Pyrimidines and their pharmaceutical acceptable salts, and their use as medicines

Abstract: 2,6-di-, 2,4,6-, 2,5,6-tri- or 2,4,5,6-tetra-­ substituted pyrimidines, and 2,6-di-substituted pyridines. These compounds are useful for treatment of neurological deseases.

Description: This invention relates to novel pyrimidines or their pharmaceutically acceptable salts, and to novel therapeutic compositions for use in the treatment of neurological diseases of the peripheral and central nervous systems of animals containing the above compounds as active ingredients. Japanese Patent Publication No. 23,394/1971 discloses that aminopyrimidines represented by the following formula wherein A represents an alkylene group having up to 16 carbon atoms, or a lower alkylene group substituted by an amino group or a C₂₋₅ acylamino group, M represents H, Na, K, NH₄, Mg, Ca or an organic basic ammonium salt, and n is a value equal to the atomic valency of M, have interesting therapeutic activity, particularly as an anti-melanchoric agent and psychoanaleptic agent in the field of psychosis. Japanese Patent Publication No. 22044/1976 discloses that dichloro-lower aliphatic carboxylic acid salts of 2-isopropylaminopyrimidine, such as 2-isopropylaminopyrimidine dichloroacetate, are useful as a therapeutic agent for a neurological disease. Japanese Laid-Open Patent Publication No. 100477/1977 (Patent Publication No. 28548/1984) discloses that 2-isopropylaminopyrimidine phosphate is useful as a therapeutic agent for a neurological disease. Japanese Patent Publication No. 157575/1979 discloses a process for producing 2-chloropyrimidine in a high yield. A working example in this patent publication describes the preparation of 2-chloropyrimidine in a yield of 69 %. Japanese Laid-Open Patent Publication No. 393/1980 discloses a process for producing 2-isopropylaminopyrimidine in a high yield. A working example of this patent publication describes the preparation of 2-isopropylaminopyrimidine in a yield of 60 %. Japanese Laid-Open Patent Publication No. 122768/1980 discloses that a hydroxy derivative of 2-isopropylaminopyrimidine represented by the following formula wherein A⁴, A⁵ and A⁶ each represent H or OH, and at least one of them represents OH, is useful in the field of nerve regeneration and for treatment of myodystrophy. Japanese Laid-Open Patent Publication No. 145670/1980 discloses that 2-isopropylaminohalogenopyrimidines represented by the following formula wherein A₄', A₅' and A₆' each represent H or a halogen atom, at least one being a halogen atom, are useful for treatment of various neurological diseases and myodystrophy. Japanese Laid-Open Patent Publication No. 145,671/1980 discloses a process for producing a hydroxy derivative of 2-isopropylaminopyrimidine. Japanese Laid-Open Patent Publication No. 151,571/1980 discloses that 2-isopropylamino-5-halogenopyrimidines are interesting in the treatment of neurological diseases. Japanese Laid-Open Patent Publication No. 10177/1981 discloses a process for producing 2-isopropylaminopyrimidine substantially in a quantitative yield by aminolyzing 2-methylsulfonylpyrimidine with isopropylamine. Japanese Laid-Open Patent Publication No. 26880/1981 discloses a process for producing 2-isopropylaminopyrimidine which comprises reacting bis(isopropylguanidine) sulfate with 1,1,3,3-tetraethoxypropane. Japanese Laid-Open Patent Publication No. 90,013/1981 describes a therapeutic agent for myodystropy, myopathy, muscle rigidity and/or dysfunction of neuro-musclar transmission comprising substituted derivative of pyrimidine or its therapeutically acceptable salt or its metabolite as an active ingredient. However, it merely discloses various salts such as an orthophosphate, of 2-isopropylaminopyrimidine as an active compound. Japanese Laid-Open Patent Publication No. 65873/1986 discloses that 2-piperazinopyrimidines of the following formula wherein R¹ is H or aralkyl, and Y is a divalent organic group defined in the claim of this patent publication, are useful as a herbicide for paddies and upland farms. The present inventors previously provided a novel therapeutic agent for treatment of neurological diseases comprising a specific 2-piperazinopyrimidine derivative or its pharmaceutically acceptable salt (International Laid-open Publication No. WO87/04928). The present invention seeks to provide therapeutic agents for the treatment of neurological diseases and spinal breakdown, especially agents which regenerate and repair nerve cells. The present invention also seeks to provide a novel therapeutic agent for the treatment of neurological diseases and which can be applied to, for example, disorders of peripheral nerves, cerebrospinal injury and diseases of central nerves which are different from psychosis and in which abnormality in the operating system or the metabolic system of chemical transmitters is regarded as being primarily involved. The present invention additionally seeks to provide a novel therapeutic agent for the treatment of cerebral diseases which improves and restores learning and memory. The present invention further seeks to provide a novel therapeutic agent for the treatment of neurological diseases or cerebral diseases, which has few side effects such as liver trouble. The present invention provides a pyrimidine represented by the following formula (1), or a pharmaceutically acceptable salt thereof, wherein R¹ represents a hydrogen atom or a C₁-C₄ alkyl group; X represents a group of the formula a group of the formula in which R³ corresponds to optional one or at least two identical or different substituents replacing one or at least two hydrogen atoms of identical or different methylene groups, and represents a C₁-C₄ alkyl group, a hydroxyl group, a phenyl group optionally substituted by nitro, a benzyl group, a benzoyloxy group, a benzoylamino group, a C₁-C₄ alkylamino group, a di-C₁-C₄ alkylamino group, the HO(C₆H₅)₂C- group, a piperidino group, a hydroxy(C₁-C₄ alkyl) group, the C₆H₅SO₂O- group, a benzoyl group optionally substituted by halogen, a C₁-C₄ alkylsulfonylamide group or a (C₁-C₄ alkoxy)carbonyl group, and n is a number of 4, 5, 6 or 7, a group of the formula in which R⁴ represents a hydrogen atom, a C₁-C₄ alkyl group or a benzyl group, and R⁵ represents a C₁-C₄ alkyl group, an acyl group of up to 6 carbon atoms, a 2-furoyl group, a benzyl group, a 4-piperidyl group optionally substituted by benzoyl, a phenethyl group, the group or a benzoyl group optionally substituted by halogen or nitro, a group of the formula a group of the formula a group of the formula or a group of the formula Y represents a group of the formula -CH₂R⁹ wherein R⁹ represents a hydrogen atom, a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ alkylthio group, or a di-C₁-C₄ alkylamino group, a group of the formula wherein R⁶ represents a hydrogen atom, a C₁-C₄ alkyl group, a phenyl group, a benzyl group, a C₁-C₄ alkoxy group or a 2-(N,N-dimethylamino)ethyl group, and R⁷ represents a C₁-C₄ alkyl group, an acyl group of up to 6 carbon atoms, a cyclohexylcarbonyl group, a 2-furoyl group, a (C₁-C₄ alkoxy)carbonyl group, a cinnamoyl group, a benzyl group, a benzylcarbonyl group, a tosyl group, a phenoxyacetyl group, a di-C₁-C₄ alkylcarbamoyl group, a group of the formula a group of the formula a group of the formula a group of the formula a group of the formula a 4-C₁-C₄ alkylpiperazyl group, or a benzoyl group optionally substituted by halogen, nitro, C₁-C₄ alkyl, C₁-C₄ alkoxy, amino, benzoylamino or phenyl, provided that when R⁶ is a hydrogen atom, R⁷ is a benzoyl group, a group of the formula wherein R⁸ corresponds to an optional substituent replacing the hydrogen atom of the methylene group, and represents a hydrogen atom, a C₁-C₄ alkyl group, a phenyl group or a benzyl group, and m is a number of 4, 5, 6 or 7, a group of the formula a group of the formula or a group of the formula and Z represents a hydrogen atom, a halogen atom, a C₁-C₄ alkyl group or a (C₁-C₄ alkoxy) carbonyl group; provided that Y represents -CH₂R⁹ only when Z is a (C₁-C₄ alkoxy) carbonyl group; that R⁴ represents a hydrogen atom and R⁵ represents a C₁-C₄ alkyl group, an acyl group of up to 6 carbon atoms, a 2-furoyl group, a benzyl group, a phenethyl group or a benzoyl group optionally substituted by halogen or nitro, only when Y represents CH₂R⁹ and Z represents a (C₁-C₄ alkoxy) carbonyl group; and that Y can be only when X is and R⁴ is a C₁-C₄ alkyl group. The present invention also provides a compound of formula: or the p-toluenesulfonate thereof. The present invention additionally provides a compound of formula: or the p-toluenesulfonate thereof. The C₁-C₄ alkyl group represented by R¹ may be linear or branched. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl groups. The alkyl moiety of the acyl group represented by R⁵ may be linear or branched. The acyl groups of up to 6 carbon atoms have 2 to 6 carbon atoms. Examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and hexanoyl groups. Examples of the C₁-C₄ alkyl groups represented by R⁹, R⁶ and R⁷ are the same as those exemplified with respect to R¹. Examples of the acyl group represented by R⁷ are the same as those exemplified above for R⁵. Examples of the halogen and C₁-C₄ alkoxy group substituents for the benzoyl group R⁷ are fluorine, chlorine, bromine and iodine, and alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and sec-butoxy. When R⁶ is a hydrogen atom, R⁷ is a benzoyl group. Examples of the halogen atom represented by Z are fluorine, chlorine, bromine and iodine. Examples of the C₁-C₄ alkyl group represented by Z are the same as those exemplified with respect to R¹. Examples of compounds of the present invention are: (100) (104) p-Toluenesulfonate of (100) (108) (112) p-Toluenesulfonate of (108) (116) (120) p-Toluenesulfonate of (116) (124) (128) p-Toluenesulfonate of (124) (132) (136) p-Toluenesulfonate of (132) (137) (138) p-Toluenesulfonate of (137) (140) (144) p-Toluenesulfonate of (140) (149) (150) p-Toluenesulfonate of (149) (148) (152) p-Toluenesulfonate of (148) (145) (146) p-Toluenesulfonate of (145) (147) (147-1) p-Toluenesulfonate of (147) (153) (154) p-Toluenesulfonate of (153) (154-1) (154-2) p-Toluenesulfonate of (154-1) (156) (160) p-Toluenesulfonate of (156) (164) (165) Sulfate of (164) (166) Phosphate of (164) (167) Maleate of (164) (169) Naphthalenesulfonate of (164) (171) Citrate of (164) (171-1) Tartarate of (164) (171-1-1) Fumarate of (164) (168) p-Toluenesulfonate of (164) (170) Hydrochloride of (164) (170-1) (170-2) p-Toluenesulfonate of (170-1) (171-2) (171-3) p-Toluenesulfonate of (171-2) (171-4) (171-5) p-Toluenesulfonate of (171-4) (171-6) (171-7) p-Toluenesulfonate of (171-6) (171-8) (171-9) p-Toluenesulfonate of (171-8) (171-10) (171-11) p-Toluenesulfonate of (171-10) (171-12) (171-13) p-Toluenesulfonate of (171-12) (172) (176) p-Toluenesulfonate of (172) (180) (184) p-Toluenesulfonate of (180) (188) (192) p-Toluenesulfonate of (188) (196) (200) p-Toluenesulfonate of (196) (204) (208) p-Toluenesulfonate of (204) (212) (216) p-Toluenesulfonate of (212) (220) (224) p-Toluenesulfonate of (220) (228) (232) p-Toluenesulfonate of (228) (236) (240) p-Toluenesulfonate of (236) (241) (242) p-Toluenesulfonate of (241) (244) (248) p-Toluenesulfonate of (244) (252) (256) p-Toluenesulfonate of (252) (260) (264) p-Toluenesulfonate of (260) (268) (272) p-Toluenesulfonate of (268) (276) (280) p-Toluenesulfonate of (276) (284) (288) p-Toluenesulfonate of (284) (292) (296) p-Toluenesulfonate of (292) (297) (298) p-Toluenesulfonate of (297) (300) (304) p-Toluenesulfonate of (300) (305) (306) p-Toluenesulfonate of (305) (307) (307-1) Hydrochloride of (307) (308) (312) p-Toluenesulfonate of (308) (316) (320) p-Toluenesulfonate of (316) (324) (328) p-Toluenesulfonate of (324) (332) (336) p-Toluenesulfonate of (332) (380) (384) p-Toluenesulfonate of (380) (388) (392) p-Toluenesulfonate of (388) (396) (400) p-Toluenesulfonate of (396) (404) (408) p-Toluenesulfonate of (404) (412) (416) p-Toluenesulfonate of (412) (420) (424) p-Toluenesulfonate of (420) (428) (432) p-Toluenesulfonate of (428) (600) (604) p-Toluenesulfonate of (600) (608) (612) p-Toluenesulfonate of (608) (616) (620) p-Toluenesulfonate of (616) (624) (628) p-Toluenesulfonate of (624) (632) (636) p-Toluenesulfonate of (632) (640) (644) p-Toluenesulfonate of (640) (648) (652) p-Toluenesulfonate of (648) (656) (660) p-Toluenesulfonate of (656) (661) (662) Hydrochloride of (661) (664) (668) p-Toluenesulfonate of (664) (672) (676) p-Toluenesulfonate of (672) (680) (684) p-Toluenesulfonate of (680) (688) (692) p-Toluenesulfonate of (688) (696) (700) p-Toluenesulfonate of (696) (800) (804) Maleate of (800) (808) (812) Maleate of (808) (816) (820) (824) (828) Maleate of (824) (2000) (2004) p-Toluenesulfonate of (2000) (2008) (2012) p-Toluenesulfonate of (2008) (2048) (2052) Dihydrochloride of (2048) (2056) (2060) Hydrochloride of (2056) (2064) (2070) Hydrochloride of (2064) (2074) (2076) Hydrochloride of (2074) (2080) (2084) Hydrochloride of (2080) (2088) (2092) Hydrochloride of (2088) (2096) (2100) Hydrochloride of (2096) (2104) (2108) Hydrochloride of (2104) (2112) (2116) p-Toluenesulfonate of (2112) (2120) (2124) p-Toluenesulfonate of (2120) (2128) (2132) p-Toluenesulfonate of (2128) (2136) (2140) Di-p-toluenesulfonate of (2136) (2144) (2148) Dihydrochloride of (2144) (2152) (2156) Hydrochloride of (2152) (2160) (2164) Dihydrochloride of (2160) (2170) (2174) p-Toluenesulfonate of (2170) (2178) (2182) p-Toluenesulfonate of (2178) (2184) (2188) p-Toluenesulfonate of (2184) (2192) (2194) p-Toluenesulfonate of (2192) (2198) (2202) p-Toluenesulfonate of (2198) (2206) (2210) p-Toluenesulfonate of (2206) (2214) (2218) p-Toluenesulfonate of (2214) (2222) (2226) Hydrochloride of (2222) (2230) (2234) Di-p-toluenesulfonate of (2230) (2238) (2242) p-Toluenesulfonate of (2238) (2246) (2250) p-Toluenesulfonate of (2246) (2254) (2260) p-Toluenesulfonate of (2254) (2264) (2270) p-Toluenesulfonate of (2264) (2274) (2278) p-Toluenesulfonate of (2274) (2282) (2286) p-Toluenesulfonate of (2282) (2290) (2294) p-Toluenesulfonate of (2290) (2298) (2302) p-Toluenesulfonate of (2298) (2306) (2310) p-Toluenesulfonate of (2306) (2314) (2318) p-Toluenesulfonate of (2314) (2322) (2326) p-Toluenesulfonate of (2322) (2330) (2334) p-Toluenesulfonate of (2330) (2338) (2342) Dihydrochloride of (2338) (2346) (2350) Hydrochloride of (2346) The compounds of formula (1) may be produced by known methods, particularly the methods described in Japanese Laid-Open Patent Publication Nos. 140568/1986 and 87627/1986, or by treating the intermediates obtained by these methods in accordance with known methods (for example, the elimination of the protecting group by reduction). Examples 1 to 6 given hereinafter describe the production of these compounds in detail. For example, compounds of formula (1) in which Y is -NR⁶R⁷ and R⁶ is other than hydrogen may be produced by the following reaction scheme 1. Compounds of formula (1) in which X is -NR⁴R⁵ may be produced by the following reaction scheme 2. The starting compounds of formulae (II) and (III) in reaction schemes 1 and 2 may be produced by the method described in J. Chem. Soc., 1965 , pages 755-761, from as a starting material. The reactions in reaction schemes 1 and 2 are conveniently carried out at a temperature of 20 to 150 °C in a solvent such as toluene, dioxane, pyridine or water in the presence of, as required, a basic compound. The basic compound may conveniently be, for example, an organic base (such as triethylamine, pyridine and 4-dimethylaminopyridine), and an inorganic base (such as sodium carbonate and potassium carbonate). Compounds of formula (1) in which Y is CH₂R⁹, wherein R⁹ is hydrogen or a C₁-C₄ alkyl group and Z is a (C₁-C₄alkoxy)carbonyl group may be produced in accordance with the following reaction scheme 3. Specifically, by reacting compounds (IV) with (V) at a temperature of 20 to 100 °C in a reaction medium such as water, methanol, ethanol, THF and DMF, compounds of formula (1) in which Y=R¹⁰, and Z=COOR¹³ are obtained. Compounds of formula (1) in which Y is CH₂R⁹, wherein R⁹ is other than hydrogen and a C₁-C₄ alkyl group and Z is a (C₁-C₄ alkoxy)carbonyl group may be produced in accordance with the reaction scheme 4. Compound (VI) may be prepared in the same way as in Production Method No. 7 of Japanese Laid-Open Patent Publication No. 65873/1986 except that X is used instead of benzylpiperazine. Compounds of formula (1) in which Y is CH₂R⁹ and Z is COOR¹⁰ are obtained by reacting compound (VI) with R⁹H in the presence of an organic base such as pyridine or triethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride or sodium hydride in the presence of an inert solvent such as toluene or tetrahydrofuran or in the absence of solvent. Investigations of the present inventors show that the compounds of formula (1) are useful as therapeutic agents for the treatment of neurological diseases. The compounds of formula (1) are normally used in the form of a pharmaceutical composition, and are administered by various routes (e.g., oral, subcutaneous, intramuscular, intravenous, intrarhinal, skin permeation and through the rectum). The present invention also embraces a pharmaceutical preparation comprising a compound of formula (1) or its pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes, for example, acid addition salts and quaternary ammonium (or amine) salts. Examples of the pharmaceutically acceptable salts of the compound of formula (1) include salts formed from acids capable of forming pharmaceutically acceptable non-toxic acid-addition salts containing anions, such as hydrochlorides, hydrobromides, sulfates, bisulfites, phosphates, acid phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, benzoates, citrates, gluconates, glucanates, methanesulfonates, p-toluenesulfonates and naphthalenesulfonates or their hydrates, and quaternary ammonium (or amine) salts or their hydrates. The composition of this invention may be formulated into tablets, capsules, powders, granules, troches, cachet wafer capsules, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, aseptic injectables, molded cataplasmas, tapes, soft and hard gelatin capsules, suppositories, and aseptic packed powders. Examples of the pharmaceutically acceptable carrier include lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, tragacanth gum, gelatin, syrup, methyl cellulose, carboxymethyl cellulose, methylhydroxybenzoic acid esters, propylhydroxybenzoic acid esters, talc, magnesium stearates, inert polymers, water and mineral oils. Both solid and liquid compositions may contain the aforesaid fillers, binders, lubricants, wetting agents, disintegrants, emulsifying agents, suspending agents, preservatives, sweetening agents and flavoring agents. The composition of this invention may be formulated such that, after administration to a patient, the active compound is released rapidly, continuously or slowly. In the case of oral administration, the compound of formula (1) is mixed with a carrier or diluent and formed into, for example, tablets or capsules. In the case of parenteral administration, the active ingredient is dissolved in, for example a 10 % aqueous solution of glucose, isotonic salt water or sterilized water, and enclosed in vials or ampoules for intravenous instillation or injection or intramuscular injection. Advantageously, a dissolution aid, a local anesthetic agent, a preservative and a buffer may also be included into the medium. To increase stability, it is possible to lyophilize the present composition after introduction into a vial or ampoule. Another example of parenteral administration is the administration of the pharmaceutical composition through the skin as an ointment or a cataplasm. In this case, a molded cataplasm or a tape is advantageous. The composition of this invention generally contains 0.1 to 2000 mg, more generally 0.5 to 1000 mg, of the active component for each unit dosage form. The compound of formula (1) is effective over a wide dosage range. For example, the amount of the compound administered for one day usually falls within the range of 0.03 mg/kg to 100 mg/kg. The amount of the compound to be actually administered is determined by a physician depending, for example, upon the type of the compound administered, and the age, body weight and reaction condition of the patient and the administration route. The above dosage range, therefore, does not limit the scope of the invention. The suitable number of administrations is 1 to 6, usually 1 to 4, daily. The compound of formula (1) by itself is an effective therapeutic agent for disorders of the peripheral nervous system and the central nervous system. If required, it may be administered in combination with at least one other equally effective drug. Examples of such an additional drug are gangliosides, mecobalamin and isaxonine. The following Examples further illustrate the present invention. Each of the Examples showing the composition of the invention uses one of the compounds described hereinabove or another pharmaceutically active compound of formula (1) REFERENTIAL EXAMPLE 1 4-Methylamino-2-(4-phenylpiperidino)pyrimidine (compound No. 1024):- To a solution of 17.0 g (0.11 mole) of 2,4-dichloropyrimidine in 150 ml of dichloromethane was added methylamine (0.25 mole, 20 ml of 40 % methanol solution) at such a rate that the temperature of the solution was maintained at 5 °C. After the addition, the solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane. The dichloromethane layer was dried over an anhydrous sodium sulfate, and concentrated under reduced pressure to give 14.0 g (purity 80 %) of 2-chloro-4-methylaminopyrimidine. Two hundred milliliters of n-butanol was added to 3.0 g (0.02 mole) of 2-chloro-4-methylaminopyrimidine and 8.4 g (0.05 mole) of 4-phenylpiperidine, and the mixture was heated at 130 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4.0 g (yield 71 %) of the desired compound as an oil. ¹H-NMR spectrum (deuterochloroform, δ ppm): 1.4-2.0(5H, m), 2.93(3H, d, J=5.2Hz), 2.6-3.1(2H, m), 4.60(1H, m), 4.92(2H, br. d, J=12.6Hz), 5.67(1H, d, J=7.2Hz), 7.28(5H, s), 7.93(1H, d, J=7.2 Hz). In a similar manner, the following compounds were produced. (1000) (1004) (1008) (1012) (1016) (1020) (1024) (1028) (1032) (1036) (1040) (1064) (1068) (1072) (1076) (1080) (1084) (1088) (1092) (1096) (1100) (1104) (1108) (1112) (1116) (1120) (1124) (1128) (1132) (1136) (1140) (1144) (1148) (1152) (1156) (1160) The properties of the compounds (intermediate) are shown in Table 1 below. REFERENTIAL EXAMPLE 2 4-Methylamino-2-(4-phenylpiperidino)pyrimidine maleate (compound No. 1026):- A solution of 0.43 g (3.73 mmoles) of maleic acid in 10 ml of methanol was added to a solution of 1.0 g (3.73 mmoles) of 4-methylamino-2-(4-phenylpiperidino)pyrimidine in 10 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The mixed solution was concentrated under reduced pressure and washed with ether to give 1.25 g (yield 87 %) of the desired product. Melting point: 163-166 °C. ¹H-NMR spectrum (CDCl₃ solution, δ ppm): 1.6-2.2(4H, m), 2.6-3.3(5H, m), 3.04(3H, d, J=5.2Hz), 4.74(1H, br. d, J=12.6Hz), 6.30(1H, d, J=7.2Hz), 7.30(5H, m), 7.71(1H, d, J=7.2Hz), 8.40(1H, m). Similarly, the folllowing compounds were produced. (1014): maleate of (1012) (1026): maleate of (1024) (1034): maleate of (1032) (1038): maleate of (1036) (1086): maleate of (1084) (1090): maleate of (1088) (1094): maleate of (1092) (1098): maleate of (1096) (1102): maleate of (1100) (1110): maleate of (1108) (1122): maleate of (1120) (1130) maleate of (1128) (1158): maleate of (1156) (1162): maleate of (1160) The data of these compounds are given in Table 2 below. REFERENTIAL EXAMPLE 3 1-Diphenylmethylpiperazine:- 11.2 g (98 mmoles) of 1-formylpiperazine was added to 10 g (49 mmoles) of chlorodiphenylmethnae, and the solution was stirred at room temperature for 48 hours, and the mixture was extracted with water and methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 8.9 g (31.9 mmoles) of the resulting formyl compound was dissolved in 100 ml of ethanol, and 6.5 g (64 mmoles) of conc. hydrochloric acid was added, and the solution was refluxed for 1 hour. Then, the solvent was evaporated under reduced pressure, and the residue was extracted with K₂CO₃/water/CH₂Cl₂. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 6.8 g (yield 55 %) of the desired product. Melting point: 93-95 °C. ¹H-NMR spectrum (CDCl₃ solution, δ ppm): 2.33(4H, m), 2.87(4H, m), 4.19(1H, s), 7.1-7.5 (10H, m). EXAMPLE 1 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine (compound No. 164):- A solution of 5.2 g (0.037 mole) of benzoyl chloride in 50 ml of tetrahydrofuran was added at room temperature over 30 minutes to a solution of 9.0 g (0.034 mole) of 4-methylamino-2-(4-phenylpiperidino)pyrimidine in 90 ml of tetrahydrofuran and 5 ml of triethylamine. TWo hours after the end of the addition, 1 ml of pyridine was added. The mixture was then stirred for 2 days. The reaction mixture was extracted with dichloromethane. The dicloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8.8 g (yield 70 %) of the desired compound as an oil. ¹H-NMR spectrum (deuterochloroform, δ ppm): 1.4-2.0(4H, m), 2.5-3.0(3H, m), 3.55(3H, s), 4.62(2H, br. d, J=12.6Hz), 6.14(1H, d, J=7.2Hz), 7.1-7.6(10H, m), 8.06(1H, d, J=7.2Hz). Data of compounds produced in the same way as above are shown in Table 3 below. EXAMPLE 2 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine p-toluenesulfonate (compound No. 168):- A solution of 3.0 g (0.022 mole) of p-toluenesulfonic acid monohydrate in 300 ml of ethyl acetate was slowly added at room temperature to a solution of 6.0 g (0.022 mole) of 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine in 100 ml of ethyl acetate. As soon as the addition was effected, a suspension was formed. After the end of the addition, the suspension was stirred for 10 minutes. The resulting solid was separated by filtration, washed with ethyl acetate and ether, and dried to give 6.8 g (yield 83 %) of the desired compound. Melting point: 180-182 °C. ¹H-NMR spectrum (deuterochloroform, δ ppm): 1.4-2.1(4H, m), 2.35(3H, s), 2.6-3.3(3H, m), 3.56(3H, s), 4.55(2H, br. d, J=12.6 Hz), 6.60(1H, d, J=7.2 Hz), 7.0-7.9(14H, m), 8.36 (1H, d, J=7.2Hz). In the same way as above, the following compounds were produced and thier data are shown in Table 4. EXAMPLE 3 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine hydrochloride (coompound No. 170):- A solution of 0.27 g (0.0027 mole) of concentrated hydrochloric acid in 2 ml of CH₃OH was slowly added to a solution of 1.0 g (0.0027 mole) of 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine in 10 ml of chloroform. After the addition, the mixture was concentrated under reduced pressure to give 1.1 g (yield 100 %) of the desired product. Melting point: 80-84 °C. ¹H-NMR spectrum (deuterochloroform, δ ppm) 1.4-22(4H, m), 2.6-3.4(3H, m), 3.56(3H, s), 2.2(2H, m), 6.69(1H, d, J=7.2Hz), 7.0-7.7(10H, m), 8.1(1H, d, J=7.2Hz). In the same way as above, the following compounds were produced, and their data are given in Table 5. The following compounds were obtained by the same method as in Example 3 except that sulfuric acid, phosphoric acid, etc. were used instead of hydrochloric acid. EXAMPLE 4 Production of 2-isopropylamino-4-methyl-5-methoxycarbonylpyrimidine (compound No. 800):- 18.2 g (0.12 mole) of 1-amidinoisopropylamine sulfate was added to a solution of 13.0 g (0.12 mole) of potassium t-butoxide in 200 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. Then, 18.5 g (0.12 mole) of ethyl 2-methoxymethyleneacetoacetate was added at 0 °C over 30 minutes, and the mixture was stirred for 3 hours. The solvent was evaporated, and the residue was extracted with ether and purified by silica gel column chromatography to give 10.6 g (yield 44 %) of the desired product as a yellow solid. Melting point: 118-119 °C. ¹H-NMR spectrum (deuterochloroform, δ ppm) 1.26(6H, d, J=7Hz), 2.66(3H, s), 3.87(3H, s), 4.25(1H, sex, J=7Hz), 5.40(1H, br. s), 8.80(1H, s). EXAMPLE 5 Production of 2-piperidino-4-methoxymethyl-5-methoxycarbonylpyrimidine (compound No. 820):- Sodium hydride (0.19 g; 7.8 mmoles) was added to 50 ml of methanol, and 2.1 g (7.8 mmoles) of 2-piperidino-4-chloromethyl-5-methoxycarbonylpyrimidine was added at room temperature. The mixture was stirred for 3 hours. After the solvent was evaporated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.90 g (yield 44 %) of the desired product as a white solid. Melting point: 89-92 °C. ¹H-NMR spectrum (deuterochloroform, δ ppm): 1.70(6H, m), 3.54(3H, s), 3.86(3H, s), 3.92(4H, m), 4.83(2H, s), 8.82(1H, s). In the same way as above, the following compounds were obtained. Compound No. Yield (%) Melting point (°C) ¹H-NMR spectrum (CDCl₃ solution, δ ppm) 808 53 Oil 1.35(3H, t, J=7Hz), 1.66(6H, m), 2.44(3H, s), 3.90(2H, s), 3.92(4H, m), 4.30(2H, q, J=7Hz), 8.80(1H, s) 816 35 Oil 1.40(3H, t, J=7Hz), 1.70(6H, m), 2.21(3H, s), 3.92(4H, m), 4.06(2H, s), 4.36(2H, q, J=7Hz), 8.91(1H, s) 824 90 Oil 1.22(6H, d, J=8Hz), 1.33(3H, t, J=8Hz), 2.36(6H, s), 3.84(2H, s), 5.5(1H, br,s), 8.78(1H, s) EXAMPLE 6 Production of 2-isopropylamino-4-methyl-5-methoxycarbonylpyrimidine maleate (compound No. 804):- 2.48 g (11.9 mmoles) of 2-isopropylamino-4-methyl-5-methoxycarbonylpyrimidine and 1.38 g (11.9 mmoles) of maleic acid were dissolved in a mixture of 20 ml of ethanol and 20 ml of chloroform, and the solution was stirred for 3 hours. The solvents were evaporated, and ether was added for crystallization at 0 °C. The desired product was obtained in an amount of 3.21 g (yield 83 %) as pale yellow crystals. Melting point: 75-79 °C. ¹H-NMR spectrum (deuterochloroform, δ ppm): 1.33(6H, d, J=7Hz), 2.85(3H, s), 3.95(3H, s), 4.36(1H, sex, J=7Hz), 6.40(2H, s), 9.08(1H, br, s). In the same way as above, the following compounds were produced. Compound No. Yield (%) Melting point (°C) ¹H-NMR spectrum (CDCl₃ solution, δ ppm) 812 74 115.5-118.5 1.40(3H, t, J=7Hz), 1.68(6H, m), 3.08(3H, s), 3.92(4H, m), 4.34(2H, q, J=7Hz), 4.72(2H, s), 6.32(2H, s), 8.90(1H, s) 828 67 111-121 1.30(6H, d, J=8Hz), 1.40(3H, t, J=8Hz), 3.07(6H, s), 4.34(2H, q, J=8Hz), 4.66(2H, s), 6.32(2H, s), 8.92(1H, s) EXAMPLE 1B Tablets each containing 10 mg of an active ingredient were prepared by the following procedure. Per tablet Active ingredient 10 mg Corn starch 55 mg Crystalline cellulose 35 mg Polyvinyl pyrrolidone (as 10 % aqueous solution) 5 mg Carboxymethyl cellulose calcium 10 mg Magnesium stearate 4 mg Talc 1 mg Total 120 mg The active ingredient, corn starch and crystalline cellulose were passed through an 80-mesh sieve and thoroughly mixed. The mixed powder was granulated together with the polyvinyl pyrrolidone solution, and passed through an 18-mesh sieve. The resulting granules were dried at 50 to 60 °C and again passed through an 18-mesh sieve to adjust their sizes. The carboxymethyl cellulose calcium, magnesium stearate and talc, which had been passed through an 80-mesh sieve, were added to the granules. They were mixed and tableted by a tableting machine to produce tablets each having a weight of 120 mg. EXAMPLE 2B Tablets each containing 200 mg of an active ingredient were produced by the following procedure. Per tablet Active ingredient 200 mg Corn starch 50 mg Crystalline cellulose 42 mg Silicic anhydride 7 mg Magnesium stearate 1 mg Total 300 mg The above components were passed through an 80-mesh sieve and thoroughly mixed. The resulting mixed powder was compression-molded to produce tablets each having a weight of 300 mg. EXAMPLE 3B Capsules each containing 100 mg of an active ingredient were produced by the following procedure. Per capsule Acive ingredient 100 mg Corn starch 40 mg Lactose 5 mg Magnesium stearate 5 mg Total 150 mg The above components were mixed, passed through an 80-mesh sieve, and thoroughly mixed. The resulting mixed powder was filled into capsules in an amount of 150 mg for each. EXAMPLE 4B Injectable preparations in vials each containing 5 mg of an active ingredient were produced by the following procedure. Per vial Active ingredient 5 mg Mannitol 50 mg Just prior to use, these compounds were dissolved in 1 ml of distilled water for injection, and administered. EXAMPLE 5B Injectable preparations in ampoules each containing 50 mg of an active ingredients were produced in accordance with the following recipe. Per ampoule Active ingredient 50 mg Sodium chloride 18 mg Distilled water for injection proper amount Total 2 ml EXAMPLE 6B An adhesive patch containing 17.5 mg of an active ingredient was produced by the following procedure. Ten parts of poly(ammonium acrylate) was dissolved in 60 parts of water. Two parts of glycerin diglycidyl ether was dissolved under heat in 10 parts of water. Furthermore, 10 parts of polyethylene glycol (grade 400), 10 parts of water and 1 part of an active ingredient were stirred to form a solution. While the aqueous solution of poly(ammonium acrylate) was stirred, the aqueous solution of glycerin diglycidiyl ether and the solution containing the active ingredient, polyethylene glycol and water were added and mixed. The resulting solution for hydrogel was coated on a pliable plastic film so that the rate of the active ingredent was 0.5 mg per cm². The surface was covered with releasing paper and cut to a size of 35 cm² to form an adhesive patch. EXAMPLE 7B An adhesive patch containing 10 mg of an active ingredient was produced by the following procedure. An aqueous sol is prepared from 100 parts of poly(sodium acrylate), 100 parts of glycerin, 150 parts of water, 0.2 part of triepoxypropyl isocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25 parts of propylene glycol and 15 parts of the active ingredient. The sol was then coated to a thickness of 100 micrometers on the non-woven fabric surface of a composite film composed of a rayon non-woven fabric and a polyethylene film to form an adhesive layer containing the drug. The amount of the release aids (isopropyl myristate and propylene glycol) contained in this layer was about 30 % by weight. The adhesive layer was then crosslinked at 25 °C for 24 hours, and a releasing film was bonded to the adhesive layer surface. The entire film was then cut into pieces each having an area of 35 cm². The biological activities in vitro of the compounds of formula (1) on cells of the nervous system were tested. The cells tested were, for example, mouse neuroblastoma cell line neuro-2a (Dainippon Pharmaceutical Co., Ltd.) and NS-20Y, which have been established as the cells of the nervous system. The above nerve cells were grown in an incubator at 37 °C in the presence of 5 % carbon dioxide gas exponentially, and then cultivated for a certain period of time together with the compounds of the invention. The results demonstrate that the compounds of the invention have nerve cell growth promoting activity and neurite formation and sprouting promoting activity which are markedly higher with a significance than a control, and are equal to, or higher than, isaxonine as a control drug (the compound described in Japanese Patent Publication No. 28548/1984). The biological activities of the compounds of the invention on rat PC-12 pheochromocytoma cell line were also tested. When NGF is added to PC-12 cells, the neurites sprout. It was shown that when the compound of this invention is added at this time, the binding of NGF to the PC-12 cells and the up-take of NGF into the cells increased, and that the sprouting of the neurites also increased. When the effect of the compounds of this invention on the binding of NGF to rabbit superior cervical ganglion was examined, they were found to promote the NGF binding. Rats having crushed sciatic nerves were prepared as a model of peripheral nervous disorder, and the effects of the compounds of this invention on it were tested. It was made clear that the compounds of the present invention have an effect of promoting recovery of the interdigit distance and the weight of the soleus muscle to normal values. Rat and mouse models of central nervous disorders were prepared, and the pharmacological effects of the compounds of this invention were tested. Specifically, nigral dopamine cells of the rat brain were chemically destroyed by injecting a very small amount of 6-hydroxydopamine to induce motor imbalance. Two weeks later, dopamine cells of fetal brain were transplanted into the lesioned side of the caudate nucleus of the rat brain and an attempt was made to improve the motor trouble. Specifically, beginning on the day of transplantation, the compound of the invention was intraperitoneally administered every day over 2 weeks, and the activity of the compounds of the invention on the improvement of the motor imbalance and the growth of the transplanted cells were examined. It was found that the compounds of the invention have a promoting effect on the improvement of the motor trouble. Rats and mice having nerve trouble caused by mercury poisoning were prepared and the activity of the compounds of the invention was tested. The compounds of the invention were found to have a promoting effect on the improvement of the condition and recovery to a normal condition, a curative effect on chemical-induced disorders and an effect of improving and recovering learning and memory. Thus, it has been made clear that the compounds of this invention are useful as agents for improving or curing various neurological diseases of mammals, such as troubles in peripheral and central nerves, and also as agents for improving learning and memory. Various types of neuropathy including, for example, various peripheral nerve disorders accompanied by motorgenic, sensory or objective flex retardation, and alcohol-induced or drug-induced, diabetic and metabolic, or idiopathic peripheral nerve disorders, including traumatic, inflammatory or immunological nerve root lesions may be cited as such neurological diseases. More specific examples include facial palsy, sciatic nerve paralysis, spinal muscular atrophy, muscular dystrophy, myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, acute disseminated cerebromyelitis, Guillan-Barre syndrome, postvaccinal encephalomyelitis, SMON disease, dementia, Alzheimer syndrome, a condition after cranial injury, cerebrospinal injury, neural injury disorders which occur in cerebral ischemia, sequela of cerebral infarction or cerebral hemorrhage and rheumatism. These examples are not limitative. By a toxicity test, the compounds of this invention were found to have only weak toxicity and side effects, and be used as safe and useful medicines. EXPERIMENTAL EXAMPLE 1 The effects of the compounds of this invention on neuroblastoma cells were examined by the following method. Mouse neuro 2a cells in the logarithmic growth period in the Dulbecco's modified Eagle's medium [DMEM, containing 100 units/ml of penicillin G sodium and 100 micrograms/ml of streptomycin sulfate] containing 10 % of FCS were seeded in a 48-well plate so that the number of cells was 1,000 cells/well, and cultured for one day in 0.25 ml of the culture fluid in each well in an incubator containing 5 % of carbon dioxide gas in air at 37 °C. Then, a 4 % aqueous glutaraldehyde solution in the same amount as a medium (0.25 ml) was added, and the culture fluid was left to stand at room temperature for 2 hours to fix the cells. After washing with water, a 0.05 % aqueous solution of methylene blue was added to stain the cells. Under a microscope, the number of cells containing outgrown neurites (cells having at least one neurite with a length of at least two times as large as the long diameter of the cell) was counted visually, and the proportion of these cells in the entire cells was calculated. The well was observed over 5 or more visual fields (at least 2 % of the entire surface area of the well) continuous to the left and right from a mark put at the center of the well, and more than 200 cells were counted. One drug compound was used in 6 different concentrations at most, and three runs were conducted for each concentration. The results were expressed as a mean ±S.D., and the results are shown in Table 9. Mouse neuroblastoma cells NS-20Y were similarly cultured in a dish coated with polyornithine, and the effects of the compounds were examined. The results obtained after 24 hours and 48 hours from the start of culturing are shown in Table 10. EXPERIMENTAL EXAMPLE 2 Therapeutic effect on rats with crushed sciatic nerves:- The therapeutic effect of the compound of the invention was tested on rats having crushed sciatic nerves as a model of peripheral nervous disorder using (1) a change in the action of the hind paw with the crushed sciatic nerves and (2) a change in the weight of the muscle as an index of the course of degeneration and regeneration of peripheral nerves. In the experiment, male Wistar rats (6 weeks old), seven per group, were used. The sciatic nerves were crushed by a method similar to the method of Yamatsu et al. (see Kiyomi Yamatsu, Takenori Kaneko, Akifumi Kitahara and Isao Ohkawa, Journal of Japanese Pharmacological Society, 72 , 259-268 (1976)) and the method of Hasegawa et al. (see Kazuo Hasegawa, Naoji Mikuni and Yutaka Sakai, Journal of Japanese Pharmacological Society, 74 , 721-734 (1978). Specifically, under anesthesia with pentobarbital (40 mg/kg, i.p.), the left side sciatic nerve was exposed at the femur, and a specific site of the exposed sciatic nerve was crushed for 30 seconds by using a hemostat. After the crushing, the opetation site was immediately sutured. Thereafter, vincristine known to retard the regeneration of the peripheral nerve was intraperitoneally administered in a dose of 100 g/kg once a week. Compounds of the invention were selected as test drugs, and administered intraperitoneally once a day from the day of crushing to 30th day from then. To a control group, only 0.9 % saline was administered. (1) Functional change in the hind paw with crushed nerves Twitch tension, which is a transient tension incident to contraction of the dominated muscles that occurs by electrical stimulation or the like of motor nerves, as is the case with the interdigit distance to be described, is considered to reflect functional changes of the nerves and muscles. Thus, 30 days later, under aesthesia with chloral hydrate (400 mg/kg, i.p.), the twitch tension of rats was measured by the method of Kern et al. [J. Neurosci. Methods, 19 , 259 (1987)]. Specifically, the hair on the hind paw of rats was shaven, and coated with Cardiocream (a product of Nihon Denko K.K.). Then, to the skin of the hind paw, electrodes with an alligator were attached. The cathode was attached to the rear portion of the trochiter, and the anode, to a site 1 cm rearwardly of the anode electrode and 1 cm toward its back. The rat was fixed on its back, and the hind paw to be measured was fixed perpendicularly. A silk yarn, about 20 cm long, was connected at one end to the third efferent toe joint of the hind paw to be measured and at the other end to a tension transducer. Isotonic contractions of the third muscle digitus flexus were recorded on a polygraph. Electrical stimulation was effected at a voltage of 100 V for a continuous duration of 1 msec. with rectangular waves at a frequency of 2 Hz. The static tension was 15 to 30 g, and 10 stimulations were repeated 3 times with intervals of 15 seconds. The contracting force was expressed as tension (g). From the measured values of both paws, the recovery ratio (%, left/right) of the contracting force of the paw with crushed nerves was calculated. The results are shown in Table 11. Twitch tension Compound Dose (mg/kg) Number of cases Twitch tension left/right (%) Saline - 7 33.3 ± 7.0 168 10 7 48.4 ± 11.8 168 30 8 51.2 ± 13.6 296 30 8 48.1 ± 9.4 The test compounds evidently increased the recovery of twitch tension, which is an electrophysiological index, and improved symptom, over the control group. The distance between digits was measured because this is a good index which functionally shows the degeneration and regeneration of the nerve and its change can be measured with the lapse of time. By a method similar to the method of Hasegawa [Hasegawa, K., Experientia, 34 , 750-751 (1978)], the distance between the first and fifth digits of the hind paw was measured. The ratio of the measured distance to the interdigit distance in a normal hind paw was calculated and expressed in percentage (%). The interdigit distance of the hind paw with crushed nerves was less than 50 % of that in a normal hind paw immediately after the crushing. Recovery of the interdigit distance began 12 to 16 days later, and in drug-administered groups, there was evidently a tendency to accelerated recovery in comparison with the control group from about 17th day to the final day (26th). (2) Change in the weight of muscle It is known that removal of a nerve or its disorder causes atrophy of the muscle which is under its control, and the atrophy is gradually cured by re-control by the nerve. For this reason, a change in the weight of the muscle, which is quantitative, was selected as an index. Thirty days after the operation, the muscles extensor digitorum longus of both hind paws which are muscles under the control of sciatic nerves were extracted under anesthesia, and their weights were measured. The ratio of the weight of the muscle extensor digitorum longus on the crushed side to that of normal side was calculated and expressed in percentage (%). The results are shown in Table 12. Compound Dose (mg/kg) Number of cases Weight of muscle extensor digitorum longus left/right (%) Saline - 7 48.8 ± 6.4 168 10 7 52.1 ± 5.4 168 30 8 59.4 ± 11.8 296 30 8 56.9 ± 9.7 The results show that the test compounds, in comparison with the control, evidently increased the weight % of muscle extensor digitorum longus. Accordingly, these test compounds are useful as improvers and therapeutic agents for peripheral nerve disorders. EXPERIMENTAL EXAMPLE 3 Promoting effect on the improvement of motor imbalance due to injury of the rat's brain cells by transplantation of fetal cerebral cells:- Nigral dopaminergic nerve cells at the left side of the brain of 4-week old female Wistar rats (body weight 100 g) were lesioned by injecting a very small quantity of 6-hydroxydopamine. The rats showed a tendency to rotate spontaneously in a direction opposite to the lesioned side for several days, but no apparent abnormal action was observed after that. Upon administration of methamphethamine (5 mg/kg, i.p.) to the rats having the lesioned nigral dopaminergic nerve cells, they began rotational movement toward the lesioned side. After two weeks from the destruction by the administration of the drug, portions of the truncus corporis callosi containing dopamine cells (i. e., substantia nigra and the tagmentum at the abdomen side) were cut from the brain of a fetal rat of 14 to 17 days of age, cut finely, and treated with trypsin. Then, the extracted tissues were incubated at 37°C for 30 minutes, and the tissues were subjected to pipetting to form a suspension. Five microliters of the suspension was transplanted each into two sites of the caudate nucleus of the lesioned side (10 microliters in total, about 10⁵ cells). Compound No. 168 of the invention was administered in a dose of 156 mg/kg (i.p.) for 4 days from the day of transplantation, then with a suspension of 7 days, for 10 days in a dose of 50 mg/kg (i.p.) from the 11th day. Compound No. 296 was administered in a dose of 153 mg/kg, and then 50 mg/kg, in accordance with the same schedule. The rotational movements induced by administration of methamphetamine were examined 2 weeks and 1 week before, and 2 (or 3), 4, 6 and 8 weeks after, the transplantation and the administration of the drug. The number of rotational movements for the first one minute was counted at intervals of 10 minutes after the administration of methamphetamine, and the total number of rotational movements counted six times was averaged to find a mean number of the rotational movements. The results are shown in Table 13. The results show that the test compounds are useful as improvers and therapeutic agents for cental nerve disorders. Compound -1 W 3 W 4 W 6 W 8 W 168 13.3±7.8 9.1±5.6 4.5±4.5 1.5±3.9 0.8±2.1 296 13.2±4.1 8.4±5.0 3.1±3.4 0.9±2.3 1.0±1.5 Physiological saline 16.7±9.1 11.2±9.6 5.3±8.3 2.8±5.4 2.2±6.0 EXPERIMENTAL EXAMPLE 4 Improvement of learning and memory of mice with nerve disorder induced by mercury poisoning, and recovery effect:- Male BalbC strain mice, 7 weeks old, were first caused to learn a T-shaped maze three times in a week so that they run straight from a starting point to a safety area. Then, methylmercury chloride (MMC for short) was administered orally in a dose of 6 mg/kg/day for 6 days to male Balb C strain mice (7 weeks old). A group of mice to which saline was administered in a dose of 0.1 ml/10 g/day was used as a control group. Beginning with the day next to the day of administering MMC, compounds of the invention were intraperitoneally administered over 10 days. On the sixth day after administration of the drug (namely, on the 12th day after start of the experiment), learning of the T-shaped maze was resumed, and the running behaviors of the mice were observed. The number of mice which could be experimented in the T-shaped maze on the 10th and 11th days after the resumption (21st and 22nd days after the start of the experiment) was counted and expressed as a denominator. The number of mice which ran to the safety area within 5 seconds at least 8 times out of ten trial runnings was counted and expressed as a numerator. The decrease in the number of the test animals was due to death by MMC poisoning. The time (seconds) required for the animals to run to the safety area was measured, and the mean ± standard error (SE) was calculated. The results demonstrate the effect of the compounds of the invention to improve learning and momory of the mice and their recovery effect. EXPERIMENTAL EXAMPLE 5 The acute toxicity of the compounds of the invention was examined by the following method. Male ddy-strain 5-week old mice, 4-6 per group, were used as experimental animals. Each of the compounds was intraperitoneally (i.p.), and the toxicity of the compound was assessed 24 hours after the administration. The results are shown in Table 14. The compounds of formula (1) provided by this invention have a promoting effect on the proliferation of nerve cells and the formation and sprouting of neurites and a nerve regenerating effect and a motor function recovering effect in rats and mice having nerve disorders, and can be used suitably for improving and curing neurological diseases such as disorders of peripheral nerves or central nerves and dementia. They are expected to be used also suitably for the recovery, improving and curing of neurological diseases caused by nervous tissues and cells which have to do with perceptive and sensory functions and an autonomic function. It has been found that the compounds of the invention have biological activities equal to, or higher than, those of isaxonine and mecobalamin as a control as shown in Experimental Examples 1 to 4 and Tables 9 to 14. The toxicity of the compounds of this invention are generally weak as shown in Experimental Example 5. Thus, the compounds of this invention are generally considered to be highly active and highly safe drugs and very useful with weak toxicity.

Claims: A pyrimidine represented by the following formula (1), or a pharmaceutically acceptable salt thereof, wherein R¹ represents a hydrogen atom or a C₁-C₄ alkyl group; X represents a group of the formula a group of the formula in which R³ corresponds to optional one or at least two identical or different substituents replacing one or at least two hydrogen atoms of identical or different methylene groups, and represents a C₁-C₄ alkyl group, a hydroxyl group, a phenyl group optionally substituted by nitro, a benzyl group, a benzoyloxy group, a benzoylamino group, a C₁-C₄ alkylamino group, a di-C₁-C₄ alkylamino group, the HO(C₆H₅)₂C- group, a piperidino group, a hydroxy(C₁-C₄ alkyl) group, the C₆H₅SO₂O- group, a benzoyl group optionally substituted by halogen, a C₁-C₄ alkylsulfonylamide group or a (C₁-C₄ alkoxy)carbonyl group, and n is a number of 4, 5, 6 or 7, a group of the formula in which R⁴ represents a hydrogen atom, a C₁-C₄ alkyl group or a benzyl group, and R⁵ represents a C₁-C₄ alkyl group, an acyl group of up to 6 carbon atoms, a 2-furoyl group, a benzyl group, a 4-piperidyl group optionally substituted by benzoyl, a phenethyl group, the group or a benzoyl group optionally substituted by halogen or nitro, a group of the formula a group of the formula a group of the formula or a group of the formula Y represents a group of the formula -CH₂R⁹ wherein R⁹ represents a hydrogen atom, a C₁-C₄ alkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ alkylthio group, or a di-C₁-C₄ alkylamino group, a group of the formula wherein R⁶ represents a hydrogen atom, a C₁-C₄ alkyl group, a phenyl group, a benzyl group, a C₁-C₄ alkoxy group or a 2-(N,N-di-methylamino)ethyl group and R⁷ represents a C₁-C₄ alkyl group, an acyl group of up to 6 carbon atoms, a cyclohexylcarbonyl group, a 2-furoyl group, a (C₁-C₄ alkoxy) carbonyl group, a cinnamoyl group, a benzyl group, a benzylcarbonyl group, a tosyl group, a phenoxyacetyl group, a di-C₁-C₄ alkylcarbamoyl group, a group of the formula a group of the formula a group of the formula a group of the formula a group of the formula a 4-C₁-C₄ alkylpiperazyl group, or a benzoyl group optionally substituted by halogen, nitro, C₁-C₄ alkyl, C₁-C₄ alkoxy, amino, benzoylamino or phenyl, provided that when R⁶ is a hydrogen atom, R⁷ is a benzoyl group, a group or the formula wherein R⁸ corresponds to an optional substituent replacing the hydrogen atom of the methylene group, and represents a hydrogen atom, a C₁-C₄ alkyl group, a phenyl group or a benzyl group, and m is a number of 4, 5, 6 or 7, a group of the formula a group of the formula or a group of the formula and Z represents a hydrogen atom, a halogen atom, a C₁-C₄ alkyl group or a (C₁-C₄ alkoxy)carbonyl group; provided that Y represents -CH₂R⁹ only when Z is a (C₁-C₄ alkoxy)carbonyl group; that R⁴ represents a hydrogen atom and R⁵ represents a C₁-C₄ alkyl group, an acyl group of up to 6 carbon atoms, a 2-furoyl group, a benzyl group, a phenethyl group or a benzoyl group optionally substituted by halogen or nitro, only when Y represents CH₂R⁹ and Z represents a (C₁-C₄ alkoxy) carbonyl group; and that Y can be only when X is and R⁴ is a C₁-C₄ alkyl group. A compound according to claim 1 in which the pharmaceutically acceptable salt is selected from hydrochlorides, hydrobromides, bisulfites, phosphates, acidic phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, benzoates, citrates, glucanates, methanesulfonates, p-toluene-sulfonates, naphthalenesulfonates and quaternary ammonium salts. A compound of formula or the p-toluenesulfonate thereof. A compound of formula or the p-toluenesulfonate thereof. A therapeutical composition for use in the treatment of neurological diseases comprising a compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 4 as an active ingredient. Use of a compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 4, in the preparation of a pharmaceutical composition containing said compound or salt as active ingredient for use in the treatment of neurological diseases. A compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 4 for use in the treatment of neurological diseases.

Inventors: AWAYA AKIRA, HORIKOMI KAZUTOSHI, KIHARA NORIAKI, KITAHARA TAKUMI, MIZUCHI AKIRA, SASAKI TADAYUKI, TAKESUE MITSUYUKI, TOMINO IKUO, AWAYA, AKIRA, HORIKOMI, KAZUTOSHI, KIHARA, NORIAKI, KITAHARA, TAKUMI, MIZUCHI, AKIRA, SASAKI, TADAYUKI, TAKESUE, MITSUYUKI, TOMINO, IKUO
Applicants: MITSUI PETROCHEMICAL IND, MITSUI PHARMACEUTICALS, MITSUI PETROCHEMICAL INDUSTRIES, LTD., MITSUI PHARMACEUTICALS, INC.
Application year: 1989
Main classification: C07D239
IPC codes: C07D401, C07D213, C07D409, C07D405, C07D453, C07D239, C07D487