(5-(2-AMINOMETHYL-IMIDAZOL-1-YL)-1,3-DIALKYL-1H-PYRAZOL-4-YL)(ARYL)METHANONES AND PROCESSES FOR THEIR PRODUCTION

Abstract: [5-(2-aminomethyl-imidazol-1-yl)-1,3-dialkyl-1H-pyrazol-­ 4-yl](aryl)methanones of formula as cognition activators are disclosed. Also disclosed are proces­ ses for their production and pharmaceutical compositions comprising the new compounds.

Description: [5-(2-AMINOMETHYL-IMIDAZOL-1-YL)-1,3-DIALKYL-1H-PYRAZOL 4-YLj (APYL)METHANONES AND PROCESSES POP. THEIR PRODUCTION US Patent 3,915,981 describes the compound of the formula EMI1.1 which is said to possess protective activities on cerebral hypoxic or anoxic conditions and is used for the treatment of cerebral dysfunction, e.g., cerebral arteriosclerosis, cerebral apoplexy, and head trauma. US Patent 3,763,179 describes a broad class of compounds similar to the above-mentioned patent as sedatives and tranquilizers. The generic structural EMI1.2 Finally, US Patent 3,927,011 describes compounds of the generic formula EMI1.3 having the same biological activity as in US Patent 3,915,981. The compounds of the present invention, described below, are cognition activators and are useful in treating senility and induced amnesia. The present invention relates to new 15-(2-amino- methyl-imidazol-1-yl)-1,3-dialkyl-lH-pyrazol-4-yl]taryl) methanones. More particularly, the invention relates to compounds of the formula EMI2.1 and pharmaceutically acceptable acid-addition salts thereof, and to a method for the production of the foregoing compounds; where R1 and R2 are alkyl having one to six carbon atoms, R3 and R4 are hydrogen or alkyl having one to six carbon atoms, R5 and R6 are hydrogen, alkyl having one to six carbon atoms, phenyl lower alkyl, or phenyl lower alkyl substituted by halo, alkyl having one to four carbon atoms, alkoxy having one to four carbon atoms or trifluoromethyl, or when taken together form a 5- or 6-membered saturated ring with the nitrogen atom and may be further interrupted in the ring by an additional nitrogen or oxygen atom and which 5- or 6-membered ring may be substituted by alkyl having one to six carbon atoms, and Ar is phenyl, phenyl substituted by halo, alkyl having one 'two four carbon atoms, alkoxy having one to four-carbon atoms, or trifluoromethyl; 2- or 3-thienyl or 2- or 3-thienyl substituted by alkyl having one to four carbon atoms. The terms "alkyl" and "lower alkyl," unless otherwise indicated, are intended to mean a straight or branched hydrocarbon chain having at most six carbon atoms. When R5 and R6 are taken together, they form a 5- or 6-membered ring with the nitrogen atom resulting in the pyrrolidine or piperidino group which groups may be further substituted by alkyl having one to four carbon atoms such as, for example, methyl and ethyl. The 5- or 6-membered ring further may be interrupted by an additional heteroatom such as nitrogen or oxygen to form groups such as piperazino or morpholino which groups may also be substituted by alkyl having one to four carbon atoms such as, for example, methyl or ethyl. The free bases of the invention form acidaddition salts with any of a variety of organic and inorganic acids. Pharmaceutically acceptable acid-addition salts are formed with such acids as hydrochloric, sulfuric, nitric, phosphoric, acetic, citric, tartaric, succinic, salicylic, maleic, malic, lactic, gluconic, and pamoic acids. In most cases, salts with one equivalent of a mineral acid or a strong organic acid are stable chemical derivatives. The free bases and their salt forms are interconvertible by adjustment of the pF. The free bases are produced by basification and the acid-addition salts are produced by acidification. They differ in solubility properties but, in general, are otherwise equivalent for the purposes of the invention. Preferred embodiments of the invention are the compounds of the formula I and pharmaceutically acceptable acid addition salts, where R1 and R2 are methyl or ethyl, R2 and R3 are hydrogen, methyl, or ethyl, R5 and R6 are hydrogen, methyl, ethyl or when taken together with nitrogen form an unsubstituted or methyl substituted pyrrolidino, piperidino, piperazino or morpholino group and Ar is phenyl, phenyl substituted by chloro or fluoro, or 2- or 3-thienyl. Other preferred embodiments are the following compounds and pharmaceutically acceptable acidaddition salts. 15- 2-aminomethyl P5-nethyl -1H-imidazol-1-yl )-, 3-dimethyl-lH-pyrazol-4-yl](2-chlorophenyl)methanone dihydrochloride (Example 1); [5-((2-dimethylaminomethyl)-5-methyl-1H-imidazol-1- yl)-1,3-dimethyl-lH-pyrazol-4-yl](2-chlorophenyl) methanone (Example 2); (2-chlorophenyl)-[1,3-dimethyl-5[2-(1-pyrrolidinylmethyl)- 1H-imidazol-1-yl]-1H-pyrazol-4-yl]methanone dihydrochloride (Example 3), and (2-chlorophenyl) [1,3-dimethyl-5-[4,5-dimethyl-2-l4-methyl-piperazin- 1-yl)methyl]-1H-imidazol-1-y1]-1H-pyrazol-4-yl] methanone (Example 4). In accordance with the present invention, the foregoing compounds of formula I, wherein R5 and R6 are hydrogen, can be prepared by hydrolyzing a compound of the formula EMI4.1 wherein R1, R2, R3, R4 and Ar have the same definitions as in formula I, and when R5 is other than hydrogen, reacting a compound of the formula II with an excess amount of an aldehyde of the formula RsCHO in the presence of formic acid. The hydrolysis of the compounds of the formula II is carried out under aqueous acid conditions at room or elevated temperatures. Preferred conditions involve heating at the boiling point of the mixture with concentrated acid, such as, hydrochloric acid. The reductive alkylation reaction using an excess of aldehyde in the presense of formic acid is preferably carried out at elevated temperatures, such as from 50-150 C or preferably from 80-120"C. The compounds of the formula II can be prepared as described in US patents 4,075,408 and 4,105,851. In accordance with the present invention, the compounds of the formula I can be prepared by displac ing the hydroxyl group on a compound of the formula EMI5.1 with an amine of the formula RsR6NH wherein R1, Rz, R3, R4, R5, R6, and Ar have been previously defined. The above displacement reaction is first carried out by activating the hydroxyl group on a compound of formula III. Thus, a compound of the formula III is first reacted with an acid halide of an acid which is capable of forming an ester that is readily displaced by a nucleophile. For example, a compound of the formula III is first treated with p-toluenesulfonyl chloride or methanesulfonyl chloride in the presence of an acid acceptor, such as an organic base, for example, triethylamine. The resulting activated ester is reacted with an excess of the appropriate amine of the formula RSR6NH in an inert organic solvent at room temperature or just below room temperature, for example, from 0-30"C or preferably 15-25'C. Organic solvents are those that are inert but polar enough to dissolve the starting materials such as, for example, tetrahydrofuran. The compounds of the formula III are in turn prepared by first reacting a compound of the formula EMI6.1 wherein R2, R1, and Ar have been defined above, with an imidazole of the formula EMI6.2 wherein R3 and R4 have been defined above, and then treating the resulting product with aqueous formaldehyde. The first step is carried out using an equimolar amount of sodium hydride at room or below room temperature then warmed slowly to elevated temperature Gf approximately 1000C. The reaction is carried out in an organic aprotic solvent such as, dimethylformamide, N,N-dimethylacetamide and the like. The second step is conveniently carried out in formalin (37% aqueous formaldehyde) at the boiling point of the reaction mixture. The starting materials of the formula IV are prepared as described in J. Org. Chem. 36, 2542 !1971). The compounds of this invention are new chemical compounds of value as pharmacological agents. More specifically, they are cognition activators which are potentially useful in treating patients suffering from senility. The compounds also find use in the treatment of induced amnesia. The compounds of this invention may be administered orally in the form of tablets, capsules, syrups, etc or parenterally by being dissolved in an appropriate isotonic solution. The effectiveness of the aforementioned compounds is determined by the test given below which is designed to show the compounds ability to reverse amnesia produced by an electroconvulsive shock. One hundred male mice (Carworth, CF-1 strain, 19-21 g at time of shipment) are divided into five groups of 20 mice each. Each mouse is placed, one at a time, on a small shelf attached to the outside wall of a test box. In this position the mouse is suspended in space. Therefore, the mouse is motivated to step from the shelf through a conveniently placed small hole into the interior of the box. As soon as the mouse has all four feet within the semidarkened interior of the box, the grid floor of the box Is electrified (1.5 milliamps, 3 second duration) to produce a strong pain-fear reaction from the animal. About five seconds thereafter, the mouse is removed from the test box and placed in a group holding cage. Two hours after the above training, the mice are given a single electroconvulsive shock produced by 20 milliamps delivered for 1.0 seconds through the ears. Immediately thereafter, the mice are returned to the holding cage. Two hours after the convulsive treatment, the mice are administered orally through a trachea tube with the chemical being assessed. Usually three doses of the chemical will be tested at a time. One hour after the drug treatment, the mice are tested for memory of the painful foot shock received within the shelf-box apparatus. This testing is accomplished by once again placing each mouse on the small shelf attached to the test box. Any mose that stays on the shelf for 60 seconds without entering the box is counted as remembering the painful foot shock received within the box five hours earlier. Any mouse entering the box within the 60-second period is counted as having amnesia for the painful event. Using this 60-second criterion, appropriate control experiments show: 1) 100 percent of mice will enter the box if no foot shock is delivered during the original training, (painful foot shock is necessary if the mice are to develop an aversion to entering the test box) 2) 100 percent of mice will enter the box under the foregoing conditions even when treated with electroconvulsive shock at the three-hour point prior to testing (electroconvulsive shock treatment itself does not generate a fear of entering the test box). The five groups of mice are treated as follows: Group 1. Ceiling Control Group: 2. Base Line Control Group: 3. 1st Drug Dose Group: 4. 2nd Drug Dose Group: 5. 3rd Drug Dose Group: Treatments Placebo Electroconvulsive shock, Placebo Electroconvulsive shock, 5-aminomethyl-imidazolyl-l - yl-1,3-dialkyl-1H-pyrazol-4- yl aroyl methanone Electroconvulsive shock, 5-aminomethyl-imidazolyl-l - yl-l, 3-dialkyl-lH-pyrazol-4- yl aroyl methanone Electroconvulsive shock, 5-aminomethyl-imidazolyl-l yl-l, 3-dialkyl-lfl-pyrazol-4- yl aroyl methanone The percentage of amnesia reversal is determined as follows for each drug group: : percent Drug group-Base line control group X 100 amnesia = Ceiling control group-base line reversal control group The following criteria is used in interpreting the percent of amnesia reversal scores: 40 percent or more 5active = A) 25 to 39 percent (borderline = C) and 0 to 29 percent (inactive = N). The following table reports the percent of amnesia reversal of orally administered [(5-(2-aminomethyl)-5-methyl-1H- imidazol-l-yl)-1,3-dimethyl-lH-pyrazol-4-yl](2- chlorophenyl)methanone dihydrochloride. Table 1 Dose mg/kg 0.63 1.25 2.50 5.00 20.00 80.00 % Amnesia 20 40 40 62 87 44 Reversal Rating N A A A P, A A Accordingly, the present invention includes the compounds of the formula I in the form of pharmaceutical compositions for treating senility or amnesia comprising an effective amount of a compound of the invention with a pharmaceutically acceptable carrier. The present invention further includes a method of treating senility or amnesia by administering, preferably orally, to a mammal, an effective amount of a compound of the formula I in the form of a phar maceutlcal composition. The estimated mammalian dosage for a 70 kg subject is from 1 to 1500 mg/day (0.014 mg to 21.4 mg/kg of weight per day). Preferably 25 to 750 mg/day (0.36 mg to 10.7 mg/kg of weight per day) optionally in divided portions. Table 2 reports results obtained over a different range of doses than in Table 1 on further examples of the invention. Table 2 Percent Amnesia Reversal (Rating) EMI10.1 <tb> Example <SEP> Dose <SEP> mg/kg <SEP> <tb> Number <SEP> | <SEP> 1 <SEP> <SEP> 10 <SEP> 100 <tb> <SEP> 2 <SEP> 64(A) <SEP> 64(A) <SEP> 85(A) <tb> <SEP> 3 <SEP> 79(A) <SEP> 27(C) <SEP> 25(C) <tb> <SEP> 4 <SEP> 36(C) <SEP> 91(A) <SEP> 54(A) <SEP> <tb> The invention is further illustrated by the following examples: : Example 1 Synthesis of [5 -((2-aminomethyl)-5-methyl-1H-imidazol- l-yl)-1,3-dimethy-l-pyrazol-4-yl (2-chlorophenyl) methanone dihydrochloride A solution of 15.0 grams of 4-(2-chlorophenyl)1,6-dihydro-1,3,9-trimethylimidazo[(1,2-a]pyrazolo- (4,3-f) (l,4)diazepine (US patents 4,075,408 and 4,105,851) is dissolved in 100 ml of concentrated hydrochloric acid and the solution is refluxed 22 hours. The solution is concentrated at reduced pressure and the resulting glass is dissolved in 100 ml of hot isopropanol. The solution is concentrated again and the resulting sclid is recrystallized from anhydrous ethanol. The crystals are isolated by filtration, washed with anhydrous diethyl ether and dried in vacuo to yield the title compound. The compound melts at 218-219µC with decomposition. Example 2 Synthesis of [5-((2-(dimethylaminomethyl)-5-methyl-1H- imidazol-1-yl)1,3-dimethyl-1H-pyrazol-4-yl] (2-chlorophenyl) methanone A solution of 5.0 grams of 4-(2-chlorophenyl)1,6-dihydro-1,3,9-trimethylimidazo[1,2-a]pyrazolo- t4,3-3[1,43 diazepine is dissolved in four grams of 37% formaldehyde solution and five grams of formic acid is added and the mixture is heated at 100 C fcr 16 hours. The solution is concentrated at reduced pressure, dissolved in water and neutralized with excess 50% sodium hydroxide solution. The product is extracted with methylene chloride and the organic solution dried over anhydrous magnesium sulfate. The mixture is filtered, concentrated, and triturated with anhydrous diethyl ether. The product is isolated by filtration and dried in vacuo at 100C. The title compound has a melting point 145-146.5eC. Example 3 (2-chlorophenyl)-[1,3-dimethyl-5-[2-(1-pyrrolidinylmethyl)- 1H-imidazol-1-yl]-1H-pyrazol-4-yl]methanone dihydrochloride A suspension of 3.3 g (0.01 mol) of (2-chloro phenyl)El,3-dimethyl-5-(2-hydroxymethyl-1E-imidazol-1- yl)lH-pyrazol-4-yl3methanone (C) in 50 ml of methylene chloride is cocled to -50C and 1.4 g of methanesulfonyl chloride is added. Triethylamine (2 ml) is added dropwise to the stirred suspension to give a solution after stirring overnight at 20eC, The solution is washed with a saturated solution of NAHC03, dried over anhydrous MgSO4 and evaporated in vacuo to give 3.7 g of the mesyl ester of the starting material. The mesyl ester 3.7 g (0.01 mol) is dissolved in 50 ml of tetrahydrofuran and 2.5 g (0.035 mol) of pyrrolidine is added. After standing at 20 C for 20 hours, the mixture is evaporated in vacuo. The residue is redissolved in methylene chloride; the solution is washed with sodium bicarbonate solution, dried over anhydrous MgS04 and evaporated. The residual oil is dissolved in 10 ml of tetrahydrofuran, treated with 3 ml of 20% isopropanolic hydrogen chloride, and diluted with ethyl acetate to induce crystaliization. The product is isolated by filtration as the dihydrochloride salt with a melting point of 190-192"C. Starting Material The starting material (2-chloropheny1)5-(lH- imidazol-l-yl ) l-pyrazol-4-yl) methanone (B) is obtained as follows: A solution of 54 g (0.2 mol) of (5-chloro-1,3 dimethyl-lH-pyrazol-4-yl) (2-chlorophenyl) methanone (A) LJ. Org. Chem. 36 2542 (1971)) and 18 g (0.24 mol) of imidazole in 300 ml of dimethylformamide is treated portionwise with 10 g (0.2 mol) of sodium hydride (50% dispersion in oil) at 15-30eC under nitrogen. The mixture is warmed slowly to 1000C with stirring and maintained at this temperature for three hours and then evaporated in vacuo. The residue is dissolved in a mixture of 300 ml of methylene chloride and 150 ml of water. The organic layer is separated and washed (extracted) with 1N sodium hydroxide. The organic solution is dried over anhydrous MgSO4 and concentrated and diluted with petroleum ether to give 55 g of (2-chlorophenyl)E5-(lH-imidazol-l-yl)- 1, 3-dimethyl-lH-pyrazol-4-yl) methanone (B), mp 93-95µC. The starting material (2-chlorophenyl)il,3- dimethyl-5-t2-hydroxymethyl-lH-imida zol-l-yl)-lH- pyrazol-4-yl)methanone (C) is obtained as follows: A mixture of 30 g (0.2 mol) of B and 100 g of 37% formalin is stirred and refluxed for 52 hours, and evaporated in vacuo. The oil is dissolved in hot toluene: the toluene solution is washed with hot water, then is extracted with 250 ml of 1N hydrochloric acid. The acid extract is made basic with concentrated ammonium hydroxide. The precipitated product is collected by filtration to give 15.6 g of (2-chiorophenyl) El, 3-dimethyl-5-E2-hydroxymethyl-lH- imidazol-l-yl)-lH-pyrazol-4-yl)methanone with a melting point of 183-185 C. Example 4 (2-Chlorophenyl) 1 , 3-dimethyl-5-4, 5-dimethyl-2- [(4-methyl-piperazin-1-yl)methyl]-1H-imidazol-1-yl] lH-pyrazol-4-yl )methanone By the same procedure described in Example 3 a solution of 3.6 g (0.01 mol) intermediate C' (R1R2R3R4 = CH3; Ar = 2-chlorophenyl) in 50 ml methylene dichloride is treated with 1.4 g of methanesulfonyl chloride in the presence of triethylamine. The resulting mesyl ester is treated with 3 g N-methylpiperazine in tetrahydrofuran for 20 hours at 20µC. The crude product is purified by passage through neutral alumina and isolate as the dihydrochloride salt (3 g). The crude hydrochloride salt is recrystallized from chloroform-ether to give 1.6 g (33%) mp 175-180 C. The starting material (2-chlorophenyl)l,3- dimethyl-5-(4,5-dimethyl-1H-imidazol-1-yl)-1H- pyrazol-4-yl methanone is obtained as follows: A solution of 54 g (0.2 mol) of (5-chloro-1,3 dimethyl-lH-pyrazol-4-yl) (2-chlorophenyl) methanone (A) and 20 g (0.2 mol) of 4,5-dimethylimidazole in 250 ml of dimethylformamide is treated with 10 g (0.2 mol) of sodium hydride (50% dispersion in oil) and stirred at 90-1000C for- four hours to give 46 g of (2-chlorophenyl) [1,3-dimethyl-5-(4,5-dimethyl-1H- imidazol-l-yl)-lH-pyrazol-4-yl]methanone, mp 141-143 CC from ethyl acetate - petroleum ether (B') (RlR2R3R4 = CH3, Ar = 2 chlorophenyl). Intermediate (2-chlorophenyl)[1,3-dimethyl-5-[4, 5-dimethyl-2-hydroxymethyl-1H-imidazol-1-yl)-1H- pyrazol-4-yl)methanone (wit) is obtained as follows: 1,3-Dimethyl-5-(4,5-dimethyl-1H-imidazol-1-yl)- l13-pyrazoi-4-ylj rethanone twenty grams, 0.06 mol is heated at 105 CC for 18 hours in 60 ml of 37% formalin to yield 11 g (51%) of (2-chlorophenyl) [1,3-dimethyl-5-[4,5-dimethyl-2-hydroxymethyl-1H- imidazol-1-yl)-1H-pyrazol-4-yl] methanone (B'), with a melting point of 156-1590C after recrystallization from diethyl ether. For the sake of clarity, all the radicals "R", labelled in the description with a subscript, have been labelled in the claims with the corresponding superscript.

Claims: CLAIMS: for the designated states BE, CH, FR, DE, GB, IT, LI, LU, NL, SE 1. A compound having the following general formula I EMI16.1 or a pharmaceutica]ly acceptable acid-addition salt thereof, wherein; 1 2 R and R , which may be the same or different, are alkyl radicals having from one to six carbon atoms; R3 and R4, which may be the same or different, are hydrogen atoms or alkyl radicals, having from one to six carbon atoms; ; R5 and R6, which may be the same or different, are hydrogen atoms, alkyl radicals having from one to six carbon atoms, phenyl lowe* C1 6,alkyl radicals, phenyl lower,C1 6,alkyl radicals substituted by a halo atom, an alkyl radical having from one to four carbon atoms, or a trifluoromethyl radical; or, when taken together, R5 and R6 form, with the N atom to which they are attached, a 5- or 6-membered saturated ring which may contain a further nitrogen atom or an oxygen atom, and which ring may be singly or multiply substituted by an alkyl radical having from one to six carbon atoms; and Ar is a phenyl radical; a phenyl radical substituted by a halo atom, an alkyl radical having from one to four carbon atoms, an alkoxy radical having from one to four carbon atoms, or a trifluoranethyl radical; a 2- or 3-thienyl radical; or a 2- or 3-thienyl radical substituted by an alk raa c;l having from one to four carbon atoms. 2. A compound according to Claim 1, wherein: 2 each of R and R2 is a methyl radical or an ethyl radical; each of R2 and R3 is a hydrogen atom, a methyl radical, or an ethyl radical; each of R5 and R6 is a hydrogen atom, a methyl radical, or an ethyl radical; or R5 and when taken together and with the nitrogen atom to which they are attached, form an unsubstituted or methyl-substituted pyrrolidino, piperadino, piperazino, or morpholino group; and Ar is a phenyl radical substituted by a chloro or fluoro atom; or a 2- or 3-thienyl radical. 3. A compound according to Claim 2, which is [5-((2-aminomethyl)-5-methyl-1H-imidazol-1- yl)-1,3-dimethyl-lH-pyrazol-4-yl](2-chlorophenyl) methanone dihydrochloride. 4. A compound according to Claim 2, which is (2-chlorophenyl)-[1,3-dimethyl-5[2-(1- pyrrolidinylmethyl)-lH-imidazol-1-yl]-lH-pyrazol -4-yl]methanone dihydrochloride. 5. A compound according to Claim 2, which is [5-((2-dimethyl-aminomethyl)-5-methyl-1H- imidazol-1-yl)-1,3-dimethyl-1H-pyrazol-4-yl](2- chlorophenyl)-methanone. 6. A compound according to Claim 2, which is (2-chlorophenyl)-[1,3-dimethyl-5-[4,5-dimethyl- 2-[(4-methyl-piperazin-1-yl)-methyl]-lH-imidazol- 1-yl]-lH-pyrazol-4-yl]methanone. 7. A process for preparing a compound of the general formula I as defined in Claim 1, wherein R5 and RE are hydrogen atoms, which process comprises hydrolyzing a compound of the formula EMI18.1 herein R1 R2 R 3 R4 and Ar are as defined in Claim 1. 8. A process for preparing a compound of the general formula I as defined in Claim < , wherein R6 is a hydrogen atom and RS is other than a hydrogen atom, which process comprises reacting a compound of the formula EMI18.2 with an aldehyde of the formula R5CHO in the presence of formic acid, wherein R1, R2, R3, 4, RS and Ar are as defined in Claim 1. 9. A process for preparing a compound of the general formula I as defined in Claim 1, which process comprises displacing the hydroxyl group on a compound of the formula EMI19.1 with an amine of the formula R5R6NH wherein R1, R2, R3, R4 , R5, R6 , and Ar are as defined in Claim 1. 10. A pharmaceutical composition for treating senility or amnesia, comprising an effective amount of a compound as claimed in any one of Claims 1 to 6, and a pharmaceutically acceptable carrier. CLAIMS: for the designated state AT 1. A process for preparing a compound having the following general formula I: EMI20.1 or a pharmaceutically acceptable acid-addition salt thereof, wherein; R1 and R2, which may be the same or different, are alkyl radicals having from one to six carbon atoms; R3 and R', which may be the same or different, are hydrogen atoms or alkyl radicals, having from one to six carbon atoms; ; R5 and R6, which may be the same or different, are hydrogen atoms, alkyl radicals having from one to six carbon atoms, phenyl lower,C1 6,alkyl radicals, phenyl lower, C16, alkyl radicals substituted by a halo atom, an alkyl radical having from one to four carbon atoms, or a trifluoromethyl radical; or, when taken together, R5 6 and R form, with the N atom to which they are attached, a 5- or 6-membered saturated ring which may contain a further nitrogen atom or an oxygen atom, and which ring may be singly or multiply substituted by an alkyl radical having from one to six carbon atoms; and Ar is a phenyl radical; a phenyl radical substituted by a halo atom, an alkyl radical having from one to four carbon atoms or a trifluoromethyl radical; a 2- or 3-thienyl radical; or a 2- or 3-thienyl radical substituted by an alkyl radical having from one to four carbon atoms, which process comprises displacing the hydroxyl group on a compound of the formula EMI21.1 with an amine of the formula R5R6NH wherein R1, R2, R3, R4 , R5, R6 and Ar are as defined above. 2. A process for preparing a compound of the general formula I as defined in Claim 1, wherein R5 and R6 are hydrogen atoms, which process comprises hydrolyzing a compound of the formula EMI21.2 wherein R1, R25 R3, R4 and Ar are as defined in Claim 1. 3. A process for preparing a compound of the general formula I as defined in Claim ', wherein R6 is a hydrogen atom and R5 is other than a hydrogen atom, which process comprises reacting a compound of the formula EMI22.1 with an aldehyde of the formula R5CHO in the presence of formic acid, wherein Rll R2 R3 R4 5 and Ar are as defined in Claim 4. A process according to Clam 1,2, or 3, wherein: each of RÚ and Rê is a methyl radical or an ethyl radical; each of R2 and R3is a hydrogen atom, a methyl radical, or an ethyl radical: 5 6. -each of R and R is a bydrogen atuum, a methyl radical, or an ethyl radical; or R5 and R6, when taken together and with the nitrogen atom to which they are attached, form an unsubstituted or methyl-substituted pyrrolidino, piperadino, piperazino, or morpholino group; and Ar is a phenyl radical substituted bya chloro or fluoro atom; or a 2- or 3-thienyl radical 5. A process according to C1= m 1 or 2, for preparing the compound [5-((2-aminomethyl)-5-methyl-1H-imidazol-1- yl)-1,3-dimethyl-lH-pyrazol-4-yl3(2-chlorophenyl) methanone dihydrochloride 6. A process according to Claim l, for preparing the compound (2-chlorophenyl)-[3- dimethyl-5[2-(1-pyrrolidinylmethyl)-1H-imidazol-1- yl-H-pyrazol-4yl)methanone dihydrochloride. 7. A process according to Claim l, for preparing the compound [5-((2-dimethyl-aminomethyl)- 5-methyl-lH-imidazol-1-yl)-1,3-dimethyl-lH-pyrazol- 4-yl](2-chlorophenyl)-methanone. 8. A process according to Claim 1, for preparing the compound (2-chlorophenyl)-[l,3- dimethyl-5-[4,5-dimethyl-2-[(4-methyl-piperazin-l- yl)-methyl]-1H-imidazol-1-yl]-1H-pyrazol-4-yl] methanone. 9. A process for preparing a pharmaceutical composition for treating senility or amnesia, comprising combining an effective amount of a compound prepared in accordance with any one of Claims 1 to 8 with a pharmaceutically acceptable carrier.

Inventors: BUTLER, DONALD EUGENE, DE WALD, HORACE ALBERT
Applicants: WARNER-LAMBERT COMPANY
Application year: 1984
Main classification: C07D403
IPC codes: A61P25, A61K31, C07D403