclic amine compound having the following formula (XXV) and a pharmacologically acceptable salt thereof: wherein J is a monovalent group selected from wherein Y in the formula (l) is a hydrogen atom or a C 1-6 alkyl group; V in the formula (k) is a hydrogen atom or a C 1-6 alkoxy group; W 1 and W 2 in the formula (n) are each a hydrogen atom, a C 1-6 alkyl or a C 1-6 alkoxy group; W 3 in formula (n) is a hydrogen atom or a C 1-6 alkyl group; and the phenyl group A in the formulae (a)-(g), (j), (l) and (q) may optionally be substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group; K is a phenylalkyl group wherein the phenyl may optionally be substituted by a C 1-6 alkyl group which may optionally be halogenated, a C 1-6 alkoxy group, a nitro group, a halogen atom, a carboxyl group, a benzyloxy group, a C 1-6 alkoxycarbonyl group, an amino group, a C 1-6 monoalkylamino group, a C 1-6 dialkylamino group, a carbamoyl group, a C 1-6 acylamino group, a cyclohexyloxycarbonyl group, a C 1-6 alkylaminocarbonyl group, a C 1-6 alkylcarbonyloxy group, a hydroxyl group, a formyl group or a C 1-6 alkoxy-C 1-6 alkyl group; and r is an integer of from 0 to 6, with the proviso that if r is 0, then J is neither the group (a) nor the group (q), and with the proviso that if K is a benzyl group and r is 0, then J is not the group (d). Preferably r is 2. According to a further aspect, the present invention provides a cyclic amine of the formula: In addition, the invention provides a therapeutical composition which comprises a pharmacologically effective amount of the cyclic amine compound having the formula (XXV) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. The use is also provided of any of the above amine compounds, including those excluded by the provisos concerning the index r " and group J " , for preparing a medicament for the treatment of a disease caused by acetylcholinesterase activity. In a further aspect, the use is also provided of a cyclic amine compound of the general formula: wherein the phenyl group of the quinazolinone moiety may optionally be substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group, and K and r are as defined in Claim 1 or a pharmacologically acceptable salt thereof, for preparing a medicament for the treatment of a disease caused by acetylcholinesterase activity. Preferably, the cyclic amine compound in this aspect has the formula: Examples of C 1-6 alkyl groups present in the above compounds include straight-chain or branched alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopenthyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2 trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl groups. Among them, methyl, ethyl, propyl and isopropyl groups are preferable. A methyl group is the most preferable. Preferred C 1-6 alkoxy groups are derived from such alkyl groups. The phenyl ring "A" in the above formulae (a)-(g), (j), (l) and (q) may be substituted with a lower alkyl group having 1 to 6 carbon atoms, preferably a methyl group, or a lower alkoxy group having 1 to 6 carbon atoms, preferably a methoxy group. In the present invention, the term "pharmacologically acceptable salt" include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide, and phosphate, and those of organic acids, such as formate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate, and toluenesulfonate. Further, when a certain kind of substituent is selected, the compound of the present invention may form, e.g., alkali metal salts such as a sodium or potassium salt, alkaline earth metal salts such as a calcium or magnesium salt, organic amine salts such as a salt with trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, or N,N'-dibenzylethylenediamine. Moreover, the compounds of the present invention may have an asymmetric carbon atom depending upon the kind of the substituent and, therefore, have stereoisomers. They are, of course, within the scope of the present invention. The compound of the present invention may be prepared by various processes. Representative processes for preparing the compound of the present invention will now be described. Process A When J is a monovalent group derived from a cyclic amide compound selected from among the monovalent groups j, k and l, the compound of the present invention can be prepared also by the following process: wherein R 10 and R 11 are each a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, r is an integer of 1 to 6, p is an integer of 1 to 3 and Z is a group represented by the formula -CH 2 -or a group represented by the formula wherein R 12 is a hydrogen atom or a lower alkyl group. Specifically, a substituted 1,2,3,4-tetrahydro-5H-1-benzazepin-2-one is allowed to condense with a substituted N-benzyl-4-(2-halogenoethyl)piperidine represented by the general formula (XIII) in a solvent, e.g., dimethylformamide, in the presence of, e.g., sodium hydride, thereby preparing a compound (XIV) which is one of the object compounds. Process B When J is a group represented by the formula, the compound of the present invention can be prepared also by the following process: Specifically, 2-hydroxymethylnicotinic acid lactone (XV) is reacted with a substituted N-benzyl(2-aminoethyl)-piperidine represented by the general formula (XVI) by an ordinary method to prepare a compound represented by the general formula (XVII) which is one of the object compounds. The reaction temperature is preferably about 200°C. Process C When J in the general formula (I) is a group represented by the formula , the compound of the present invention can be prepared also by the following process: Specifically, a substituted 2,3-dihydroxypyrrolo(3,4-b)benzene represented by the general formula (XVIII) is reacted with a substituted N-benzyl(2-halogenoethyl)piperidine represented by the general formula (XIII) in the presence of, e.g., sodium hydride, in a solvent, such as dimethylformamide, while heating the reaction mirture, thereby preparing a compound (XIX) which is one of the object compounds. The compounds thus prepared and acid addition salts thereof represented by the general formula (I) are useful for treatment of various kinds of senile dementia, in particular senile dementia of the Alzheimer type. The invention will be described in view of its therapeutical usefulness together with pharmacologically experimental data. Experimental Example 1 In vitro acetylcholinesterase inhibitory action A mouse brain homogenate was used as an acetylcholinesterase source and the esterase activity thereof was determined according to the method of Ellman et al. Ellman, G.L., Courtney, K.D., Andres, V., and Featherstone, R.M., (1961) Biochem. Pharmacol., 7 , 88-95. Acetylthiocholine as a substrate, a sample to detect and DTNB were added to the mouse brain homogenate, followed by incubation. The amount of a yellow substance formed by the reaction between the thiocholine and DTNB was determined in the absorbance at 412 nm in terms of the acetylcholinesterase activity. The acetylcholinesterase inhibitory activity of the sample was expressed in terms of inhibitory concentration 50% (IC 50 ). The results are shown in Table 1. Compound AChE inhibitory activity IC 50 (µM) Compound AChE inhibitory activity IC 50 (µM) 5 0.10 6 0.017 8 0.013 52 0.80 9 0.051 54 1.0 10 0.009 56 0.017 11 0.063 62 0.0075 12 0.040 65 0.0016 67 0.10 70 0.28 176 0.004 Experimental Example 3 Action on passive avoidance learning impairment induced by scopolamine See Z.Bokolanecky & Jarvik:Int.J.Neuropharmacol, 6 , 217-222(1967). Male Wister rats were used as the test animal and a step-through light and dark box was used as an apparatus. A sample to detect was orally administered one hour before the training and the rats were treated with 0.5 mg/kg (i.p.) of scopolamine 30 min. before the training. In a training experiment, the animal was placed into a light room and, just after the animal had entered into a dark room, a guillotine door was closed, followed by delivery of an electric shock from the gid of the floor. After six hours, the animal was again placed into a light room for a retention experiment, and the time taken for the animal to enter the dark room was measured for evaluation of the effect of the sample. The difference in the response time between the physiological saline administration group and the scopolamine administration group was taken as 100%, and the effect of the sample was expressed in terms of the percentage antagonism by the sample (Reverse %). The results are shown in Table 3. Compd. No. Dose (mg/kg) Reverse % 69 0.5 22 1.0 38 The number of animals per dose was 10 to 17. NE: non-effective The above-described pharmacological experiments revealed that the compound of the present invention had a potent acetylcholinesterase inhibitory action. Therefore, the objects of the present invention are to provide a novel compound effective for various kinds of dementia and the sequelae of cerebrovascular diseases, to provide a process for preparing the same, and to provide a novel pharmaceutical comprising the same as an effective ingredient. A representative compound of the present invention (Compd. No. 69 in the above Table 3) was applied to toxicity tests on rats. As a result, all the compounds exhibited a toxicity of 100 mg/kg or more, i.e., exhibited no serious toxicity. The compound of the present invention is effective for treatment, prevention, remission, improvement, etc. of various kinds of senile dementia, particularly senile dementia of the Alzheimer type; cerebrovascular diseases accompanying cerebral apoplexy, e.g. cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis, head injury, etc.; and aprosexia, disturbance of speech, hypobulia, emotional changes, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes, etc. accompanying encephalitis, cerebral palsy, etc. Further, the compound of the present invention has a strong and highly selective anticholinesterase action, which renders the compound of the present invention useful also as a pharmaceutical based on this kind of action. Specifically, the compound of the present invention is effective for, for example, Huntington's chorea, Pick's disease and delayed ataxia or tardive dyskiaesia other than senile dementia of the Alzheimer type. When the compound of the present invention is used as a pharmaceutical for these diseases, it may be orally or parenterally administered. In general, it is parenterally administered in the form of injections, such as intravenous, subcutaneous, and intramuscular injections, suppositories, or sublingual tablets. The does will remarkably vary depending upon the symptom; age, sex, weight, and sensitivity of patients; method of administration; time and intervals of administration and properties, dispensing, and kind of pharmaceutical preparations; kind of effective ingredients, etc., so that there is no particular limitation with respect to the dose. Normally the compound may be administered in a dose of about 0.1 to 300 mg, preferably 1 to 100 mg, per day per adult, ordinarily in one to four portions. Pharmaceutical preparations in the dosage form of, e.g., injections, suppositories, sublingual tablets, tablets, and capsules are prepared according to a method which is commonly accepted in the art. In preparing injections, the effective ingredient is blended, if necessary, with a pH modifier, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent, a preservative, etc., followed by preparation of an intravenous, subcutaneous, or intramuscular injection according to an ordinary method. In this case, if necessary, it is possible to lyophilize these preparations according to an ordinary method. Examples of the suspending agents include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate. Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, and an ethyl ester of castor oil fatty acid. Examples of the stabilizer include sodium sulfite, sodium metasuifite, and ether, and examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. [Examples] The present invention will now be described in more detail with reference to the following Examples. It is needless to say that the technical scope of the invention of the present invention is not limited to these Examples only. In the following examples, all of the NMR values are those of the compounds measured in free form. Example 5 2-[4'-(1'-Benzylpiperidine)ethyl]-2,3-dihydro-1-oxypyrrolo[3,4-b]pyridine dihydrochloride 12.6 g of 2-hydroxymethylnicotinic acid lactone and 40 g of 4-(2-aminoethyl)benzylpiperazine were stirred in a sealed tube at 200°C for 7 hr. Thereafter, the reaction mixture was purified by making use of a silica gel column, and a hydrochloride of the purified product was prepared by an ordinary method, thereby preparing 6.37 g of dihydrochloride of the object compound. m.p. (°C): 143.5-145°C • elementary analysis: C 21 H 25 N 3 O·2HCl C H N calculated (%) 61.77 6.66 10.29 found (%) 61.49 6.68 9.98 Example 6 2-[4'-(1'-Benzylpiperidine)ethyl]-2,3-dihydro-5,6-dimethoxyoxypyrrolo[3,4-b]benzene hydrochloride 0.5 g of 2,3-dihydro-5,6-dimethoxyoxypyrrolo[3,4-b]benzene was dissolved together with a catalytic amount of potassium iodide in DMF. 0.21 g of sodium hydride (60%) was added to the resulting solution while cooling and stirring the solution. Thereafter, 1 g of 2,3-dihydro-5,6-dimethoxyoxypyrrolo[3,4-b]-benzene was added thereto, and the mixture was stirred at 80°C for 4 hr. After the completion of the stirring, H 2 O was added thereto, followed by extraction with chloroform. The chloroform phase was washed with water and dried (over MgSO 4 ). The solvent was distilled off, and the residue was purified with silica gel, thereby preparing an oleaginous object compound. A hydrochloride of the object compound was prepared by an ordinary method, thereby obtaining about 0.2 g of a creamy crystal. molecular formula; C 24 H 30 N 2 O 3 ·2HCl 1 H-NMR(CDCl 3 ) δ ; 1.12∼3.4(9H,m), 2.72 ∼3.00(2H,m), 3.48(2H,s), 3.62(2H,t), 3.95(6H,s), 4.26(2H,s), 6.90(1H,s), 7.28(6H,s) Example 8 3-[2-(1-Benzyl-4-piperidyl)ethyl-2-(1H,3H)-quinazolinone 25.6 g of 4-[N-(o-aminobenzyl)ethyl]-1-benzylpiperidine, 15 g of 1,1'-carbonyldiimidazole, and 100 mℓ of methanol were heated under reflux for 12 hr. After the completion of the reaction, the reaction mixture was poured into water, extracted with methylene chloride and dried over magnesium sulfate. The solvent was distilled off in vacuo therefrom. The residue was purified by silica gel column chromatography (5% MeOH-CH 2 Cℓ 2 ) and recrystallized twice from ethyl acetate, thereby preparing 3.0 g the title compound. molecular formula; C 22 H 27 N 3 O 1 H-NMR(CDCl 3 ) δ ; 1.0 ∼2.1(9H,m) 2.7 ∼3.0(2H,m) 3.2 ∼3.6(4H,m) 4.4 (2H,s) 6.5 ∼7.4(8H,m) 7.75(1H,s) Example 9 1-[4'-(1'-Benzylpiperidine)ethyl-1,2,3,4-tetrahydro-4-methyl-5H-[1,4]-benzodiazepin-2-one dihydrochloride 0.35 g of sodium hydride was suspended in 0.5 mℓ of dimethylformamide (DMF). The suspension was stirred while cooling it with ice, and 0.52 g of 1,2,3,4-tetrahydro-4-methyl-5H-[1,4]-benzodiazepin-2-one dissolved in 3 mℓ of DMF was dropwise added thereto, followed by stirring at room temperature for 30 min. 0.81 g of N-benzyl-4-(2-chloromethyl)piperidine hydrochloride dissolved in 3 mℓ of DMF was dropwise added thereto, and the mixture was stirred at 60 to 70°C for 7 hr. The reaction mixture was poured into ice/water and extracted with methylene chloride. The extract was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography. A hydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 0.17 g of a pale yellow amorphous substance (yield: 13.5%). molecular formula; C 24 H 31 N 3 O·2HCl 1 H-NMR(CDCl 3 ) δ ; 1.25∼2.02(9H,m) 2.52 (3H,s) 2.79∼2.95(2H, bd) 3.10(2H, s) 3.48(2H,s) 3.54(2H,s) 3.91(2H, bt) 7.14∼7.45(9H,m) Example 10 1-[4'-(1'-Benzylpiperidine)ethyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-2-one hydrochloride 0.27 g of sodium hydride was suspended in 0.5 mℓ of dimethylformamide (DMF). The suspension was stirred while cooling it with ice. 0.60 g of 1,2,3,4-tetrahydro-5H-1-benzazepin-2-one dissolved in 4 mℓ of DMF was dropwise added thereto. The mixture was heated at 60°C for 15 min and then cooled with ice. 1.02 g of N-benzyl-4-(2-chloromethyl)piperidine hydrochloride was added thereto, and the mixture was stirred at 60°C for 3.5 hr. The reaction mixture was left to stand for cooling, poured into ice/water, and extracted with methylene chloride. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography. A hydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 1.40 g of the title compound (yield: 94.8%). molecular formula; C 24 H 30 N 2 O·HCl 1 H-NMR(CDCl 3 ) δ ; 1.20∼1.92(11H,m) 2.20 ∼2.24(4H, bs) 2.60∼2.88(4H,m) 3.44 (2H,s) 7.12∼7.24(9H,m) Example 11 N-[4-(1'-Benzylpiperidyl)ethyl]-5,6,11,12-tetrahydrodibenzo[b,f]azocin-6-one hydrochloride 2.24 g of 5,6,11,12-tetrahydrobenzo[b,f]azocin-6-one and 60% sodium hydride were added to 20 mℓ of dimethylformamide. The mixture was stirred at 60°C for 1 hr, and 0.7 g of 1-benzyl-4-chloroethylpiperidine was added thereto, followed by the reaction for an additional 3.5 hr. The reaction mixture was poured into 20 mℓ of water, extracted with ethyl acetate, washed with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off therefrom in vacuo. The residue was purified by silica gel column chromatography (5% MeOH in CH 2 Cℓ 2 ), thereby preparing 0.6 g of the title compound. molecular formula; C 29 H 32 N 2 O·HCl 1 H-NMR(CDCl 3 ) δ ; 1.1 ∼2.2(9H,m) 3.7 ∼4.1(4H,m) 4.15∼4.5(2H,m) 4.46 (2H,s) 6.8 ∼7.4(13H,m) Example 12 10-[4'-(1'-Benzylpiperidine)ethyl]-10,11-dihydro-5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-one hydrochloride 0.25 g of sodium hydride was suspended in dimethylformamide (DMF). The suspension was stirred while cooling it with ice. 0.58 g of 10,11-dihydro-5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-one dissolved in 5 mℓ of DMF was dropwise added thereto. The mixture was stirred at 40 to 50°C for 20 min and then cooled with ice. 0.71 g of 4-(aminoethyl)-1-benzylpiperidine was added thereto, and the mixture was stirred at 45 to 55°C for 6 hr. The reaction mixture was poured into ice/water and extracted with methylene chloride. The organic phase was washed with a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography. A hydrochloride of the purified product was prepared by an ordinary method. Thus there was obtained 0.78 g of a pale yellow amorphous substance (yield: 65.4%). molecular formula; C 28 H 31 N 3 O·HCl 1 H-NMR(CDCl 3 ) δ ; 1.20∼1.91(11H,m) 2.60∼3.00(2H,bs) 3.22(3H,s) 3.41 (2H,s) 6.87∼7.08(3H, m) 7.08(9H,m) 7.64(1H,dd) Examples 51-56, 58-71 and 176 The compounds synthesized in the same manner as that of Examples 5, 6 and 8-12 are shown in Table 4.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, FR, GB, IT, LU, NL, SE A cyclic amine compound having the following formula (XXV) or a pharmacologically acceptable salt thereof: wherein J is a monovalent group selected from wherein Y in the formula (l) is a hydrogen atom or a C 1-6 alkyl group; V in the formula (k) is a hydrogen atom or a C 1-6 alkoxy group; W 1 and W 2 in the formula (n) are each a hydrogen atom, a C 1-6 alkyl or a C 1-6 alkoxy group; W 3 in formula (n) is a hydrogen atom or a C 1-6 alkyl group; and the phenyl group A in the formulae (a)-(g), (j) , (l) and (q) may optionally be substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group; K is a phenylalkyl group wherein the phenyl may optionally be substituted by a C 1-6 alkyl group which may optionally be halogenated, a C 1-6 alkoxy group, a nitro group, a halogen atom, a carboxyl group, a benzyloxy group, a C 1-6 alkoxycarbonyl group, an amino group, a C 1-6 monoalkylamino group, a C 1-6 dialkylamino group, a carbamoyl group, a C 1-6 acylamino group, a cyclohexyloxycarbonyl group, a C 1-6 alkylaminocarbonyl group, a C 1-6 alkylcarbonyloxy group, a hydroxyl group, a formyl group or a C 1-6 alkoxy-C 1-6 alkyl group; and r is an integer of from 0 to 6, with the proviso that if r is 0, then J is neither the group (a) nor the group (q), and with the proviso that if K is a benzyl group and r is 0, then J is not the group (d). A cyclic amine compound or pharmaceutically acceptable salt thereof according to Claim 1, wherein r is 2. A cyclic amine of any one of the formulae: A pharmaceutical composition which comprises a pharmacologically effective amount of a cyclic amine compound according to any preceding Claim, or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier. The use of: (a') a cyclic amine compound according to any preceding Claim; (b') a compound of general formula (XXV) of Claim 1 in which r is 0 and J is either the group (a) or the group (q); (c') a compound of general formula (XXV) of Claim 1 in which K is benzyl, r is 0 and J is the group (d); or (d') a pharmacologically acceptable salt of any of (a'), (b') or (c') above; for preparing a medicament for the treatment of a disease caused by acetylcholinesterase activity. The use of a cyclic amine compound of the general formula wherein the phenyl group of the quinazolinone moiety may optionally be substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group, and K and r are as defined in Claim 1 or a pharmacologically acceptable salt thereof, for preparing a medicament for the treatment of a disease caused by acetylcholinesterase activity. The use according to Claim 6, wherein the cyclic amine compound has the formula: The use as claimed in any of Claims 5-7, wherein the medicament is effective against senile dementia. The use as claimed in Claim 8, wherein the medicament is effective against senile dementia of the Alzheimer type. Claims for the following Contracting States : ES, GR A process for preparing a pharmaceutical composition effective against a disease due to acetylcholinesterase activity comprising the step of mixing a pharmaceutically acceptable carrier and a cyclic amine compound having the following formula (XXV) or a pharmacologically acceptable salt thereof: wherein J is a monovalent group selected from wherein Y in the formula (l) is a hydrogen atom or a C 1-6 alkyl group; V in the formula (k) is a hydrogen atom or a C 1-6 alkoxy group; W 1 and W 2 in the formula (n) are each a hydrogen atom, a C 1-6 alkyl or a C 1-6 alkoxy group; W 3 in formula (n) is a hydrogen atom or a C 1-6 alkyl group; and the phenyl group A in the formulae (a)-(g), (j), (l) and (q) may optionally be substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group; K is a phenylalkyl group wherein the phenyl may optionally be substituted by a C 1-6 alkyl group which may optionally be halogenated, a C 1-6 alkoxy group, a nitro group, a halogen atom, a carboxyl group, a benzyloxy group, a C 1-6 alkoxycarbonyl group, an amino group, a C 1-6 monoalkylamino group, a C 1-6 dialkylamino group, a carbamoyl group, a C 1-6 acylamino group, a cyclohexyloxycarbonyl group, a C 1-6 alkylaminocarbonyl group, a C 1-6 alkylcarbonyloxy group, a hydroxyl group, a formyl group or a C 1-6 alkoxy-C 1-6 alkyl group; and r is an integer of from 0 to 6, with the proviso that if r is 0, then J is neither the group (a) nor the group (q), and with the proviso that if K is a benzyl group and r is 0, then J is not the group (d). A process according to Claim 1, wherein r in formula (XXV) is 2. A process for preparing a pharmaceutical composition effective against a disease due to acetylcholinesterase activity comprising the step of mixing a pharmaceutically acceptable carrier and a cyclic amine of any one of the formulae: The use of: (a') a cyclic amine compound according to any preceding Claim; (b') a compound of general formula (XXV) of Claim 1 in which r is 0 and J is either the group (a) or the group (q); (c') a compound of general formula (XXV) of Claim 1 in which K is benzyl, r is 0 and J is the group (d); or (d') a pharmacologically acceptable salt of any of (a'), (b') or (c') above; for preparing a medicament for the treatment of a disease caused by acetylcholinesterase activity. The use of a cyclic amine compound of the general formula wherein the phenyl group of the quinazolinone moiety may optionally be substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group, and K and r are as defined in Claim 1 or a pharmacologically acceptable salt thereof, for preparing a medicament for the treatment of a disease caused by acetylcholinesterase activity. The use according to Claim 5, wherein the cyclic amine compound has the formula: The use as claimed in any of Claims 4-6, wherein the medicament is effective against senile dementia. The use as claimed in Claim 7, wherein the medicament is effective against senile dementia of the Alzheimer type.

Inventors: ARAKI SHIN, HIGURASHI KUNIZOU, IIMURA YOUICHI, KARIBE NORIO, KOSASA TAKASHI, KOZASA MICHIKO, KUSOTA ATSUHIKO, OGURA HIROO, SASAKI ATSUSHI, SUGIMOTO HACHIRO, TSUCHIYA YUTAKA, YAMANISHI YOSHIHARU, YAMATSU KIYOMI, ARAKI, SHIN, HIGURASHI, KUNIZOU, IIMURA, YOUICHI, KARIBE, NORIO, KOSASA, TAKASHI, KOZASA, MICHIKO, KUSOTA, ATSUHIKO, OGURA, HIROO, SASAKI, ATSUSHI, SUGIMOTO, HACHIRO, TSUCHIYA, YUTAKA, YAMANISHI, YOSHIHARU, YAMATSU, KIYOMI
Applicants: EISAI CO LTD, EISAI CO., LTD.
Application year: 1988
Main classification: C07D207
IPC codes: C07D211, C07D401