JPH0314568A - Pyrimidines and pharmaceutically usable its salts - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H or alkyl; X is a group of formula II, III (R<2> is R<1>, phenyl, etc.), VI ((n) is 4-7; R<3> is alkyl, OH, phenyl, etc.), etc.; Y is CH2R<9> (R<9> is R<1>, alkoxy, etc.), NR<6>R<7> (R<6> is R<1>, phenyl, benzyl, etc.; R<7> is alkyl, acyl, etc.; Z is H, halogen, alkyl, etc.] and a compound of formula V (A1 and A3 are CH or N; A2 is a group of formula VI; R<11> is alkyl; R<12> is halogen, phenyl, etc.). EXAMPLE:4-(N-Methylbenzamino)-2-(4-phenylpiperidino)pyrimidine. USE:A treating agent for nervous diseases or cerebral diseases. Side effects such as hepatic damages are reduced. PREPARATION:For example, a compound of formula VII is reacted with a compound of formula: R<6>-Cl to provide the compound of formula I wherein Y is NR<6>R<7> (R<6> is the group excluding H).

Description

Detailed Description of the Invention <Industrial Application Field> The present invention relates to novel pyrimidines or pharmaceutically acceptable salts thereof, and neurological diseases of the peripheral nervous system and central nervous system of animals for which they are effective. The present invention relates to a novel therapeutic agent.

<Prior art> Japanese Patent Publication No. 46-23394 describes the following formula, where A
is alkylene up to C+a, or lower alkylene substituted with an amino group or a lower acylamino group of C2-8; M is H, Na, K, NH, Mg%C
a or an organic basic ammonium salt: and n is M
Aminopyrimidines of interest have therapeutic activity, with a valence equal to that of
It has been disclosed that it has activity as an antidepressant or psychostimulant, particularly in the field of psychosis treatment.

Japanese Patent Publication No. 51-22.044 discloses that dichlorolower aliphatic carponate salts of 2-isopropylaminopyrimidine, such as dichloroacetate salts of 2-isopropylaminopyrimidine, are useful as therapeutic agents for neurological diseases. It is disclosed that

Japanese Unexamined Patent Publication No. 52-100,477 (Japanese Patent Publication No. 59-28
．． No. 548) discloses that 2-isopropylaminopyrimidine phosphate is useful as a therapeutic agent for neurological diseases.

Japanese Patent Publication No. 54-157,575 discloses a method for producing 2-chloropyrimidine in a high yield, and includes a specific example in which 2-chloropyrimidine was obtained with a yield of 69%. is listed.

JP-A No. 55-393 discloses a method for producing 2-isopropylaminopyrimidine in high yield, and its examples include 2-isopropylaminopyrimidine obtained in 60% yield. Specific examples are described.

JP-A-55-122.768 describes the following formula, where A4, A6 and A6 each represent H or OH, and at least one of these represents OH. It has been disclosed that hydroxy derivatives of 2-isopropylaminopyrimidine are useful in the field of nerve regeneration and in the treatment of muscular dystrophy.

JP-A No. 55-145.670 describes that in the following formula 22, A 4 % A I' and A1 are each H
or a halogen atom, at least one of which is a halogen atom. ing.

JP-A-55-145.671 discloses a method for producing a hydroxy derivative of 2-inglobylaminopyrimidine.

JP-A-55-151.571 discloses that 2-isopropylamino-5-halogenopyrimidine is of interest in the treatment of neurological diseases.

JP-A-56-10,177 discloses a method for producing 2-inglobylaminopyrimidine in a substantially quantitative yield by aminolysing 2-methylsulfonylpyrimidine with isoprobylamine. has been done.

JP-A-56-26880 discloses a method for producing 2-isopropylaminopyrimidine by reacting bis(isoprobylguanidine) sulfate with 1.1.3.3-tetraethoxypropane. ing.

JP-A No. 56-90.013 discloses a treatment for muscular dystrophic myopathy, muscle stiffness disease, and/or muscle nerve transmission deficiency using a pyrimidine substituted derivative, a therapeutically acceptable salt thereof, or a metabolite thereof as an effective ingredient. agent is listed. However, this publication only discloses various salts including the orthophosphate of 2-inglobylaminopyrimidine as active compounds.

In Japanese Patent Application Laid-open No. 61-65,873, the following formula is written:
Rl is H or aralkyl, and Y is a divalent organic group specified in the claims of the same publication.The 2-biperazinopyrimidine derivative represented by the following is a weed killer for paddy fields and fields. It is disclosed that it is used as an agent.

In addition, the present inventor has previously provided a novel therapeutic agent for neurological diseases containing a specific 2-piperazinopyrimidine derivative or a pharmaceutically acceptable salt thereof (International Publication No. w
o 8 7/0 4 9 2 8).

Problems to be Solved by the Invention> An object of the present invention is to provide novel pyrimidines and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a therapeutic agent for neurological diseases comprising the novel compound of the present invention.

Still another object of the present invention is to provide a novel therapeutic agent for neurological diseases that has the effect of regenerating and repairing nerve cells.

Still another object of the present invention is to provide a novel therapeutic agent for neurological diseases that can be applied to peripheral nerve disorders, bone marrow damage, and the like.

Still another object of the present invention is to develop a novel method that can be applied to disorders of the central nervous system, which are different from neurological diseases in which abnormalities in neurotransmitter action systems, metabolic systems, etc. are considered to be primarily involved. The purpose is to provide therapeutic drugs for neurological diseases.

Still another object of the present invention is to provide a novel therapeutic agent for brain diseases that has the effect of improving and restoring learning and memory.

Still another object of the present invention is to develop a novel compound for use in neurological or brain diseases, which comprises a comprehensively excellent and useful compound that has fewer side effects such as liver damage and has appropriate pharmacological action for the treatment of neurological or brain diseases. The aim is to provide therapeutic drugs for patients with cancer.

Further objects and advantages of the present invention will become apparent from the description below.

<Means for Solving the Problems> and <Operation> According to the present invention, the above objects and advantages of the present invention are achieved by the following formula (1) "wherein R1 is a hydrogen atom or a lower alkyl group; is a hydrogen atom, a lower alkyl group, a 7-enyl group, a benzyl group or an α-(p-chloro7-enyl)penzyl group), and is substituted with one or more hydrogen atoms of a methylene group of the following formula: 7-enyl group, benzyl group, penzoyloxy group, penzoylamino group, lower alkyl group, which corresponds to one or two or more same or different substituents, and may be substituted with a lower alkyl group, hydroxyl group, nitro group, benzyl group, penzoyloxy group, penzoylamino group, lower alkyl group amino group,
di-lower alkylamino group, H O (C aH s) *C group, piperidino group, hydroxy lower alkyl group, C, H. one SO20 group, a benzoyl group optionally substituted with halogen, a lower alkylsulfonylamide group or a lower alkoxy carbonyl group, and n is a number of 4, 5, 6 or 7), R4 / -N ( Here, R' is hydrogen, a lower alkyl group or a benzyl group, and Rs is substituted with a lower alkyl group, a lower acyl group, a 2-7 loyl group, a benzyl group, or a benzoyl group. a penzoyl group which may be substituted with a nitro group), or a di-lower alkylamino group), a formula R1/-N (where R6 is a hydrogen atom, a lower alkyl group, a 7-enyl group, benzyl group, lower alkoxyl group or 2-(N,N-dimethylamino)ethyl group,
And R' is a lower alkyl group, a lower acyl group, a cyclohexylcarbonyl group, a 2-7-royl group, a lower alkoxycarbonyl group, a cinnamoyl group, a benzyl group, a penzylcarbonyl group, a tosyl group, a phenoxyacetyl group. , di-lower alkyl group, rubamoyl group, 2-chenyl group, etc. Y is a group of the following formula CH2R' (where R' is hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a piperazyl group) or a benzoyl group which may be substituted with a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, an amino group, a bezoylamino group or a 7-enyl group, provided that when R6 is a hydrogen atom, R7 is a pezoinole group), a phenethyl group or a benzoyl group optionally substituted with a halogen atom or a nitro group, and Y is CH. R'
and only when Z is a lower alkoxy carbonyl group, and 'k! ' Corresponds to a substituent replacing an elementary atom, and is a hydrogen atom, a lower alkyl group, a 7-enyl group, or a benzyl group, and m is 4, 5, 6, or 7; and Z is a hydrogen atom, a halogen atom, lower alkyl group, or lower alkoxy group, provided that t, Y are Cl-1t
R' is only when Z is a lower alkoxy carbonyl group, and R1 is hydrogen when R6 is a lower alkyl group, lower acyl group, 2-furoyl group, benzyl group, or \ Ri group. This can only be achieved by pyrimidines or pharmaceutically acceptable salts thereof.

In the above formula (I), R1 is a hydrogen atom or a lower alkyl group.

The lower alkyl group may be linear or branched, and preferably has 1 to 4 carbon atoms. Examples include methyl, ethyl, n-proyl, is
o-propyl, n-butyl, sec-butyl, iso-
Mention may be made of butyl and (butyl).

In the above formula (I), X is the following formula It is a group represented by

R2 in the above formula is a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, or an α-(p-chlorophenyl)benzyl group. As the lower alkyl group, the same groups as those exemplified for R' can be exemplified.

In addition, R3 corresponds to a substituent substituting the hydrogen atom of the methylene group, and includes a phenyl group, a benzyl group, a benzoyloxy group, a penzoylamino group, which may be substituted with a lower alkyl group, a hydroxyl group, a nito group, Lower alkylamino group, di-lower alkylamino group, H O (C * H s)
1 YuC group, 7 biperidi groups, hydroxy lower alkyl group,
C a H s SO x O − group, a benzoyl group optionally substituted with halogen, a lower alkylsulfonylamide group or a lower alkoxy carbonyl group, and n is a number of 4, 5, 6 or 7. . As the lower alkyl group, the same groups as those exemplified for R1 can be exemplified for any of the above lower alkyl groups.

Further, R' is hydrogen, a lower alkyl group or a benzyl group, and R5 is a lower alkyl group, a lower acyl group, a 2
-7 loyl group, benzyl group, 4-piperidyl which may be substituted with benzoyl group, or benzoyl group which may be substituted with halogen atom or nitro group.

Examples of lower alkyl groups for R4 and R5 include the same groups as those exemplified for Rl.

The alkyl portion of the lower acyl group represented by R5 may be linear or branched.

An acyl group having 2 to 6 carbon atoms is preferred, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, hexanoyl, and the like.

Further, in the above formula (I), Y is a group of the following formula, and R' is a lower alkyl group, a lower acyl group, a cyclohexylluponyl group, a 2-furoyl group, a lower alkoxyluponyl group, a cinnamoyl group, These are groups represented by a benzyl group, a penzylcarbonyl group, a tosyl group, a 7-enoxyacetyl group, a di-lower alkylcarbamoyl group, and a 2-chenyl group.

In the above formula, R1 is hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, or a di-lower alkylamino group, and R6 is a hydrogen atom, a lower alkyl group, a 7-enyl group, a benzyl group, a lower alkoxy group, or a 2- It is a (N.N-dimethylamino)ethylbiperazyl group, or a benzoyl group which may be substituted with a halogen atom, a nitro group, a lower alkoxy group, an amino group, a benzoylamino group or a 7-enyl group.

As the lower alkyl group in R'', R0 and R7, R
The same groups as exemplified for 1 can be exemplified.

Examples of the lower acyl group for R7 include the same ones as exemplified for R5.

Further, the halogen atom and lower alkoxy group as a substituent of the benzoyl group of RF include, for example, fluorine, chlorine, bromine and iodine, and carbon atoms such as methoxy, ethoxy, proboxy, improboxy, butoxy, imbutoxy, sec-butoxy, etc. Examples include 1 to 4 alkoxy groups. However, when R1 is a hydrogen atom, R2 is a benzoyl group.

Furthermore, in the above formula (1), Z is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine. Further, as the lower alkyl group, the same groups as those exemplified for Rl can be mentioned.

According to the present invention, in addition to the compound represented by the above formula (A), the following formula (2) where A1 is -CH1 or -N1, and A2,
A, is CH1 or -N=, R1 is a lower alkyl group, and RI2 is a phenyl group, a 2-furyl group, or a 2-furyl group, which may be substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group. When -CH1 is a chenyl group, A, is -CH1, and A, is -CH1.
When N-, A. and A, is -CH-, or a pharmaceutically acceptable salt thereof is provided.

In the above formula (2), R'' is a lower alkyl group, and R'!
is a halogen atom, a 7-enyl group, a 2-7lyl group, or a 2-chenyl group which may be substituted with a lower alkyl group or a lower alkoxy group.

As a lower alkyl group in the definition of R and R'' (11
2) The p-toluenesulfonic acid salts in (108) can be the same as those exemplified for Rl.

Also, At is 1CH1 or 1N1, (120) (116) p1 Toluene sulfonate and And A is 1CH1 or 1N1.

, when A, and A2 are one CH, A, is yoCH-, and when A2 is -N=, A1 (128) (124) p toluenesulfonate and A, ha - It is CH-.

Examples of the metal compounds represented by the above formulas (1) and (2) of the present invention include the following compounds.

(136) (132) p-toluenesulfonate (104) (100) p-toluenesulfonate (138) (137) p-toluenesulfonate (144) (140) p-toluenesulfone Acid salt (154) (153) p-toluenesulfonate (150) (149) p-toluenesulfonate (154-2) (154-1) p-toluenesulfonate (156) (152 ) (148) toluenesulfonate (160) (156) p-toluenesulfonate (146) (145) toluenesulfonate (165) (164) sulfate (166) (164) phosphorus Acid salt (167) Maleate (169) of (164) Naphthalenesulfonate (147-1) of (164) p-Toluenesulfonate (171) of (147) Citrate (171) of (164) -1) (164) tartrate (171-1-1) (164) hepmarate (168) (164) p-toluenesulfonate (170) (164) hydrochloride (171 9) (171-8) p-toluenesulfonate (170-2) (170 I) p-toluenesulfonate (171-11) (171-10) p-toluenesulfonate (171 3) ( 171-2) p-toluenesulfonate (171-13) (171-12) p-toluenesulfonate (171-5) (171-4) p-toluenesulfonate (176) (172 ) p-toluenesulfonate (171 7) (171-6) p-toluenesulfonate (184) (180) p-toluenesulfonate (224) (220) p-toluenesulfonate (192) (188) toluenesulfonate (232) (228) p-toluenesulfonate (200) (196) p- toluenesulfonate (240) (236) p- Toluenesulfonate (208) (204) p-Toluenesulfonate (242) (241) p-Toluenesulfonate (216) (212) p-Toluenesulfonate (248) (244) p-toluenesulfonate (256) (252) p-toluenesulfonate (296) (292) p-toluenesulfonate (264) (260) p-toluenesulfonate (298) (297 ) p-toluenesulfonate (272) (268) p-toluenesulfonate (304) (300) p-toluenesulfonate (280) (276) p-toluenesulfonate (306) (305) p-toluenesulfonate (288) (284) p-toluenesulfonate (307 l) (307) hydrochloride (312) (308) p-toluenesulfonate (352) ( p-toluenesulfonate (320) of (348) p-toluenesulfonate (360) of (356) p-toluenesulfonate (328) of (324) 368) (364) p-toluenesulfonate (336) (332) p-toluenesulfonate (376) (372) p-toluenesulfonate (344) (340) p-toluenesulfonic acid salt (384) (380) p-toluenesulfonate (424) (420) p-toluenesulfonate (392) (388) p-toluenesulfonate (432) (428) p-toluene Sulfonate (400) (396)! )-toluenesulfonate (604) (600) p-toluenesulfonate (408) (404) p-toluenesulfonate (612) (608) p-toluenesnolephonate (416) (412) p-toluenesulfonate (620) (616) p-toluenesulfonate (628) (624) p-toluenesulfonate (660) (656) p-toluenesulfonate CI , CH, (636) (632) p-toluenesulfonate (662) (661) hydrochloride (644) (640) p-toluenesulfonate (668) (664) p-toluenesulfonic acid salt (652) (648) p-toluenesnorefonate (676) (672) p-toluenesulfonate (812) (808) maleate (684) (680) p-toluenesulfone (692) (688) p-Toluenesulfonate (700) (696) p-Toluenesulfonate (828) (824) Maleate (804) (800) Maleate (2004) ) (2000) p-toluenesulfonate (2012) (2008) p-toluenesulfonate (2036) (2032) p-toluenesulfonate (2020) (2016) p-toluenesulfonate ( 2044) (2040) p-toluenesulfonate (2022 l) (2022) p-toluenesulfonate (2052) (2048) dihydrochloride (2023-1) (2023) p-toluenesulfonic acid Salt (2060) Hydrochloride of (2056) (2028) p-Toluenesulfonate of (2024) (2070) Hydrochloride of (2064) (2108) Hydrochloride of (2104) (2076) Hydrochloride of (2074) (2116) (2112) p-tonoleenesnolephonate (2084) (2080) hydrochloride (2124) (2120) p-toluenesulfonate (2092) (2088) hydrochloride (2132) ( (2128) p-toluenesulfonate (2100) (2096) hydrochloride (2140) (2136) p-toluenesulfonate (2182) (2178) p-toluenesulfonate (2148) (2144) Dihydrochloride (2188) (2184) p-Toluenesulfonate (2156) (2152) Hydrochloride (2194) (2192) p-Toluenesulfonate (2164) Dihydrochloride (2160) 2202) (2198) p-toluenesulfonate (2174) (2170) p-toluenesulfonate (2210) (2206) p-toluenesulfonate (2218) (2214) p-toluenesulfonate (2260) (2254) p-toluenesulfonate (2226) (2222) hydrochloride (2270) (2264) p-toluenesulfonate (2234) (2230) dip-toluenesulfonate (2278 ) (2274) p-Toluenesulfonate (2242) (2238) p-Toluenesulfonate (2286) (2282) p-Toluenesulfonate (2250) (2246) p-Toluenesulfonate (2294) ) (2290) p-toluenesulfonate (2302) (2298) p-toluenesulfonate (2342) (2338) dihydrochloride (2310) (2306) p-toluenesulfonate (2350) ( 2346) Hydrochloride Compounds of the above formulas (I) and (2) of the present invention can be prepared by methods known per se, in particular JP-A-6! The methods described in p-toluenesulfonate (2318) (2314) and the intermediates obtained by these methods are carried out by methods known per se (for example, protection (reductive removal of the group).

Examples 1 to 6, which will be described later, include Manufacture of each compound (2326) (2322) p Toluene sulfonate The manufacturing method is described in detail.

For example, in the general formula (1), when Y is one NR"R' and R6 is a group other than a hydrogen atom, the following reaction formula (2334) (2330) is prepared. It can be produced by the method shown in 1 ml of p-tonolerensnorefonate.

Reaction Scheme 1 Also, for example, in general formula (I), X is one NR i
When a compound of R 6 is to be produced, it can be produced by the method shown in Reaction Scheme 2 below.

Reaction Scheme 2 The starting compounds (ff) of Reaction Schemes 1 and 2 are suitably carried out at a temperature of 20 to 150°C, if necessary in the presence of a basic compound. As basic compounds, organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium carbonate and potassium carbonate are preferably used.

When attempting to produce a compound in which Y is CH2Rs, R9 is hydrogen or a lower alkyl group, and 2 is a lower alkoxy carbonyl group in the general formula (I), they can be combined according to Scheme 3 below.

Reaction scheme 3 0 κ1 J. Chem. Soc. , l 9 6 5, 7
It can be produced by the method described on pages 55-761.

Reactions of Reaction Schemes 1 and 2 are carried out in a solvent such as toluene, dioxane, pyridine or water, ie compounds (IV) and (V) are reacted in water, methanol, ethanol, T
Compound (r) (Y=R" Z=C
OOR”) is obtained.

In addition, when attempting to produce a compound in which Y is CH, R''R'' is hydrogen, and Z is a lower alkoxy group other than a lower alkyl group in the general formula (r), the compounds can be synthesized according to Scheme 4 below. be able to.

Reaction scheme 4 (Vl) That is, the compound (VT) is described in JP-A No. 61-65873 [
Production method 7], X can be used in place of pendylbiperazine to perform the same synthesis, and this (V
I) and R'H 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, or an inert compound such as toluene or THF. By reacting in a solvent or without a solvent, compound (I) (Y-CH,R', Z-COORIO)l! 6
.

The compound of general formula (2) can also be produced in the same manner as the compound of general formula (I).

According to the research conducted by the present inventors, it has been revealed that the compounds of the above formulas (I) and (2) of the present invention are useful as therapeutic agents for neurological diseases.

The compounds of formula (I) and (2) are usually used in the form of pharmaceutical compositions and are administered by various routes such as oral, subcutaneous, intramuscular, intravenous, intranasal, percutaneous and rectal routes.

The present invention encompasses pharmaceutical formulations containing a pharmaceutically acceptable carrier and a compound of general formula (I) or (2) or a pharmaceutically acceptable salt thereof as the active ingredient. Pharmaceutically acceptable salts include, for example, acid addition salts or quaternary ammonium (or amine) salts.

Pharmaceutically acceptable salts of the compounds (1) and (2) include, for example, hydrochloride, hydrobromide, i-acid,
bisulfate, phosphate, acid phosphate, acetate, maleate, fumarate, succinate, lactate, tartrate, benzoate, citrate, curconate, saccharate, Salts formed from certain acids or their hydrates in the form of non-toxic acid addition salts containing pharmaceutically acceptable anions such as methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, etc. Contains quaternary ammonium (or amine) salts or their hydrates.

The compositions of the invention can be used, for example, in tablets, capsules, powders, granules, troches, cassettes, elixirs, emulsions, emulsions, syrups, suspensions, aerosols, ointments, sterile syringes, shaped poultices, soft and hard gelatins. It can be in forms such as capsules, suppositories and sterile packaged powders. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, microcrystalline cellulose, gum arabic, calcium phosphate, alginate,
Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, gum tragacanth, gelatin, syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzom x ster, proylhydroxybenzoate, talc, magnesium stearate,
Inert polymers, water or mineral oil.

Either solid or liquid compositions may contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweetening or flavoring agents, and the like, as described above. The composition can also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

For oral administration, compounds of formula (I) or (2) are mixed with carriers and diluents and placed in the form of tablets, capsules, and the like. For parenteral administration, the active ingredient is dissolved in 10% aqueous dextrose, isotonic saline, sterile water, or similar liquid and packaged in vials or ampoules to be administered intravenously by infusion or injection, or by intramuscular injection. will be sealed. Advantageously, solubilizing agents, local anesthetics, preservatives and buffers may also be included in the vehicle. To increase stability, the composition can also be lyophilized after being poured into vials or ampoules. Other examples of parenteral administration include preparations administered transdermally in the form of ointments and sachets. In this case, certain types of vaps or tapes are advantageous.

The composition has a dosage of 0.1 to 2000 per unit dosage form.
+ag, more commonly 0.5 to 1000 mg of active ingredient.

Compounds of formula (I) and (2) are effective over a wide dosage range. For example, daily dosages usually range from 0-03 mg/kg to 100 mg/kg. The actual amount of compound administered will be determined by the physician depending on the compound being administered and on the age, weight, response, severity of the patient's symptoms, route of administration, etc. of the individual patient. Therefore, the above dosage ranges are not intended to limit the scope of the invention.

The appropriate number of doses per day is 1 to 6 times, usually 1 to 4 times.

The compounds of formulas (1) and (2) are effective therapeutic agents for peripheral and central nervous disorders by themselves, but if necessary, they can also be administered in combination with one or more other similarly effective drugs. can. Additional drugs such as Ki include gangliosides, mecobalamin, and isaxonin.

Formulation examples and biological activities of compounds (I) and (2) used in the present invention will be explained in more detail in a series of Example B and Examples below, but the present invention is not limited thereto. Examples of the compositions shown below include one of the compounds described in the text as the active component or the general formula (1) or (
Using one of the other pharmaceutical compounds included in 2).

Examples Reference Example 1 17.0 g (0.1 to 1 monore) of 4-methylamino-2-(4-phenylpiperidino)pyrimidine (Compound No. 1024) dissolved in dichloromethane was dissolved in 2.
A solution of 4-dichloropyrimidine was added with methylamine (0.
25 mol, 40% methanol solution 20 mO at a temperature of 5
Additions were made at a rate that maintained the temperature. 1 at room temperature after the addition is complete.
Stirred for 2 hours. 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 to obtain 14.0 g (purity: 80%) of 2-chloro-4-methylaminopyrimidine.

2-chloro 4-methylaminopyrimidine 3. Og(0
．． 02 mol) and 8.4 g (0.02 mol) of 4-7 enylpiperidine.
05 mol) and added 200 mQ of n-butanol to 130
Heated at ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4.0 g of the target product as an oil.
(yield: 71%).

'H-NMR spectrum (deuterochloroform δppm)
:1.4-2.0 (5H, m), 2.93 (3H1d,
J-5.2Hz), 2.6 to 3.1 (2H, resistance, 4.
60 (IH, m), 4.92 (2H%br.d, J-1
2.6Hz), 5.6 7(l H, d1 J-7.2
Hz), 7.28 (5H,s), 7.93 (IH1d
, J-7.2HZ) The following compounds were produced in the same manner.

CH. The above compound (intermediate) The physical property values are shown in Table 1 below. show.

Table 1 Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) 4-methylamino 2 dissolved in lQmQ of methanol
-(4-7enylbiperidino)pyrimidine 1.0g (3
．． 73 mmol) was treated with a loml2 methanol solution of 0.43 g (3.73 mmol) of maleic acid, and 1
I stirred for hours. By concentrating this under reduced pressure and washing with ether, 1.25g (yield 87%) of the target product was obtained.
Obtained.

Melting point: 163-166°C 'H-NMR spectrum (CDCff, solution, δppm
): 1.6-2.2 (4HS m), 2.6-3.3
(5}{, m), 3.0 4 (3H, d, J = 5.2
Hz), 4.74 (2H, br, dS J-12.6H
z), 6.3 0 (l H% d, J-7.2Hz
), 7.30 (5H, m), 7.7 1 (IHS d,
J-7.2Hz), 8.40 (lH, m) The following compound was produced in the same manner.

(1014) (1012) maleate (10
26) Maleate salt of (1024) (1034)
Maleate salt of (1032) (1038)
Maleate of (1036) (1086) (10
84) Maleate (1090) (1088)
Maleate of (10!94) Maleate of (1092) (1098) Maleate of (1096) (1102) Maleate of (1100) (
1110) Maleate salt of (1108) (112
2) Maleate salt of (1120) (1130)
Maleate salt of (1128) (1158) (
1156) Maleate (1162) (116
0) maleate salt The physical properties of these compounds are shown in the second table below.
Shown in the table.

Table 2 (continued) Table 2 (continued) Example 1 64) 9.0 g (0.034 mol) of 4-methylamino-2-(4-phenylbiperidino)pyrimidine was added to 90 mQ of tetrahydrofuran and 51I112 of triethylamine. ) was added with a solution of 5.2 g (0.037 mol) of benzoyl chloride in 50 mff of tetrahydrofuran at room temperature for 30 minutes. Two hours after the end of the addition, pyridine IItIQ was added. After that 2
The mixture was stirred for several days. The reaction mixture was extracted with dichloromethane, the dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography 7E.
8.8 g (yield 70%) of the target product was obtained as an oily substance.

'H-NMR spectrum (deuterochloroform, δppm
): 1.4-2.0 (4HSm), 2.5-3.0
(3 H, m), 3.5 5 (38%s), 4. 6
2 (2 H, br%d.J=12.6Hz), 6.
1 4 (l H, d, J-7.2Hz), 7.1
~7.6 (l OH, m), 8.06 (IH, d,
J-7.2Hz) Physical property values of compounds produced in the same manner are shown in Table 3 below.

Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued!S) Table 3 (continued) 3 Table (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Table 3 (continued) Implementation Example 2 6.0 g (0.02
2 mol) of 4-(N-methylpenzamino)-2-(4
-7 enylbiperidino)pyrimidine solution, 300 m
A solution of 3.0 g (0.0 2 2 mol) of P-toluenesulfonic acid monohydrate dissolved in ethyl acetate from a was added slowly at room temperature. A suspension formed upon addition. After the addition was complete, the mixture was stirred for IO minutes. Filter the raw solid,
By washing with ethyl acetate and alcohol and drying, 6.8 g (yield: 83%) of the target product was obtained.

Melting point 180-182°C 'H-NMR spectrum (It chloroform δppm)
: 1.4-2.1 (4 H, m), 2.3 5 (3
H, s) 2.6-3.3 (3H, m), 3.5 6 (
3 H, s) 4.55 (2H, br%d% J=1
2.6Hz) 6.60 (LH, d, J=7.2Hz)
7.0 to 7.9 (148m), 8.36 (IH, d, J-7.2HZ) The physical property values of the following compounds produced in the same manner are shown in Table 4.

Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 Table (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 ( (Continued) Table 4 (Continued) Table 4 (Continued) Table 4 (Continued) Table 4 (Continued) Table 4 (Continued) Example 3 No. 170) 1 ・Ol dissolved in 700 form of 1 Omff (0.0027 mol) of 4-(N-methylbenzamino)-2-(4-7enylpiveridino)pyrimidine dissolved in 2 ml of CH,OH
．． 271 (0.0027 mol) of concentrated hydrochloric acid was added slowly. After the addition, it was concentrated under reduced pressure to obtain the desired product i.p. i
I (yield 100%) was obtained.

Melting point 80-84°C1'H-NMR spectrum (deuterochloroform, δppm)
1.4-2.2 (4H.m), 2.6-3.4 (3
H, m), 3.56 (3H, s), 4.8 (2H,
m), 6.69 (IH, d, J -7.2Hz),
7.0-7.7 (l OH, m), 8.1 (IH,
d, J-7.2Hz) Table 5 shows the physical properties of the following compounds produced in the same manner.

The following compounds were obtained in the same manner as in Example 3 in Table 5, using sulfuric acid, phosphoric acid, etc. instead of hydrochloric acid.

Preparation of Example 4 To a 20On+Q methanol solution of 13.07 (0.12 mol) of Heeb l. (0.12 mol)
was added and stirred at room temperature for 30 minutes, and then diluted with 18.52 (0.1
2 mol) was processed in 30 minutes and stirred for 3 hours. After distilling off the solvent, it was extracted with ether and purified using silica gel column chromatography to obtain the desired product as a yellow solid.
1 (yield 44%) was obtained.

'H-NMR spectrum (deuterochloroform, δppm)
1.70 (6H, m), 3.54 (3H, s), 3.
86 (3H.s), 3.92 (4H.m), 4-
83 (2H, s), 8.82 (LH, s) The following compounds were obtained in the same manner.

Example 6 2-isopropylamino-4-methyl-5 in a mixed solvent of ethanol 20m (2, chloroform 201112) Melting point: 118-119°C 'H-NMR spectrum (deuterium chloroform, δppm)
1.26 (6H, d, J-7Hz), 2.66 (3H
, s), 3.87 (3H, s), 4-25 (IH,
sex, J=7Hz), 5.40 (IH, br, s
), 8.80 (IH, s) Example 5 Preparation Sodium hydride in 50 ml of methanol 0.1 97
(7.8 mmol) was added thereto, and 2-biveridino-4-chloromethyl-5-methoxycarbonylpyrimidine 2.1F (7.8 mmol) was added thereto at room temperature, followed by stirring for 3 hours. After the solvent was distilled off, water was processed and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography 7E to obtain 0.901 (yield: 44%) of the desired product as a white solid.

Melting point 289-926a 1-methoxycarbonylpyrimidine 2.4 89 (lL9
mmol) and maleic acid 1.382 (11.9
mmol) was dissolved and stirred for 3 hours. After evaporation of the solvent, ether was added and the mixture was crystallized at 0.degree. C. to obtain 3.2H (yield: 83%) as a pale yellow crystal.

Melting point: 75-79°C'} {-NMR spectrum (J!Chloaform, δpp
m) 1.33 (6H, d, J-7Hz), 2.85
(3H.s), 3.95 (3H,s), 4.36 (I
H, sex, J-7Hz), 6.40 (2H, s)
, 9.08 (IH, br, s) The following compound was obtained in the same manner.

Example IB Tablets containing 10 mg of active ingredient are manufactured as follows.

10mg per tablet 55mg 35mg 5mg Active Partial Corn Starch Crystalline Cellulose Polyvinylpyrrolidone (as a 10% aqueous solution) Carboxymethylcellulose Calcium lOmg Magnesium Stearate 4mg Talc
lmg total 120mg Pass the active ingredients, starch and crystalline cellulose through an 80 mesh sieve and mix thoroughly. The obtained powder is mixed with a polyvinylpyrrolidone solution and granulated, and then passed through an 18 mesh sieve. The granules produced in this way are
Dry at 60°C and sieve again using an 18 mesh sieve. Pass it through an 80 mesh sieve in advance;
Carpoxymethyl cellulose canolecium and magnesium stearate and talc are added to the granules and after mixing, tablets each weighing 120+ ng are produced by a tablet machine.

Example 2B Tablets containing 200 mg of active bokmin are manufactured as follows.

Active per tablet 200 mg Corn starch 50 mg Microcrystalline cellulose 42 mg Light anhydrous silicic acid 7 mg Magnesium stearate 1 mg Total 300+ng Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The powder obtained is compressed to produce tablets weighing 300 IIg.

Example 3B Capsules containing 100 mg of active bokmin are prepared as follows.

Active ingredients per capsule 100mg corn starch 40mg lactose
5mg Magnesium Stearate 5mg Total 150mg Mix some of the above and pass through an 80 mesh sieve to mix thoroughly. The obtained powder is filled into capsules in an amount of 150 mg each.

Example 4B A ready-to-dissolve injection in a vial containing 5 mg of active extract is produced as follows.

When using 50 mg of active mannitol per vial, dissolve in 1 mjl of distilled water for injection and use.

Example 5B An ampoule-filled injection containing 50 mg of active extract is produced as follows.

Active Sodium Chloride Injection Distilled Water 50 mg per ampoule 18 mg Total dosage 2 ml Example 6B An adhesive patch containing 17.5 mg of Active Sodium Chloride is prepared as follows.

10 parts of ammonium polyacrylate are dissolved in 60 parts of water. Meanwhile, add 2 parts of glycerin diglycidyl ether to 10 parts of water.
Dissolve while heating. Furthermore, in the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water, and 1 part of active ingredient were dissolved with stirring.

Next, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution containing an active component of polyethylene glycol were added and mixed to form a drug-containing water-containing gel solution, and the active component was placed on a flexible plastic film in a square centimeter area. 0.5m per hit
The mixture was coated in an amount of 1.5 g, and the surface was covered with release paper and cut into 35 square centimeters to prepare a preparation.

Example 7B An adhesive patch containing active lomg is produced as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin
150 parts of water, 0.2 parts of trieboxyprobyl isocyanurate, 100 parts of ethanol, 25 parts of isoprobyl myristate, 25 parts of propylene glycol, and 5 parts of active ingredient were prepared. Next, this sol solution was applied to a thickness of 100 μm on the nonwoven surface of a composite film made of a rayon nonwoven fabric and a polyethylene film to form a drug-containing adhesive layer. The content of release auxiliary substances (isoprobil myristate and brobylene glycol) contained in this layer is approximately 201! The amount was %.

Thereafter, it was crosslinked at 25°C for 24 hours, a release film was attached to the adhesive interface, and the product was cut into 35 square centimeters to prepare a preparation.

The biological activity of the compounds of the present invention represented by formulas (1) and (2) above on nervous system cells was tested in vitro. Mouse neuroblastoma neuro, which has been established as a nervous system cell,
-2a strain (Dainippon Pharmaceutical Co., Ltd.) and NS-20Y strain. The nerve cells were grown to the logarithmic growth phase in a 5% carbon dioxide incubator at 37°C, and then cultured with the compound of the present invention for a certain period of time.

As a result, the compound of the present invention significantly increased neuronal cell proliferation compared to the control culture, and was equivalent to or higher than the control drug isaxonin (compound described in Japanese Patent Publication No. 59-28548). It was revealed that it has promoting activity, neurite shape, and neurite outgrowth promoting activity.

In addition to the neuroblastic tumor cells described above, the biological activity of the compounds of the present invention was tested against rat adrenal medullary cell line PC-12. When the PC-12 cell line is treated with the addition of NGF, neurites extend; however, when the compound of the present invention is added to the PC-12 cell line, the binding of NGF to the PC-I2 cells and the uptake of NGF into the cells are inhibited. It was also shown that neurite outgrowth was increased.

Furthermore, rabbit maxillary ganglion cells (superior cer
When the effect of the compounds of the present invention on the binding of NGF to the Vicalgang Ion was investigated, it was found that the compounds of the present invention promote NGF binding.

Next, we created a rat with a sciatic nerve crush, which is a peripheral neuropathy model, and tested the effects of the compound of the present invention.
It has been revealed that the compound of the present invention has a promoting effect on the recovery of the extensor longus muscle weight and the soleus muscle weight to normal values.

Furthermore, central nervous system disorder models were created in rats, mice, etc., and the efficacy of the compounds of the present invention was tested. That is, first, substantia nigra dobamine cells in rat brains were chemically destroyed by microinjection of 6-hydroxydopamine, causing movement disorders. Two weeks later, fetal brain dopamine cells were transplanted into the caudate nucleus on the damaged side of the rat brain in order to improve movement disorders. That is, from the day of transplantation, the compound of the present invention was administered intraperitoneally every day for two weeks, and the effects on improvement of movement disorders and growth of transplanted cells were investigated. It has been revealed that the compound of the present invention has a promoting effect on improving movement disorders and the like.

In addition, mice and rats with neurological damage due to mercury poisoning were created and the activity of the compound of the present invention was tested.
It has been shown to have symptoms improvement, promotion effect on recovery to normal state, therapeutic effect, learning memory improvement, recovery effect, etc.

In this way, the compounds of the present invention can improve and improve various neurological diseases such as peripheral nerve disorders and central nervous disorders in mammals.
It has been revealed that it is useful as a therapeutic agent or as an agent for improving learning and memory. Representative examples of these nervous system diseases include various neuropathies. For example, various peripheral neuropathies with motor, sensory and/or objective reflex slowing, including nerve root lesions of traumatic or inflammatory origin, immunological causes, and alcohol- or drug-induced or Examples include metabolic disorders such as diabetes, and idiopathic peripheral neuropathy. The compounds of the present invention can also be applied to various brain disorders including central nervous system disorders. More specific examples of these diseases include facial nerve palsy, sciatic nerve palsy, spinal muscular atrophy, muscular dystrophy, myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, and acute disseminated cerebrospinal disease. inflammation, Guillain-Barre syndrome, post-vaccination encephalitis, SMON, dementia, Alzheimer's syndrome,
Cranial injury prognosis, cerebral ischemia, cerebral infarction or cerebral hemorrhage sequelae,
Examples include, but are not limited to, brain and bone marrow contusions and rheumatism. Furthermore, when the compound of the present invention was tested for toxicity, it was found that the compound had low toxicity and could be used as a safe drug.

Experimental Example 1 The effects of the compounds according to the present invention on neuroblastic tumor cells were investigated using the following method.

That is, medium Dul containing 10% fetal bovine serum FCS
becco's Modified Eagle's
Medium [DMEM, penicillin G sodium (
Cells of the mouse neuro-2a strain in the logarithmic phase were incubated at 1,0 in 1 containing 100 units/mQ) and streptomycin sulfate (100 μj/ml).
The cells were plated in a 48-well plate at 0.00 cells/well (tell). Each well 0.25m
The cells were cultured for 1 day in a carbon dioxide incubator containing 5% carbon dioxide gas in the air at 37° C. using 12 culture fluids, and then changed to a medium containing each drug and FCS and further cultured for 24 hours. Next, the same amount (0.25 mQ) of 4% glutaraldehyde solution as the medium was added, and the cells were fixed by standing at room temperature for 2 hours. After washing with water, 0.05% methylene blue aqueous solution was added to stain the cells, and neurite outgrowth cells were macroscopically observed under a microscope (cells were defined as cells having i or more processes with a length of at least twice the major axis of the cell). were counted and determined as a percentage of the total number of cells. At least 5 visual fields (at least 2% of the total surface area of the well) were observed on the left and right sides centered around the mark made on the bottom of the well, and at least 200 cells were counted. The maximum 6 drug concentrations were taken, and 3 experiments were conducted for each drug concentration, and the values are the average ± S. D. It was expressed as The results are shown in Table 9.

In addition, mouse neuroblastic tumor cells NS-20Y were similarly cultured on polyornithine-coated dishes.
The effects of each agent were investigated. The results after 24 hours and 48 hours of culture are shown in Table 1O.

Table 9 Effect on neuro-2a Table 9 (continued) Table 9 (continued) Table 9 (continued) Table 9 (continued) Table 9 (continued) Table 9 (continued) Table 9 (continued) Table 10 Table 10 (continued) Table IO (Continued) Table 10 (Continued) Experimental Example 2 Therapeutic effect on rats with sciatic nerve crush: The therapeutic effect of the compound of the present invention on rats with sciatic nerve crush in a peripheral neuropathy model was determined by (1) functional improvement of the hindlimb on the side of crush. (2) Changes in muscle weight were examined as indicators of peripheral nerve degeneration and regeneration processes.

For the experiment, male Wistar rats (6 weeks old) were divided into groups T to 8.
I used two. Sciatic nerve crush was treated using the method of Yamazu et al.
9-268 (1976)) and the method of Hasegawa et al. (Kazuo Hasegawa, Naoji Mikuni, Yutaka Sakai, Japanese Pharmacological Journal, 74,
721-734 (1978)). That is, under bentobarbital anesthesia (40 ml/
kl,i. p. ), the left sciatic nerve was exposed at the buttock, and a certain part of the nerve was crushed for 30 seconds using hemostatic forceps with a width of 2 mm.

After the crush injury was completed, the surgical site was immediately sutured. Then, 100 μl/k of pincristin, which is known to delay peripheral nerve regeneration, was administered. , administered intraperitoneally once a week.

The compound of the present invention was selected as a test drug and administered intraperitoneally once a day from the same day of the crush injury until the 30th day.

A 0.9% physiological saline administration group was established as a control group.

0) Functional changes in the hindlimb on the side of crush It is thought that this will be reflected.

Therefore, after 30 days, rats were treated with chloral hydrate (40
0ml/kl, i. p. ) Under anesthesia, the method of Kern et al. (J. Neurosci. Methods,
twitch according to 9.259 (1987))
The tension was measured.

Specifically, after shaving the hind limbs of the rat, electrodes with alligator clips were attached to the skin of the hind limbs, which had been coated with cardiocream. Place the negative electrode behind the greater trochanter, the positive electrode 1cm behind it,
The site was 1 cm from the dorsal side. The rat was fixed in a supine position, and the hindlimb on the measurement side was fixed vertically. One end of a silk thread approximately 20 cm in length was connected to the distal joint of the third barb of the hindlimb on the measurement side, and the other end was connected to a tension transducer, and the isotonic contraction of the #1 flexor muscle during electrical stimulation was recorded on a polygraph. did. The electrical stimulation had a voltage of ioov and a duration of 1 msec. Frequency 2Hz
The stimulation was performed 10 times with a resting tension of 15 to 309 and repeated 3 times at 15 second intervals. Contraction force is tensi
on l, and the recovery rate (%, left/right) of the contractile force on the crush side was determined from the measured values of both limbs. The results are shown in Table 11.

Table 1 1 twitch tension test compounds showed electrophysiological index tw
It clearly enhances the recovery of itch tension,
Symptoms improved.

We conducted measurements in females, which is a good indicator of nerve degeneration and regeneration from a functional perspective, and also has the advantage of being able to orally measure changes in nerve degeneration and regeneration.

The distance between the bells was measured using Hasegawa's method.
K. ,Experientia, 3 4, 750 ~
75 1XI 978)
and the fifth gong, and the ratio of the distance on the crushed side to the distance on the normal side was determined. The distance between injuries on the crush side showed a value less than 50% of the normal side immediately after the crush injury. Recovery of the interproximal distance began after 12 to 16 days, and there was a clear tendency for the drug-administered group to recover faster than the control group from around 17 days to the final measurement day 26 days later.

(2) Change in muscle weight It is known that denervation or damage to the nerve causes atrophy of the muscles it controls, and that this gradually recovers with reinnervation of the nerve. We chose change as an indicator. Thirty days after the surgery, the weights of the extensor longus muscles of both hind legs, which are muscles innervated by the sciatic nerve, were measured under anesthesia. Then, the ratio of the weight of the extensor latitus longus muscle on the compressed side to the muscle weight on the normal side was determined and expressed as a percentage. The results are shown in Table 12.

Table 12 Extensor longus muscle weight Test compounds significantly increased % extensor longus muscle weight compared to control
was shown to increase

These results indicate that the test compound is an agent for improving peripheral neuropathy.
It has been shown to be useful as a therapeutic agent.

Experimental Example 3 Promoting effect of fetal brain cell transplantation on improvement of motor disorders caused by rat brain cell damage.

The substantia nigra dobamine cells on the left side of the brain of 4-week-old female Wista-type rats (body weight lool) were destroyed by microinjection of the drug 6-hydroxydobamine, and the rats showed a tendency to spontaneously rotate to the side opposite to the destroyed side for several days. However, there were no apparent behavioral abnormalities thereafter. When methamphetamine (5 m'i/kl, ip) was administered to rats with fractures, rotational movement occurred on the fracture side.

Two weeks after drug destruction, the part containing dopamine cells (substantia nigra and ventral tegmentum) was excised from the brainstem of the rat fetal brain at embryonic day 14 to 17, cut into pieces, and treated with trypsin.
C. for 30 minutes, and then the tissue was made into a suspension by pivoting. Next, apply this suspension to the caudate nucleus on the destroyed side at 2 locations of 5μα for a total of 10
μα (approximately 10′ cells) was transplanted.

The test compound of the present invention, for example compound (168), was administered at 1 5 6 mg/kg i.p. for 4 days from the day of transplantation. p. , 50mg/kg for 10 days from day 11 after 7 days
i. p. administered. Compound (2 9 6) was administered at 1 5 3 mg/kg, followed by 5
0 mg/kg was administered. Rotational movements induced by methamphetamine administration were performed at 2 weeks, 1 week, 2 (or 3) weeks, 4 weeks, 6 weeks, and 8 weeks before transplantation and drug administration.
I looked into it a week later. The number of rotational movements was counted for the first minute six times every 10 minutes after methamphetamine administration, and the average number of rotational movements per minute was calculated by adding up the total number of rotational movements. The results are summarized in Table 13.

These results showed that the test compound was useful as an ameliorating agent and therapeutic agent for central nervous system disorders.

Table 13 Experimental Example 4 Improving learning and memory in mice with neurological damage caused by mercury poisoning.
recovery effect.

Seven-week-old male BalbC mice were placed in a T-maze three times during one week in a safe area from the starting point.
Maze learning was performed by running in a straight line to y area). Thereafter, 5 ml/kl/day of methylmercury chloride (hereinafter abbreviated as MMC) was orally administered to the 8-week-old mice for 6 days. Q. Raw food was used as a control group. lmQ/l(N7
Groups of mice were given daily doses. After the completion of MMC administration, the compound of the present invention was intraperitoneally administered for 10 days starting from the next day. On the 6th day of drug administration, ie, the 12th day of the experiment, maze learning was restarted using a T-maze, and the running behavior of the mice was observed. 10th day after restarting (21st day of experiment start) 8th and 11th day (22nd day of experiment start)
The denominator is the number of mice tested in the T-maze, and the IO
At least 8 times out of the 8 running trials, the standard (sa) was reached within 5 seconds.
The number of mice that reached the fety area) was expressed as a numerator. Along the way, the number of cases decreased due to deaths due to MMC poisoning. The mean value and standard deviation (S.E.) of the time (seconds) required to travel to the safe area was also calculated.

It was found that the compound of the present invention has learning, memory improvement, and recovery effects in mice.

Experimental Example 5 The acute toxicity of the compound according to the present invention was investigated by the following method.

That is, 4 to 6 5-week-old male ddy mice were used as one group. The compound was dissolved or suspended in physiological saline and administered intraperitoneally (i.p.), and toxicity was determined 24 hours after administration. The results are shown in Table 14.

Table 14 Mouse Acute Toxicity Table 14 (Continued) Table 14 (Continued) Table 14 (Continued) Effects of the Invention> As described above, the compound of the general formula of the present invention inhibits the proliferation of nervous system cells and the formation and elongation of neurites. It has a promoting effect on
It also has nerve regeneration effects, motor function recovery effects, and learning and memory improvement and recovery effects in neuropathic rats and mice, making it suitable for use in the improvement and treatment of neurological patients with peripheral nerve disorders, central nervous disorders, dementia, etc. It can be done. It is also expected to be suitably used for the recovery, improvement, and treatment of nervous system diseases caused by disorders of nervous tissues and cells involved in perceptual/sensory functions and autonomic functions.

As shown in Experimental Examples d to 4 and Tables 9 to 14, the compounds of the present invention were found to have biological activity equivalent to or higher than that of controls such as isaxonine and mecobalamin. Furthermore, the toxicity of the compounds of the present invention is generally weak, as shown in Experimental Example 5. The compounds of the present invention are thus generally considered to be highly active, less toxic, and highly safe drugs.

Claims (1)

[Claims] 1. The following formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) Here, R^1 is a hydrogen atom or a lower alkyl group; X is the following formula ▲ Numerical formula, There are chemical formulas, tables, etc.▼,▲mathematical formulas, chemical formulas,
There are tables, etc.▼(Here, R^2 is a hydrogen atom, lower alkyl group, phenyl group, benzyl group, or α-(p-chlorophenyl)benzyl group), ▲There are mathematical formulas, chemical formulas, tables, etc.▼( Here, R^3 corresponds to one or two or more same or different substituents substituting one or more hydrogen atoms of the same or different methylene group, and represents a lower alkyl group, a hydroxyl group, a nitro phenyl group, benzyl group, benzoyloxy group, benzoylamino group, lower alkylamino group, which may be substituted with a group;
Di-lower alkylamino group, HO(C_5H_5)_2C- group, piperidino group, hydroxy lower alkyl group, C_5H_5SO_2O- group,
a benzoyl group, a lower alkylsulfonylamide group, or a lower alkoxycarbonyl group which may be substituted with halogen, and n is a number of 4, 5, 6 or 7)
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Here, R^4 is hydrogen, a lower alkyl group, or a benzyl group, and R
^5 may be substituted with a lower alkyl group, lower acyl group, 2-furoyl group, benzyl group, or benzoyl group 4
- Piperidyl group, phenethyl group or ▲Mathematical formula, chemical formula, table, etc.▼ group or benzoyl group which may be substituted with a halogen atom or nitro group), ▲Mathematical formula, chemical formula, table, etc.▼ , ▲Mathematical formula, chemical formula,
There are tables, etc. ▼ % formula or ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ is a group represented by the following formula; Y is the following formula CH_2R^9 (where R^9 is hydrogen, lower alkyl group, lower alkoxy group, lower alkylthio group or di-lower alkylamino group), formula ▲ mathematical formula, chemical formula, table, etc. ▼ (where R^6 is a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group,
a lower alkoxyl group or a 2-(N,N-dimethylamino)ethyl group, and R^7 is a lower alkyl group, a lower acyl group, a cyclohexylcarbonyl group, a 2-furoyl group, a lower alkoxycarbonyl group, a cinnamoyl group,
Benzyl group, benzylcarbonyl group, tosyl group, phenoxyacetyl group, di-lower alkylcarbamoyl group, 2-
Thienyl group, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ groups, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ groups, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ groups, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ groups , ▲There are mathematical formulas, chemical formulas, tables, etc.▼ groups or 4-lower alkylpiperazyl groups, or substituted with halogen atoms, nitro groups, lower alkyl groups, lower alkoxy groups, amino groups, benzoylamino groups, or phenyl groups. However, when R^6 is a hydrogen atom, R^7 is a benzoyl group), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Here, R^8 is Corresponds to a substituent substituting the hydrogen atom of a methylene group, and is a hydrogen atom, a lower alkyl group, a phenyl group, or a benzyl group, and m is a number of 4, 5, 6, or 7), ▲ Formula, Chemical formula,
It is a group represented by ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼; and Z is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxycarbonyl is a group, provided that Y is CH_2R^
9 is only when Z is a lower alkoxycarbonyl group, and R^4 is hydrogen when R^5 is a lower alkyl group, lower acyl group, 2-furoyl group, benzyl group,
A phenethyl group or a benzoyl group optionally substituted with a halogen atom or a nitro group, and Y is CH_2R
In ^9, only when Z is a lower alkoxycarbonyl group, and Y is ▲ has a mathematical formula, chemical formula, table, etc. ▼, ▲ has a mathematical formula, chemical formula, table, etc. ▼ or ▲ has a mathematical formula, chemical formula, table, etc. Yes, ▼ can be X
is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R^
A pyrimidine or a pharmaceutically acceptable salt thereof, which is only when 4 is a lower alkyl group. 2. The pharmaceutically acceptable salts mentioned above are hydrochloric acids, hydrobromides, sulfates, bisulfates, phosphates, acid phosphates, acetates, maleates, fumarates, and succinates. , lactate,
tartrate, benzoic acid, citrate, gluconate, saccharide, methanesulfonate, p-toluenesulfonate,
A compound according to claim 1 selected from the group consisting of naphthalene sulfonate and quaternary ammonium salt. 3. Formula (2) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(2) Here, A_1 is =CH- or -N=, and A_2▲There are mathematical formulas, chemical formulas, tables, etc.▼ is = CH-, -N= or, A_3 is =CH- or -N=, R^1^
1 is a lower alkyl group, R^1^2 is a phenyl group optionally substituted with a halogen atom, a lower alkyl group or a lower alkoxy group,
2-furyl group or 2-thienyl group. However, when A_1 is -N=, A_2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and when A_1 and A_2 are =CH-, A_3 is =CH-, and A_2
is -N=, A_1 and A_3 are =CH-, or a pharmaceutically acceptable salt thereof. 4. The pharmaceutically acceptable salts mentioned above are hydrochloric acids, hydrobromides, sulfates, bisulfates, phosphates, acid phosphates, acetates, maleates, fumarates, and succinates. , lactate,
tartrate, benzoic acid, citrate, gluconate, saccharide, methanesulfonate, p-toluenesulfonate,
4. A compound according to claim 3 selected from the group consisting of naphthalene sulfonate and quaternary ammonium salt. 5. A therapeutic agent for neurological diseases, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 6. The pharmaceutically acceptable salts mentioned above are hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, maleate, fumarate, and succinate. , lactate, tartrate, benzoic acid, citrate, gluconate, saccharide, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate and quaternary ammonium salt. The therapeutic agent according to claim 5. 7. A therapeutic agent for neurological diseases, comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof as an active ingredient. 8. The above pharmaceutically acceptable salts include hydrochloric acids, hydrobromides, sulfates, bisulfates, phosphates, acid phosphates, acetates, maleates, fumarates, and succinates. , lactate,
tartrate, benzoic acid, citrate, gluconate, saccharide, methanesulfonate, p-toluenesulfonate,
The therapeutic agent according to claim 7, which is selected from the group consisting of naphthalene sulfonate and quaternary ammonium salt.