JP2561689B2 - Neurological drug - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel therapeutic agent for neurological diseases of the peripheral nervous system and central nervous system of animals. More specifically, the specific 2-
The present invention relates to a novel therapeutic agent for neurological diseases containing a piperazinopyrimidine derivative or a pharmaceutically acceptable salt thereof.

BACKGROUND ART In the treatment of neurological diseases, that is, central nervous system diseases and peripheral nervous system diseases, research and application of therapeutic agents for the central nervous system have been vigorously carried out. At present, few therapeutic agents are put to practical use worldwide.

JP-A-52-34912 discloses a medicine effective for medical treatment caused by impaired nerve stimulation transmission in the central nervous system and peripheral nervous system, which comprises dispersing or dissolving ganglioside in a medium. There is. Only the ganglioside, which is a natural glycolipid disclosed in this publication (a product called clonassial Cronassial is on sale in Italy), and mecobalamin, a kind of vitamins, have been clinically applied to peripheral nervous system diseases. The effect is not always sufficient.

Japanese Patent Publication No. 59-28548 discloses the following formula 2-isopropylaminopyrimidine orthophosphate represented by and a therapeutic agent for peripheral nerve disease containing the same are disclosed. The compounds disclosed in the above publication (generic name Isaxonine phosphate, abbreviated as isaxonine, abbreviated as isaxonine hereinafter), as synthetic products, as far as the inventors know, are used for clinical research of peripheral neuropathy. The first compound (Lanouvelle Presse Medicale, Vol. 16, 1189-1280 (19
82)), but it does not seem to be commercially available at present, and no synthetic compound is known to be used for the treatment of peripheral neuropathy.

Factors that affect the growth and regeneration of nerves are known in the living body, and are called nerve growth factor (NGF) or neurotrophic factor. These factors are high molecular weight proteins, and there are still many technical problems to be solved for adaptation to neurological diseases.

JP-A-59-222424 discloses that a ganglioside mixture extracted from bovine brain or a single component in the ganglioside is involved in the growth of neural primary culture cells or neuroblastoma cells, neurite formation, and neurite outgrowth. It is disclosed to act proactively and to have a similar effect to mecobalamin in animal models of neuropathy. Furthermore, as described above, ganglioside is actually clinically used for the treatment of peripheral neuropathy and central neuropathy (different from psychosis).

However, ganglioside is a natural extract derived from different kinds of animals, and has a problem of antigenicity of its own or impurities, and it is difficult to set a standard as a uniform and stable substance in pharmaceuticals. There is also.

On the other hand, JP-A-59-144765 discloses the following formula (I) In the formula, one of P and Q is hydrogen, a hydroxyl group or a lower alkyl group, the other is hydrogen, and X is a group described below.

CO-R ₁ group (R ₁ is a lower alkyl group), (R ₂ is hydrogen, lower alkyl, phenyl, p-hydroxyphenyl, benzyl, p-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl or 3-indolylmethyl group, R ₃ is hydrogen; lower alkylcarbonyl;
Benzoyl; glycine, phenylglycine, alanine,
Valine, leucine, isoleucine, phenylalanine,
An acyl group derived from an amino acid selected from tyrosine, serine, threonine or tryptophan; or an acyl group derived from a dipeptide composed of two kinds of the above amino acids, or R ₂ and R ₃ both represent an ethylene group Form. ), AlK-COOY group (AIK is a linear or side chain alkylene group having 1 to 4 carbon atoms, Y is hydrogen or a lower alkyl group), AlK-CH ₂ OZ (AlK is the same as above, Z is hydrogen) , Lower alkyl, (lower alkoxy) -lower alkyl, lower alkylcarbonyl group), AlK-CO-W (AlK is the same as above, W
Is a lower alkyl group).

2- (1-Piperazinyl) pyrimidines having ## STR3 ## or pharmaceutically acceptable acid addition salts thereof are disclosed.

The publication describes that the compound of formula (I) or an acid addition salt thereof has dopaminergic psychotherapeutic activity.

JP 59-144,766 discloses a dicarboxylic acid and acid addition salt of 2- (1-piperazinyl) pyrimidine and a good psychoactive activity of this compound having a dopaminergic mechanism.
In particular, it is described to have antipsychotic activity, antidepressant activity and tranquilizing activity.

JP-A-59-155316 discloses the following formula Wherein R ¹ is hydrogen or a hydroxy group, R ² is hydrogen or an alkyl group having 1 to 6 carbon atoms, and a 2-piperazinopyrimidine or a pharmaceutically acceptable acid addition salt thereof represented by A drug having dopaminergic psychotropic activity as an active ingredient is disclosed.

Further, in International Publication WO85 / 00168, the following formula 2- (1-piperazinyl) pyrimidine.2 represented by
-It is disclosed that naphthalene sulfonate and this compound have a dopamine psychotropic effect.

However, in each of the above four publications, 2-
It has not been described or suggested that piperazinopyrimidines have the effect of regenerating nerve cells or can be applied to peripheral neuropathy, central neuropathy other than psychosis, and the like.

Therefore, an object of the present invention is to provide a novel therapeutic drug for neurological diseases.

Another object of the present invention is to provide a novel therapeutic agent for neurological diseases, which has an 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 disorders of peripheral nerves.

Still another object of the present invention is a neurotransmitter action system,
It is an object of the present invention to provide a novel therapeutic drug for neurological diseases applicable to disorders of the central nervous system different from psychosis which is considered to be primarily involved in abnormalities of metabolic system and the like.

That is, the neurological disease referred to in the present invention is a disorder of the central nervous system different from the psychosis which is considered to be primarily involved in disorders of peripheral nerves in mammals or abnormalities in the action system and metabolic system of neurotransmitters. It refers to disorders.

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

DISCLOSURE OF THE INVENTION According to the present invention, the above objects and advantages of the present invention can be achieved by Here, R ¹ is a hydrogen atom, an acyl group having 2 to 4 carbon atoms, or 2 to 2 carbon atoms.
5 is an alkoxycarbonyl group, an alkoxycarbonylmethyl group having 3 to 5 carbon atoms, a benzyl group, a 3,4-dimethoxybenzoyl group or a 3,4-methylenedioxybenzyl group; R ² is a hydrogen atom, an amino group or a carbon atom. A monoalkylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or 2 carbon atoms
R ³ is a hydrogen atom, an alkoxycarbonyl group having 2 to 4 carbon atoms, a dialkylaminocarbonyl group having 1 to 9 carbon atoms in each alkyl group, an alkoxy group having 1 to 5 carbon atoms, or A hydroxyethyl group; or R ² and R ³ together with the carbon atom to which they are attached, represent a 5-7 membered carbocycle or heterocycle in which the heteroatom is N, O or S. R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkylthio group having 1 to 4 carbon atoms, and a pyrimidine represented by: or a pharmaceutically acceptable salt thereof. The present invention is achieved by a therapeutic agent for a neurological disease, characterized in that

In the above formula (I), R ¹ is a hydrogen atom and has 2 to 4 carbon atoms.
An acyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms,
It is an alkoxycarbonylmethyl group having 3 to 5 carbon atoms, a benzyl group or a 3,4-methylenedioxybenzyl group.

Examples of the acyl group having 2 to 4 carbon atoms include acetyl, propionyl, butyroyl, isobutyroyl and the like.

Examples of the alkoxycarbonyl group having 2 to 5 carbon atoms include methoxycarbonyl and ethoxycarbonyl.

Examples of the alkoxycarbonylmethyl group having 3 to 5 carbon atoms include methoxycarbonylmethyl and ethoxycarbonylmethyl.

In the above formula (I), R ² is a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an alkoxycarbonyl group having 2 to 4 carbon atoms.

Examples of the monoalkylamino group having 1 to 4 carbon atoms include methylamino, ethylamino, propylamino, isopropylamino and sec-butylamino.

Examples of the alkoxy group having 1 to 5 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy and tert-butoxy.

As an alkoxycarbonyl group having 2 to 4 carbon atoms, R ¹
The same groups as described above for can be exemplified.

In the above formula (I), R ³ is a hydrogen atom and has 2 to 4 carbon atoms.
The number of carbon atoms of each alkoxycarbonyl group and each alkyl group is 1.
To a dialkylaminocarbonyl group having 1 to 9 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or a hydroxyethyl group.

As an alkoxycarbonyl group having 2 to 4 carbon atoms, R ¹
The same groups as described above for can be exemplified.

Examples of the dialkylaminocarbonyl group having 1 to 9 carbon atoms in each alkyl group include dimethylaminocarbonyl, diethylaminocarbonyl, diisopropylaminocarbonyl and dibutylaminocarbonyl.

As the alkoxy group having 1 to 5 carbon atoms, the same groups as described above for R ² can be exemplified.

Further, in the above formula (I), R ² and R ³ are, together with the carbon atom to which they are bonded, a 4- to 7-membered carbocycle or a heteroatom in which a heteroatom is N, O or S. A ring can be formed.

Examples of the group in which R ² and R ³ are taken together include (a), CH _{2 l1,} where l ₁ is a number of 2, 3 or 4. Wherein X is ═O or N—R ⁵ , R ⁵ is a hydroxyl group, a benzylsulfonyloxy group or a toluenesulfonyloxy group, and ₁₂ is a number of ₂ , 3 or 4. Here, R ⁶ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxyalkyl group in which an alkyl group having 2 to 4 carbon atoms is substituted with an alkoxy group having 1 to 4 carbon atoms, and R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and l ₃ is 2 and l ₄ is 0, or l ₃ is 0 and l ₄ is 1, Wherein R ⁹ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and l ₅ is a number of 2 or 3. Here, R ¹⁰ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an acyl group having 1 to 4 carbon atoms, or a carbamoylmethyl group, and l ₆ is a number of 1 or 2. Here, R ¹¹ is a hydrogen atom, a formyl group, or a carbon number of 1 to 4.
Is an alkyl group or a C7-C9 aralkyl group,
R ¹² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, a hydroxyalkyl group having 2 to 4 carbon atoms, and an alkyl group having 2 to 4 carbon atoms has 1 to 4 carbon atoms. An alkoxyalkyl group substituted with an alkoxy group, a benzyl group or a cycloalkyl group having 3 to 6 carbon atoms, Here, R ¹³ and R ¹⁴ are the same or different, each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and ₁₇ is a number of 0, 2 or 3, (h) -E-G-here in, E-G _{is, -OCH 2 CH 2 -, -} OC (CH 3) = CH
_{-, -CH 2 OCO -, -} OCOCH 2 -, - CH 2 C (CH 3) OCO-, -N (CH 3) CH 2 CH 2 -, - CH = CH-CH = CH-, -CH = C _{(OCH 3) -C (OCH 3} ) = CH-, or The group represented by is preferably exemplified.

Examples of the alkyl group having 1 to 4 carbon atoms of R ^{6 in} the above (C) include methyl, ethyl, propyl, isopropyl,
Butyl, sec-butyl, iso-butyl, tert-butyl and the like can be mentioned.

As the alkoxyalkyl group in which the alkyl group having 2 to 4 carbon atoms of R ⁶ is substituted with the alkoxy group having 1 to 4 carbon atoms,
For example, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, methoxybutyl and the like can be mentioned.

Examples of the alkyl group having 1 to 4 carbon atoms of R ⁷ and R ⁸ include R ⁶
The same thing as what was described about can be illustrated.

As the alkyl group having 1 to 4 carbon atoms for R ^{9 in} the above (d), the same ones as described for R ⁶ can be exemplified.

Examples of the alkyl group having 1 to ¹⁰ carbon atoms of R ^{10 in} the above (e) include methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, nonyl, decyl and the like.

Examples of the acyl group having 1 to 4 carbon atoms of R ¹⁰ include formyl, acetyl, propionyl, butyroyl and the like.

As the alkyl group having 1 to 4 carbon atoms for R ^{11 in} the above (f), the same ones as described for R ⁶ can be exemplified.

Further, as the aralkyl group having 7 to 9 carbon atoms for R ¹¹ ,
For example, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl, 3
-Phenylethyl and the like can be mentioned.

As the alkyl group having 1 to 4 carbon atoms for R ^12, the same ones as those described for R ⁶ can be exemplified.

Examples of the alkenyl group having 3 to 4 carbon atoms for R ¹² include allyl, 4-methylallyl, and 3-methylallyl.

Examples of the hydroxyalkyl group having 2 to 4 carbon atoms for R ¹² include 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxypropyl, 2-hydroxybutyl and the like.

As the alkoxyalkyl group in which the alkyl group having 2 to 4 carbon atoms of R ¹² is substituted with the alkoxy group having 1 to 4 carbon atoms, the same ones as described above for R ⁶ can be exemplified.

As the alkyl group having 1 to 4 carbon atoms for R ¹³ and R ^{14 in} the above (g), the same ones as exemplified for R ⁶ can be exemplified.

Furthermore, in the above formula (I), as the alkyl group having 1 to ⁴ carbon atoms for R ⁴ , the same groups as described above for R ⁶ can be exemplified.

Examples of the alkylthio group having 1 to ⁴ carbon atoms for R ⁴ include methylthio, ethylthio, propylthio, butylthio, isopropylthio, sec-butylthio and the like.

For the sake of convenience, specific examples of the compound represented by the above formula (I), which is the active ingredient of the therapeutic agent for neurological diseases of the present invention, include R ² and R ³
According to the definition of, it is divided into several groups and exemplified below.

A compound in which R ² and R ³ are not bonded, Maleates of (104) and (102) Maleates of (108) and (106) (112), (110) maleate Maleates of (116) and (114) (120), (118) Maleate Maleates of (124) and (122) (128), (126) Maleate (132), (130) Maleate Maleate of (136), (134) (140), (138) 2-naphthalene sulfonate mp 215 ~ 217 ℃ (144), (142) hydrochloride R ² and R ³ are combined to form a group CH _{2 l1 represented} by the following formula (I)
-A Here, the definitions of R ¹ , R ⁴ and l ₁ are the same as above.

A compound represented by mp107-113 ° C (202), (200) hydrochloride mp300 ° or more (206), (204) maleate mp165-167 ℃ R ² and R ³ combine, Is the following formula Wherein the definitions of R ¹ , R ⁴ , X and l ₂ are the same as those defined above, Hydrochloride of (302), (300) mp288-290 ℃ (decomposition) R ² and R ³ combine to form a group The following formula (I) -b is Wherein the definitions of R ¹ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , l ₃ and l ₄ are the same as above, wherein: (406), (404) Hydrochloride mp 300 ℃ or above (408), (404) Maleate mp179-182 ℃ (410), (404) Oxalate mp254-256 ℃ (412), (404) P-toluene sulfone vinegar mp224-2
55 ℃ (414), (404) citrate mp187 ~ 188 ℃ (416), (404) tartrate mp230 ~ 232 ℃ (decomposition) (418), (404) phosphate mp286 ~ 289 ℃ ( Decomposition) (420), (404) 2-naphthalene sulfonate mp282
~ 283 ℃ (decomposition) (424), (422) hydrochloride mp 300 ℃ or more (428), (426) Hydrochloride mp257-259 ℃ (430), (426) Maleate mp158-160 ℃ (434), (432) 2-naphthalene sulfonate mp74 ~
82 ° C (438), (436) 2-naphthalene sulfonate mp234
℃ ~ 239 (decomposition) (446), (444) maleate mp181-183 ℃ (450), (448) 2-naphthalene sulfonate mp211
~ 212 ° C Hydrochloride of (454), (452) (466), (464) Hydrochloride mp 300 ° or more (468), (464) Maleate mp181-183 ° C (decomposition) R ² and R ³ are bound to form a group. The following formula (I) -d is Here, the definitions of R ¹ , R ⁴ , R ⁹ and l ₅ are the same as above, and the compound represented by: (502), (500) hydrochloride R ² and R ³ combine to form a group The following formula (I) -e is Here, the definitions of R ¹ , R ⁴ , R ¹⁰ and l ₆ are the same as above, and the compound represented by: mp182-183 ℃ (602), (600) hydrochloride mp300 ℃ or higher (604), (600) maleate mp193-195 ℃ (606), (600) phosphate mp300 ℃ or higher (608), (600) naphthalene sulfonate mp 272 ~ 273
℃ (612), (610) Hydrochloride mp 245-250 ℃ (616), (614) Hydrochloride mp 300 ℃ or above (620), (618) Hydrochloride mp 300 ℃ or above Hydrochloride of (624), (622) mp250-255 ℃ (decomposition) Hydrochloride of (628), (626) mp275-280 ℃ (decomposition) (638), (636) maleate mp 151-152 ℃ (642), (640) Maleate mp202-203 ℃ (646), (644) maleate mp134-136 ℃ (650), (648) 2-naphthalene sulfonate mp260
~ 263 ℃ (decomposition) (654), (652) 2-naphthalene sulfonate mp276
~ 277 ℃ (decomposition) (670), (668) 2-naphthalene sulfonate mp180
~ 184 ° C (674), (672) 2-naphthalene sulfonate mp70 ~
77 ° C (678), (676) 2-naphthalene sulfonate mp236
~ 237 ℃ (decomposition) R ² and R ³ combine to form a group The following formula (I) -f Here, the definitions of R ¹ , R ⁴ , R ¹¹ and R ¹² are the same as above, and the compound represented by: (701), (700) hydrochloride, Hydrochloride of (707), (706) Hydrochloride of (710), (708) mp277-279 ℃ Hydrochloride of (713), (712) Hydrochloride of (715), (714) (744), (742) Hydrochloride mp 300 ℃ or above Hydrochlorides R ² and R ^{3 of} (748) and (746) combine to form a group The following formula (I) -g is Here, the definitions of R ¹ , R ⁴ , R ¹³ , R ¹⁴ and l ₇ are the same as above, and the compound represented by: (802), (800) hydrochloride The following formula (I), in which R ² and R ³ are combined to form a group EG
-H Wherein the definitions of R ¹ , R ⁴ and EG are the same as above, wherein: (902), (900) hydrochloride mp 294 ℃ (decomposition) (906), (904) Hydrochloride mp 300 ℃ or above (910), (908) maleate mp183-185 ℃ (914), (912) 2-naphthalene sulfonate mp160
~ 162 ° C Hydrochloride of (918), (916) mp274-276 ℃ (decomposition) (922), (920) p-toluenesulfonate mp214-2
18 ℃ (decomposition) (936), (934) Maleate Hydrochloride of (940), (938) The compound of the above formula (I) used as the active ingredient of the present invention can be prepared by a method known per se, especially JP-A-61-1405.
68, JP-A-61-87627 and JP-A-61-1040568, and the intermediates obtained by these methods are treated by a method known per se (for example, reductive removal of a protecting group). Can be manufactured. In Examples 1A to 48A described later, the production method of each compound is described in detail.

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 formulation containing a pharmaceutically acceptable carrier and a compound of 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.

Examples of the pharmaceutically acceptable salt of the compound (1) include, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acidic 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.

The composition of the present invention includes, for example, tablets, capsules, powders, granules, troches, cachets, elixirs, emulsions, solutions,
Syrups, suspensions, aerosols, ointments, sterile syringes, molded pups, tapes, soft and hard gelatin capsules,
It can be in the form of suppositories, pellets, lyophilized powders and microspheres lyophilized powders, aseptic packaging powders and the like. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline 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 may contain fillers, binders, lubricants, wetting agents, disintegrating agents, emulsifying and suspending agents, preservatives, sweetening agents 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, the compounds of formula (I) are mixed with carriers and diluents and made into tablets, capsules and the like.
For parenteral administration, the active ingredient is dissolved in 10% dextrose in water, isotonic saline, sterile water or a similar liquid and placed in vials or ampoules to be administered intravenously by infusion or injection or by intramuscular injection. It is sealed.
Advantageously, solubilizers, local anesthetics, preservatives and buffers can also be included in the medium. To increase stability, the composition can be lyophilized after injection into vials and ampoules. 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.

The composition comprises 0.1 to 2000 mg per unit dosage form,
More commonly it contains 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
To 100 mg / kg. The actual amount of the compound to be administered will be determined by the doctor depending on the compound to be administered and the age, weight, reaction of the individual patient, degree of symptom of the patient, administration route and the like. Therefore, the above dosage range does not limit the scope of the present invention. It is appropriate that the daily dosage is 1 to 6 times, 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 in combination with one or more other similar drugs, if necessary. Such additional agents include ganglios, mecobalamin, isaxonin and the like.

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

Examples Example 1A 2- (4-benzylpiperazino) -5,6-dihydro-6
-Oxofuro [2,3-d] pyrimidine (Compound No. 92
0): (1), 2- (4-benzylpiperazino) -4-hydroxypyrimidine-5-acetic acid ethyl ester (JP-A-61-1
Manufactured according to Reference Example 70 of No. 140568) 20g (56.1mmo
l), 7.5 g of 85% KOH tablets (114 mmol) and ethanol 320
The ml mixture was refluxed for 1 hour and the reaction mixture was concentrated to give a solid. Hydrochloric acid and saturated aqueous sodium hydrogen carbonate were added to adjust the pH to 4, and the mixture was concentrated again. The obtained crude crystals were recrystallized from water to obtain 2- (4-benzylpiperazino) -4-hydroxypyrimidine-5-acetic acid 17 g (yield 92%) as a colorless solid. ¹ H-NMR spectrum (CDCl ₃ -CD ₃ OD solution, δppm): 2.62 (4H, m), 3.36 (2H, s), 3.65 (6H, m), 7.
38 (5H, m), 7.60 (1H, s).

(2) 40 g of 3.28 g (10 mmol) of the compound obtained in (1) above
It was dissolved in 1 l of chloroform, 4.2 g (20 mmol) of trifluoroacetic anhydride was added to the resulting solution, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added for extraction. The purple solid obtained by drying and concentrating the organic layer was reslurried with ethyl acetate to obtain the title compound as colorless crystals (1.42 g, yield 46%).

Melting point: 164.5-166.5 ° C (decomposition), infrared absorption spectrum (CHCl ₃ solution, cm ^-1 ): 1821, 1631, 1559. ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.52 (4H, m), 3.58 (2H, s), 3.70 (2H, 2 s), 3.86 (4H, m), 7.36 (5H, m) , 8.12 (1H,
s).

Example 2A 2- (4-benzylpiperazino) -5,6-dihydro-6
-Oxofuro [2,3-d] pyrimidine p-toluenesulfonate (Compound No. 922): 0.16 g (0.5 mmol) of the compound (920) obtained in Example 1A.
To the solution was added 30 ml of ethyl acetate and heated to give a solution. A solution of 0.086 g (0.5 mmol) of p-toluenesulfonic acid in ethyl acetate (5 ml) was added to this solution, and the precipitated crystals were filtered to obtain 0.23 g (yield 96%) of crystals of the title compound.

Melting point: 214-218 ° C (decomposition) Example 3A 2- (4-benzylpiperazino) -5,6-dihydro-7
2-Methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine 2-naphthalenesulfonate (Compound No. 43
4): 2- (4-benzylpiperazino) -5,6-dihydro-
1.29 g (4.0 mmol) of 7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (prepared according to Reference Example 54 of JP-A-61-140568) was dissolved in 200 ml of ethanol,
2-Naphthalenesulfonic acid 0.83 g (4.0 mm
ol) in ethanol (20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture is concentrated to give the title compound as a colorless solid.
2.1 g was obtained.

Melting point: 74-82 ° C, ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 3.12 (3H, s), 3.35 (8H, m), 3.52 (2H, s), 4.
32 (2H, bs), 7.52 (5H, m), 7.5-8.3 (8H, m).

Example 4A 2- (4-Acetylpiperazino) -5,6-dihydro-7
-Methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 440): 2-piperazino-5,6-dihydro-7-methyl-6-
Oxo (7H) pyrrolo [2,3-d) pyrimidine
Manufactured according to Reference Example 55 of −140568) 1.44 g (6.18 m
mol), 1.01 g of triethylamine and chloroform (20
1.02 g (10.0 mmol) of acetic anhydride was added dropwise to the solution consisting of (ml) and the mixture was stirred at room temperature for 15 minutes. Ethyl acetate was added to the solid product obtained by concentrating the reaction mixture, and the mixture was reslurried at 50 ° C. After allowing to cool, 1.02 g of the title compound (yield 60
%) As crude crystals. This crystal was recrystallized with chloroform / ethyl acetate = 1/10 to obtain a pure product.

Melting point: 194-195 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.16 (3H, s), 3.20 (3H, s), 3.43 (2H, 2 s), 3.5-4.0 (8H, m), 7.92 (1H, s).

Example 5A 5,6-Dihydro-7-methyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine phosphate (Compound No. 418) 5,6-dihydro-7-methyl -6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine
Manufactured according to Reference Example 55 of −140568) 1.4 g (6.0 mmo
To a solution of l) in ethanol (40 ml) was added a solution of 0.6 g of phosphoric acid in ethanol (10 ml). The precipitated crystals were collected to obtain 1.5 g of the desired product (yield 76%).

Mp: 286~289 ℃ (decomposition), ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 3.0 (4H, m), 3.09 (3H, s), 3.49 (2H, s), 3.9
0 (4H, m), 7.99 (1H, s).

 Similarly, the following compounds were produced.

Example 6A 2- (4-Benzylpiperazino) -6- (1-methylpropyl) -5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (Compound No. 656) 2 3.0 g (8 mmol) of-(4-benzylpiperazino) -4-chloromethylpyrimidine-5-ethyl acetate (prepared according to Reference Example 41 of JP-A-61-140568) was dissolved in 30 ml of n-butanol to prepare 1 -Methylpropylamine 5.9 g (80
mmol) was added. The mixture was stirred at 60 ° C for 3 hours and at 130 ° C for 4 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate and water. After separating the aqueous layer, the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous MgSO ₄ , ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.7 g of the desired product (yield 23
%) Was obtained.

Melting point: 131-134 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 0.88 (3H, t, J = 7Hz), 1.24 (3H, d, J = 7Hz),
1.52 (2H, m), 2.52 (4H, m), 3.58 (2H, s), 3.
96 (4H, m), 4.12 (2H, s), 4.30 (1H, m), 7.36
(5H, m), 8.68 (1H, s).

 Similarly, the following compounds were produced.

Example 7A 2- (4-benzylpiperazino) -6-acetyl-5-
Oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (Compound No. 664) 2- (4-benzylpiperazino) -5-oxo-5,6
-Dihydro (7H) pyrrolo [3,4-d] pyrimidine (prepared according to Reference Example 42 of JP-A-61-140568) 2.0 g (6.
5 mmol) and 60 ml of tetrahydrofuran, 60% NaH
0.3 g (7.5 mmol) was added at 20 ° C. and the mixture was stirred for 10 minutes. Thereafter, 2 ml of acetyl bromide was added and the mixture was stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with CH ₂ Cl ₂ and the solvent was evaporated. The residue was subjected to silica gel column chromatography (CH ₂ Cl ₂ : MeO
H = 95: 5) to obtain 1.0 g of the desired product (yield 44%).

Melting point 176-178 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.54 (4H, m), 2.65 (3H, s), 3.58 (2H, s), 4.
02 (4H, m), 4.60 (2H, s), 7.36 (5H, m), 8.74
(1H, s).

Example 8A 2- (4-Benzylpiperazino) -6-carbomoylmethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-
d] pyrimidine (Compound No. 666) 2- (4-benzylpiperazino) -6-ethoxycarbonylmethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 1.0 g (2.5 mmol, the compound 662 of Example 6A), 28% aqueous ammonia (3.6 g, 59 mmol) and ethanol (4 ml) were added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, water and CH ₂ Cl ₂ were added for extraction. After separating the aqueous layer, the CH ₂ Cl ₂ layer was dried over anhydrous MgSO ₄ . CH ₂ Cl ₂ was distilled off under reduced pressure, and the residue was washed with ethyl acetate to give 0.5 g of the desired product (yield
57%).

Melting point: 229 to 232 ° C (decomposition), ¹ H-NMR spectrum (CDCl ₃ -DMSO-d ₆ solution, δppm): 2.52 (4H, m), 3.58 (2H, s), 3.96 (4H, m), 4 .
22 (2H, s), 4.39 (2H, s), 7.36 (5H, m) 8.65
(1H, s).

Example 9A 6-Acetyl-2-piperazino-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (Compound No. 648) 6-acetyl-2- (4-benzylpiperazino) ) -5
0.8 g of -oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (2.4 mmol, compound 664 of Example 7A), 10% Pd
A mixture of 0.2 g of C / C and 40 ml of ethanol was stirred under a hydrogen atmosphere at 70 ° C. for 4 hours. After completion of the reaction, Pd / C was separated and ethanol was distilled off under reduced pressure to obtain 0.56 g of the desired product (yield 90%).

Melting point: 164-167 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.66 (3H, s), 2.96 (4H, m), 3.98 (4H, m), 4,
62 (2H, s), 8.75 (1H, s).

 The following compounds were produced in the same manner.

Example 10A 6-Acetyl-2-piperazino-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine naphthalene-2-sulfonate (Compound No. 650) 6-acetyl-2 -Piperazino-5-oxo-5,6-
Dihydro (7H) pyrrolo [3,4-d] pyrimidine 0.20 g (0.
77 mmol of a compound 648) of Example 9A) in 20% methylene chloride in ethanol (25 ml) was added with naphthalene-2-sulfonic acid 1
A solution of 0.17 g of the hydrate in ethanol (10 ml) was added. The precipitated crystals were separated to obtain 0.24 g of the desired product (yield 67%).

Melting point: 260-263 ° C (decomposition), ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 2.68 (3H, s), 3.42 (4H, m), 4.26 (4H, m), 4.
78 (2H, s), 7.6 to 8.3 (7H), 9.03 (1H, s).

 Similarly, the following compounds were produced.

Example 11A 2- (4-benzylpiperazino) -5,6-dihydro-5.7
-Dimethyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 456) (1), 1-amidino-4-benzylpiperazine sulfate
2.67 g (10 mmol), tert-C ₄ H ₉ OK1.12 g (10 mmol), tert
-C ₄ H ₉ mixture of 2-formyl-3-methyl succinate ethyl OH12ml [Zhur.Obshchei Khim., 30, 2250 (196
0)] 2.16 g (10 mmol) in tert-C ₄ H ₉ OH (3 ml) was added and then refluxed for 6 hours. After cooling, water and CHCl ₃ were added for extraction, the CHCl ₃ layer was dried over anhydrous HgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : CH ₃ OH = 95: 5) to give 2- (4-benzylpiperazino) -5- (1-ethoxycarbonylethyl) -4-hydroxypyrimidine 0.68. g (yield 23%) was obtained.

Melting point: 145-148 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.17 (3H, t, J = 7Hz), 1.39 (3H, d, 7Hz), 2.56
(4H, m), 3.56 (3H, m), 3.74 (4H, m), 4.04
(2H, q, J = 7Hz), 7.35 (5H, m), 7.68 (1H,
s).

(2), 4.6 g of the compound obtained in the same manner as in (1) above
A solution of (12.4 mmol) and 35 g of phosphorus oxychloride was refluxed for 2 hours. The reaction solution was poured into water, extracted with ether, the ether layer was dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure to 2
3.2 g of-(4-benzylpiperazino) -5- (1-ethoxycarbonylethyl) -4-chloropyrimidine (yield 67
%) As an oil. ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.24 (3H, t, J = 7Hz), 1.48 (3H, d, 7Hz), 2.50
(4H, m), 3.56 (2H, s), 3.82 (5H, m), 4.16
(2H, q, J = 7Hz), 7.34 (5H, m), 8.18 (1H,
s).

(3) 3.2 g (8.2 mmol) 4 of the compound obtained in (2) above
A mixture of 1.3 g (16.5 mmol) of 0% CH ₃ NH ₂ methanol solution and 7 ml of ethanol was placed in a pressure vessel and heated at 120 ° C. for 6 hours. Then, the solvent was removed under reduced pressure, water was added, and the organic layer extracted with chloroform was dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 2.1 g of the desired product (yield 75
%) Was obtained.

Melting point 142-146 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.44 (3H, d, J = 7Hz), 2.52 (4H, m), 3.19 (3
H, s), 3.41 (1H, q, J = 7Hz), 3.57 (2H, s),
3.87 (4H, m), 7.35 (5H, m), 7.90 (1H, s).

Example 12A 5,6-Dihydro-5,7-dimethyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 444) 2- (4-benzylpiperazino)- 5,6-dihydro-
1.9 g (5.6 mmol, compound 456 of Example 11A) of 5,7-dimethyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine and 10
Dissolve 0.2 g of Pd-C in 70 ml of ethanol.
The mixture was stirred at 0 ° C for 4 hours. After completion of the reaction, Pd-C was separated and ethanol was distilled off under reduced pressure to obtain 1.26 g of the desired product (yield 91%).

Melting point: 167.2 to 169.2 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.44 (3H, d, J = 7Hz), 2.94 (4H, m), 3.22 (3
H, s), 3.42 (1H, q, J = 7Hz), 3.82 (4H, m),
7.92 (1H, s).

Example 13A 5,6-Dihydro-5,7-dimethyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine maleate (Compound No. 446) 5,6-dihydro-5 0.27 g of 1,7-dimethyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine (1.
To a solution prepared by dissolving 2 mmol of the compound 444) of Example 12A in 20 ml of ethanol, a solution of 0.14 g (1.2 mmol) of maleic acid in ethanol (6 ml) was added. Target crystals
0.26 g (59% yield) was obtained.

Melting point: 181-183 ° C, ¹ H-NMR spectrum (DMSO_d ₆ solution, δppm): 1.34 (3H, d, J = 7Hz), 3.10 (3H, s), 3.20 (4
H, m), 3.55 (1H, d, J = 7Hz), 3.96 (4H, m),
6.05 (2H, s), 8.10 (1H, s).

Example 14A 2- (4-benzylpiperazino) -5,6-dihydro-6
-Oxo-5,5,7-trimethyl (7H) pyrrolo [2,3-d]
Pyrimidine (Compound No. 458) 2- (4-benzylpiperazino) -5,6-dihydro-
4.0 g (12.4 mmol) of 7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (prepared according to Reference Example 54 of JP-A-61-140568) was dissolved in 200 ml of tetrahydrofuran, % NaH (2.5 g, 62.5 mmol) was added at 20 ° C. and the mixture was stirred for 10 minutes. Then, 4 ml of methyl iodide was added and stirred for 1 hour. The reaction solution was poured into water, extracted with CH ₂ Cl ₂ , and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 1.3 g of the desired product (yield 30%).

Melting point: 76-79 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.36 (6H, s), 2.50 (4H, m), 3.19 (3H, s), 3.
54 (2H, s), 3.86 (4H, m), 7.34 (5H, m), 7.88
(1H, s).

Compound 682 was similarly converted to 2- (4-benzylpiperazino) using ethyl bromoacetate instead of methyl iodide.
2-5 instead of -5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine and methyl iodide
-(4-Benzylpyrazino))-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine (JP-A-61)
Compound 1404 was prepared in the same manner using 2- (4-benzylpiperazino) -5,6-dihydro-6-methyl-5-).
Oxo (7H) pyrrolo [3,4-d] pyrimidine
Compound 680 was synthesized in the same manner using (produced according to Reference Example 44 of -140568).

Example 15A 5,6-Dihydro-6-oxo-2-piperazino-5,5,7-
Trimethyl (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 448) 2- (4-benzylpiperazino) -5,6-dihydro-
6-oxo-5,5,7-trimethyl (7H) pyrrolo [2,3-
d] Pyrimidine 1,1 g (3.1 mmol, compound 45 of Example 14A)
8), a mixture of 10% Pd-C 0.1 g and ethanol 40 ml was stirred under a hydrogen atmosphere at 70 ° C. for 4 hours. After allowing to cool, separate Pd-C,
Ethanol was distilled off under reduced pressure to obtain 0.76 g of the desired product (yield 94%).
%) Was obtained.

Melting point: 113-116 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.38 (6H, s), 2.94 (4H, m), 3.22 (3H, s), 3,
83 (4H, m), 7.90 (1H, s).

2- (4-benzylpiperazino) -5,6-dihydro-
6-oxo-5,5,7-trimethyl (7H) pyrrolo [2,3-
d] Compound 6 prepared in Example 14A instead of pyrimidine
The following compounds were similarly prepared using 82, 684, and 680.

Example 16A 5,6-Dihydro-6-oxo-2-piperazino-5,5,7-
Naphthalene-2-sulfonate of trimethyl (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 450) 5,6-dihydro-6-oxo-2-piperazino-5,5,7
-Trimethyl (7H) pyrrolo [2,3-d] pyrimidine 0.20g
(0.77 mmol, compound 448 of Example 15A) in ethanol (10
ml) solution, naphthalene-2-sulfonic acid monohydrate 0.17
A solution of g (0.77 mmol) in ethanol (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was washed with ether to obtain 0.2 g of the desired product (yield 81%).

Melting point: 211-212 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.36 (6H, s), 3.15 (3H, s), 3.36 (4H, m), 4.
15 (4H, m), 7.55 (2H, m), 7.90 (5H, m), 8.44
(1H, s).

5,6-dihydro-6-oxo-2-piperazino-5,5,7
The following compounds were similarly prepared using the compounds 672, 676, 668 prepared in Example 15A instead of -trimethyl (7H) pyrrolo [2,3-d] pyrimidine.

Example 17A 5,6-Dihydro-7-methyl-2 [4- (3,4-methylenedioxyphenylmethyl) piperazino] -6-oxo (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 436 ) Piperonyl alcohol 2.5g (16.4mmol), SOCl ₃ 2,3g
A solution of (19.3 mmol) and 100 ml of CH ₂ Cl ₂ was stirred for 1 hour.
Then 5,6-dihydro-7-methyl-6-oxo-2-
3.8 g (1) of piperazino (7H) pyrrolo [2,3-d] pyrimidine (prepared according to Reference Example 55 of JP-A-61-140568)
6.3 mmol) and 2.5 g of triethylamine were added, and the mixture was stirred for 30 minutes and then refluxed for 2 hours. The reaction solution was poured into water, extracted with CH ₂ Cl ₂ , and dried over anhydrous MgSO ₄ . The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain 0.5 g of the desired product (yield 8%).

Melting point: 122 to 124 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 2.47 (4H, m), 3.14 (3H, s), 3.25 (2H, s), 3.
43 (2H, s), 3.82 (4H, m), 5.91 (2H, s), 6.74
(2H, s), 6.87 (1H, s), 7.86 (1H, s).

Example 18A 5,6-Dihydro-7-methyl-2 [4- (3,4-methylenedioxyphenylmethyl) piperazino] -6-oxo (7H) pyrrolo [2,3-d] pyrimidine naphthalene-2
-Sulfonate (Compound No. 438) 5,6-dihydro-7-methyl-2 [4- (3,4-methylenedioxyphenylmethyl) piperazino] -6-oxo (7H) pyrrolo [2,3-d ] Pyrimidine 1.0 g (2.7 mmol, compound 436 of Example 17A), naphthalene-2-sulfonic acid 1
Hydrate 0.6 g (2.7 mmol), CH ₂ Cl ₂ 50 ml, ethanol 50 ml
The solution of was stirred at room temperature for 1 hour. After that, the solvent was distilled off under reduced pressure, and the residue was washed with ethanol to obtain 1.4 g of the desired product (yield 90%).
%) Was obtained.

Melting point: 234 to 239 ° C (decomposition), ¹ H-NMR spectrum (DMSO_d ₆ _CDCl ₃ solution, δppm): 3.12 (3H, s), 3.36 (8H, m), 3.48 (2H, s), 4.
32 (2H, s), 6.05 (2H, s), 6.95 (2H, m), 7.12
(1H, s), 7.52 (2H, m), 7.90 (5H, m), 8.25
(1H, s).

Example 19A 2- (4-Ethoxycarbonylpiperazino) -5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-
d] Pyrimidine (Compound No. 442) 2- (4-benzylpiperazino) -5,6-dihydro-
2.0 g (6.2 mmol) of 7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine (prepared according to Reference Example 54 of JP-A-61-140568), 0.3 g of 60% NaH (6.8 mmol) ), Tetrahydrofuran 60 ml, ethyl chloroformate 2.0 g
(18.4 mmol) was added and stirred for 2 hours. The post-wash solution was poured into water and extracted with CH ₂ Cl ₂ . The organic layer was dried over anhydrous MgSO ₄ , the solvent was evaporated, and the residue was purified by silica gel column chromatography to obtain 0.5 g of the desired product (yield 26%).

Melting point: 170-171 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.30 (3H, t, J = 7Hz), 3.23 (3H, s), 3.45 (2
H, s), 3.56 (4H, m), 3.84 (4H, m), 4.20 (2
H, q, J = 7 Hz), 7.94 (1H, s).

Example 20A 2- (4-benzylpiperazino) -5,6-dihydro-7- (2-methoxyethyl) -6-oxo (7
H) Pyrrolo [2,3-d] pyrimidine (Compound No. 460) 2- (4-benzylpiperazino) -4-chloropyrimidine-5-ethyl acetate 30.0 g (0.08 mol, JP-A-61-1405)
No. 68 Reference Example 71), ethanol 200m
12.02 g (0.16 mol) of methoxyethylamine was added and the mixture was heated in an autoclave at 150 ° C. for 7 hours. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 19.1 g of the title compound (yield 65%) ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.51 (4H, m ), 3.38 (3H, s), 3.44 (2H, s), 3.57 (2
H, s), 3.82 (8H, m), 7.36 (5H, s), 7.92 (1H, s).

Example 21A 5,6-Dihydro-7- (2-methoxyethyl) -6-oxo-2-piperazino (7H) pyrrolo [2,3
-D] pyrimidine (Compound No. 426) 2- (4-benzylpiperazino) -5,6-dihydro-
13.0 g (35.4 mmol, compound 460 of Example 20A) of 7- (2-methoxyethyl) -6-oxo (7H) pyrrolo [2,3-d] pyrimidine was dissolved in 180 mol of ethanol to give 10% palladium-carbon. Hydrogenation was carried out in the presence of 1.3 g at atmospheric pressure of 70 ° C. for 1.5 hours. After passing through the catalyst, ethanol was distilled off under reduced pressure to obtain 9.82 g of the title compound (yield-100%). ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.92 (4H, m), 3.38 (3H, s), 3.44 (2H, s), 3.80 (8
H, m), 7.92 (1H, s).

Example 22A 5,6-Dihydro-7- (2-methoxyethyl) -6-oxo-2-piperazino (7H) pyrrolo [2,3
-D] Pyrimidine maleate (Compound No. 430) 5,6-dihydro-7- (2-methoxyethyl) -6-
Oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine 3.0 g (11 mmol, compound 426 of Example 21A) in ethanol (100 ml) was added to maleic acid 1.3 g (11 mmol) in ethanol (30 ml). Was added and stirred for 1 hour. The precipitated crystals were collected to obtain 3.3 g of the desired product (yield 76%).

Melting point: 158-160 ° C. ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 3.2 to 3.8 (13H), 3.95 (4H, m), 6.06 (2H, s), 8.06
(1H, s).

Example 23A 2- (4-benzylpiperazino) -5,7-dihydro-5-oxofuro [3,4-d] pyrimidine (Compound No. 924) (1) .2- (4-benzylpiperazino) -4-Chloromethylpyrimidine-5-carboxylic acid ethyl ester 5.0 g
(13.3 mmol, produced according to JP-A-61-140568 Reference Example 41), ethanol 80 ml, 85% potassium hydroxide 2.64 g (4
0.0 mmol) was added and the mixture was refluxed for 30 minutes. Ethanol was concentrated under reduced pressure, water was added to dissolve the residue, and the pH was adjusted to about 4 with concentrated hydrochloric acid. The formed crystals were filtered and washed with acetone to obtain 1.93 g of 2- (4-benzylpiperazino) -4-hydroxymethylpyrimidine-5-carboxylic acid as crystals (yield 44%).

Mp: 252~253 ℃ (decomposition) ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 3.16 (4H, m), 4.00 (6H, m), 4.80 (2H, s), 7.54 (5
H, m), 8.79 (1H, s).

(2). The carboxylic acid obtained in (1) above 0.40 g (1.22 mmo
To l), 50 ml of benzene, 0.15 g (1.48 mmol) of acetic anhydride and 0.12 g (1.46 mmol) of sodium acetate were added, and the mixture was refluxed for 10.5 hours. A 10% aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain 0.15 g of the title compound (yield 40%). ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.54 (4H, m), 3.58 (2H, s), 4.00 (4H, m), 5.04 (2
H, s), 7.36 (5H, s), 8.75 (1H, s).

Example 24A 5,7-Dihydro-5-oxo-2-piperazinofuro [3,4-d] pyrimidine (Compound No. 908) 2- (4-benzylpiperazino) -5,7-dihydro-
1.5 g of 5-oxofuro [3,4-d] pyrimidine (4.8 mmol,
A mixture of the compound 924) of Example 23A, 0.2 g of 10% Pd-C, and 60 ml of ethanol was stirred at 70 ° C for 4 hours under a hydrogen atmosphere.
After completion of the reaction, Pd-C was separated and ethanol was distilled off under reduced pressure to obtain 1.0 g of the desired product (yield 94%).

Melting point: 159 to 160 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.05 (1H, s), 2.95 (4H, m), 3.97 (4H, m), 5.03 (2
H, s), 8.74 (1H, s).

Example 25A 5,7-Dihydro-5-oxo-2-piperazinofuro [3,4-d] pyrimidine maleate (Compound No. 910) 5,7-dihydro-5-oxo-2-piperazinofuro [3,4 -D] pyrimidine 0.22 g (1.0 mmol, compound 908 of Example 24A) in ethanol (30 ml) was added with maleic acid 0.1.
A solution of 2 g (1.0 mmol) of ethanol (15 ml) was added, and the mixture was stirred at room temperature for 1 hour. Remove the precipitated crystals to obtain the desired product
0.20 g (yield 60%) was obtained. Melting point: 183-185 ° C., ¹ H-NMR spectrum (DMSO-d ₆ solution, δ ppm): 3.28 (4H, m), 4.12 (4H, m), 5.25 (2H, s), 6.03 (2
H, s), 8.92 (1H, s).

Example 26A 2- (4-benzylpiperazino) -6,7-dihydro (5H) cyclopentapyrimidine (Compound No. 20
8) 32.43 g (0.121 mol) of 1-amidino-4-benzylpiperazine sulfate was added to a solution of 6.55 g (0.121 mol) of sodium methoxide in ethanol (500 ml), and 2-hydroxymethylenecyclopenta was added to the obtained suspension. Non 13.6g [0.1
21 mol, WT Caldwell et al., J. Am. Chem. Soc., 63 , 2188
Synthesis by the method described in (1941)] in ethanol (90 ml) was added dropwise over 1 hour. After the dropwise addition, the mixture was refluxed for 8 hours, ethanol was distilled off, then concentrated and purified by silica gel column chromatography to obtain 2.18 g of the title compound (yield 6%).

Melting point: 90 to 95 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.04 (2H, quinter, J = 7Hz), 2.52 (4H, m), 2.78 (2H,
t, J = 7Hz), 2.81 (2H, t, J = 7Hz), 3.56 (2H, s), 3.8
3 (4H, m), 7.35 (5H, s), 8.12 (1H, s).

Example 27A 6,7-Dihydro-2-piperazino (5H) cyclopentapyrimidine (Compound No. 200) 2- (4-benzylpiperazino) -6,7-dihydro (5
H) cyclopentapyrimidine 2.0 g (6.79 mmol, Example 26A
Compound 208) was dissolved in 40 ml of ethanol and hydrogenated in the presence of 0.20 g of 10% palladium-carbon at normal pressure of 70 ° C. Four
After a lapse of time, the catalyst was passed and ethanol was distilled off to obtain 1.38 g of the title compound as crystals (yield 99%).

Melting point: 107-113 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.05 (2H, quinter, J = 7Hz), 2.80 (2H, t, J = 7Hz), 2.
83 (2H, t, J = 7Hz), 2.96 (4H, m), 3.81 (4H, m), 8.1
3 (1H, s).

Example 28A 6,7-Dihydro-2-piperazino (5H) cyclopentapyrimidine hydrochloride (Compound No. 202) 6,7-Dihydro-2-piperazino (5H) cyclopentapyrimidine 0.47 g (2.30 mmol, Example 27A Compound 200)
Was dissolved in 5 ml of ethanol, 0.22 g (2.57 mmol) of concentrated hydrochloric acid was added, the mixture was stirred at room temperature for 10 minutes, 40 ml of acetone was added, and the mixture was further stirred for 10 minutes. The precipitated crystals were filtered to obtain 0.22 g of the title compound (yield 40%).

Melting point:> 300 ° C., ¹ H-NMR spectrum (DMSO-d ₆ solution, δ ppm): 2.00 (2H, quinter, J = 7Hz), 2.78 (4H, t, J = 7Hz), 3.
12 (4H, m), 3.96 (4H, m), 8.24 (1H, s), 9.33 (2H, b
r).

Example 29A 2- (4-benzylpiperazino) -5,6-dihydrofuro [2,3-d] pyrimidine (Compound No. 926) (1). 2-hydroxymethylene butyrolactone sodium salt 10.0 g [73.5 mmol, JOFisse in 360 ml of ethanol
ki et al., J. Org., Chem. 29 , 2670 (1964)], 1-amidino-4-benzylpiperazine sulfate 19.6 g (73.3 mmol), and the mixture was refluxed for 5 hours. After the ethanol was distilled off, water was added and the mixture was extracted with chloroform. The chloroform layer was dried, concentrated, and purified by silica gel column chromatography to obtain 6.66 g of 2- (4-benzylpiperazino) -4-hydroxy-5- (2-hydroxyethyl) pyrimidine as crystals. (Yield 29
%).

Melting point: 166-170 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.56 (6H, m), 3.56 (2H, s), 3.60-3.90 (6H, m), 7.
35 (5H, s), 7.67 (1H, s).

(2). To 2.0 g (6.36 mmol) of the compound obtained in (1) above,
Add thionyl chloride (40 ml) at 0 ° C, then at 0 ° C for 4 hours
It was stirred for 12 hours. Excess thionyl chloride was distilled off under reduced pressure,
Water was added to dissolve the residue, and the mixture was made alkaline with 2N-aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was dried, concentrated, and purified by silica gel column chromatography to give 1.03 g of the title compound as crystals (yield 55%).

Melting point: 121-123 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.48 (4H, m), 3.09 (2H, t, J = 7Hz), 3.55 (2H, s),
3.81 (4H, m), 4.60 (2H, t, J = 7Hz), 7.34 (5H, s),
7.99 (1H, s).

Example 30A 5,6-Dihydro-2-piperazinofuro [2,3
-D] pyrimidine (Compound No. 900) 2- (4-benzylpiperazino) -5,6-dihydrofuro [2,3-d] pyrimidine 1.21 g (4.08 mmol, Example 29A)
Compound 926) was dissolved in 40 ml of ethanol and hydrogenated in the presence of 0.14 g of 10% palladium-carbon at normal pressure of 70 ° C. Four
After a lapse of time, the catalyst was passed and ethanol was distilled off to obtain 0.81 g of the title compound as crystals (yield 96%).

Melting point: 74-78 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.49 (1H, s), 2.92 (4H, m), 3.12 (2H, dt, J = 1,7H
z), 3.80 (4H, m), 4.62 (2H, t, J = 7Hz), 8.00 (1H,
t, J = 1Hz).

Example 31A 5,6-dihydro-2-piperazinofuro [2,3
-D] pyrimidine hydrochloride (Compound No. 902) 5,6-dihydro-2-piperazinofuro [2,3-d] pyrimidine 0.23 g (1.12 mmol, compound 900 of Example 30A) was dissolved in 10 ml of ethanol and concentrated hydrochloric acid. 0.12 g (1.18 mmol) was added and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered out and washed with acetone to obtain 0.27 g of the title compound (yield-100%).

Mp: 294 ° C. (decomposition), ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 3.16 (6H, m), 3.92 (4H, m), 4.70 (3H, t, J = 8Hz),
8.10 (1H, s), 9.54 (2H, br).

Example 32A 2- (4-benzylpiperazino) -4,6-dimethylfuro [2,3-d] pyrimidine (Compound No. 928) 1-amidino-4-benzylpiperazine sulfate 14.45 g
DMSO 15 ml, 85% potassium hydroxide 3.57 g (54.1 mmol)
4.1 mmol), 3-carbomethoxy-5-hexyne-2-
On 10.0g [64.9mmol, KESchulte et al., Arch.Phar
m., 295 , 627 (1962).]
Heated at ° C for 4.5 hours. After adding water and extracting with chloroform, the chloroform layer was washed with water and saturated saline,
Dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow oil (4.84 g, yield 28%). ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 2.36 (3H, d, J = 1 Hz), 2.47 (3H, s), 2.51 (4H, m),
3.55 (2H, s), 3.87 (4H, m), 6.17 (1H, q, J = 1H
z), 7.34 (5H, s).

Example 33A 4,6-Dimethyl-2-piperazinofuro [2,3
-D] pyrimidine (Compound No. 904) 2- (4-benzylpiperazino) -4,6-dimethylfuro [2,3-d] pyrimidine 4.23 g (13.1 mmol, Example 32A)
Compound 928) was dissolved in 50 ml of ethanol, and hydrogenated in the presence of 0.40 g of 10% palladium-carbon at atmospheric pressure of 70 ° C. After 5 hours the catalyst was passed over and the catalyst was washed with chlororum. The ethanol layer and chloroform layer are combined and concentrated,
Recrystallized from ethanol to give 1.94 g of the title compound.
Was obtained as crystals (yield 64%).

Melting point:> 300 ° C., ¹ H-NMR spectrum (CDCl ₃ -DMSO-d ₆ solution, δ ppm): 2.40 (3H, d, J = 1 Hz), 2.50 (3H, s), 3.19 (4H, m),
4.12 (4H, m), 6.35 (1H, q, J = 1Hz).

Example 34A 4,6-Dimethyl-2-piperazinofuro [2,3
-D] Pyrimidine hydrochloride (Compound No. 906) 0.81 g (3.49 mmol, compound 904 of Example 33A) 4,6-dimethyl-2-piperazinofuro [2,3-d] pyrimidine was heated to 200 ml of ethanol, Dissolved and concentrated hydrochloric acid 0.39g (3.84g
mmol) was added and the mixture was stirred at room temperature for 30 minutes. Ethanol was distilled off under reduced pressure, and the residue was washed with acetone to obtain 0.88 g of the title compound as crystals (yield 94%).

Melting point:> 300 ° C., ¹ H-NMR spectrum (DMSO-d ₆ solution, δ ppm): 2.36 (3H, d, J = 1 Hz), 2.50 (3H, s), 3.12 (4H, m),
3.98 (4H, m), 6.57 (1H, q, J = 1Hz), 9.60 (2H, br).

Example 35A 2- (4-benzylpiperazino) -5,6-dihydro-7-methyl (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 930) (1) 2- (4-benzylpipepe) Radino) -5,6-dihydro-7-methyl-6-oxo (7H) hiroro [2,3-
d] Pyrimidine (manufactured according to Reference Example 54 of JP-A-61-140568) 8.0 g and 400 ml of ethanol were mixed with 2.24 g of sodium borohydride and heated under reflux for 1.5 hours. After the reaction solution was concentrated, water and ethyl acetate were added to the residue for extraction.
The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography (methanol: chloroform = 1: 10) and recrystallized from toluene to give 2- (4-benzylpiperazino) -5- (2-hydroxyethyl). 2.4 g of colorless crystals of 4-methylaminopyrimidine were obtained. Melting point 119-1
20 ° C, yield 30%. ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.3 to 2.7 (6H, m), 2,94 (3H, d, J = 4.3Hz), 3.5
5 (2H, s), 3.6 to 3.9 (6H, m), 5.50 (1H, brd, J
= 4.3Hz) 7.2 to 7.5 (5H, m), 7.61 (1H, s).

(2) 8.0 g of the compound obtained in (1) above and 80 pyridine
ml was cooled to −10 to 0 ° C., and a solution of 5.3 g of p-toluenesulfonyl chloride in 100 ml of pyridine was added dropwise thereto. After the dropping, the mixture was reacted at 0 to 5 ° C for 6 hours. A solution of 2.5 g of sodium hydrogencarbonate in 30 ml of water was gradually added to the reaction solution, and the mixture was further stirred for 15 minutes. To this, 200 ml of water and 300 ml of ethyl acetate were added, and after extraction, the ethyl acetate layer was washed with 200 ml of water.
The ethyl acetate layer was dried over anhydrous sodium sulfate, and ethyl acetate was evaporated. The residue is 100 m in tetrahydrofuran
A suspension obtained by washing 2.4 g of 60% sodium hydride with hexane was suspended in tetrahydrofuran and added thereto. After reacting at room temperature for 5 hours, 10 ml of ice water was gradually added, and then the solvent was distilled off. 200 ml of water and 300 ml of ethyl acetate were added to the residue, the aqueous layer was separated, the ethyl acetate layer was washed with 200 ml of water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (acetone: hexane = 1: 1) to obtain 1.6 g of the desired product, a brownish brown crystal. Yield 21%, melting point: 105-107 ° C. ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.48 (4H, m), 2.84 (2H, t, J = 9Hz), 3.50 (2
H, t, J = 9Hz), 3.55 (2H, s), 3.78 (4H, m),
7.34 (5H, s), 7.60 (1H, s).

Example 36A 5,6-Dihydro-7-methyl-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 91
2) 2- (4-benzylpiperazino) -5,6-dihydro-
1.4 g of 7-methyl (7H) pyrrolo [2,3-d] pyrimidine (compound 930 of Example 35A) and 0.14 g of 10% pd / c in ethanol 1
5 ml was added, and the mixture was stirred under hydrogen atmosphere at 60 ° C. for 8 hours. After cooling, 10% pd / c was separated and the solvent was distilled off to obtain 0.94 g of the desired product as colorless crystals. Melting point: 63-65 ° C, yield 95%. ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.90 (2H, t, J = 9Hz), 2.92 (4H, m), 3.48 (2
H, t, J = 9Hz), 3.74 (4H, m), 7.62 (1H, s).

Example 37A 5,6-Dihydro-7-methyl-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine 2-naphthalenesulfonate (Compound No. 914) 5,6-dihydro-7-methyl- 2-piperazino (7H)
Pyrrolo [2,3-d] pyrimidine (Compound 91 of Example 36A
2) A solution of 0.26 g of 2-naphthalenesulfonic acid monohydrate in 10 ml of ethanol was added to a solution of 0.25 g of ethanol in 10 ml. The solvent was distilled off to obtain 0.49 g of the desired product as colorless crystals.

Melting point: 160-162 ° C, yield 100%. ¹ H-NMR spectrum (DMSO-d ₆ solvent, δppm): 2.88 (3H, s), 2.7 to 3.7 (8H, m), 7.4 to 8.1 (7
H, m), 8.14 (1H, s).

Example 38A 2- (4-benzylpiperazino) -7,8-dihydro-7-methyl-5-oxo (5H) pyrano [4,3-
d] Pyrimidine (Compound No. 932) 0.5 g of 4,6-dioxo-2-methyloxane, 2.0 ml of methyl orthoformate and 50 ml of acetic anhydride were stirred at 130 ° C. for 3 hours. After the reaction, the solvent was distilled off with an evaporator to obtain a liquid substance. 1.04 g of 1-amidino-4-benzylpiperazine sulphate was added to 10 ml of 2% KOH solution and stirred at room temperature for 30 minutes, then the above liquid substance was added to the solution and stirred at room temperature for 1 hour. After the reaction, methanol was distilled off, 30 ml of water was added, and the mixture was extracted with 50 ml of methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and then subjected to silica gel column chromatography (methylene chloride: ethyl acetate = 2: 1).
0.82 g of the title compound was obtained as a white solid (yield 62%). ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.56 (3H, d, J = 8.6Hz), 2.56 (4H, m), 2.84 (2
H, d, J = 7.6Hz), 3.60 (2H, s), 4.00 (4H,
m), 4.70 (1H, m), 7.38 (5H, s), 8.86 (1H,
s).

Example 39A 7,8-Dihydro-7-methyl-5-oxo-
2-Piperazino (5H) pyrano [4,3-d] pyrimidine (Compound No. 916) 2- (4-Benzylpiperazino) -7,8-dihydro-
0.15 g of 7-methyl-5-oxo (5H) pyrano [4,3-d] pyrimidine (compound 932 of Example 38A) was added to 30 m of ethanol.
The solution was dissolved in 1 l, 30 mg of 10% pd / c was added under nitrogen atmosphere, and the mixture was stirred at 50 ° C for 2 hours. After the reaction, pd-c was passed and the solution was concentrated to obtain 0.12 g of solid (yield 99%). ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.52 (3H, d, J = 6.8Hz), 2.84 (2H, d, J = 7.6H)
z), 2.94 (4H, m), 3.96 (4H, m), 4.64 (1H,
m), 8.86 (1H, s).

Example 40A 7,8-Dihydro-7-methyl-5-oxo-
2-Piperazino (5H) pyrano [4,3-d] pyrimidine hydrochloride (Compound No. 918) 7,8-Dihydro-7-methyl-5-oxo-2-piperazino (5H) pyrano [4,3-d ] Pyrimidine (Example 39A
Compound 916) in 0.12 g was added with 5 ml of a saturated ethanol solution of hydrochloric acid, the mixture was stirred at room temperature for 10 minutes and then concentrated to obtain 0.13 g of the title compound as a solid. Melting point 274-276 ° C (decomposition).

Example 41A 2- (4-benzylpiperazino) -5,6-dihydro-4,7-dimethyl-6-oxo (7H) pyrrolo [2,3
-D] Pyrimidine (Compound No. 462) (1) 3.1 g of potassium hydroxide was added to 200 ml of ethanol and stirred for 30 minutes, then 12.4 g of 1-amidino-4-benzylpiperazine sulfate was added and stirred for 10 minutes at room temperature. did. To this solution was added 12.4 g of diethyl acetylsuccinate and the mixture was refluxed for 2 hours, then 200 ml of toluene was added and refluxed for 3 hours. After the reaction, ethanol was distilled off and the mixture was poured into 50 ml of a hydrochloric acid aqueous solution. NaHCO ₃ was added to this solution to neutralize it, and the precipitated solid was washed with water and dried over P ₂ O ₅ to give 2.55 g of white solid 2- (4-benzylpiperazino) -5-ethoxy. Carbonylmethyl-4-hydroxy-6-methylpyrimidine was obtained (15% yield). ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 1.36 (3H, t, J = 7.6Hz), 2.25 (3H, s), 2.57 (4
H, m), 3.55 (2H, s), 3.69 (2H, s), 3.77 (4
H, m), 4.24 (4H, q, J = 7.6Hz), 7.51 (5H,
s).

(2) 2.7 g of the compound obtained in (1) above and 20 g of phosphorus oxychloride were refluxed for 3 hours. After phosphorus oxychloride was distilled off under reduced pressure, 10 ml of toluene was added and the solid was collected. This solid was stirred with 50 ml of methylene chloride and 50 ml of saturated aqueous sodium bicarbonate solution for about 1 hour. The toluene layer and methylene chloride layer were combined, dried over anhydrous sodium sulfate, and the solution was concentrated.2.
61 g of brown-brown solid 2- (4-benzylpiperazino) -5-ethoxycarbonylmethyl-4-chloro-6
-Methylpyrimidine was obtained (92% yield). ¹ H-NMR spectrum (DMSO-d ₆ solution, δppm): 1.26 (3H, t, J = 7.6Hz), 2.35 (3H, s), 2.48 (4
H, m), 3.56 (2H, s), 3.65 (2H, s), 3.82 (4
H, m), 4.18 (2H, q, J = 7.6Hz), 7.34 (5H,
s).

(3) A 40% methylamine methanol solution containing 2.61 g of the compound obtained in (2) above and 1.04 g of methylamine was dissolved in ethanol, and the mixture was stirred in a 50 ml autoclave at 120 ° C. for 18 hours under a nitrogen atmosphere. After allowing to cool, the precipitated red crystals were passed through to obtain a solid. Concentrate the solution to 3 ml, 2
The next crystal was obtained. The primary crystal and the secondary crystal were combined to obtain 1.56 g of the title compound as a red crystal (yield 62%). ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.22 (3H, s), 2.50 (4H, m), 3.18 (3H, s), 3.
34 (2H, s), 3.56 (2H, s), 3.86 (4H, m), 7.35
(5H, s).

Example 42A 5,6-Dihydro-4,7-dimethyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine (Compound No. 464) 2- (4-benzylpiperazino)- 5,6-dihydro-
1.57 g (4.6 mmol) of 4,7-dimethyl-6-oxo (7H) pyrrolopyrimidine (Compound 462 of Example 41A) was dissolved in 60 ml of ethanol, and 10 mg of pd / c (500 mg) was added thereto under a nitrogen atmosphere. Stir for hours. After the reaction, pd-c was passed and the solution was concentrated to obtain 1.04 g of the title compound as a pale yellow solid (yield 91%). ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 2.24 (3H, s), 2.92 (4H, m), 3.20 (3H, s), 3.
36 (2H, s), 3.82 (4H, m).

Example 43A 5,6-Dihydro-4,7-dimethyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine hydrochloride (Compound No. 466) 5,6-dihydro-4, 0.20 g of 7-dimethyl-6-oxo-2-piperazino (7H) pyrrolo [2,3-d] pyrimidine was dissolved in 20 ml of ethanol saturated with hydrochloric acid, stirred at room temperature for 10 minutes, and then concentrated to give 0.21 g of pale yellow. The title compound was obtained as a solid. Melting point 300 ° C or higher.

Example 44A 2- (4-ethoxycarbonylmethylpiperazino) -4
-Methyl isopropylaminopyrimidine-5-carboxylate (Compound No. 100) Methyl 2-piperazino-4-isopropylaminopyrimidine-5-carboxylate (Reference Example of JP-A-61-140568)
0.5 g (3.1 mmol) of ethyl bromoacetate was added to a solution of 0.9 g (3.2 mmol) prepared according to 69), 10 ml of CHCl ₃ and 0.54 g (5.3 mmol) of triethylamine, and the mixture was stirred at room temperature for 6 hours. Then, add water and CHCl ₃ for extraction, and extract the CHCl ₃ layer with anhydrous water.
It was dried over MgSO ₄ . CHCl ₃ was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.0 g of the desired product (yield 88%).

Melting point: 78 to 79 ° C, ¹ H-NMR spectrum (CDCl ₃ solution, δppm): 1.27 (6H, d, J = 7Hz), 1.31 (3H, t, J = 7Hz),
2.64 (4H, m), 3.27 (2H, s), 3.82 (3H, s), 3.
96 (4H, m), 4.22 (2H, q, J = 7Hz), 4.26 (1H,
m), 7.94 (1H, br.d, J = 7Hz), 8.59 (1H, s).

Example 45A 2-Piperazino-5- (2-hydroxyethyl) -4-
Methylaminopyrimidine (Compound No. 138) 2- (4-benzylpiperazino) -5- (2-hydroxyethyl) -4-methylaminopyrimidine 0.8 g (2.45
mmol), 10% Pd-C 0.1 g, and ethanol 10 ml were stirred under a hydrogen atmosphere at 60 ° C. for 7 hours. After allowing the reaction mixture to cool, the catalyst was removed in excess and the liquid was concentrated to give the title compound.
56 g (yield 96%) was obtained as crystals.

Melting point: 195-197 ° C., ¹ H-NMR (CDCl ₃ -DMSO-d ₆ solution, δ ppm): 2.50 (2 H, t, J = 7 Hz), 2.92 (3 H, s), 2.98 (4
H, m), 3.62 (2H, t, J = 7Hz), 3.84 (4H, m),
6.45 (1H, br), 7.58 (1H, s).

Example 46A 2-Piperazino-5- (2-hydroxyethyl) -4-
2-Naphthalenesulfonic acid salt of methylaminopyrimidine (Compound No. 140) 2-piperazino-5- (2-hydroxyethyl) -4
-Methylaminopyrimidine 0.19 g (0.8 mmol) in ethanol 30 ml solution, 2-naphthalene sulfonic acid 0.18 g (0.8 mm
ol) in 10 ml of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated, the precipitated solid was washed with ether-
It was slurried with a mixed solvent of toluene-ethanol. The solid was filtered and dried under reduced pressure to obtain 0.2 g of the title compound (yield 54%) as colorless crystals.

Melting point: 215 to 217 ° C. Example 47A 6,7-Dimethoxy-2- (4- (3,4-dimethoxybenzoylpiperazino) quinazoline (Compound No. 944) 1- (3,4-dimethoxybenzoyl) piperazine (special It was synthesized by the method described in Kaisho 56-150072.) 125 mg and 2-chloro-6,7-dimethoxynazoline 112 mg were added with 2 ml of isoamyl alcohol and stirred for 5.5 hours at 120 ° C. After isoamyl alcohol was distilled off. Purified by thin layer chromatography (ethyl acetate) to give 102m of the title compound as colorless crystals.
g was obtained (47% yield). Melting point 188-190 ° C. ¹ H-NMR (CDCl ₃ solution, δppm): 3.78 (4H, brs), 3.94 (3H, s), 3.97 (3H, s),
3.99 (3H, s), 4.04 (3H, s), 4.1 (4H, brs), 6.
8 to 7.2 (5H, m), 8.85 (1H, s).

Example 48A According to the method described in JP-A-61-140568, compounds included in the above formula (I) of the present invention, namely compound numbers (204), (206), (300), (302), (304). ), (306), (308), (40
0, (402), (404), (406), (408), (420), (42
2), (424), (428), (432), (452), (454), (50
0, (502), (504), (506), (600), (602), (60
4), (606), (603), (610), (612), (614), (61
6), (618), (620), (622), (624), (626), (62
8), (630), (632), (634), (700), (701), (70
2), (704), (706), (707), (708), (710), (71
2), (714), (716), (718), (720), (722), (72
4), (726), (728), (730), (732), (734),
(736), (738), (740), (742), (744), (746), (74
8), (800), (802), (804), (806), (936), (93
8), (940) and (942) were manufactured in the same manner.

The physical properties of some compounds in the compound number 700 are shown below.

Compound 734 Melting point: 170-172 ° C Infrared absorption spectrum (KBr tablet; cm ^-1 ) 1657, 1618, 1578 ¹ H-nuclear magnetic resonance spectrum (deuterated chloroform; ppm) 1.33 (6H, t, J = 7.2), 1.66 ( 1H, s), 2.17 (3
H, d, J = 1.3), 2.94 (4H, m), 3.97 (6H, m),
7.10 (1H, q, J = 1.3), 9.24 (1H, s) Compound 714 Melting point: 143 ° C Infrared absorption spectrum (KBr tablet: cm ^-1 ) 3325, 1660, 1622, 1576 ¹ H-nuclear magnetic resonance spectrum (heavy) Dimethyl sulfoxide; ppm) 0.88 (3H, t, J = 8Hz), 1.66 (2H, m), 2.75 (4
H, t, J = 6Hz), 2.8 (overlap with 1H, 2.75), 3.76 to 3.9
1 (6H, m), 6.22 (1H, d, J = 8Hz), 7.73 (1H,
d, J = 8 Hz), 9.08 (1 H, s) Compound 712 Melting point: 161 ° C. Infrared absorption spectrum (KBr tablet: cm ⁻¹ ) 3430, 1652, 1618, 1584 ¹ H-nuclear magnetic resonance spectrum (deuterated chloroform; ppm) 1.31 (6H, d, J = 8Hz), 2.92 (4H, br.s), 3.92 (4
H, br.s), 5.05 (1H, sel, J = 8Hz), 6.2 (1H, br.
s), 6.29 (1H, d, J = 8Hz), 7.83 (1H, d, J = 8H)
z), 9.08 (1H, s) Compound 700 Melting point: 252.8 ° C (Ethanol recrystallization) mass .: 231 (M ⁺ ) ¹ H-nuclear magnetic resonance spectrum: (δ: ppm in DMSO d-6) 2.87 (4H, br.s), 3.88 (4H, br.s), 5.73 (1H, d,
J = 7Hz), 6.98 (1H, d, J = 7Hz), 9.02 (1H, s) Compound 740 Melting point: 231.7 ° C Mass spectrum: 349 (molecular ion peak) Infrared absorption spectrum (KBr tablet: cm ^-1 ) 3400, 2920, 1654, 1617, 1574 ¹ H-nuclear magnetic resonance spectrum (heavy dimethyl sulfoxide; ppm) 1.24 (3H, t, J = 7Hz), 2.96 (4H, br.s), 3.80 ~
4.12 (8H, m), 7.24 (5H, s), 7.80 (1H, s), 8.
06 (1H, s) Compound 708 Melting point: 149-152 ° C Infrared absorption spectrum (KBr CHCl ₃ ; cm ^-1 ) 1655, 1645, 1620, 1575 ¹ H-nuclear magnetic resonance spectrum (deuterated chloroform; ppm) 1.34 (3H, t, J = 7Hz), 1.87 (1H, br.s), 2.94 (4
H, t, J = 6Hz), 3.96 (6H, m), 6.27 (1H, d, J
= 8Hz), 7.29 (1H, d, J = 8Hz), 9.22 (1H, s) Compound 706 Oil Condition ¹ H- nuclear magnetic resonance spectrum (deuterochloroform; δppm) 2.93 (4H, m ), 3.50 (3H, s ), 3.94 (4H, m), 4.
40 (1H, br.s), 6.25 (1H, d, J = 8Hz), 7.25 (1
H, d, J = 8 Hz), 9.23 (1 H, s) Compound 742 Melting point: 300 ° C. or higher Infrared absorption spectrum (Nudiol; cm ⁻¹ ) 3400, 1688, 1655 ¹ H-NMR spectrum (CDCl ₃ solution, δ ppm): 1.40 (3H, t, J = 7.0Hz), 2.95 (4H, m), 4.08 (6
H, m), 8.19 (1H, s), 9.20 (1H, s), 10.55 (1
H, s) Example 1B Tablets containing 10 mg of active ingredient are prepared as follows.

Per tablet Active ingredient 10 mg Corn starch 55 mg Crystalline cellulose 35 mg Polyvinylpyrrolidone 5 mg (as a 10% aqueous solution) Carboxymethylcellulose calcium 10 mg Magnesium stearate 4 mg Talc 1 mg Total 120 mg Active ingredient, starch and crystalline cellulose are passed through 80 mesh sieve and mixed thoroughly To 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. Calcium carboxymethylcellulose and magnesium stearate and talc, which have been previously sieved with 80 mesh, are added to the granules and, after mixing, a tablet weighing 120 mg each is produced in a tablet machine.

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

Per tablet Active ingredient 200 mg Corn starch 50 mg Crystalline cellulose 42 mg Light anhydrous silicic acid 7 mg Magnesium stearate 1 mg Total 300 mg The above ingredients are passed through an 80 mesh sieve and mixed thoroughly. 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.

Per capsule Active ingredient 100 mg Corn starch 40 mg Lactose 5 mg Magnesium stearate 5 mg Total 150 mg Mix the above ingredients and pass through a 80 mesh sieve and mix thoroughly. 150 mg of the obtained powder is filled into capsules.

Example 3B-1 A capsule containing 5 mg of the active ingredient is prepared as follows.

Per capsule Active ingredient 5 mg Corn starch 10 mg Lactose 5 mg Magnesium stearate 5 mg Total 25 mg Mix the above ingredients and pass through a 80 mesh sieve and mix thoroughly. 25 mg of the obtained powder is filled into capsules.

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

 Per vial Active ingredient 5 mg Mannitol 50 mg Dissolve with 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 Appropriate amount 2 ml Example 6B An adhesive patch preparation containing 17.5 mg of active ingredient is produced as follows.

10 parts of ammonium polyacrylate are dissolved in 60 parts of water. Meanwhile, 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 dissolved by stirring. 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 m of the active ingredient is produced as follows.

100 parts sodium polyacrylate, 100 parts glycerin,
Water 150 parts, triepoxypropyl isocyanurate 0.2
Parts, ethanol 100 parts, isopropyl myristate 25
Parts, 25 parts of propylene glycol and 15 parts of the active ingredient were mixed to prepare an aqueous sol solution. Next, this sol solution was applied to the non-woven fabric surface of a composite film composed of rayon non-woven fabric and polyethylene film to a thickness of 100 μm to form an adhesive layer containing a drug. The content of release assisting 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 attached to the interface of the pressure-sensitive adhesive, and this was further cut into 35 square centimeters to give a preparation.

Example 8B Poly (dl-lactic acid-glycolic acid) copolymer (75:25)
(Molecular weight of about 2000) was converted to methylene chloride: n-propanol (4:
1) Dissolved in 200 ml to prepare a 5% solution. Next, 100 mg of the active ingredient was added to 50 ml of methylene chloride: n-propanol (4: 1).
The solution suspended in was added to the above-mentioned copolymer methylene chloride: n-propanol solution and mixed with a stirrer at 1,000 rpm to obtain a mixed solution. This mixed solution was added to 1000 ml of a 1% hyaluronic acid aqueous solution which had been kept at 40 ° C. in advance, and the mixture was stirred at a speed of 500 rpm to be emulsified to generate a microsphere containing an active ingredient. Next, the microspheres were collected by centrifugation, washed 6 times with distilled water which had been kept at 40 ° C. in advance, and dried under reduced pressure at room temperature. The above steps were all performed aseptically.

Example 9B Active ingredient 10 mg, poly dl lactic acid (number average molecular weight 2000) 100 m
g methylene chloride / ethanol mixed solution (volume mixing ratio 5:
1) Dissolve in 0.6 ml, 0.5% polyvinyl alcohol aqueous solution 2
After emulsifying and dispersing in 00 ml with a homogenizer, the mixture was stirred for about 4 hours and dried in an o / w type liquid to solidify the oil phase. The generated microspheres were collected by a centrifuge, washed with purified water, redispersed in water and freeze-dried to obtain a powder. All the above steps were performed aseptically.

The biological activity of the compounds of formula (I) on neural cells was tested in vitro. As a neural cell, the established human neuroblastoma tumor cell GOTO strain (Sekiguchi, M., Oota, T., Sak
akibara, K., Inui, N. & Fujii, G., Japan.J.Exp.Med., 49 , 6
7-83 (1979)) and neuroblastoma cell line NB-1 (Miy
ake, S., Shimo, Y., Kitamura, T., Nojyo, Y., Nakamura, T., I
mashuku, S.and Abe, T., The Autonomic Nergous System,
10 , 115-120 (1973)), and mouse neuroblastoma n
Examples include euro-2a (Dainippon Pharmaceutical) and NS-20Y. 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 formula (I) was significantly more significant than that of the control culture, and was equal to or higher than that of the control drug isaxonin (compound described in Japanese Patent Publication No. 59-28548). It was revealed to have cell proliferation promoting activity, neurite formation and neurite outgrowth promoting activity.

In addition to the above neuroblastoma cells, the biological activity of the compound of formula (I) of the present invention was tested against rat adrenal medulla cell line PC-12. In the PC-12 cell line, the neurites are elongated by the addition treatment of NGF. At that time, when the compound (I) of the present invention is added, the binding of NGF to the PC-12 cells and the intracellular formation of the NGF are performed. 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.

Further, when the compound (I) of the present invention is added to each nerve cell or spinal cord cell of rat, mouse fetus, neonatal or juvenile brain, neurite formation and neurite outgrowth of each nerve cell are promoted. Rukoto has been shown.

Next, rats or mice crushing the sciatic nerve, the common sciatic nerve, or the tibial nerve, which is a model of peripheral neuropathy, were prepared, and the effects of the compound of the present invention were tested. Unit for the number, thickness, and total cross-section of regenerative nerves that reach a nerve site that is a certain distance away from the crushed site for recovery of muscle mass to normal values such as muscle, extensor longus muscle, and tibialis muscle In order to improve the number of myelinated nerve axons per area (axon density), the minor axis of the myelinated axons and the ratio of the axon area to the unit area (axon occupancy), the compound of the present invention (I ) Has a promoting effect.

Further, it was shown that when the compound (I) of the present invention was administered to a mouse in which the sciatic nerve, the common sciatic nerve and the like were cut, the germination and elongation of regenerated axons were promoted. Further, when the sciatic nerve was cut and the rat was sutured with a thread, the tibial nerve was cut and the rat was sewn or the nerve and the semitendinosus muscle were cut, and the rat with the muscle sewn was administered with the compound (I) of the present invention, It was revealed that the compound (I) of the present invention promotes repair and regeneration of nerves and muscles. In addition, when the compound (I) of the present invention was administered to rats with cut hypoglossal nerve, optic nerve, etc., rats, rats with damaged spinal cord, cats, rabbits, monkeys, etc. It was also clarified that the repair and recovery of the will be promoted.

Further, a central nervous system disorder model was prepared in rats, mice, etc., and the efficacy of the compound (I) of the present invention was tested. That is,
First, nigral dopamine cells in rat brain were chemically destroyed by microinjection of 6-hydroxydo-pamine to cause motility disorder. 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 ip every day for 2 weeks, and the effects on the improvement of motility disorder and the growth of transplanted cells were examined. Compound (I) of the present invention
Was found to have a promoting effect on improvement of movement disorders.

Further, when the compound (I) of the present invention was administered to a rat or mouse in which a disorder was caused by injecting inbotenoic acid, kainic acid, etc. into the brain, repair of the disorder and promotion of recovery were observed.

In addition, when rats, mice, etc., which were neuropathy caused by mercury poisoning were prepared and tested for the activity of the compound (I) of the present invention, promotion of repair / regeneration of each nerve and spinal cord was observed, and symptoms were improved and normal. It was shown to have a promoting effect on the recovery to the condition and a therapeutic effect.

Thus, it was revealed that the compound (I) of the present invention is useful as an ameliorating / therapeutic agent for various nerve diseases such as peripheral neuropathy and central neuropathy in mammals.

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. More specifically, facial nerve palsy, sciatic nerve palsy, median nerve palsy, radial nerve palsy, ulnar nerve palsy, carpal syndrome, common peroneal nerve palsy, etc. nerve constriction syndrome (constriction neuropathy), compression Neuropathy, dysplasia (neuroaplasia), neurapra
xia), spinal muscular atrophy, muscular dystrophy, myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, post-vaccination encephalitis, SMON, dementia, Alzheimer's syndrome, spinal cord injury,
Cranial injury prognosis, cerebral ischemia, cerebral infarction or cerebral hemorrhage sequelae,
Examples include, but are not limited to, rheumatism.
Furthermore, when the toxicity test of the compound of the present invention was conducted, it was found that its toxicity was weak and that it could be used as a safe drug.

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

That is, the culture medium containing the fetal calf serum (FCS) of the neuroblastoma GOTO strain in the logarithmic growth phase [45% RPMI 1640 medium, 45%
Made of Modified Eagle's Medium (MEM medium) and 10% FCS, containing penicillin G sodium (100 unit / ml) and streptomycin sulfate (100 μg / ml)], using 35 mm polystyrene dish (Corning)
Then, 2 ml each was dispensed at 2 to 6 × 10 ⁴ cells / dish and cultured at 37 ° C. for 1 to 2 days in a carbon dioxide incubator containing 5% carbon dioxide in the air. Then after removing this culture,
2 ml of new serum-free culture medium (consisting of 50% RPMI medium and 50% MEM medium, penicillin G sodium, streptomycin sulfate containing the same amount as above) was added, and at the same time, pre-sterilized various concentrations of each compound were added. PBS solution (phosphate buffered saline) was added to each dish. And
After culturing for 24 hours, the number of viable cells was measured, and at the same time, photographs were taken, and the number and length of neurites per cell were measured from the photographs. The number of viable cells was counted by resistance to erythrosin dye staining in 3 to 6 dishes, and the number and length of neurites were measured in 6 photographs (200 or more cells per sheet).

In addition, as a simple evaluation method, the ratio of the number of cells with neurite length equal to or longer than the major axis of cells of the human-derived GOTO strain and the mouse-derived neuro-2e strain divided by the total number of cells The method of obtaining was also used. The results are shown in Table 1 and Table 2.
Shown in

Furthermore, the following method was also adopted for the purpose of testing the effect of the sample.

That is, double land Dulbecco's Modifie containing 10% FCS
Mouse neu in logarithmic growth phase in d Eagle's Medium (DMEM)
Cells of the ro-2a strain were seeded on a 48-well plate at 1,000 cells / well. After culturing for 1 day in a culture solution of 0.25 ml in each well, the medium was changed to a medium containing each sample and FCS and further cultured for 24 hours. Next, the same amount as the double land (0.25
ml) of 4% glutaraldehyde solution and added to room temperature for 2
The cells were left to stand for a period of time and fixed. After washing with water, 0.05% methylene blue aqueous solution was added to stain the cells, and macroscopically, under the microscope, neurite outgrowth cells (cells having at least one protrusion having a length at least twice the major axis of the cell) were counted. , And the percentage of the total number of cells was calculated. Five or more consecutive visual fields on the left and right (2% or more of the total surface area of the well) were observed centering on the mark on the bottom of the center of the well, and the number of cells was counted for 200 or more. A maximum of 6 concentrations of one drug was taken, and 3 cases were carried out for each drug concentration, and the numerical values were expressed as an average value ± SD. The results are shown in Table 3.

Example 2C Therapeutic effect on sciatic nerve crush rat: The therapeutic effect of the compound (408) of the present invention on sciatic nerve crush rat of peripheral neuropathy model is (1) behavioral change of crushed hind limb and (2) muscle weight. Was examined as an indicator 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 (1979)) and Hasegawa et al.'S method (Kazuo Hasegawa, Naoji Mikuni, Yutaka Sakai, Journal of Japanese Pharmacology, 74 , 721-734 (197).
8) See)). That is, the left sciatic nerve was exposed in the femoral region under vent barbital anesthesia (40 mg / kg, ip). Was crushed for 5 minutes. After the operation, they were randomly assigned to each test group.

The compound (408) of the present invention was selected as a drug, and was intraperitoneally administered once a day from the same day of crushing to the 22nd day. As a control group, a mecobalamin (manufactured by Gedeon Richter Ltd.) administration group and a 0.9% physiological saline administration group were provided. Each measurement item is over time after crushing (Days 1, 4, 7, 10, 14, 17, 21, 23)
Was measured.

(1) Behavior change of hind limb after crushing It is a good index showing functional degeneration and regeneration of nerves,
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%. The average value and standard error (SE) are shown in Table 4.

When the measured values of the test group showed a significant difference by Student's t-test with respect to the physiological saline administration part as a control, the shoulder of the numerical value was on the right shoulder, and the one of p <0.05 was marked with *, and p <0.01. Those marked with ** are added.

The finger-to-finger distance between crushes is about half (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 sample-administered group and the mecobalamin-administered group showed a clear tendency toward quicker recovery than the saline-fed group,
A significant difference was also shown compared to the saline group. The recovery progressed on the 23rd.

(2) Changes in muscle weight It is known that denervation or nerve damage causes atrophy of the muscles under its control, which gradually recovers due to reinnervation of the nerves. Using quantitative changes in muscle weight as an index I chose. Twenty-three days after the operation, the soleus muscles of both hind limbs were excised under pentobarbital anesthesia and the weight thereof 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)
The results are shown in Table 4.

In another experimental study, in the saline-administered group, muscle weight began to decrease from the second day of crushing, reaching about 90% of the normal side, and 10 to 14
By day it was at the lowest of around 40% and muscle atrophy reached its highest. After that, gradually began to recover.

In the present experiment, on the 21st day, it was revealed that the group administered with the compound of the present invention promoted muscle weight recovery in a dose-dependent manner with a significant difference compared with the group administered with saline.

Example 2C-1 Restorative Treatment Effect on Sciatic Nerve Cutting Rat After cutting the right sciatic nerve of Wistar rat weighing 200 g at 1 cm proximal from the popliteal bifurcation, sutured with 10-0 nylon thread,
Immediately after the operation, the compound (604) of the present invention was administered at 1 mg / kg / day (1 mg
Group), 5 mg / kg / day (5 mg group) was intraperitoneally administered, and only saline was administered (control group). 1 week to 6 after surgery
Ink is applied to the hind paws of the rat every week until week, and the finger-to-finger distance ratio
The Toe Spread Index (TSI) [distance between the first and fifth fingers on the normal side-this distance on the experimental side / this distance on the normal side] was measured. In addition, every week, 5 sciatic nerves in each group were stimulated with sciatic notches, and an electromyogram induced by a needle electrode inserted into the gastrocnemius muscle was recorded, and then the posterior tibial nerve was collected at the ankle joint level and A thin sliced sample was prepared by embedding Epon by the method. The number of myelinated axons per unit area (axon density), the minor axis of the myelinated axons, and the ratio of the axon area to the unit area (axon occupancy rate) were determined by 800 times light microscopy. Furthermore, the process of axon regeneration was observed by electron microscopy.

[Results] According to the wilcoxon test, TSI was 5 mg group at 2 weeks.
The 1 mg group was smaller than the control group (p <0.05). In histological examination, regenerating axons were observed from 3 weeks in each group, and small minifascicles were formed at 6 weeks. Axon density is 5 weeks
The 5 mg group was larger than the 1 group (p <0.05), and it was 5 m with the 1 mg group in 6 weeks
The g group was larger than the control group (p <0.01). The axon minor axis was significantly larger in the 5 mg group than in the 1 mg group at 4 weeks (p <0.
05). The axon occupancy rate was higher in the 5 mg group at 5 weeks than in the 1 mg group and the control group (p <0.01), and at 6 weeks, higher in the 1 mg group and the 5 mg group than in the control group (p <0.01). From the above, it was considered that the compound (604) of the present invention acts to promote nerve regeneration.

Example 2C-2 Therapeutic Effect on Peripheral Nerve / Muscle Transected Rats Sciatic nerve / semitendinosus muscles (tibia side) and semitendinosus muscles of male 9-week-old SD rats were paralyzed and the muscles were immediately sutured. . Immediately after the operation, the compound (604) of the present invention was intraperitoneally administered at 5 mg / kg / day in a group of 30 animals and a group in which only saline was administered (control group)
30 rats, 36 intact rats without surgery and a group to which only saline was administered (intact group) were prepared and administered continuously for 12 weeks. The number of nerve / muscle junction end plates, the number and ratio of muscle fiber types, and density were measured every week.

[Results] With the compound (604) of the present invention, the number of nerve / muscular junction end plates at the second week after surgery was 2.5 times that of the control group, and the rate of increase was increased. In addition, compound (604) transiently increased the number of muscle fibers by 1.5 times that in the normal intact group at 4 weeks (p
<0.01), whereas the control group showed a decrease of 10% compared to the intact group. Then, at the 8th week, the number of muscle fibers in the compound (604) -administered group returned to the normal value, whereas in the control group, it was 30% at the 12th week.
% Muscle fiber loss occurred (p <0.01). In this experimental system, denervation side (tibia side) muscle fiber loss is remarkable, but the compound (604) of the present invention promotes nerve re-innervation and can prevent muscle fiber loss almost completely. Therefore, it is considered to be a drug effective for the improvement and treatment of the above-mentioned various neurological / muscular disorders.

Example 2C-3 Therapeutic effect on organomercurial toxic neuropathy rats WKA rats weighing 250 to 270 g were divided into 3 groups of 6 rats each, and methylmercury chloride (MMC) was administered once, 4 mg / kg, stomach Administered 8 times every other day using a sonde, and 1 week after the end of administration,
Compound 1 of the present invention (604) was intraperitoneally administered to group 1 at 10 mg / kg every day for 8 weeks, and mecobalimin (MCB) at 0.5 mg / kg to group 2.
kg was administered intraperitoneally every day for 8 weeks, and saline was similarly administered to the 3 groups. After the administration, the rats in each group were sacrificed and the neurospinal lesions were observed morphologically. In the saline-administered group, a large number of abnormal fibers (15 to 20%) were found in the peripheral nerve, whereas in the compound (604) -administered group and the MCB-administered group, the abnormal nerve numbers were
The average was 3.5% and the average was 5.2%, which was extremely small, and the therapeutic effect of these drugs was shown. Regarding degeneration in the posterior cord of the spinal cord, a large number (average 12 to 20 fibers / posterior cord of the spinal cord) degenerated nerve was observed in the saline-administered group, while in the MCB-administered group an average of 5
~ 8 fibers / posterior cord of the spinal cord, almost no degenerative fibers were observed in the compound (604) administration group, and the high therapeutic effect of the compound (604) on spinal branch degeneration was clarified. The compounds of the present invention were considered to be effective.

Example 3C Effect of promoting motility disorder caused by rat brain cell injury on improvement by fetal brain cell transplantation.

Female Wistar 4-week-old rats (body weight: 100 g) were disrupted by left-sided substantia nigra dovamine cells by microinjection of 6-hydroxydo-bamine. The disrupted rats showed a tendency for spontaneous rotation on the side opposite to the disruption for several days, but thereafter showed no behavioral abnormality. Administration of methamphetamine (5 mg / kg, ip) to disrupted rats caused a rotational movement on the disrupted side.

Two weeks after the drug destruction, a part containing dovamine cells (substantia nigra and ventral tegmental part) was excised from the brain stem of rat fetal brain on day 14 to 17 of embryo, and after subdivision, trybusin treatment, 37 ° C,
After 30 minutes of incubating, 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 rotational movements was counted 6 times every 10 minutes after the administration of methamphetamine for the first 1 minute, and the average number of rotational movements per minute was calculated in total.

 The results are summarized in Table 5.

From the results shown in Table 5, 2 weeks and 4 after drug administration
The weekly rats have a reduced rotational movement number as compared to the rats fed the saline, and the compound (I) has an effect of promoting nerve repair and regeneration,
It became clear that it had a motor function recovery effect.

Example 4C The acute toxicity of the compound of 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.
The compound was dissolved in physiological saline and administered orally (PO), and toxicity was evaluated 24 hours after administration. The results are shown in Tables 6 and 7.

EFFECTS OF THE INVENTION The compound of the general formula (I) of the present invention has a promoting effect on the proliferation of neural cells and the formation and extension of neurites as described above, and also has a nerve regeneration effect in neuropathy rats, mice and the like. And has a motor function recovery effect, and can be suitably used for amelioration and treatment of nervous system diseases such as peripheral neuropathy and central neuropathy. Further, it is expected to be preferably used for recovery and improvement treatment of nervous system diseases caused by disorders of nerve tissues / cells involved in sensory / sensory functions and autonomic functions.

As shown in Example 1C, Table 1, Table 2 and Table 3, the compound (I) of the present invention was demonstrated to have biological activity equivalent to or higher than that of the control isaxonin. Further, the toxicity of the compound (I) of the present invention is generally weak as shown in Example 4C, Table 6 and Table 7. Thus, the compound (I) of the present invention is generally considered to be a highly safe drug having high activity and low toxicity.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display part C07D 487/04 140 9271-4C C07D 487/04 140 150 9271-4C 150 491/048 9271-4C 491/048 ( 72) Inventor, Kenei Kamakura City, Kanagawa Prefecture, 12-1225, Yukinoshita (72) Inventor, Kaori, 103-chome, Hagiwara-cho, Mobara-shi, Chiba Prefecture (72) Tadayuki Sasaki, 2142, Togo, Mobara-shi, Chiba Prefecture (72) Inventor Keiichi Yokoyama 2-103-9 Misono, Iwakuni-shi, Yamaguchi Prefecture (72) Hiroyasu Ono 1-2-6 Muroroki-cho, Iwakuni-shi, Yamaguchi Prefecture (72) Inventor Houji Kato Kuga-gun, Yamaguchi Prefecture Waki 3-5-3 Waki (72) Inventor Takumi Kitahara 1-4-3 Misono, Otake City, Hiroshima Prefecture (72) Inventor Ikuo Tomino 1-2-7 Misono, Otake City, Hiroshima Prefecture (72) Invention Shigeru Isayama 49-20-506 Motoyoyogicho, Shibuya-ku, Tokyo

Claims (10)

(57) [Claims] 1. The following formula (I) Here, R ¹ is a hydrogen atom, an acyl group having 2 to 4 carbon atoms, or 2 to 5 carbon atoms.
Is an alkoxycarbonyl group, an alkoxycarbonylmethyl group having 3 to 5 carbon atoms, a benzyl group, a 3,4-dimethoxybenzoyl group or a 3,4-methylenedioxybenzyl group; R ² is a hydrogen atom, an amino group, or a carbon number A monoalkylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or 2 carbon atoms
R ³ is a hydrogen atom, an alkoxycarbonyl group having 2 to 4 carbon atoms, a dialkylaminocarbonyl group having 1 to 9 carbon atoms in each alkyl group, an alkoxy group having 1 to 5 carbon atoms, or hydroxy. Is an ethyl group; or R ² and R ³ together with the carbon atom to which they are attached form a 4- to 7-membered carbocycle or heterocycle in which the heteroatom is N, O or S And R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or 1 carbon atom.
A therapeutic agent for a neurological disease, which comprises as an active ingredient a pyrimidine represented by: or an pharmaceutically acceptable salt thereof, which is an alkylthio group of 4 to 4. 2. The following formula (Ia) Here, the definition of R ¹ and R ⁴ is the same as in the above formula (I), and ₁₁ is a number of 2, 3 or 4, and pyrimidines represented by: or a pharmaceutically acceptable salt thereof. The therapeutic agent according to claim 1, which is an active ingredient. 3. The following formula (Ib) Here, the definitions of R ¹ and R ⁴ are the same as those in the above formula (I), X is ═O or ═N—R ⁵ , and R ⁵ is a hydroxyl group, a benzenesulfonyloxy group or a toluenesulfonyloxy group. The therapeutic agent according to claim 1, wherein the active ingredient is a pyrimidine or a pharmaceutically acceptable salt thereof represented by the formula 1, and 12 is a number of ₂ , 3 or 4. 4. The following formula (Ic Here, the definitions of R ¹ and R ⁴ are the same as those in the above formula (I), and R ⁶ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or 2 carbon atoms.
An alkyl group having 4 to 4 is an alkoxyalkyl group substituted with an alkoxy group having 1 to 4 carbon atoms; R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; 1 ₃ claims to and 1 ₄ 0 as or 1 ₃ and 1 ₄ 0 is 1, in represented by pyrimidines or a pharmaceutically acceptable salt of the active ingredient in Paragraph The remedy of paragraph 1. 5. The following formula (Id Here, the definitions of R ¹ and R ⁴ are the same as those in the above formula (I), R ⁹ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and ₁₅ is a number of 2 or 3. The therapeutic agent according to claim 1, which comprises a pyrimidine represented by or a pharmaceutically acceptable salt thereof as an active ingredient. 6. The following formula (Ie) Here, the definitions of R ¹ and R ⁴ are the same as those in the above formula (I), and R ¹⁰ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1 carbon atom.
To 4 is an acyl group or a carbamoylmethyl group, and ₁₆ is a number of 1 or 2, wherein the active ingredient is a pyrimidine represented by: or a pharmaceutically acceptable salt thereof. The listed remedy. 7. The following formula (If Here, the definition of R ¹ and R ⁴ is the same as the above formula (I), R ¹¹ is a hydrogen atom, a formyl group, an alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 9 carbon atoms, R ¹² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and 3 carbon atoms.
To alkenyl group, C2 to C4 hydroxyalkyl group, C2 to C4 alkyl group substituted with C1 to C4 alkoxy group, benzyl group, or C3 to C6 The therapeutic agent according to claim 1, which comprises, as an active ingredient, a pyrimidine represented by: or a pharmaceutically acceptable salt thereof, which is a cycloalkyl group of 8. The following formula (Ig Here, the definition of R ¹ and R ⁴ is the same as in the above formula (I), R ¹³ and R ¹⁴ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and ₁₇ is The therapeutic agent according to claim 1, which comprises a pyrimidine represented by the following formula, which is a number of 0, 2 or 3, or a pharmaceutically acceptable salt thereof as an active ingredient. 9. The following formula (Ih Here, the definitions of R ¹ and R ⁴ are the same as those in the above formula (I), and EG is —OCH ₂ CH ₂ —, —OC (CH ₃ ) ═CH—, —CH ₂ OCO—, — _{OCOCH 2 -, - CH 2 C} (CH 3) OCO-, -N (CH 3) CH 2 CH 2 -, - CH = CH-CH = CH-, -CH = C (OCH 3) -C (OCH 3 ) = CH-, or The therapeutic agent according to claim 1, which comprises a pyrimidine represented by: or a pharmaceutically acceptable salt thereof as an active ingredient. 10. The pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, maleate, fumarate, Succinate,
A claim selected from the group consisting of lactate, tartrate, benzoic acid, citrate, gluconate, sugar, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate and quaternary ammonium salts. The therapeutic drug according to item 1.