JP2628707B2 - Pyrimidines and their pharmaceutically acceptable salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to novel pyrimidines or pharmaceutically acceptable salts thereof, and neuronal diseases of the peripheral nervous system and central nervous system of animals containing them as an active ingredient. It relates to a novel therapeutic agent.

<Conventional technology> JP-B-46-23394 discloses the following formula. Here, A is an alkylene in which one, or an amino group or has been lower alkylene substituted by a lower acylamino group of C _{2 to 5} up to C _16; M is _{H, Na, K, NH 4} , Mg, Ca
Or an organic basic ammonium salt; and n is a valence equal to the valency of M. The aminopyrimidines of formula
It is disclosed that it has activity as an antidepressant or psychostimulant, especially in the field of psychosis treatment.

JP-B-51-22044 discloses that dichloro lower aliphatic carboxylate of 2-isopropylamino-pyrimidine, for example, dichloroacetate of 2-isopropylamino-pyrimidine, is useful as a therapeutic agent for neuropathy. ing.

JP-A-52-100477 (JP-B-59-28548) discloses that 2-isopropylaminopyrimidine phosphate is useful as a therapeutic agent for neurological diseases.

Japanese Patent Publication No. 54-157575 discloses a method for producing 2-chloropyrimidine in high yield, and in the examples, specific examples of obtaining 2-chloropyrimidine in 69% yield are described. Have been.

Japanese Patent Application Laid-Open No. 55-393 discloses a method for producing 2-isopropylaminopyrimidine in a high yield. In the examples, 2-isopropylaminopyrimidine was obtained at a yield of 60%. An example is provided.

JP-A-55-122768 discloses the following formula: Here, A ⁴ , A ⁵ and A ⁶ each represent H or OH, and at least one of them represents OH. The hydroxy derivative of 2-isopropylaminopyrimidine represented by And is useful for treating muscular dystrophy.

JP-A-55-145670 discloses the following formula: Here, A ₄ ′, A ₅ ′ and A ₆ ′ each represent H or a halogen atom, and at least one of them is a halogen atom. 2-isopropylaminohalogenopyrimidine represented by It is disclosed that it is useful for treating neuropathy and muscular dystrophy.

JP-A-55-145671 discloses a method for producing a hydroxy derivative of 2-isopropylaminopyrimidine.

JP-A-55-151571 discloses that 2-isopropylamino-5-halogenopyrimidine is of interest in treating neurological diseases.

JP-A-56-10177 discloses a method for producing 2-isopropylaminopyrimidine in a substantially quantitative yield by aminolysis of 2-methylsulfonylpyrimidine with isopropylamine.

JP-A-56-26880 discloses a method for producing 2-isopropylaminopyrimidine by reacting bis (isopropylguanidine) sulfate with 1,1,3,3-tetraethoxypropane.

JP-A-56-90013 discloses the treatment of muscular dystrophy, myopathy, myotonia and / or muscular nerve transmission deficiency using a substituted pyrimidine derivative or a therapeutically acceptable salt or metabolite thereof as an active ingredient. Agents are described. However, the publication only discloses various salts including 2-isopropylaminopyrimidine orthophosphate as active compounds.

JP-A-61-65873 discloses the following formula Here, R ¹ is H or aralkyl, Y is a divalent organic group specified and described in the claims of the publication, and a 2-piperazinopyrimidine derivative represented by It is disclosed to be used as a herbicide for upland fields.

In addition, the present inventors have previously provided a novel therapeutic agent for a neurological disease containing a specific 2-piperazinopyrimidine derivative or a pharmaceutically acceptable salt thereof (International Publication No.
WO 87/04928).

<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 a neurological disease 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 having an effect of nerve cell regeneration and repair.

Still another object of the present invention is to provide a novel therapeutic agent for neurological diseases applicable to disorders of peripheral nerves.

Yet another object of the present invention is a neurotransmitter action system,
An object of the present invention is to provide a novel therapeutic agent for a neurological disorder applicable to a disorder of the central nervous system different from a mental illness in which an abnormality such as a metabolic system is considered to be primarily involved.

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

Still another object of the present invention is to provide a novel neurological or cerebral disease comprising a totally excellent and useful compound having few side effects such as liver injury and having a suitable pharmacological action for treating a neurological or brain disease. To provide a remedy for medical use.

Still other objects and advantages of the present invention will be apparent from the following description.

<Means for Solving the Problems> and <Action> According to the present invention, the above objects and advantages of the present invention are represented by the following formula (I) Here, X is (i) the following formula (I) -1 Here, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ² is a phenethyl group, a cyclohexyl group, a phenyl group, a benzyl group or a piperidyl group, or may be substituted with a piperidino group. A good lower alkyl group having 1 to 4 carbon atoms, wherein the piperidyl group may be substituted by a lower alkyl group having 1 to 4 carbon atoms, or R ¹ and R ² are taken together to form Together with the nitrogen atom to which Forming a heterocyclic group selected from the group consisting of: wherein R ³ is a cyclohexyl group, a 4-pyridyl group, a benzoyl group or a lower alkyl group having 1 to 4 carbon atoms, or substituted with a chlorine or lower alkoxyl group. Or an alkylaminocarbonyl group mono- or di-substituted by an alkyl group having 1 to 6 carbon atoms, wherein R ³¹ and R ³² are the same or different and each is a hydrogen atom or a lower An alkoxyl group, and the heterocyclic group is a phenyl group, a benzyl group, a phenylthio group, a CN group, a lower alkoxycarbonyl group or May be mono-substituted or may be mono- or penta-substituted by a lower alkyl group having 1 to 4 carbon atoms, and may be substituted by a polymethylene group having 3 to 5 carbon atoms on an adjacent ring member carbon. Or (ii) the following formula (I) -2-SR— ⁴ (I) -2, wherein R ⁴ is a lower group having 1 to ⁴ carbon atoms. Y is an amino group or a substituted amino group mono- or di-substituted by a lower alkyl group having 1 to 4 carbon atoms, and Z is a group having 2 carbon atoms. Or a lower alkoxycarbonyl group having 2 to 5 carbon atoms, or Y and Z are taken together to form a divalent group -YZ As- Here, R ⁵ is a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a lower alkoxy group having 1 to 4 carbon atoms. Here, R ⁶ is a lower alkyl group having 1 to 4 carbon atoms, a group represented by the formula, and a pyrimidine represented by the formula: or a pharmaceutically acceptable salt thereof.

In the above formula (I), X is (i) the following formula (I) -1 Or (ii) a group represented by the following formula (I) -2-SR ⁴ ... (I) -2.

In the above formula (I) -1, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms.

The lower alkyl group may be linear or branched, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, is
o-butyl and t-butyl can be mentioned.

In the above formula (I) -1, R ² is a phenyl group, a cyclohexyl group, a phenyl group, a benzyl group or a piperidyl group, or a lower alkyl group having 1 to 4 carbon atoms which may be substituted by a piperidino group. .

The piperidyl group may be substituted with a lower alkyl group having 1 to 4 carbon atoms. In any of the above cases, the same specific examples as described above can be exemplified as the lower alkyl group having 1 to 4 carbon atoms.

Further, in the above formula (I) -1, R ¹ and R ² together form the following formula together with the nitrogen atom to which they are bonded. A heterocyclic group selected from the group consisting of: All of these heterocyclic groups are phenyl, benzyl, phenylthio, CN, lower alkoxycarbonyl or May be mono-substituted or may be mono- or penta-substituted by a lower alkyl group having 1 to 4 carbon atoms, and may be substituted by a polymethylene group having 3 to 5 carbon atoms on an adjacent ring member carbon. May be.

As the lower alkoxycarbonyl group, those having 1 to 4 carbon atoms of a lower alkoxy moiety are preferable.
Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl and the like can be mentioned.

Examples of the lower alkyl group having 1 to 4 carbon atoms include the same as those described above.

Polymethylene groups having 3 to 5 carbon atoms are trimethylene, tetramethylene and pentamethylene, which, together with the adjacent ring member carbon to which they are attached, have 5 members, 6 members and Form a 7-membered ring.

Further, the substituent R ^{3 at} the 4-position of the piperazino group may be a cyclohexyl group, a 4-pyridyl group, a benzoyl group or a lower alkyl group having 1 to 4 carbon atoms, or may be substituted with a chlorine or lower alkoxy group. It is a good phenyl group or an alkylaminocarbonyl group mono- or di-substituted by an alkyl group having 1 to 6 carbon atoms.

Examples of the lower alkyl group further include an n-hexyl group in addition to those described above.

The lower alkoxy group is, for example, one having 1 carbon atom.
Preferred are lower alkoxy groups of 4 to 4, such as methoxy,
Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy and the like can be mentioned.

Examples of the alkylamino group of the alkylaminocarbonyl group include, for example, methylamino, ethylamino, n-
Propylamino, iso-propylamino, n-butylamino, t-butylamino, n-pentyl, n-hexyl, dimethylamino, diethylamino, di-n-propylamino, ethylmethylamino, di-iso-propylamino, di-n- Butylamino, cyclohexylamino and the like can be mentioned.

In addition, R ³¹ and R ³² are the same or different and are a hydrogen atom or a lower alkoxyl.

The lower alkoxyl group preferably has 1 to 4 carbon atoms, and examples thereof include the same as those described above.

Further, in the above formula (I) -2, R ⁴ has 1 to 1 carbon atoms.
4 is a lower alkyl group. Specific examples of the lower alkyl group include the same as those described above.

Examples of the group represented by the above (I) -2 include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, sec-butylthio, t-butylthio and the like.

In the above formula (I), Y represents an amino group (—N
H ₂ ) or lower alkyl having 1 to 4 carbon atoms and mono-
Or a di-substituted substituted amino group.

Specific examples of the lower alkyl having 1 to 4 carbon atoms and the substituted amino group (alkylamino group) include the same as those described above.

In the formula (I), Z is a methyl group substituted with a lower alkoxycarbonyl group having 2 to 5 carbon atoms or a lower alkoxycarbonyl group having 2 to 5 carbon atoms.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl and sec-butoxycarbonyl.

Further, in the formula (I), Y and Z together
As a divalent group -YZ-, the following formula In the above formula, each of R ⁵ , R ⁶ and R ⁷ has 1 to 4 carbon atoms.
Wherein the lower alkyl group of R ⁵ may be substituted with a lower alkoxyl group having 1 to 4 carbon atoms, to form a group represented by the following formula:

The compound represented by the above formula (I) of the present invention includes:
For example, the following compounds can be exemplified.

(A) -YZ- A compound representing: (102) (100) hydrochloride, (104) (100) maleate, (108) the maleate salt of (106), (112) maleate of (110), (116) (114) hydrochloride, (118) (114) maleate, (502) (500) hydrochloride, (112) (120) hydrochloride, (126) the hydrochloride salt of (124), (129) (128) hydrochloride (506) the hydrochloride salt of (504), (510) (508) hydrochloride, (514) (512) hydrochloride, (518) (516) hydrochloride, (522) (520) hydrochloride, (138) the maleate salt of (136), (526) (524) hydrochloride (530) (528) hydrochloride (534) (532) hydrochloride (538) (536) hydrochloride (542) p-toluenesulfonic acid salt of (540) (175) (174) hydrochloride (177) (176) hydrochloride (546) (544) hydrochloride (550) (548) hydrochloride (554) (552) hydrochloride (557) (556) hydrochloride (559) (558) hydrochloride (588) (586) hydrochloride (562) (560) hydrochloride (566) (564) hydrochloride (570) (568) hydrochloride (574) (572) hydrochloride (578) (576) hydrochloride (582) (580) hydrochloride (B) -YZ A compound representing: (204) the hydrochloride salt of (202), (210) hydrochloride (215) (214) hydrochloride (239) (238) hydrochloride (241) a hydrochloride of (240) (C) a compound wherein Y and Z each independently represent a monovalent group; (402) (400) hydrochloride, (406) The maleic acid salt of (404) and the compound of the above formula (I) of the present invention can be prepared by a method known per se, in particular, JP-A-61-140568 and JP-A-61-87627.
And the intermediates obtained by these methods can be prepared in a manner known per se (for example by reductive removal of protecting groups).
Can be produced by treating with In Examples 1 to 14 described later, the production methods of each compound are described in detail.

For example, the compound (I) of the present invention can be more specifically produced by the following method.

(A) the following formula (I) -A Here, the definitions of R ¹ , R ² and R ⁵ are the same as those in the above (I). When producing a compound represented by the following formula (V), Wherein R ¹ and R ^{2 have} the same definitions as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms, and a compound represented by the following formula (VI): R ⁵ NH _2. · · · · (VI) defined herein R ⁵ is reacted with an amine represented in the same to the above formula (I),.

The above reaction can be carried out according to Reaction Scheme 1 as described through the starting materials.

Reaction scheme 1 can be carried out, for example, as follows. Compounds (II) and (III) are reacted in a reaction solvent such as, for example, water, methanol, ethanol, tetrahydrofuran, dimethylformamide at a temperature of 0 to 100 ° C. for 0.5 to 10
The reaction is carried out for a time to produce compound (IV). Compound (I
V) is reacted with phosphorus oxychloride without solvent or in an inert solvent such as dichloroethane to produce compound (V). Next, the compound (V) is reacted with the compound (VI) in an alcohol solvent such as isopropanol or ethanol at a temperature of 80 to 150 ° C. to give a compound (I)
-A can be produced.

The above intermediate (IV) of Reaction Scheme 1 can also be produced according to the following Reaction Scheme 1 ′.

Reaction scheme 1 'can be carried out, for example, as follows. Compounds (VII) and (VIII) can be prepared in an alcoholic solvent such as butanol, amyl alcohol, etc.
The reaction is performed at a temperature of 00 ° C. to produce compound (III).
Compound VIII is compound (I) in Reaction Scheme 1.
It can be produced by using S-methylisothiourea instead of I).

The compounds included in the above formula (IA) are as follows by the compound number: 100, 106, 110, 114, 500, 120, 124, 128, 144, 146,
148, 150, 152, 154, 156, 158, 160, 162, 164, 166,
524, 528, 532, 536, 540, 168, 170, 174, 176, 178,
544, 548, 552, 556, 558, 560, 564, 568, 572, 575,
576, 580, 582, 180, 182, 184 (b) The following formula (IB Here, the definition of R ⁵ is the same as in the above formula (I), and R ³⁰ is a lower alkyl group having 1 to 4 carbon atoms, a benzoyl group or an alkyl group having 1 to 6 carbon atoms, which is mono- or di-. - in preparing the substituted alkyl amino group, a compound represented by the, (b ¹⁾ the following formula (IX) Here ,, the definition of R ⁵ are the same as above-mentioned formula (I), in the compound represented here by the following formula ^{(X) R 33 -Q ····· (} X), R 33 is the number of carbon atoms A lower alkyl group of 1-4, a benzoyl group or a dialkylaminocarbonyl group disubstituted with an alkyl group of 1-6 carbon atoms;
A is, in either reacted with compounds represented by, or (b ²⁾ compound and formula of the formula ^{(IX) (XI) R 34} -NCO ····· (XI) wherein the halogen atom, R ³⁴ Is an alkyl group having 1 to 6 carbon atoms.

The above reaction can be represented by the following reaction scheme 2.

Reaction Scheme 2 can be performed as follows. When a compound in which R ³³ is a lower alkyl group having 1 to 4 carbon atoms is used as the compound of the formula X, the compound (I
X) and (X) are reacted at a temperature of 20 to 100 ° C. in a solvent such as ethanol in the presence of an inorganic base such as potassium carbonate, and R ³⁰ is a lower alkyl group having 1 to 4 carbon atoms. Compounds of formula (IB can be prepared.

When a compound in which R ³³ is a benzoyl group or a dialkylaminocarbonyl group di-substituted by an alkyl group having 1 to 6 carbon atoms is used as the compound of the formula (X), the compounds (IX) and ( X) is reacted with a basic organic solvent such as pyridine at a temperature of 20 to 100 ° C. to obtain a dialkylaminocarbonyl in which R ³⁰ is a benzoyl group or disubstituted by an alkyl group having 1 to 6 carbon atoms. The group of formula (I
Compound B can be prepared.

In the above formula (X), Q is a halogen atom, and is chlorine, bromine or iodine.

When the isocyanate of the formula (XI) is used, the compounds (IX) and (XI) are reacted at 20 to 100 ° C. in a solvent such as tetrahydrofuran or toluene in the presence of a basic organic compound such as triethylamine. And R ³⁰ has 1 to 1 carbon atoms.
The compound of formula (IB), which is a monoalkylaminocarbonyl group mono-substituted with an alkyl group of No. 6, can be produced.

The compounds included in the above formula (IB) are represented by the following compound numbers: 130, 132, 504, 508, 512, 516, 520, 136, 140, 142.

(C) The following formula (IC Here, the definitions of R ¹ , R ² and R ⁶ are the same as in the above formula (I). When producing a compound represented by the following formula: (c ¹ ) Here, the definitions of R ¹ and R ² are the same as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms, and a compound represented by the following formula (XIII) R ⁶ NH _2. (XIII) Here, the definition of R ⁶ is the same as that of the above formula (I), or the compound is reacted with a compound represented by the following formula: or (c ² ) Here, the definition of R ⁶ is the same as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms, and a compound represented by the following formula (XV) Here, the definition of R ¹ and R ² is the same as in the above formula (I), and the compound is reacted with

The above reaction can be carried out according to Reaction Scheme 3 or Reaction Scheme 4 when described from the starting materials.

Reaction scheme 3 can be carried out, for example, as follows.

Compounds (II) and (XVIII) (wherein R is carbon number 1-4)
Is reacted with a reaction solvent such as water, methanol, ethanol, tetrahydrofuran or dimethylformamide at a temperature of 0 to 100 ° C., preferably for 0.5 to 10 hours, to give a compound (XII) Generate Compound (XII) is reacted with compound (XIII) in an alcohol such as water, methanol or ethanol, or a solvent such as tetrahydrofuran, dimethylformamide, toluene or xylene at a temperature of 0 to 150 ° C., preferably for 0.5 to 20 hours. Thereby, the compound (IC can be produced.

Reaction scheme 4 can be carried out, for example, as follows.

The compound (IC) can be produced by reacting the compound (XIV) with the compound (XV) in an alcohol solvent such as butanol or aer alcohol at a temperature of 80 to 150 ° C. The reaction of the compound (XIV) with the reaction scheme 3 Can be produced using S-methylisothiourea instead of compound (II).

The above formula (compounds included in the IC are represented by the compound numbers as follows: 200, 202, 206, 208, 210, 212, 214, 216, 218, 584,
220, 222, 224, 226, 228, 230, 232, 234, 236, 238,
240.

(D) The following formula (ID Here, the definitions of R ¹ and R ² are the same as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms. ) Here, the definition of R ¹ , R ² and R is the same as described above. A compound represented by the following formula is reacted with ammonia.

The above reaction can be represented by the following reaction scheme 5.

Reaction Scheme 5 can be performed as follows. Compound (XVI) can be produced according to reaction scheme 1 in place of compound (V) according to reaction scheme 1 using a dialkyl 2-ethoxymethylenemalonate such as diethyl 2-ethoxymethylenemalonate in place of compound (III). The reaction between compound (XVI) and NH ₃ can also be carried out in the same manner as in Reaction Scheme 1 to produce compound (ID).

The compound included in the formula (ID is, for example, Compound No. 40
0 compound.

(C) The following formula (IE Here, the definitions of R ¹ and R ² are the same as in the above formula (I), and R is independently an alkyl group having 1 to 4 carbon atoms. A compound represented by the formula (V) and the following formula (XVII) Here, R is independently an alkyl group having 1 to 4 carbon atoms to react with each other.

The above reaction can be represented by the following reaction scheme 6.

Reaction Scheme 6 can be performed as follows. In the reaction scheme 1, with respect to the compound (V),
Compound (IE) can be produced by reacting compound (XVI) in place of compound VI.

The compound included in the formula (IE is, for example, Compound No. 40
4 compound.

Further, a pharmaceutically acceptable salt of the compound of the above formula (I) can be produced as follows. The hydrochloride converts the corresponding compound of formula (I) to, for example, toluene, ether,
It can be produced by dissolving in a solvent such as ethanol or ethyl acetate and blowing hydrogen chloride gas or adding concentrated hydrochloric acid.

Hydrochlorides are, for example, compounds having the following compound numbers: 102, 114, 502, 122, 126, 129, 506, 510, 514, 518,
522, 526, 530, 534, 538, 175, 177, 546, 550, 554,
557, 562, 566, 570, 574, 578, 582, 204, 211, 215,
239, 241, 400, 588.

Similarly, by using maleic acid and p-toluenesulfonic acid instead of hydrochloric acid, the corresponding maleate and p-toluenesulfonic acid can be used.
Toluenesulfonate can be obtained.

Such salts include the following compounds: 104, 108, 112, 118, 138, 404 (maleate), 542 (p-toluenesulfonate).

According to the study of the present inventors, the compound of the above formula (I) of the present invention was found to be useful as a therapeutic agent for neurological diseases.

The compound of formula (I) is usually used in the form of a pharmaceutical composition and is administered by various routes such as oral, subcutaneous, intramuscular, intravenous, intranasal, transdermal and rectal routes.

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

The pharmaceutically acceptable salts of the compound (I) include, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, maleate,
Pharmaceuticals such as fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, sugar, methanesulfonate, p-toluenesulfonate and naphthalenesulfonate And hydrates thereof and quaternary ammonium (or amine) salts or hydrates thereof formed from acids which form non-toxic acid addition salts containing an acceptable anion.

Compositions of the present invention include, for example, tablets, capsules, powders, granules, troches, cachets, elixirs, emulsions, emulsions,
Syrups, suspensions, aerosols, ointments, sterile syringes, molded pups, tapes, soft and hard gelatin capsules,
It can be in the form of suppositories and sterile packaged powders.
Examples of pharmaceutically acceptable carriers include lactose, glucose, sucrose, sorbitol, mannitol, corn starch,
Microcrystalline cellulose, gum arabic, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, tragacanth gum, gelatin, syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate , Inert polymers, water or mineral oil, and the like.

Either solid or liquid compositions can contain fillers, binders, lubricants, wetting agents, disintegrating agents, emulsions and suspending agents, preservatives, sweetening or flavoring agents and the like, as described above. The compositions may also be formulated so that the active ingredient is released rapidly, sustained or delayed after administration to the patient.

For oral administration, the compounds of formula (I) are mixed with carriers and diluents and formed into tablets, capsules and the like.
For parenteral administration, the active ingredient is dissolved in 10% aqueous glucose solution, isotonic saline, sterile water or similar liquids, and administered in a vial or ampoule for intravenous infusion or injection or by intramuscular injection. Sealed.
Advantageously, solubilizing agents and local anesthetics, preservatives and buffers can also be included in the vehicle. To increase stability, the composition can be lyophilized after injection into a vial or ampoule. In other cases of parenteral administration, there are preparations for transdermal administration as ointments and cataplasms. In this case, a molded pulp or a tape is advantageous.

0.1 to 2000 mg per unit dosage form of the composition,
More usually, it contains from 0.5 to 1000 mg of active ingredient.

The compounds of formula (I) are effective over a wide dosage range. For example, the daily dose is usually 0.003mg / kg
Or within the range of 100mg / kg. The actual amount of compound administered will be determined by the physician, depending on the compound to be administered and on the age, weight, response, severity of the patient's condition, route of administration, etc., of the individual patient. Therefore, the above dosage ranges do not limit the scope of the invention. The appropriate number of times of administration per day is 1 to 6, usually 1 to 4 times.

The compounds of formula (I) are effective therapeutic agents for peripheral neuropathy and central nervous system disorders by themselves, but can also be administered, if necessary, in combination with one or more other active compounds. Such additional agents include gangliosides, mecobalamin, isaxonine and the like.

The preparation examples and biological activities of compound (I) used in the present invention will be described in more detail in a series of Examples B and Examples, but the present invention is not limited thereto. The composition examples given below use one of the compounds described in the text or one of the other pharmaceutical compounds included in the general formula (I) as an active ingredient.

<Example> Example 1 2-isopropylamino-5,6-dihydro-
7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 100) 2-isopropylamino-4-hydroxypyrimidine-5-acetic acid ethyl ester 2.26 g (9.45 mmol) and phosphorus oxychloride 26.2 g was added and the mixture was heated under reflux for 3 hours. After the reaction mixture was concentrated under reduced pressure, chloroform and ice water were added,
Neutralized with sodium bicarbonate. The chloroform layer was separated, the solvent was distilled off, and the residue was purified by silica gel chromatography to give 1.80 g of 2-isopropylamino-4-chloropyrimidine-5-acetic acid ethyl ester (yield 74
%, Melting point: 67-71 ° C). 1.05 g (13.5 mmol) of a 40% methylamine methanol solution and 10 ml of ethanol were added thereto, and the mixture was reacted at 120 ° C. for 7 hours using an autoclave. To this was added water, extracted with chloroform, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 0.50 g (yield 35%) of the desired product.

Melting point: 120-123 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.28 (6H, d, J = 5 Hz), 3.20 (3H, s), 3.44 (2
H, s), 4.20 (1H, quint, J = 5Hz), 5.0 (1H, b
r.), 7.90 (1H, s) The following compounds were produced in the same manner.

Example 2 Ethyl 2-morpholino-4-diethylaminopyrimidine-5-acetic acid ester (Compound No. 404) Phosphorus oxychloride was added to 3.35 g (12.5 mmol) of 2-morpholino-4-hydroxypyrimidine-5-acetic acid ethyl ester.
1.7 ml was added and the mixture was heated under reflux for 4 hours. After the reaction mixture was concentrated under reduced pressure, methylene chloride and ice water were added, and the mixture was neutralized with sodium hydrogen carbonate. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 15 ml of ethanol and 7.0 g (95.7 mmol) of diethylamine were added thereto, and the mixture was reacted at 120 ° C. for 7 hours using an autoclave. Water was added thereto, extracted with methylene chloride, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 2.8 g of the desired product as an oil (yield 56%). ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.16 (6H, t, J = 7 Hz), 1.24 (3H, t, J = 7 Hz),
3.20 (4H, q, J = 7Hz), 3.44 (2H, s), 3.74 (8
H, s), 4.16 (2H, q, J = 7 Hz), 7.80 (1H, s) Example 3 2-butylaminocarbonylpiperazino-5,
6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 130) 2-piperazino-5,6-dihydro-7-methyl-6
Oxo (7H) pyrrolo [2,3-d] pyrimidine 0.5 g (2.14m
mol), 30 ml of THF, 1 ml of triethylamine and 0.43 g (4.34 mmol) of n-butyl isocyanate were added, and the mixture was stirred at room temperature for 3 hours. This was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain the desired product.
0.15 g (yield 21%) was obtained.

Melting point: 168-178 ° C. (decomposition) ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 0.95 (3H, t, J = 7 Hz), 1.45 (4H, m), 3.20 (3
H, s), 3.24 (2H, s), 3.50 (4H, m), 3.85 (4
H, m), 4.44 (1H, m), 7.92 (1H, s) Example 4 2-Diethylaminocarbonylpiperazino-
5,6-dihydro-7-methyl-oxo (7H) pyrrolo [2,3
-D] pyrimidine (Compound No. 132) 2-piperazino-5,6-dihydro-7-methyl-6-
Oxo (7H) pyrrolo [2,3-d] pyrimidine 0.6 g (2.6 mm
ol), 15 ml of pyrimidine and 0.35 g (2.6 mmol) of diethylaminocarbamoyl chloride were added and reacted at 70 ° C. for 2 hours. This was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 0.24 g (yield 28%) of the desired product.

Melting point: 84.5-86.0 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.16 (6H, t, J = 7 Hz), 3.22 (3H, s), 3.29 (8
H, m), 3.44 (2H, s), 3.84 (4H, m), 7.93 (1
H, s) Example 5 2-benzoylpiperazino-5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 504) 2-piperazino-5, 6-dihydro-7-methyl-6
Oxo (7H) pyrrolo [2,3-d] pyrimidine 1.0 g (4.3 mm
ol), 1 g of triethylamine, 50 ml of methylene chloride, and 0.6 g (4.3 mmol) of benzoyl chloride were added, and reacted at room temperature overnight. This was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.1 g (yield 76%) of the desired product.

Melting point: 158-160 ° C ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 3.19 (3H, s), 3.43 (2H, s), 3.80 (8H, m), 7.
43 (5H, m), 7.90 (1H, s) Example 6 2-Methylthio-5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 134) To 4.84 g (21.2 mmol) of 2-methylthio-4-hydroxypyrimidine-5-acetic acid ethyl ester was added phosphorus oxychloride 5
9.0 g was added, and the mixture was heated under reflux for 3 hours. After the reaction mixture was concentrated under reduced pressure, chloroform was added and the mixture was neutralized with an aqueous sodium hydrogen carbonate solution. The chloroform layer was concentrated under reduced pressure. To this were added 20 ml of ethanol and 3.48 g (44.9 mmol) of a 40% methanol solution of methylamine, and the mixture was reacted at 100 ° C. for 5 hours using an autoclave. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure, treated with activated carbon in ethanol, and recrystallized to obtain 1.50 g (yield 36%) of the desired product.

Melting point: 183 to 185 ° C (decomposition) ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 2.60 (s, 3H), 3.28 (s, 3H), 2.54 (s, 2H), 8.
14 (S, 1H) Example 7 2-isopropylamino-5,6-dihydro-
Hydrochloride of 7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 102) 2-Isopropylamino-5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [ 2,3-d] pyrimidine 0.4
9 g (2.4 mmol) was dissolved in 30 ml of toluene, and hydrogen chloride gas was blown therein. After concentrating this under reduced pressure, it was washed with hexane to obtain 0.53 g (yield 92%) of the desired product.

Melting point: 272-275 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.38 (6H, d, J = 5 Hz), 3.30 (3H, s), 3.60 (2
H, br.s), 4.30 (1H, br.), 7.90 (1H, br.), 8.90
(1H, br.).

The following compounds were produced in the same manner.

Example 8 2-isopropylamino-5,6-dihydro-
Maleic acid salt of 7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 104) 2-Isopropylamino-5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine 6.3
7 g (30.9 mmol) was dissolved in 50 ml of ethyl acetate,
3.58 g (30.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The obtained crystals were separated and 8.90 g of the desired product (yield 90
%)Obtained.

Melting point: 158-160 ° C. ¹ H-NHR spectrum (DMSO-d ⁶ solution, δ ppm): 1.24 (6 H, d, J = 6 Hz), 3.12 (3 H, s), 3.50 (2
H, s), 3.9-4.2 (1H, m), 6.20 (2H, s), 7.90
(1H, s) The following compounds were produced in the same manner.

Example 9 2- (4-pyridylpiperazino) -5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-
d] Pyrimidine p-toluenesulfonate (Compound No. 542) 2- (4-pyridylpiperazino) -5,6-dihydro-
0.18 g (0.6 mmol) of 7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine in chloroform-methanol 30
A 5 ml solution of chloroform-methanol in which 0.1 g (0.6 mmol) of p-toluenesulfonic acid was dissolved was added to the ml solution, and the mixture was stirred at room temperature for 1 hour. Thereafter, the solvent was distilled off under reduced pressure, and the precipitated crystals were washed with hexane to give the desired product in an amount of 0.25.
g (90% yield).

Melting point: 195-200 (decomposition), ¹ H-NMR spectrum (CDCl ₃ -CD ₃ OD solution, δ ppm): 2.37 (3H, s), 3.23 (3H, s), 3.49 (2H, s), 3.
7-4.2 (8H, m), 7.06 (2H, d, J = 7Hz), 7.20 (2
H, d, J = 7 Hz), 7.76 (2H, d, J = 7 Hz), 7.96 (1
H, s), 8.16 (2H, d, J = 7 Hz).

Example 10 2-isopropylamino-5-oxo-6
Methyl-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (Compound No. 202) 2.2 g (32 mmol) of isopropylamine, 5.18 g (37 mmol) of s-methylisothiourea sulfate, and 20 ml of water at room temperature For 24 hours. Thereafter, water was distilled off under reduced pressure, and ethyl 4-chloro-2-ethoxymethyleneacetoacetate was added to the residue.
8 g (35 mmol) and 30 ml of methanol were added, and 1.4 g of sodium hydroxide was added. After stirring for 2 hours, 27 g (348 mmol) of a 40% methylamine methanol solution was added dropwise. After completion of the dropwise addition, stirring was further continued for 2 hours, and the precipitated crystals were collected by filtration. The crystals were extracted with water and chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.8 g (yield 12%) of the desired product.

Melting point: 201-202 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.27 (6H, d, J = 7 Hz), 3.12 (3H, s), 4.20 (2
H, s), 4.27 (1H, m), 5.50 (1H, brs), 8.63 (1
H, s).

Example 11 2-morpholino-6-methyl-5-oxo-
5,6-Dihydro (7H) pyrrolo [3,4-d] pyrimidine (Compound No. 232) 4-chloromethyl-5-ethoxycarbonyl-2-methylthiopyrimidine 79 g (320 mmol) in methanol 300 ml
And dissolved in 50 g of a 40% methylamine methanol solution (6 g
40 mmol) was added dropwise over 15 minutes and stirred for 15 hours. The product is separated and dried to give 2-methylthio-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d].
11 g (18% yield) of pyrimidine were obtained. Next, 1.5 g (7.7 mmol) of the obtained product and 3.4 g (38.5 mmol) of morpholine were dissolved in 20 ml of n-amyl alcohol and heated under reflux for 7 hours. The reaction solution was cooled and the precipitated crystals were separated to obtain 0.75 g (yield 42%) of the desired product.

Melting point: 184-187 ° C (decomposition) ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 3.16 (3H, s), 3.85 (8H, m), 4.24 (2H, s), 8.
68 (1H, s) In the same manner, the following compound was produced.

Example 12 2-piperidino-4-aminopyrimidine-5
-Carboxylic acid methyl ester (Compound No. 400) To 2-5.6 g (23.6 mmol) of 2-piperidino-4-hydroxypyrimidine-5-carboxylic acid methyl ester were added 50 ml of ethylene dichloride and 10 ml of phosphorus oxychloride, and the mixture was heated under reflux for 5.5 hours. After the reaction mixture was concentrated under reduced pressure, chloroform and water were added, and the mixture was neutralized with sodium hydrogen carbonate. The chloroform layer was separated and the solvent was distilled off. Add 70ml THF, 2
27.8 g of 5% ammonia hydroxide was added, and the mixture was reacted at 70 ° C. for 1.5 hours using an autoclave. This is concentrated under reduced pressure,
Recrystallized from toluene / hexane to give 5.0 g of the desired product (yield
90%). ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.62 (6H, m), 3.82 (3H, s), 3.80 (4H, m), 8.
Example 13 N-methyl-2- (4-benzylpiperazino) -4,5-pyrimidinedicarboxylic acid imide (Compound No. 300) 2- (4-benzylpiperazino) -4, To 19.9 g (50 mmol) of diethyl 5-pyrimidinedicarboxylate, 8.4 g (150 mmol) of potassium hydroxide, 50 ml of ethanol and 10 ml of water were added.
The mixture was stirred at room temperature for 1 hour and at 40 ° C for 2 hours. Hydrochloric acid was added thereto to adjust the pH to 3, and the crystals formed were separated and washed with ethyl acetate. Dissolve 18.1 g of these crystals in 527 ml of methylene chloride,
21.3 g (211 mmol) of triethylamine and thionyl chloride
12.5 g (105 mmol) were added. After stirring for 1 hour at room temperature,
Cool to −78 ° C. and add 40% methylamine methanol solution 8.17
g (105 mmol) was added, and the mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained solid was washed with water. To 14.4 g of this solid, 3.32 g of sodium acetate (40.4 mmo
l) and 41.3 g (404 mmol) of acetic anhydride were added and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was stirred for 30 minutes. The obtained solid was purified by silica gel column chromatography to obtain 9.72 g (yield 56%) of the desired product.

Melting point: 158.5-159.8 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 2.56 (4H, t, J = 4 Hz), 3.18 (3H, s), 3.58 (2
H, s), 4.06 (4H, m), 7.36 (5H, s), 8.72 (1
H, s) Example 14 2-isopropylamino-5-oxo-6
Hydrochloride of methyl-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (Compound No. 204) 2-Isopropylamino-5-oxo-6-methyl-
5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 0.56
g (2.7 mmol) and 6 ml of chloroform in a solution of concentrated hydrochloric acid 0.2
7 g (2.7 mmol) was added and stirred for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, and the residue was washed with ether.
0.6 g (92% yield) was obtained.

Melting point: 178-183 ° C (decomposition) The following compounds were produced in the same manner.

Example 1B A tablet containing 10 mg of active ingredient is prepared as follows.

Per tablet Active ingredient 10mg Corn starch 55mg Crystalline cellulose 35mg Polyvinylpyrrolidone 5mg (as 10% aqueous solution) Carboxymethyl cellulose calcium 10mg Magnesium stearate 4mg Talc 1mg Total 120mg Active ingredient, starch and crystalline cellulose are thoroughly mixed through an 80 mesh sieve I do. The obtained powder is mixed with a polyvinylpyrrolidone solution, granulated, and passed through an 18-mesh sieve. The granules thus produced are dried at 50-60 ° C. and sized again with an 18 mesh sieve. The carboxymethylcellulose calcium and magnesium stearate and talc, previously sieved through a 80 mesh screen, are added to the granules and mixed, after which tablets are weighed 120 mg each with a tablet machine.

Example 2B A tablet containing 200 mg of active ingredient is prepared as follows.

Per tablet Active ingredient 200mg Corn starch 50mg Microcrystalline cellulose 42mg Soft anhydrous silicic acid 7mg Magnesium stearate 1mg Total 300mg The above ingredients are thoroughly mixed through 80 mesh sieve. The resulting powder is compression molded to produce tablets weighing 300 mg.

Example 3B A capsule containing 100 mg of active ingredient is prepared as follows.

Active ingredient per capsule 100mg Corn starch 40mg Lactose 5mg Magnesium stearate 5mg Total 150mg Combine the above ingredients, pass through 80 mesh sieve and mix thoroughly. The obtained powder is filled into capsules 150 mg at a time.

Example 4B A vial ready-to-use injection containing 5 mg of the active ingredient is prepared as follows.

 When using 5 mg of active ingredient per vial and 50 mg of mannitol, dissolve in 1 ml of distilled water for injection and use.

Example 5B An ampoule containing an active ingredient containing 50 mg is prepared as follows.

Active ingredient per ampoule 50 mg Sodium chloride 18 mg Distilled water for injection qs 2 ml Example 6B A sticky patch preparation containing 17.5 mg of active ingredient is prepared as follows.

Dissolve 10 parts of ammonium polyacrylate in 60 parts of water. On the other hand, 2 parts of glycerin diglycidyl ether are dissolved in 10 parts of water while heating. On the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water and 1 part of the active ingredient are stirred and dissolved. Then, while stirring the aqueous solution of ammonium polyacrylate, the aqueous solution of the drug-containing hydrogel containing the aqueous solution of glycerin diglycidyl ether and the aqueous solution of the active component of polyethylene glycol was mixed and added to a flexible plastic film. mg, and the surface was covered with release paper and cut into 35 square centimeters to give a preparation.

Example 7B An adhesive patch containing 10 mg of the active ingredient is prepared as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin,
150 parts of water, trialpoxypropyl isocyanurate 0.2
Parts, 100 parts of ethanol, 25 parts of isopropyl myristate
Parts, propylene glycol 25 parts and an active ingredient 15 parts to prepare a mixed aqueous sol solution. Next, this sol solution was applied to a nonwoven fabric surface of a composite film composed of a rayon nonwoven fabric and a polyethylene film to a thickness of 100 μm to form a drug-containing pressure-sensitive adhesive layer. The content of auxiliary release substances (isopropyl myristate and propylene glycol) contained in this layer is about 20
% By weight. Thereafter, crosslinking was carried out at 25 ° C. for 24 hours, a release film was adhered to the interface of the pressure-sensitive adhesive, and this was cut into 35 square centimeters to obtain a preparation.

The biological activity of the compounds of formula (I) on neural cells was tested in vitro. As neuronal cells, established mouse neuroblastoma neuro-2a strain (Dainippon Pharmaceutical) and NS
-20Y strain. The nerve cells were grown to a logarithmic growth phase in a 5% CO 2 incubator at 37 ° C., and then cultured with the compound of formula (I) for a certain period of time. As a result, the compound of the formula (I) was significantly different from the control culture with a significant difference, and also had a neuronal nervous system equivalent to or greater than that of the control drug isaxonine (compound described in JP-B-59-28548). It was revealed that it has cell growth promoting activity, neurite formation and neurite outgrowth promoting activity.

In addition to the above-described neuroblastoma cells, the biological activity of the compound of the formula (I) of the present invention against the rat adrenal medulla cell line PC-12 was tested. In the PC-12 cell line, neurites elongate by adding NGF. At this time, when the compound (I) of the present invention is added, binding of NGF to PC-12 cells and the intracellular conversion of NGF Uptake was shown to increase.

Furthermore, rabbit cervical ganglion cells (superior cervical gang)
When the effect of the compound (I) of the present invention on the binding of NGF to lion) was examined, it was found that the compound promotes NGF binding.

Next, a rat having a crushed sciatic nerve, which is a peripheral neuropathy model, was prepared and tested for the effects of the compounds of the present invention. The recovery of the distance between the toes and the muscle weight of the soleus muscle to normal values was examined. It was revealed that the compound (I) of the present invention has a promoting effect.

Furthermore, a central nervous system disorder model was prepared in rats, mice and the like, and the efficacy of the compound (I) of the present invention was tested. That is,
First, substantia nigra dopamine cells in rat brain were chemically destroyed by microinjection of 6-hydroxydopamine, resulting in motor impairment. Next, two weeks later, fetal brain dopamine cells were transplanted into the caudate nucleus on the disrupted side of the rat brain to improve dyskinesia. That is, from the day of transplantation, the compound (I) of the present invention
Was administered intraperitoneally for 2 weeks every day, and the effect on the improvement of movement disorder and the growth of transplanted cells was examined. It has been clarified that the compound (I) of the present invention has a promoting effect on improvement of dyskinesia and the like.

In addition, mice and rats, etc., which had neuropathy caused by mercury poisoning were prepared and tested for the activity of the compound (I) of the present invention. It was shown to have improvement and recovery effects.

Thus, it is apparent that the compound (I) of the present invention is useful as an agent for improving / treating various neurological diseases such as peripheral and central nervous disorders in mammals, or an agent for improving learning and memory. Was done.

As these nervous system diseases, various neuropathies can be exemplified. For example, various peripheral neuropathies with motility, sensory and / or objective reflex delays, including traumatic or inflammatory, radiculopathy of immunological origin, and alcohol and drug- Metabolic and idiopathic peripheral neuropathy such as diabetic and the like. The compound (I) of the present invention can also be applied to various cerebral disease disorders including central nervous system disorders. More specific examples of these diseases include facial palsy, sciatic palsy, spinal muscular atrophy, muscular dystrophy, myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, acute disseminated cerebrospinal cord Inflammation, Guillain-Barre syndrome, post-vaccination encephalitis,
Smon, dementia, Alzheimer's syndrome, skull injury prognosis,
Examples include, but are not limited to, cerebral ischemia, cerebral infarction or cerebral hemorrhage sequelae, and rheumatism. Further, a toxicity test of the compound of the present invention revealed that the compound was weak in toxicity and could be used as a safe drug.

Experimental Example 1 The effect of the compound according to the present invention on neuroblastoma cells was examined by the following method.

That is, Dulbecco's medium containing 10% fetal calf serum FCS
s Modified Eagle's Medium [DMEM, penicillin G sodium (100 unit / ml) and streptomycin sulfate (10
0 μg / ml) in mice in the logarithmic growth phase neuro-2
Set the cells of strain a to 1,000 cells / well,
Plated in a 48-well plate. Each well was cultured in 0.25 ml of the culture solution at 37 ° C. for 1 day in a carbon dioxide incubator containing 5% carbon dioxide in the air, and then changed to a medium containing each drug and FCS, and further cultured for 24 hours. Next, the same volume as the medium (0.25ml)
Of 4% glutaraldehyde was added and left at room temperature for 2 hours to fix the cells. After washing with water, a 0.05% methylene blue aqueous solution is added, the cells are stained, and neurite outgrowth cells (cells having one or more protrusions having a length twice or more the major axis of the cells) are visually counted under a microscope. And the ratio to the total cell number was determined. Five or more visual fields (2% or more of the total surface area of the well) were observed continuously from left to right, centering on the mark at the bottom of the center of the well, and 200 or more cells were counted. A maximum of six concentrations of one drug were taken, and three cases were carried out for one drug concentration, and the numerical values were expressed as mean ± SD. Table 1 shows the results.

In addition, as with mouse neuroblastoma cell NS-20Y,
The cells were similarly cultured on polyornithine-coated dishes, and the effect of each agent was examined. Table 24 shows the results after 24 hours and 48 hours of culture.
2 is shown.

EXPERIMENTAL EXAMPLE 2 Therapeutic effect on sciatic nerve crushed rats: Therapeutic effect of compound (118) of the present invention on sciatic nerve crushed rats in peripheral neuropathy model was determined by (1) behavioral change of crushed hindlimb and (2) muscle weight Were tested as indicators of peripheral nerve degeneration and regeneration processes.

For the experiment, male Wistar rats (6 weeks old) were grouped in 7 groups.
Used. The sciatic nerve crush was performed by the method of Yamazu et al. (Kiyomi Yamazu, Takeminori Kaneko, Masafumi Kitahara, Isao Ohkawa, Jpn Pharmacology, 72 , 259
268 (1976)) and the method of Hasegawa et al. (Kazuo Hasegawa, Naoji Mikuni, Yutaka Sakai, Journal of Pharmaceutical Sciences, 74 , 721-734 (197
8)). That is, under pentobarbital anesthesia (40 mg / kg, ip), the left sciatic nerve was exposed at the thigh, and the center of the tibial nerve and the peroneal nerve was 5 mm from the bifurcation. Crushed for minutes. After the operation, they were randomly assigned to each test group.

As a drug, the compound (118) of the present invention was selected and administered intraperitoneally once a day from the same day of crushing until the 22nd day. As a control group, a mecobalamin (Gedeon Richter Ltd.) administration group and a 0.9% physiological saline administration group were provided. Each measurement item is daily after crush (Days 1, 4, 7, 10, 14, 17, 21, and 23)
Was measured.

(1) Behavioral change of the hind limb on the crush side It is a good index showing the degeneration and regeneration of nerves from a functional aspect.
In addition, the inter-finger distance measurement, which has the advantage of being able to measure the variation over time, was performed.

Hasegawa's method (Hasegawa, K., Exper)
ientia, 34 , 750-751) (1978)), the distance between the first and fifth fingers of the hind limb was measured.

The ratio of the distance on the crush side to the distance on the normal side is calculated and expressed in%, and the average value and the standard error (SE) are shown in Table 3.

For the physiological saline administration group as a control, those in which the measured value of the test group had a significant difference by the Student's t-test are shown on the right shoulder of the numerical value, those with p <0.05 are marked with *, and those with p <0.01 Are marked with *** and those with p <0.001 are marked with ***.

The distance between fingers on the crushed side is about half of that on the normal side (50
%), And the state of downward tendency continued until the 10th day, and no difference was observed between the groups. On the 14th and 17th days, the recovery of each group administered with the drug progressed, but there was no significant difference from the saline group. On the 21st day, the specimen administration group and the mecobalamin administration group clearly tended to recover faster than the saline group,
There was also a significant difference compared to the raw diet group. The recovery progressed on the 23rd.

(2) Changes in muscle weight It is known that atrophy of muscles under its control is caused by denervation or nerve damage, and it is known that it gradually recovers by reinnervation of nerves. I chose. Twenty-three days after the operation, the soleus muscles of both hind limbs were excised under pentobarbital anesthesia and their weight was measured. The ratio of the weight of the crushed soleus muscle to the normal soleus muscle weight was determined and expressed as%. The average of the measured values of each group is the standard error (SE)
Are shown in Table 3.

Experimental Example 3 The effect of promoting dyskinesia due to rat brain cell damage on improvement by fetal brain cell transplantation.

The substantia nigra dopamine cells of female Wistar 4-week-old rats (body weight 100 g) were destroyed by microinjection of 6-hydroxydopamine. The ruptured rats showed a tendency to spontaneously rotate on the side opposite to the rupture side for several days, but thereafter apparently showed no behavioral abnormalities. Administration of methamphetamine (5 mg / kg, ip) to disrupted rats caused a rotational movement on the disrupted side.

Two weeks after drug destruction, a portion containing dopamine cells (the substantia nigra and the ventral tegmental portion) was cut out from the brain stem of the fetal rat brain on days 14 to 17 of the embryo, and after fine cutting, trypsin treatment, 37 ° C,
After incubating for 30 minutes, the tissue was suspended by pipetting. Then, the suspension was transplanted to the caudate nucleus on the disrupted side at a total of 10 μl (approximately 10 ⁵ cells) at two sites in 5 μl portions.

From the day of transplantation, the drug was administered at 100 mg / kg ip for two consecutive days. Rotational movements induced by methamphetamine administration were performed at 2 weeks, 1 week, 2 weeks and 4 weeks before transplantation and drug administration.
After a week, they were examined. The number of rotations was counted for the first minute six times every 10 minutes after the administration of methamphetamine, and the average number of rotations per minute was calculated in total.

 The results are summarized in Table 4.

Experimental example 4 Learning, memory improvement and recovery effects of mice induced by neurological disorders due to mercury poisoning.

Male BalbC 7-week-old mice were preliminarily placed in a T-maze three times a week in a safety area (safety area) from the starting point.
The maze was learned to run straight to a). Thereafter, methyl mercury chloride (hereinafter abbreviated as MMC) was added at 6 mg / k.
The mice were orally administered to g / day 8-week-old mice for 6 days. As a control group, a group of mice to which 0.1 ml / 10 g / day of saline was administered was provided. After the end of MMC administration, from the next day, to adjust the number of moles of Compounds 102 and 116 of the present invention, 69.5 mg / kg / day and 76.9 mg / kg / day, respectively.
It was administered intraperitoneally for 10 days a day. Day 6 of drug administration, ie, start of experiment
Maze learning was resumed in the T-type maze from day 12, and the running behavior of the mice was observed. The number of mice that were able to perform experiments in the T-maze on the 10th day (day 21 of the experiment) and the 11th day (22nd day) after resumption was used as the denominator. (The number of mice that reached the safety area within 5 seconds) was expressed as a numerator. The decrease in the number of cases on the way is MM
Due to death due to C poisoning. It also calculates the average value of the time required to travel to the safety area (seconds) ± standard error (SE),
Both are shown in Table 5. It was revealed that the compound (I) of the present invention has learning, memory improving and recovery effects in mice.

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

That is, as a group of animals, male ddy 5 week old mice and 5 male Wistar 8 week old rats were used as one group.
Compounds were dissolved in physiological saline and administered orally (PO) or intraperitoneally (ip), and toxicity was determined 24 hours after administration. The results are shown in Tables 6 and 7.

<Effect of the Invention> As described above, the compound of the general formula (I) of the present invention has a promoting effect on the proliferation of nervous cells and the formation and elongation of neurites. It has a regeneration effect, motor function recovery effect, learning and memory improvement recovery effect, and can be suitably used for improvement and treatment of nervous system patients such as peripheral neuropathy, central nervous system disorder and dementia. Also,
It is expected to be suitably used for recovery, improvement, and treatment of nervous system diseases caused by disorders of nervous tissues and cells involved in sensory / sensory functions and autonomic functions.

As shown in Experimental Examples 1 to 4 and Tables 1 to 5, the compound (I) of the present invention was found to have a biological activity equal to or higher than that of the control isoxanin and mecobalamin. The toxicity of the compound (I) of the present invention is generally weak as shown in Experimental Example 5 and Table 6. Thus, the compound (I) of the present invention is generally considered to be a highly safe drug having high activity and low toxicity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication C07D 487/04 140 C07D 487/04 140 (72) Inventor Akira Mizuchi 2141 Togo, Togo, Mobara City, Chiba Prefecture (72) Inventor Takuo Nakano 20-21, 2231 Kamigo-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture (72) Inventor Ikuo Tomino 1-2-7 Misono, Otake-shi, Hiroshima Prefecture 2-4-9, Waki (72) Inventor: Sanko Takei 5-1-2-2, Sozuka-cho, Iwakuni-shi, Yamaguchi Prefecture (72) Inventor: Hoji Kato 3-53-3, Waki, Waki-cho, Kuga-gun, Yamaguchi Prefecture ( 72) Inventor Keiichi Yokoyama 2-103-9 Missho, Iwakuni-shi, Yamaguchi Prefecture

Claims (5)

(57) [Claims] (1) The following formula (I) Here, X is (i) the following formula (I) -1 Here, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ² is a phenethyl group, a cyclohexyl group, a phenyl group, a benzyl group or a piperidyl group, or may be substituted with a piperidino group. A good lower alkyl group having 1 to 4 carbon atoms, wherein the piperidyl group may be substituted by a lower alkyl group having 1 to 4 carbon atoms, or R ¹ and R ² are taken together to form Together with the nitrogen atom to which Forming a heterocyclic group selected from the group consisting of: wherein R ³ is a cyclohexyl group, a 4-pyridyl group, a benzoyl group or a lower alkyl group having 1 to 4 carbon atoms, or substituted with a chlorine or lower alkoxyl group. Or an alkylaminocarbonyl group mono- or di-substituted by an alkyl group having 1 to 6 carbon atoms, wherein R ³¹ and R ³² are the same or different and each is a hydrogen atom or a lower An alkoxyl group, and the heterocyclic group is a phenyl group, a benzyl group, a phenylthio group, a CN group, a lower alkoxycarbonyl group or May be mono-substituted or may be mono- or penta-substituted by a lower alkyl group having 1 to 4 carbon atoms, and may be substituted by a polymethylene group having 3 to 5 carbon atoms on an adjacent ring member carbon. Or (ii) the following formula (I) -2-SR— ⁴ (I) -2, wherein R ⁴ is a lower group having 1 to ⁴ carbon atoms. Y is an amino group or a substituted amino group mono- or di-substituted by a lower alkyl group having 1 to 4 carbon atoms, and Z is a group having 2 carbon atoms. Or a lower alkoxycarbonyl group having 2 to 5 carbon atoms, or Y and Z are taken together to form a divalent group -YZ As- Here, R ⁵ is a lower alkyl group having 1 to 4 carbon atoms which may be substituted with a lower alkoxy group having 1 to 4 carbon atoms. Here, R ⁶ is a lower alkyl group having 1 to 4 carbon atoms, and is a group represented by the following formula. However, when X is a group represented by the formula (I) -2,
Y and Z are above A pyrimidine or a pharmaceutically acceptable salt thereof represented by the formula: 2. The method of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, maleate, fumarate, Succinate,
Claims selected from the group consisting of lactate, tartrate, benzoic acid, citrate, gluconate, sugar, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate and quaternary ammonium salts. Item 1. The compound according to Item 1. 3. The formula (I) Here, X is (i) the following formula (I) -1 Here, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ² is a phenethyl group, a cyclohexyl group, a phenyl group, a benzyl group or a piperidyl group, or may be substituted with a piperidino group. A good lower alkyl group having 1 to 4 carbon atoms, wherein the piperidyl group may be substituted by a lower alkyl group having 1 to 4 carbon atoms, or R ¹ and R ² are taken together to form Together with the nitrogen atom to which Forming a heterocyclic group selected from the group consisting of: wherein R ³ is a cyclohexyl group, a 4-pyridyl group, a benzoyl group or a lower alkyl group having 1 to 4 carbon atoms, or substituted with a chlorine or lower alkoxyl group. Or an alkylaminocarbonyl group mono- or di-substituted by an alkyl group having 1 to 6 carbon atoms, wherein R ³¹ and R ³² are the same or different and each is a hydrogen atom or a lower An alkoxyl group, and the heterocyclic group is a phenyl group, a benzyl group, a phenylthio group, a CN group, a lower alkoxycarbonyl group or May be mono-substituted or may be mono- or penta-substituted by a lower alkyl group having 1 to 4 carbon atoms, and may be substituted by a polymethylene group having 3 to 5 carbon atoms on an adjacent ring member carbon. Or (ii) the following formula (I) -2-SR— ⁴ (I) -2, wherein R ⁴ is a lower group having 1 to ⁴ carbon atoms. Y is an amino group or a substituted amino group mono- or di-substituted by a lower alkyl group having 1 to 4 carbon atoms, and Z is a group having 2 carbon atoms. Or a lower alkoxycarbonyl group having 2 to 5 carbon atoms, or Y and Z are taken together to form a divalent group -YZ As- Here, R ⁵ is a lower alkyl group having 1 to 4 carbon atoms. Here, R ⁶ is a lower alkyl group having 1 to 4 carbon atoms, a group represented by the formula: or a pyrimidine represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. Drugs for neurological disorders. 4. The method of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, maleate, fumarate, Succinate,
Claims selected from the group consisting of lactate, tartrate, benzoic acid, citrate, gluconate, sugar, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate and quaternary ammonium salts. Item 4. The therapeutic agent according to Item 3. 5. A method for producing a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, comprising: (a) the following formula (I) -A Here, the definitions of R ¹ , R ² and R ⁵ are the same as in the above formula (I). When producing a compound represented by the following formula (V): Wherein R ¹ and R ^{2 have} the same definitions as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms, and a compound represented by the following formula (VI): R ⁵ NH _2. (VI) wherein R ⁵ has the same definition as in the above formula (I), and is reacted with an amine represented by the formula: or (b) the following formula (I) -B Here, the definition of R ⁵ is the same as in the above formula (I), and R ³⁰ is a lower alkyl group having 1 to 4 carbon atoms, a benzoyl group or an alkyl group having 1 to 6 carbon atoms, which is mono- or di-. - in preparing the substituted alkyl amino group, a compound represented by the, (b ¹⁾ the following formula (IX) Here, the definition of R ⁵ is the same as that of the above formula (I), and a compound represented by the following formula (X): R ³³ -Q (X) wherein R ³³ has 1 to 4 carbon atoms. A lower alkyl group, a benzoyl group or a dialkylaminocarbonyl group di-substituted by an alkyl group having 1 to 6 carbon atoms;
Is a halogen atom, or (b ² ) a compound of the above formula (IX) and a compound of the following formula (XI) R ³⁴ -NCO (XI) where R ³⁴ is the number of carbon atoms (C) reacting with a compound represented by the following formula (I): Here, the definitions of R ¹ , R ² and R ⁶ are the same as in the above formula (I). When producing a compound represented by the following formula: (c ¹ ) Here, the definitions of R ¹ and R ² are the same as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms, and a compound represented by the following formula (XIII) R ₆ NH _2. ··· (XIII) wherein the definition of R ⁶ is the same as that of the above formula (I), or is reacted with a compound represented by the formula: or (c ² ) Here, the definition of R ⁶ is the same as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms, and a compound represented by the following formula (XV) Wherein the definition of R ¹ and R ² is the same as that of the above formula (I), or a reaction with a compound represented by the following formula; or (d) the following formula (I) -D Here, the definitions of R ¹ and R ² are the same as in the above formula (I), and R is an alkyl group having 1 to 4 carbon atoms. Here, the definitions of R ¹ , R ² and R are the same as described above. A compound represented by the following formula is reacted with ammonia, or (e) the following formula (I) -E Here, the definitions of R ¹ and R ² are the same as in the above (I), and R is each independently an alkyl group having 1 to 4 carbon atoms. A compound represented by V and the following formula (XVII) Wherein R is independently an alkyl group having 1 to 4 carbon atoms, and is reacted with a compound represented by the formula, and then, if necessary, with an acid.