WO2000073306A1 - 2-arylpurine-9-acetamide derivatives, process for the preparation thereof, medicinal compositions containing the same and intermediates of the derivatives - Google Patents

Abstract

2-Arylpurine-9-acetamide derivatives represented by general formula (I) or pharmaceutically acceptable acid addition salts thereof, which selectively act on BZφ3 receptor and are useful as therapeutic and preventive drugs for central diseases such as anxiety-related diseases, depression and epilepsy. In said formula (I) R1 is lower alkyl, cycloalkyl, cycloalkylated lower alkyl, or the like; R2 is lower alkyl, substituted or unsubstituted phenyl, or the like; R3 is hydrogen or the like; R4 is hydrogen, lower alkyl, cycloalkyl, halogeno, lower alkoxy, or the like; A is substituted or unsubstituted phenyl or the like; W is hydrogen, lower alkyl, halogeno, lower alkoxy, lower alkylthio, lower alkanoyl, or the like.

Description

 Specification

TECHNICAL FIELD The present invention relates to a 2-arylpurine-9-acetoamide derivative, a method for producing the same, a pharmaceutical composition containing the same and an intermediate of the compound.

 The present invention relates to a novel 2-arypulprin-9-acetoamide derivative which selectively acts on a peripheral benzodiazepine receptor.

 Background art

Mammalian tissues, including humans, have three benzodiazepine (hereinafter sometimes abbreviated as “BZ”) recognition sites, which are “central ( _{ω ι} , ω ₂ )” and “peripheral ( omega ₃₎ "Benzojiazepin is referred to as receptor (hereinafter, respectively" _ΒΖ ω ι receptor ", also referred to as" 8Σ 0 ^ ₂ receptor "and" Betazetaomega ₃ receptor "). Among them, the central type ΒΖ receptor is γ-aminobutyric acid of the central nervous system (hereinafter sometimes referred to as “GABA”). _A — BZ receptor-binding of BZ-based compounds present on C 1 -ion channel complex. In contrast to peripheral sites, peripheral BZ receptors are widely distributed in central and peripheral tissues and organs (brain, kidney, liver, heart, etc.). In particular, endocrine organs such as the adrenal gland and testis, and mast cells, lymphocytes, macrophages, platelets, and other cells that are deeply involved in the inflammation-immune system have a high density of peripheral BZ receptors. Interest in its physiological role is growing. On the other hand, peripheral BZ receptors in the brain are abundant in the mitochondrial membrane of glial cells and are involved in the uptake of cholesterol into the mitochondrial membrane. It is thought to affect the synthesis pathway. Therefore, stimulation of peripheral BZ receptors stimulates the production of neurosteroids in the brain, and these steroids are neurosteroids that are present on the GABA _A- BZ receptor-C1-ion channel complex. It is thought to bind to recognition sites (different from benzodiazepine receptors) and affect the C1 ion channel opening process [Roraeo, E. et al., J. Pharmacol. Exp. Ther., 262, 971 -978 (1992)]. Compounds having a non-BZ skeleton and exhibiting selective affinity for peripheral BZ receptors have been reported in Japanese Patent Application Laid-Open No. 58-201756 (= EP-A-94271), Etc., but there are no compounds that have been put into practical use as pharmaceuticals.

 The following compounds are known as compounds having a non-BZ skeleton and exhibiting selective affinity for peripheral BZ receptors.

 Japanese Patent Application Laid-open No. Sho 62-5946 [US Pat. No. 4,788,199, EP-A-205375 (patent family)] discloses that an amide represented by the following formula binds to peripheral BZ receptors, It is described as being useful as an antispasmodic and antianginal agent, and as a therapeutic agent for immunodeficiency symptoms.

 JP-A-2-32058 [= EP-A-346208, USP-5026711 (patent family)] discloses that 4-amino-3-carboxyquinolines represented by the following formulas are peripheral-type at the mouth and in vivo. It has an affinity for the BZ receptor and is stated to be used for the prevention and treatment of cardiovascular disease in humans, or as an antiallergic agent, and for the prevention or treatment of infectious symptoms, or the treatment of anxiety symptoms I have.

JP WO 96-32383, it has an anxiolytic action Ya anti Riumachi work with acetic Amido derivatives of the following formula is applied selectively to the BZ omega ₃ receptor, treating anxiety-related diseases and immune disorders It is described that it can be used for.

[Wherein X represents one O— or one NR ⁴ —

 Represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group,

R ₂ represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group,

R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group; R ₄ represents a hydrogen atom, a lower alkyl group;

R ₅ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy (lower) alkyl group, an unsubstituted or substituted benzyloxy (lower) alkyl group, an acyloxy (lower) alkyl group, a lower alkoxy (lower) alkyl group An amino group, a mono- or di-lower alkylamino group, an acylamino group, an amino (lower) alkyl group, a nitro group, a carbamoyl group, a mono- or di-lower-alkyl rubamoyl group, a propyloxyl group, a protected carboxyl group, a carboxy ( Lower) alkyl or protected carboxy (lower) alkyl,

R ₆ represents a hydrogen atom, a lower alkyl group, a trifluoromethyl group or an unsubstituted or substituted phenyl group, or R ₅ and R ₆ together form one (CH ₂ ) n — (where , N means 3, 4, 5 or 6),

R ₇ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group or a nitro group,

R ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group]

JP WO 98-09960, is described as 2 represented by the following formula, 4-di-substituted pyrimidine down derivatives, selectively act similarly to the compounds described above in Betazetaomega ₃ receptors Have been

 [Wherein, A represents a heteroaryl group or the like. Definitions of other substituents are omitted]

The present inventors have, BZ omega ₃ receptor selectively and strongly result of intensive studies to obtain a compound that acts, 2 § Li one Lublin one 9 Aseto amide derivative represented by the below formula (I) Found that this was suitable for this purpose, and completed the present invention.

The present invention is a novel 2 Arirupu phosphorus one 9- Asetoamido derivative acting selectively and potent beta Zeta omega ₃ receptors, and has as its object to. In particular, an object of the present invention is to provide a useful compound having an anxiolytic effect. Another object of the present invention is to provide a method for producing the compound. Furthermore, an object of the present invention is to provide a pharmaceutical composition containing the compound. Another object of the present invention is to provide an intermediate for producing the compound. These and other objects and aspects will be apparent to those skilled in the art from the following description.

 According to the present invention, a 2-arylpurine-9-acetoamide derivative represented by the following formula (I):

[In the formula, R ¹ is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a hydroxy (lower) alkyl group, a halogeno (lower) alkyl group or a lower alkyl substituted with cyano. Means the group

R ² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted phenyl (lower) alkyl group \ or R ¹ and R ² Together with the nitrogen atom to which they are attached A piberidine ring, a pyrrolidine ring, a morpholine ring or a piperazine ring, a 2,3-dihydroindole ring, a 1,2,3,4 which may be substituted with one or two lower alkyl groups, respectively. May form a tetrahydroquinoline ring or a 1,2,3,4-tetrahydroisoquinoline ring,

R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy (lower) alkyl group or a protected hydroxy (lower) alkyl group;

R ⁴ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, an amino group, a mono or di (lower) alkylamino group, a lower alkoxycarbonylamino group, a hydroxy (lower) Alkyl group, protected hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, halogeno (lower) alkyl group, unsubstituted or substituted phenyl group, formyl group, carboxyl group, protected carboxyl group, A rubamoyl group or a mono- or di- (lower) alkyl radical rubamoyl group;

 A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group,

 W represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, an amino group, a mono- or di- (lower) alkylamino group, a mono- or di- (lower) alkylamino (lower) alkylamino group , Pyrrolidinyl group, piperidinyl group, butyl group, butyl group substituted with lower alkoxy or unsubstituted or substituted phenyl group.)

And a pharmaceutically acceptable acid addition salt thereof, a pharmaceutical composition containing the same and a compound represented by the following formula (IXa):

[Wherein R ⁹ is a hydroxy group, a lower alkoxy group or the following formula [C]

^{- NH (R 1 0) [} C]

(Wherein R ¹⁰ is a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) Alkyl, unsubstituted or substituted fuunyl, unsubstituted or substituted fuunyl (lower) alkynole, lower alkenyl, hydroxy (lower) alkyl, halogeno (lower) alkyl or lower alkyl substituted with cyano. means)

Wherein A, R ³ , R ⁴ and W have the same meanings as described above, and a salt thereof.

 A pharmaceutically acceptable acid addition salt of a compound represented by the formula (I) is defined as a pharmaceutically acceptable acid addition salt of the compound of the formula (I) when it has a sufficient basicity to form an acid addition salt. Means the acid addition salts that are permissible for, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and maleate, fumarate, oxalic acid Organic salts such as salt, malonate, malate, citrate, tartrate, lactate, benzoate, methanesulfonate, p-toluenesulfonate, and dalconate. Since the compound represented by the formula (I) and the pharmaceutically acceptable acid addition salt thereof may exist in the form of hydrate and Z or solvate, these hydrate and Z or Solvates are also included in the compounds of the present invention.

 The salt of the compound represented by the formula (IXa) means an acid addition salt, an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. Specifically, examples of the acid addition salt include those described in the above “Pharmaceutically acceptable acid addition salt of the compound represented by the formula (I)”. Examples of the alkali metal salt include inorganic alkali salts such as a sodium salt and a potassium salt. Examples of the alkaline earth metal salt include a calcium salt and a magnesium salt, and a salt with an organic group. Examples thereof include salts with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and dihexylhexylamine.

 The compounds of the formulas (I) and (IXa) optionally have one or more asymmetric carbon atoms and may give rise to geometric isomerism. Thus, the compounds of formula (I) may optionally exist in more than one stereoisomeric form. These stereoisomers, optical isomers, mixtures thereof and racemates are included in the compounds of the present invention.

The 2-arylpurine-19-acetoamide derivatives of the present invention are assigned the position number of the purine ring as shown in the following formula, and in the present specification, the order is determined according to this position number. Name.

 1

(Where A, W and R ⁴ mean the same as above)

 The terms used in this specification are described below.

 The lower alkyl group and the lower alkyl moiety have 1 to 1 carbon atoms unless otherwise specified.

6 means either linear or branched. Specific examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. One to four is preferred. "Lower alkoxy group" means an alkoxy group having 1 to 6 carbon atoms, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentyloxy. The term "lower alkenyl group" means a group having 3 to 6 carbon atoms having one double bond other than between the 1- and 2-positions, and examples include aryl and 2-butyr. The "cycloalkyl group" means one having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentinole, cyclohexyl, cycloheptyl, and cyclooctyl. The “cycloalkyl (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms which is substituted by the above “cycloalkyl group”, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl Are listed.

Specific examples of the “lower alkylthio group” include methylthio and ethylthio. “Hydroxy (lower) alkyl group” means a lower alkyl group substituted with a hydroxy group, and includes, for example, hydroxymethyl, 2-hydroxyhexyl, and 3-hydroxypentyl. "Protected hydroxy (lower) alkyl" means a group which is readily removed to convert to a "hydroxy (lower) alkyl" by hydrolysis or hydrogenolysis, such as acetomethyl , Benzyloxy methinole, 2-acetoxicetinole, 2-pendinoleoxyethyl, 4-clozen Examples include noroxymethyl, 3-bromobenzyl / reoxymethyl, benzoyloxymethyl 4-phenylbenzoate, 4-methylbenzyloxymethyl, and 4-methoxybenzinoleoxymethyl. The “lower alkoxy (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted by the above “lower alkoxy group”, such as methoxymethyl, ethoxymethyl, 2-methoxethyl, —Methoxypropyl.

"Lower alkanoyl group" means an alkanoyl group having 2 to 6 carbon atoms, for example, acetyl, propionyl, and butyryl. Specific examples of the “lower alkoxyl group” include methoxycarbonyl, ethoxycanoleponyl, and propoxycarbonyl. "Protected Karubokishinore group", pressurized water solutions or hydrogenolysis ^ by protecting groups which can eliminated, for example, ~ Ji alkyl group or halogen, 〇 ₁ Ji ₃ Arukiru Oyobi 〇 ₁ ～〇 ₃ Alkoxyl group protected by a benzyl group which may be substituted with one or two alkoxy groups. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycanoleponyl, and benzyloxycanolepo. Chinore, 4-black mouth pendinoleoxycarbinole,

4-methoxybenzylcarbonyl, but methoxycarbonyl, ethoxycarponyl and benzyloxycarbonyl are preferred. “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The “halogeno (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms, which is substituted with a halogen atom. Examples thereof include chloromethinole, fluoromethyl, trifluorenolomethyl,

2,2,2-Trifluoroethyl. “Lower alkyl group substituted with cyano” means an alkyl group having 1 to 4 carbon atoms substituted with a cyano group, and examples thereof include cyanomethyl and 2-cyanoethyl.

“Mono or di (lower) alkylamino group” means an amino group in which one or two alkyl groups having 1 to 4 carbon atoms are substituted, such as methylamino, ethylamino, propylamino, dimethylamino, Getylamino, dipropylamino, and ethylmethylamino. The “mono or di (lower) alkylamino (lower) alkylamino group” means an alkylamino group having 1 to 4 carbon atoms, which is substituted by the above “mono or di (lower) alkylamino group”. 2— Dimethylaminoethylamino. The “lower alkoxycarbonylamino group” means an amino group substituted by the above “lower alkoxycarbonyl group”, and includes, for example, methoxycarbonylamino and ethoxycarbonylamino. Specific examples of "mono- or di- (lower) alkyl rubamoyl groups" include methylcarbamoyl, ethylcanolebamoyl, dimethynole / levamoyl, and germinol rubamoyl.

 A specific example of the “lower alkoxy-substituted bullet group” is 1-ethoxyvinyl.

 “Unsubstituted or substituted phenyl group” is selected from halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, carboxy, lower alkoxyl ruponyl, amino, mono or di (lower) alkylamino, cyano and nitro Means a phenyl group which may be substituted by 1 to 3, for example, phenyl; 2-, 3- or 4-cyclophenyl; 2-, 3- or 4-bromophenyl; —, 3- or 4-fluorophenyl; 2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl; 2-, 3- or 4-methoxy Phenyl; 3,4-dimethoxyphenyl; 3,5-dimethoxyphenyl; 2-, 3- or 4-trifluoromethyl ^ / phenyl; 2- 3- or 4-hydroxyphenyl; 2-, 3- or 4-carboxyphenyl; 2-, 3- or 4-methoxycarbylphenyl; 2-, 3- or 4-aminophenyl; 2-, 3- or 2-, 3- or 4-dimethylaminophenol; 2-, 3- or 4-cyanophenol; 2-, 3- or 4-nitrophenyl; 3 —Chloro-4-fuzoleo phenyl; 4-fluoro-3-methoxyphenyl; 4-fluoro-3-trifluoromethylphenyl; 2,3,4-trifluorophenyl; 3,4,5-trifluorophenyl; 3,4,5-trimethoxyphenole; 3,4-diphenylole-5-trifluoromethylphenyl.

“Unsubstituted or substituted phenyl group (lower) alkyl group” means a halogen atom, lower alkyl, lower alkoxy, trinoleolomethyl, hydroxy, carboxy, lower alkoxycarbonyl, amino, mono or di (lower) alkylamino, A alkynyl group having 1 to 4 carbon atoms which is substituted by a phenyl group which may be substituted by 1 to 3 atoms selected from ano and nitro; for example, benzyl;

2-, 3- or 4-bromobenzyl; 2-, 3- or 4-fluorobenzyl; 2,4-dichlorobenzyl; 2,4-dibromobenzinole; 2,4-difluoro 2-, 3- or 4-methylbenzyl; 2-, 3- or 4-methoxybenzyl; 2-, 3- or 4-trifluoro lomethizolebenzizole; 2-, 3- or 4-hydroxybenzinole; 4-carboxybenzyl, 4-methoxycarbinolebenzyl, 2-, 3- or 4-aminobendinole; 2-, 3- or 4-methylaminobenzyl; 2-, 3- or 4-dimethylaminobenzyl; 2-, 3_ or 4-cyanobenzinole; 2-, 3- or

4-Nitrobenzil; phenethyl; 2- (4-chloropheninole) ethyl.

 Expressions [A,] and [B]

As specific examples of the group represented by the above, the above-mentioned “unsubstituted or substituted phenyl group” can be mentioned as it is. Preferred specific examples are pheninole; 4- or 3-chloro phenyl group. 4- or 3-bromophenylol; 4- or 3-phenylolenyl; 4-methoxyphenyl; 4-triphenylolomethylphenyl; 4-hydroxyphenyl.

"Unsubstituted or substituted heteroaryl group" refers to a 5-membered ring containing at least one nitrogen, oxygen or sulfur atom, which may be substituted with CiCg alkyl, a halogen atom or trifluoromethyl. Or a 6-membered monocyclic heteroaryl group or a 5-membered to 6-membered bicyclic heteroaryl group, for example, 2-, 3- or 4-pyridyl; 5-methinolay 2-pyridyl 2— or 3 _ Cheni 2- or 3-furyl; 2- (5-methyl) furyl; 2-, 4- or 5-pyrimidinole; 2- or 3-pyrazinole; 1-pyrazolyl; 2T midazolinole; 2-thiazolinole; 3f Soxazolyl; 5-methyl-3-isoxazolyl; quinolyl; isoquinolyl.

Among the compounds of the present invention, preferred are those represented by formula (I) wherein A is the following formula [式 ']

(Wherein, R ⁵ is a hydrogen atom, a halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy groups, trifluoperazine Ruo Russia methyl group, hydroxy group, carboxyl group, C ₁ -C ₃ 7 alkoxy A carbonyl group, an amino group, a mono- or di- (C ₁ -C ₃ ) alkylamino group, a cyano group or a nitro group, and R ⁶ is a hydrogen atom, a halogen atom, a Ci-C ₃ alkyl group, a C ₁ -C ₃ An alkoxy group or a hydroxy group) or a pyridyl group, a phenyl group, a thienyl group or a furyl group which may be substituted with a C i -C ₃ alkyl group, respectively. Compounds that are the same can be mentioned.

Further preferred compounds include those represented by formula (I): ^ Is an alkyl group or a C ₃ to C ₆ cycloalkyl group, and R ² is a C i to C ₄ alkyl group or the following formula [B]

(Wherein, R ⁷ is a hydrogen atom, a halogen atom, C -C ₃ alkyl group, C ₁ -C ₃ alkoxy groups, trifluoperazine Ruo Russia methyl group, hydroxy group, carboxyl group, C ₁ -C ₃ § alkoxycarbonyl group, amino group, mono- or di (Ci C ^ alkylamino group means an Shiano group or a nitro group, R ⁸ is a hydrogen atom, a halogen atom, Ci~ C ₃ alkyl group, C ₁ -C ₃ alkoxy or hydroxy or a group represented by means a group), or be replaced, respectively become the nitrogen atom and one cord R ¹ and R ² are respectively bind one or two Flip-Ji ₃ alkyl group Good Compounds which may form a piperidine ring, a pyrrolidine ring, a morpholine ring or a piperazine ring, and in which the other substituents are the same as the above-mentioned preferred compounds are mentioned. As more preferred compounds, in the formula (I), A represents the following formula [A "]

(In the formula, R ⁵¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a cyano group or a nitro group. R ⁶¹ represents a hydrogen atom, a halogen atom or a Ci Cg alkoxy group)

In a represented by group, R ¹ is a C i to C ₄ alkyl group or a C ₃ ~ C ₆ cycloalkyl group, 1¾ ² is represented by the following formula [8 ']

[B]

(Wherein, R ⁷¹ is a hydrogen atom, a halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy groups, trifluoperazine Ruo Russia methyl group, hydroxy group, amino group, refers to a Shiano group or a nitro port group And R ⁸¹ represents a hydrogen atom, a halogen atom, a C Cg alkyl group or a ~ C ₃ alkoxy group)

And compounds in which the other substituents are the same as those described above. In the formula (I), R ⁴ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, a C ₃ -C ₆ cycloanoalkyl group, a halogen atom, a Ci Cg alkoxy group, a C ₁ -C ₃ alkylthio group or a halogeno (-. ^ it is preferably a compound which is an alkyl group, a hydrogen atom, Ct C ₃ alkyl group, more preferably a compound which is C ₃ -C ₆ cycloalkyl group, the compound is a hydrogen atom is particularly preferred.

In the formula (I), a compound in which W is a hydrogen atom or a C ₃ -C ₃ alkyl group is preferred, and a compound in which W is a hydrogen atom is particularly preferred.

Particularly preferred compounds include 2-aryrubrin-19-acetamide derivatives represented by the following formula (Ia) and pharmaceutically acceptable acid addition salts thereof.

(In the formula, R ¹¹ represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a cyclopropyl group,

R ^{5 2} is a hydrogen atom, a halogen atom, a methoxy group, hydroxy group or Torifuruo Romechiru group,

R ^{7 2} is a hydrogen atom, a halogen atom, a methyl group, main butoxy group, hydroxy group or amino group)

 Specific examples of particularly suitable compounds include, for example, the following compounds.

 N-methinole N-pheninole 2-Heninole 9 H-purine 9-acetoamide (compound of Example 1),

 N-cyclopropynole N-phenyl 2-phen-2-ole 9 H-purine 9-acetamide (compound of Example 63); and

 N- (4-Chlorophenyl) -1-N-methinole 2-H-phenyl-9H-purine-19-acetamide (compound of Example 80).

 Specific examples of the compounds included in the present invention include the compounds of Table 1 and pharmaceutically acceptable acid addition salts thereof in addition to the compounds of the Examples described later.

 The following abbreviations may be used in Table 1 of the present specification and in the following Reference Examples and Examples to simplify the description.

 M e: methyl group

 E t: ethinole group

 P r: n-propyl group

 iPr: isopropyl group

 B u: n-butynole group

 i B u: isobutyl group

s B u: sec-butynole group t B u: tert-butynole group

 c P r: cyclopropyl group

 A c: acetyl group

 P h: phenyl group

 B z 1: Benzinole group

 P y: pyridyl group

 T h i: Chenyl group

 Thus, for example, 3--Ph represents a 3-chlorophenyl group, 2-F-Ph represents a 2-fluorophenyl group, and 2-Thi represents a 2-phenyl group.

R ¹ R ² R ³ R ⁴ WA

Me Ph H H H 4-Br-Ph

Me Ph H H H 2-F-Ph

Me Ph H H H 3-Py

Me Ph H Me H 2-Thi

CH ₂ CH = CH ₂ Ph HHH Ph

CH ₂ -cPr Ph HHH Ph

 Me Ph H COOH H Ph

Me Ph H COOEt H Ph

Me Ph H CONH ₂ H Ph

Me Ph H CONMe ₂ H Ph

Me Ph HH NH ₂ Ph Me Ph HH Ph Ph

Me Ph H H 1-piperidinole Ph

-(C¾) ₄ -HHH Ph

Me Ph CH ₂ OH HH 4-OMe-Ph

In the above formula (IXa), R ⁹ is a hydroxy group or the following formula [C]

— NH (R ¹⁰ ) [C]

[Wherein, R ¹⁰ represents a 〇-〇 alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₃ -C ₆ cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl ( Alkyl group, C ₃ -C ₆ alkenyl group, hydroxy (C ₁ -C ₄ ) alkyl group, halogeno (.C ₁ -C ₄ alkyl group or a C ₄ -C ₄ alkyl group substituted with cyano (phenyl) The substituent of the group is a halogen atom, a CjCs alkyl group, a C ₁ -C ₃ anoreoxy group, a trinoleolomethinole group, an amino group, a hydroxy group, a cyano group or a nitro group)]

A compound represented by the formula or a salt thereof is preferred as an intermediate.

In the formula (IXa), R ⁹ is the following formula [C]

-NH (R ¹⁰ ) [C]

(Where R ¹⁰ is the same as above)

The compound represented by the formula (I) is useful as an intermediate of the compound of the formula (I), and the compound represented by the formula (IXa) wherein R ⁹ is a hydroxy group is represented by the formula (I) and the formula (IXa). Thus, R ⁹ is useful as an intermediate of a compound of the formula [C].

 The compound of the present invention can be produced, for example, by the following method.

Production method (a)

In the formula (I), the compound wherein R ⁴ is a hydrogen atom is represented by the following formula (II)

(II)

(Wherein, RR ² , R ³ , A and the same as those described above) are cyclized in the presence of a formic acid derivative and, if necessary, deprotected. can do.

 This reaction is usually performed in the presence of a formic acid derivative without a solvent, but can also be performed in the presence of a solvent. Examples of the formic acid derivative include formamide, formic acid, and ethyl formate. Examples of the solvent used include acetic anhydride, dimethyl sulfoxide, and N-methylpyrrolidone. The reaction temperature is usually about 50 ° C. to about 250 ° C., and preferably about 100 ° C. to about 220 ° C.

 The deprotection performed as necessary is usually performed by hydrolysis or hydrogenation shown below. In the production methods (b) to (e) described below, deprotection can be similarly performed as necessary using the following method.

 The hydrolysis can be carried out according to a conventional method, for example, by contacting with water in a suitable solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used. Specific examples of acids include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid, acetic acid, propionic acid and oxalic acid. Specific examples of the base include sodium hydroxide, alkali hydroxide such as potassium hydroxide, and alkali carbonate such as sodium carbonate and potassium carbonate. The reaction temperature is usually from about 20 ° C to about 100.

 Hydrogenolysis can be carried out according to a conventional method, for example, by reacting with hydrogen in a suitable solvent in the presence of a catalyst such as palladium carbon or Raney nickel. As the solvent, for example, alcohols such as ethanol and methanol, water, acetic acid, dioxane, and tetrahydrofuran are used. The reaction temperature is usually about 0 ° C to about 80 ° C, and the reaction is carried out under normal pressure or under pressure.

Accordingly, by appropriately deprotecting a compound in which one or more substituents of RR ² and R ³ in formula (I) are protected hydroxy (lower) alkyl by the above method, the compound represented by formula (I) A compound in which the desired position of RR ² or R ³ is a hydroxy (lower) alkyl group can be obtained.

On the other hand, the compound of the formula (II) is obtained by referring to Reference Example 20 and WO 96-32383 21 and can be produced by a method according to the methods described in Examples 121 and 122.

Production method (b)

In the formula (I), R ⁴ is a lower alkyl group, a cycloalkyl group, a lower alkoxy (lower) alkyl group, a halogeno (lower) alkyl group, a hydroxy (lower) alkyl group, a protected hydroxy (lower) alkyl group, formyl The compound which is a group or an unsubstituted or substituted phenyl group is represented by the following formula (III)

(Wherein, RR ² , R ³ , RA and the same as those described above) are produced by heating to cyclize the compound, and then deprotecting if necessary be able to.

 This reaction is generally performed without a solvent, but may be performed in the presence of an acid catalyst in some cases. Examples of the acid catalyst include polyphosphoric acid, concentrated hydrochloric acid, and concentrated sulfuric acid. The reaction temperature is usually about 180 ° C to about 220 ° C.

The compound of formula (I) in which one or more substituents of R ¹ R ² , R ³ and R ⁴ are protected hydroxy (lower) alkyl is appropriately deprotected by the above-mentioned method to obtain a compound of formula (I) ), A compound wherein the desired position of RR ² , R ³ and R ⁴ is a hydroxy (lower) alkyl group can be obtained. Hereinafter, the same applies to production methods (c) to (e).

 The compound of the above formula (II) has the following formula (II)

(Where RR ² , R ³ , A and * W mean the same as above)

The compound represented by the following formula (IVa) or (IVb) R ⁴ -COX (IVa)

(R ⁴ -CO) ₂ O (IVb)

(Where X represents a halogen atom, and R ⁴ represents the same as described above)

The compound represented by _c the reaction can be prepared by reacting in the presence of a base can be carried out in the presence in a solvent-free or solvent. Examples of the solvent include halogenated hydrocarbons such as chloroform and methylene chloride, and aromatic hydrocarbons such as benzene, toluene and xylene. Examples of the base include organic bases such as pyridine and triethylamine. The reaction temperature is usually about 0 ° C to about 180 ° C, preferably about 20 ° C to about 130 ° C.

Production method (c)

 The compound of the formula (I) is represented by the following formula (V)

(Where A, W and R ⁴ mean the same as above)

And a compound represented by the following formula (VI)

Z then CH (R ³ ) —CONiR ¹ ) (R ² ) (VI)

(Wherein, Z ¹ represents a leaving atom or a leaving group, and RR ² and R ³ have the same meanings as described above.)

The compound can be produced by reacting with a compound represented by the formula and deprotecting if necessary.

The leaving atom or leaving group represented by Z ¹ in the formula (VI) is an atom or group capable of leaving in the form of HZ ¹ together with the hydrogen atom in the NH portion of the compound of the formula (V) under the reaction conditions. Means, for example, a halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfoninoleoxy, benzenesulfonyloxy, p — An arylsulfonyloxy group such as toluenesulfonyloxy. The reaction between the compound represented by the formula (V) and the compound represented by the formula (VI) can be performed in the presence of a base, without a solvent, or in a suitable solvent under normal pressure or pressure. Examples of the solvent used include toluene, xylene, dimethoxyethane, 1,2-dichloroethane, acetone, methylethylketone, dioxane, diglyme, ethylethyl acetate, dimethylformamide, and dimethylsulfoxide. Examples of the base include sodium hydride, triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about 1-10 ° C to about 150 ° C, preferably about 10 ° C to about 70 ° C.

 The compound of the formula (V) is represented by the following formula (V I I)

 (Where Α and t W mean the same as above)

Can be produced by cyclizing the compound represented by the formula (a) or (b).

 The compound of the formula (VI) can be produced by a method known per se, for example, the method described in JP-A-62-64 or a method analogous thereto.

In the formula (V), the compound wherein R ⁴ is a halogen atom is represented by the following formula (VIII)

 (Where A and * W mean the same as above)

Can be produced by halogenating a compound represented by the formula (1) with a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide or the like in a conventional manner.

Starting compound (VIII) can be produced, for example, by the method shown in Scheme 1 below. scheme

NH ₃ process 2

Cyclization

Step 3 Step 4

 (C) (D)

 (vni)

 (In the formula, R represents a lower alkyl group, Z is a halogen atom or an arylsulfonyloxy group such as a p-toluenes-norefonoleoxy group, a methanes / levoninoleoxy group, or a methanesolenonyloxy group such as a methanesolephonyloxy group or an alkenylsulfonyloxy group, etc. A and * W mean the same as above.)

Step 1: Halogenation or sulfonylation

 The halogenation is performed, for example, by reacting a compound of the formula (A) with a halogenating agent (for example, phosphorus oxychloride, phosphorus tribromide). In the sulfonolelation, for example, a compound of the formula (A) is reacted with a sulfinolelating agent (for example, methanesulfonyl chloride, p-toluenesulfuryl chloride, trifluoromethanesulfonyl chloride). This is done by letting

Step 2: Amination

The reaction between the compound of the formula (B) and ammonia is carried out at normal pressure or under pressure in the absence of a solvent or in a suitable solvent. Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ketones such as methylethyl ketone and methyl isobutyl ketone, ethers such as dioxane and diglyme, and alcohols such as ethanol, isopropanol and butanol. , Acetonitrile, dimethylformamide, dimethylsulfoxide. This reaction is preferably performed in the presence of a base. Specific examples of the base include sodium carbonate, sodium carbonate such as sodium carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate such as sodium hydrogen carbonate, and the like. Examples include tertiary amines such as potassium and triethylamine, but can also serve as an excess of ammonia. The reaction range varies depending on the type of raw material compounds, reaction conditions and the like, but is usually about 0 ° C to about 200 ° C, preferably about 20 ° C to about 100 ° C.

Step 3: Hydrolysis

 The present hydrolysis can be carried out according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used. Specific examples of acids include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid, acetic acid, propionic acid and oxalic acid. Specific examples of the base include sodium hydroxide, sodium hydroxide such as potassium hydroxide, sodium carbonate, and sodium carbonate such as carbonate carbonate. The reaction temperature is usually about 20 ° C to about 100 ° C.

Step 4: Cyclization

This reaction can be carried out by reacting a compound of the formula (D) with an azide compound. Examples of the azide compound used in this reaction include diphenylphosphoric acid azide and sodium azide. This reaction can be usually performed in the presence of a base, without a solvent, or in a suitable solvent under normal pressure or pressure. Examples of the solvent to be used include tonoleene, xylene, dimethoxetane, 1,2-dichloroethane, acetone, methylethylketone, dioxane, diglyme, ethinoleate, dimethylformamide, and dimethylsulfoxide. Examples of the base include triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about 10 to about 150, preferably about 30 ° C to about 120 ° C. Compounds of the starting material (A) are commercially available or known per se, for example, J. Am. Chem. Soc., 74, 842 (1952); Chem. Ber., 95, 937 (1962); J. Org. Chera., 29, 2887 (1964); J. Med. Chem., 35, 4751 (1992); J. Org. Chem., 58, 4490 (1993); Synthesis, 86 (1985) and WO It can be produced by the method described in Reference Example 1 of JP-A-96-32383 or a method analogous thereto. In the formula (V), the compound wherein W is a halogen atom is obtained by reacting N-lower alkanol-12-cyanoglycine ethyl ester with unsubstituted or substituted benzamidine hydrochloride in the presence of a base, It can be produced by cyclizing the obtained reaction product in the presence of phosphorus oxychloride, and is specifically shown in Reference Examples 69 and 73 below. Production method (d)

 The compound of the formula (I) is represented by the following formula (IX)

(Where A, R ³ , R ⁴ and * W mean the same as above)

And a reactive derivative thereof represented by the following formula (X)

HN (R ¹³ ) (R ²³ ) (X)

(Wherein, R ¹³ and R ²³ represent a hydrogen atom or the same as defined above for R ¹ and R ² respectively)

When one of R ¹³ and R ²³ is a hydrogen atom, the compound represented by the following formula (XIa) or (XIb)

R ²⁴ -Z ¹ (XI a)

R ¹⁴ -Z ¹ (XI b)

(Wherein, R ²⁴ represents a lower alkyl group, a cycloalkynole group, a cycloalkyl (lower) alkyl group or an unsubstituted or substituted phenyl (lower) alkyl group, and R ¹⁴ represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group means a cycloalkyl (lower) alkyl, hydroxy (lower) alkyl, halogeno (lower) lower alkyl group substituted with an alkyl group or § Bruno, Z ¹ is the same as defined above. And伹, when R ^{1 3} is a hydrogen atom reacting a compound of formula (XI a), when R ^{2 3} is a hydrogen atom shall reacting a compound of formula (XI b))

The compound can be produced by reacting with a compound represented by the formula and deprotecting if necessary.

 Reactive derivatives of the compound of formula (IX) include, for example, lower alkyl esters

(Especially methyl esters), active esters, acid anhydrides, acid halides (especially acid chlorides). Specific examples of the active ester include p-nitrophenylester, 2,4,5-trichlorophenol enoester, and N-hydroxyconodic acid imido ester. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl ester such as ethyl chlorocarbonate or isobutyl chlorocarbonate. Mixed acid anhydrides with aralkyl carbonates such as benzoyl carbonate, mixed acid anhydrides with aralkyl chlorocarbonates such as phenol carbonates, etc. Mixed acid anhydrides with alnic acid such as sovalic acid and bivalic acid can be mentioned.

When using a compound itself of formula (IX), N, N'Jishiku port to Kishirukarupoji imide, 1-Echiru ₃ i (3-dimethylaminopropyl § amino propyl) Karupojiimi de hydrochloride, N, N'Karuboeru Diimidazonole, N, N, imidylcarbodidisuccinate, 1-ethoxycanoleboninole-1, 2-ethoxy-1,2-dihydroquinoline, dipheninole phosphoryl azide, propanephosphonic anhydride, benzotriazoine The reaction can be carried out in the presence of a condensing agent such as phenyl-1-tris (dimethylamino) phosphonium hexafluorophosphate.

The reaction of the compound of the formula (IX) or a reactive derivative thereof with the compound of the formula (X) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compounds, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as dimethyl ether, tetrahydrofuran, and dioxane. , Halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as ethanol and isopropanol, ethyl acetate, acetone, acetonitrile, dimethinoleformamide, dimethyl sulfoxide, ethylene glycol, water, etc. Each of these solvents is a warworm or a mixture of two or more. Used. This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include sodium hydroxide, aluminum hydroxide such as potassium hydroxide, sodium carbonate, and carbonate such as potassium carbonate. Alkali hydrogen, sodium bicarbonate, alkali hydrogen carbonate such as hydrogen carbonate, or organic groups such as triethylamine, tributynoleamine, diisopropylinoleethylamine, and N-methylmorpholine. An excess amount of the compound of the formula (IX) may also serve as the compound. The reaction varies depending on the type of the starting compound used, etc. Usually, the temperature is about 130 ° C to about 200 ° C, preferably about -10 ° C to about 150 ° C.

 The reaction between the product obtained by the reaction of the compound of the formula (IX) with the compound of the formula (X) and the compound of the formula (XIa) or the formula (XIb) is carried out by the method described in the above-mentioned production method (c). You can do it with S.

 The compound of the formula (IX) is represented by the following formula (V)

(Where A, W and R ⁴ mean the same as above)

The compound represented by the following formula (XII)

Z — CH (R ³ ) — COOR (XII)

(Where R, R ³ and Z ¹ mean the same as above)

After reacting the compound represented by the formula, it can be produced by hydrolyzing the product according to a conventional method.

 In this reaction, the method described in the above production method (c) can be used as it is. The compounds of the formulas (XIa) and (XIb) can be produced by commercially available power or a method known per se.

Manufacturing method)

The compound of the formula (I) is represented by the following formula (XIII)

(Where RR ² , R ³ , R ⁴ and IKW mean the same as above)

In the presence of a diazotizing agent and a catalyst, a compound represented by the following formula (XIV)

 A-H (X I V)

(Where A means the same as above)

Can be produced by reacting a compound represented by the formula (1) and deprotecting if necessary.

 This reaction is generally performed without a solvent because the compound of the above formula (XIV) also functions as a solvent, but an appropriate solvent may be used. Examples of the diazotizing agent used in this reaction include alkyl nitrites such as isoamyl nitrite and tert-butyl nitrite. The catalyst used in this reaction includes cuprous oxide. The reaction temperature is usually about 50 ° C to about 200 ° C, preferably about 80 ° C to about 150 ° C.

 The compound of the above formula (XIII) is represented by the following formula (XIV)

(Where R ⁴ and * W mean the same as above)

And a compound represented by the following formula (VI)

Z then CH (R ³ ) — COISKR ¹ ) (R ² ) (VI)

(Wherein R ¹ R ² , R ³ and Z ¹ mean the same as above)

The compound can be produced by reacting with a compound represented by the formula and deprotecting if necessary.

 The reaction between the formula (XIV) and the formula (VI) can be carried out by the method described in the production method (c).

The compound of the formula (XIV) is commercially available or produced by a method known per se. be able to.

 The compound of the present invention can also be produced by the following method.

The compound of the formula (I) in which R ⁴ is a lower alkoxy group can be produced by reacting the compound of the formula (II) with tetramethoxymethane in the presence of sodium acetate. And 25.

The compound of the formula (I) in which R ⁴ is a mono- or di- (lower) alkylamino group or a lower alkoxycarbonylamino group can be produced by reacting the compound of the formula (II) with an isothiocynate. This is specifically shown in Examples 27 to 30 below. Further, the compound wherein R ⁴ is an amino group can be produced by deprotecting the compound of the formula (I) wherein R ⁴ is a lower alkoxycarbonylamino group by the above-described hydrolysis method. .

A compound in which R ⁴ is a formyl group in the formula (I) can be produced by oxidizing a compound in which R ⁴ is a hydroxy (lower) alkyl group in the formula (I) with an oxidizing agent such as manganese dioxide. This is specifically shown in Example 59 below.

In the formula (I), a compound in which R ¹ and Z or A is a phenyl group substituted with hydroxy is a compound in which the corresponding substituent is a phenyl group substituted with methoxy, and By demethylation, and specifically shown in Example 23 below.

A compound in which R ¹ and Z or A in the formula (I) are a phenyl group substituted with an amino is prepared by reducing a compound having a corresponding phenyl group substituted with a nitro by a conventional method. This is specifically shown in Example 71 below. In the formula (I), the compound in which W is a mono- or di- (lower) alkylamino group or a pyrrolidinyl group is obtained by adding a mono- or di- (lower) alkylamine or pyrrolidine to the compound in which W is a halogen atom in the formula (I). It can be produced by reacting, and is specifically shown in Examples 72 and 110 described later.

A compound in which W or R ⁴ is a lower alkoxy group or a lower alkylthio group in the formula (I) is reacted with a metal lower alkoxide or a metal thio lower alkoxide corresponding to the compound in which W is a halogen atom in the formula (I). This is specifically shown in Examples 74, 78 and 79 described later. The compound of the formula (I) wherein W is a lower alkoxybutyl group or a butyl group is prepared by reacting a compound of the formula (I) wherein W is a halogen atom with tributyl (lower alkoxyoxy) tin or tributylvinyltin, respectively. Specific examples are shown in Examples 112 and 116 described later.

 The compound of the formula (I) wherein W is a lower alkanoyl group can be produced by treating a compound of the formula (I) wherein W is a lower alkoxybutyl group with hydrochloric acid. See Figure 4.

 The product obtained by each of the above production methods can be isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation. The compound of the formula (I) having a basicity sufficient to form an acid addition salt can be converted into an acid addition salt by treating with a variety of acids according to a conventional method. Various stereoisomers of the compound of the formula (I) can be separated and purified according to a conventional method such as chromatography.

 The test results of representative compounds of the present invention are shown below, and the pharmacological properties of the compounds of the present invention will be described.

Test Example 1: Central (ω ω ₂ ) and peripheral (ω ₃ ) benzodiazepine receptor binding test

Β は The ω and ω ₂ receptor binding tests and preparation of receptor membrane preparations were performed according to the method of Stephens, DN et al. [See J. Pharmacol. Exp. Ther., 253, 334-343 (1990)]. beta Zeta omega ₃ receptor binding test and receptor article preparation, Schoemaker, the method of H. [J. Pharmacol. Exp. Ther ., 225, 61-69 (1983) refer] was carried out in accordance with.

ω ₁ ω ₂ and ω ₃ receptor membrane preparations were prepared from the cerebellum (ω i), spinal cord (ω ₂ ), or kidney (ω ₃ ) of 7-8 week old male Wistar rats, respectively, by the following procedure. . To the cerebellum or spinal cord, a 20-fold volume of ice-cold buffer (5 OmM tris-citrate buffer, pH 7.1) was added and homogenized, followed by centrifugation at 40,000 Og for 15 minutes. The obtained sediment was washed four times by the same operation, and stored frozen at 160 at 24 hours. Thaw the frozen sediment, wash with buffer, and centrifuge.Separate the sediment to obtain a buffer I for binding test (including 12 OmM sodium chloride, 5 mM chloride, 2 mM calcium chloride, and 1 mM magnesium chloride. 5 0 mM tris monohydrochloride buffer, pH 7. 4) for binding trial those suspended (1 g tissue wet weight Z 4 O ral) as BZ omega or omega ₂ receptor membrane preparation Used for the experiment. On the other hand, a 20-fold volume of ice-cold binding test buffer 11 (5 OmM sodium phosphate monophosphate buffer containing 10 OmM sodium chloride sodium phosphate, pH 7.4) was added to the kidney, and homogenized. The filtrate filtered with the overlapping gauze was centrifuged at 40,00 Og for 20 minutes. Those obtained sediment was suspended in buffer II (1 g tissue wet weight Z 10 Oral) was used for the binding assay as Betazetaomega ₃ receptor) H ^ goods.

The labeled ligand and unlabeled ligands, 82 _£ 0 ₁ Oyobi 0) in ₂ receptor binding assay ^[3 Eta] flumazenil: 8- Furuoro 5, 6 dihydric mud one 5- methyl-6- Okiso one 4 Eta f Midazo [1,5—a] [1,4] Benzodazepine-13-force Ethyl rubonate (Rol5- 1788) [final concentration (ω i: 0.3 ηΜ) (ω ₂ : 1 η Μ)] and fluetrazepam: 5 — (2-Fluorine) 1 1, 3-Jihi Draw 1

- methyl one 7-nitro one 2 Η- 1, 4- Benzojiazepin one 2-one (final concentration 1 Ο / ζΜ), the Betazetaomega ₃ receptor binding assay ^[3 Eta] 4'black port Jiazepamu: 7- Chlor-1,3-Dihydro 1-Methinole 5 _ (4-Chloro-Feninole) -1 2 Η— 1,4-Diazepine 1-2-one (Ro5--4864) (final concentration 0.5 nM ) and Jiazepamu (final concentration 100 were used, respectively. incubation _conditions, ΒΖ _ω ι and omega ₂ receptor binding for 30 min at 37 ° C for a test was carried out 15 0 min at 0 in the BZ omega ₃ receptor binding test . in addition, Β Ζ ω! and ω ₂ receptor binding studies Bikiyutarin

(bicuculline: final concentration 100 M).

The receptor binding test was performed according to the following procedure. To each test tube, add a test compound of known concentration, tritium-labeled ligand, receptor membrane sample, and buffer I or II for binding test to make a total volume of lml of the reaction solution. ^ The reaction was started by the addition of the sample. After incubation, the labeled ligand bound to the receptor was suction-filtered onto Whatman GF / B glass fiber filters using a Cellno-Poster (Brandel, USA) to terminate the reaction. Immediately, [in _{omega iota} and omega ₂ 5 Omm tris monohydrochloride buffer (pH 7.7); the omega ₃ buffer II] ice-cold buffer and at 5 m 1 3 Kaiarai Kiyoshi. The radioactivity was measured by using a scintillation counter after transferring the filter to a vial, adding 10 ml of a liquid scintillation container (ACS-II, manufactured by Amersham, USA), and incubating for a certain period of time. Specific binding was determined by subtracting the non-specific binding in the presence of unlabeled ligand from the total binding. Was. The concentration at which the test compound inhibited the specific binding amount of the labeled ligand by 50% (IC ₅ value) was determined by the logit method. IC ₅ for ω ₃ receptor binding. The values are shown in Table 2.

Incidentally, IC ₅₀ values of omega and omega ₂ receptor binding of the test compound shown in Table 2 was had shifted even more than 1000 nM values.

 Table 2

* Refers to the compound of Example 1. (Hereinafter, each means the compound corresponding to the example number) The compounds of the present invention shown in Table 2 is strongly bonded to the BZ 0 ₃ receptor. In contrast, IC ₅ of _ΒΖ ω ι and 8Σ 60 ₂ receptors for these compounds. Since the value is 1000 nM or more, compounds of the present invention will be apparent with selective and potent binding child to BZ omega ₃ receptor.

Test Example 2: Light / dark box test (Anxiolytic effect)

 Crawley, J. and Goodwin, F.K., et al. Box test [Pharmacol. Biochem.

Behav., 13, 167-170 (1980)], the presence or absence of the anxiolytic effect of the test compound was examined.

 This light-and-box test uses the habit of rodents, such as mice and rats, to prefer dark places, and uses the increase in relative residence time in bright places, which are uncomfortable environments, as an index to evaluate the anxiolytic effects of drugs. Is an effective and simple behavioral pharmacological test method for assessing In this method, many of the cholecystokinin type 1 antagonists and benzodiazepines show a positive effect.

 The bright box test consisted of a clear acrylic plate box (20 x 17 x 15 cm) illuminated by an incandescent light bulb at an illuminance of 1700 lux and a black acrylic plate box (15 x 1 7 XI 5 cm) and a device (35 X 17 X 15 cm) provided with a barrier (4.4 X 5.0 cm) at which the mouse can freely move.

 For the test, 10 male Std-ddY mice weighing 25 to 30 g were used per group. Thirty minutes after oral administration of the test compound, the mouse was placed in the center of the light box, and the time spent in the light box during the 5-minute test period was measured. Rate,%) was calculated.

The anxiolytic potency of the test compound was expressed as the minimum effective dose (MED) that statistically significantly increased the stay rate in the light box (Dunnett's method, 5% risk factor). Table 3 shows the results. Anti-anxiety effect

 Test compound

 Dare, '' 氳 氳 mg / kg

 1 * 0.1

 63 0.01

 80 0.1

 * Refers to the compound of Example 1. (Hereinafter, each means the compound corresponding to the example number)

 The compounds of the present invention shown in Table 3 showed an anxiolytic effect at a dose of 0.1 mg / kg or less.

As apparent from the above pharmacological test results, the compounds of formula (I), as well shows the selective and remarkable affinity for Betazetaomega ₃ receptor in vitro studies, anxiolytic action have you in animal studies It has excellent pharmacological effects such as anxiety-related diseases (neurosis, psychosomatic disorder, anxiety disorder and others), central diseases such as depression and epilepsy, immune neurological diseases such as multiple sclerosis, angina It is useful as a therapeutic or prophylactic for cardiovascular diseases such as hypertension and hypertension.

Betazetaomega ₃ together show a selective and remarkable affinity for the receptor, strong as the anxiolytic shows the active compound, for example, the following compounds and their pharmaceutically acceptable acid addition salts.

 (1) 2-Methyl-phenyl-2-phenyl-1-9-purine-9-acetamide (Compound of Example 1)

 (2) 1-cyclopropynole 1-phenyl-2-9-phenyl-1 9-purine 9-acetamide (Compound of Example 63)

 (3) Ν— (4-chlorophenyl) -1-methyl-2-phenyl-1-9-purine-9-acetoamide (Compound of Example 80)

The compound of the present invention may be administered orally, parenterally, or rectally. The dose varies depending on the type of the compound, the administration method, the patient's symptoms and age, but is usually 0.01 to 5 OmgZkg / day, preferably 0.0 S Srag / kg / day. The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the carrier for the preparation, a substance that is commonly used in the field of the preparation and does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch, partially alpha-monostarch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, carboxymethyl cellulose Sodium, hydroxypropyl starch, carboxymethylcellulose calcium, ion-exchange resin, methylcellenolose, gelatin, gum arabic, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, Polybutyl alcohol, alginic acid, sodium alginate, light caffeic anhydride, magnesium stearate, talc, calpoxy Polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerose gelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water, ethanol, polyoxyethylene hydrogenated castor oil ( HCO), sodium chloride, sodium hydroxide, hydrochloric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, cunic acid, glutamic acid, benzyl alcohol, methyl parahydroxybenzoate, ethyl ethyl paraoxybenzoate, and the like.

 Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, and suppositories. These preparations are prepared according to a conventional method. In addition, the liquid preparation may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of injections, the compound of the present invention is prepared by dissolving the compound in water, but may be dissolved using an isotonic agent or a solubilizing agent as necessary. Buffers and preservatives may be added.

These preparations may contain the compound of the present invention in an amount of 0.01% or more, preferably 0.1 to 70%. These preparations also include: It may contain other ingredients that are effective for palliative treatment. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples. However, the present invention is not limited to these Examples. The compound was identified by elemental analysis, mass spectrum, IR spectrum, NMR spectrum, and the like.

 In the following Reference Examples and Examples, the following abbreviations may be used for simplification of the description.

 Crystal solvent]

 A: Ethanore

 AN: Acetonitrinole

 E: Jechinoreethenore

 E A: Ethyl acetate

 H X: n — hexane

 I P: isopropanol

Reference Examples 1 to 2 1

According to the method described in Example 12 of WO 9 / 32,383, the compounds shown in Table 4 were obtained using the corresponding raw material compounds.

Reference example A

 2 Me Ph H 4-Cl-Ph

3 Me Ph H 4-OMe-Ph

4 Me Ph H 4-CF ₃ -Ph

5 Me Ph H 3-Cl-Ph

6 Me 4-OMe-Ph H Ph

7 Me 4-CN-Ph H Ph

8 Me Ph (S) -Me * Ph

9 Me Ph (R) -Me * Ph

10 Me Ph (S) -iPr * Ph

11 Me Ph (S) -iBu * Ph

12 Me Ph (S) -CH ₂ OBzl * Ph

13 Et Ph H Ph

14 Et Ph H 4-F-Ph

15 Et Ph H 4-Cl-Ph

16 Et Ph H 4-OMe-Ph

17 Me Bzl H Ph

18 Et Bzl H Ph

19 Pr Pr H Ph

20 Pr Pr H 4-CF ₃ -Ph

21 Me Me H 4-CF ₃ -Ph

: Means S or R optically active substance. Reference Example 2 2 to 4 2

 According to the method described in Example 122 of WO96 / 32383, the compounds shown in Table 5 were obtained using the corresponding raw material compounds.

 Table 5

Participants R ¹ R ² R ³ A

 22 Me Ph H 4-F-Ph

23 Me Ph H 4-C レ Ph

24 Me Ph H 4-OMe-Ph

 26 Me Ph H 3-Cl-Ph

27 Me 4-OMe-Ph H Ph

 28 Me 4-CN-Ph H Ph

 29 Me Ph (S) -Me * Ph

 30 Me Ph (R) -Me * Ph

 31 Me Ph (S) -iPr * Ph

 32 Me Ph (S) -iBu * Ph

33 Me Ph (S) -CH ₂ OBzl * Ph

 34 Et Ph H Ph

 35 Et Ph H 4-F-Ph

36 Et Ph H 4-Cl-Ph

37 Et Ph H 4-OMe-Ph

38 Me Bzl H Ph

 39 Et Bzl H Ph

 40 Pr Pr H Ph

42 Me Me H 4-CF ₃ -Ph

_T meaning S or R optically active form Reference Examples 43 to 51

 According to the method described in Example 125 of WO 96/32383, the compounds shown in Table 6 were obtained using the corresponding raw material compounds.

 Table 6

Reference R ¹ R ² R ⁴ A

 43 Me Ph Me Ph

 44 Me Ph Me 4-F-Ph

45 Me Ph Me 4-OMe-Ph

 46 Me 4-CN-Ph Me Ph

 47 Me 4-OMe-Ph Me Ph

 48 Pr Pr Me Ph

49 Me Ph CF ₃ Ph

50 Pr Pr CF ₃ Ph

Reference Example 52

 Preparation of 2- (2-phenyl-1-5-propionylamino-1-4-pyrimidininoleamino) -1-N-methyl-1-N-phenylacetamide

 2- (5-amino-1 2-phenyl-1-4-pyrimidylamino) N-methyl-1N

To a mixture of 3.0 g of phenylacetamide and 3 Om1 of pyridine was added dropwise 0.9 g of pioyl chloride at 0 ° C., followed by stirring at room temperature for 3 hours. Water and chloroform were added to the reaction mixture, the pore form layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform to purify to obtain 3.5 g of the desired product. Reference example 5 3 to 6 6

 Using the corresponding starting compounds, the reaction was carried out in the same manner as in Reference Example 52 to obtain the compounds shown in Table 7.

 Table 7

Reference example R ¹ R ² R ⁴ A

 53 Me Ph cPr Ph

54 Me Ph CH ₂ OAc Ph

55 Me Ph CH ₂ OMe Ph

56 Me Ph CH ₂ OBzl Ph

57 Me Ph Ph Ph

58 Me 4-OMe-Ph Et Ph

59 Me 4-OMe-Ph cPr Ph

60 Et Ph Et Ph

61 Pr Pr Et Ph

62 Pr Pr CH ₂ OAc Ph

63 Pr Pr Ph Ph

64 Pr Pr 4-Cl-Ph Ph

65 Me Me iPr 4-CF ₃ -Ph

Reference example 6 7

 Production of 4-amino-5-nitro-l-phenylpyrimidine

4-chloro-5-two-row 2-phenylpyrimidine 40 g, ammonium chloride A mixture of 23 g, 60 g of triethylamine and 400 ml of ethanol was heated to reflux for 2 hours. After cooling the reaction mixture, water was added and the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain 36 g of the desired product.

Melting point: 223-225 ° C

Reference Example 68

 Preparation of 4-amino-2-phenylpyrimidine 5-carboxylate

 To a mixture of 3,4-dihydro-1,4-oxo-1,2-phenyl-2-pyrimidine-1,5-carboxylate 232 g, triethylamine 339 g and dimethylhonoleamide 42 Om 1, ρ-toluenesulfuryl chloride 200 g Of dimethylformamide was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 hour. 28% aqueous ammonia was added dropwise to the reaction mixture at room temperature, and the mixture was heated under reflux for 1 hour. The reaction mixture was added to ice water, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain 180 g of the desired product.

Melting point: 116 ~ 118 ^

Reference Example 69

 69 g of benzamidine hydrochloride was added at 0-5 ° C to a mixture of 48 g of sodium methoxide of 5-acetylamino-4-amino-6-hydroxy-2-phenolepyrimidine and 5 OO ml of absolute ethanol. After stirring at 0 ° C for 30 minutes, 75 g of N-acetyl-2-cyanoglycineethyl ester was added at the same temperature, and the mixture was heated under reflux for 6 hours. After the reaction mixture was concentrated with, water was added to the residue, and concentrated hydrochloric acid was added dropwise until ρΗ4. The precipitate was collected by filtration, washed with water, and then with ethanol to obtain 40 g of the desired product.

Melting point:> 300:

Reference example 70

 5-Acetinoleamino-1 4-amino-6-Hydroxy-1 2- (4-Triphnoreolome-tinolefeninole) pyrimidine

Using 4-trifluoromethylbenzamidine hydrochloride instead of benzamidine hydrochloride in Reference Example 69, reacting and treating in the same manner as in Reference Example 69, washing with methanol Purification gave the desired product.

Melting point:> 300 ° C

Reference example 7 1

 Preparation of 4-Amino-2-phenylphenylpyrimidine-5-carboxylic acid

 Reference Example 68 179 g of 4-amino-2-phenylpyrimidine-15-carponic acid obtained in 8 g, 96 ml of an aqueous solution of sodium hydroxide (1 mo 1 ZL) and 240 ml of ethanol The mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and washed with ethanol to obtain 149 g of the desired product.

Melting point: 296-292

Reference example 7 2

 Manufacture of 2-phenyl-9H-purine

 A mixture of 35 g of 4-amino-5-nitro-2-phenylenopyrimidine obtained in Reference Example 6 7, 2 g of 10% palladium carbon and 50 Om1 of ethanol was added under a hydrogen atmosphere. Stirred at 30 for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Then, formamide 5Om1 was added, and the mixture was heated with stirring at 180 ° C for 1 hour. The reaction mixture was added to ice water, the precipitate was collected by filtration, washed with water, and then washed with acetonitrile to obtain 23.5 g of the desired product.

Melting point: 2 4 3 to 2 4 4

Reference Example 7 3

 Preparation of 6-chloro-1-8-methyl-2-phenyl-1-9H-purine

 Reference Example 6 5-Acetylamino 4-amino-6-hydroxy-1 2 obtained in 9

A mixture of 20 g of phenylvirimidine and 66 ml of phosphorus oxychloride was heated to reflux for 6 hours. The reaction mixture was added to ice water, neutralized with an aqueous sodium hydroxide solution, and the precipitate was collected by filtration, washed with water, and washed with ethanol to obtain 17 g of the desired product.

Melting point:> 300 ° C

Reference example 7 4

Preparation of 6-chloro-1-8-methyl-2- (4-trifluoromethylpheninole) -19H-purine Instead of 5-acetylamino-14-amino-6-hydroxy-12-phenylpyrimidine in Reference Example 73, 5-acetylamino-14-amino-6-hydroxy-2- (4-) obtained in Reference Example 70 was used. The reaction product was treated with trifluoromethylphenyl) pyrimidine in the same manner as in Reference Example 73, and washed with methanol to obtain the desired product. Melting point:> 300 ° C

 Reference example 7 5

 Preparation of 7, 9-dihydro-1-phenyl-1-H-purin-1-one

 Reference Example 71 Triethylamine was added at room temperature to a mixture of 15 g of 4-amino-2-phenylpyrimidine-15-potassium rubonic acid, 20 g of diphenylphosphoric acid azide and 150 ml of dimethylformamide obtained in 1 at room temperature. 8 g was added, and the mixture was stirred at 100 ° C for 5 hours. The reaction mixture was added to ice water, the precipitate was collected by filtration, washed with water, and then washed with ethanol to obtain 14 g of the desired product.

Melting point:> 300 ¾

Reference Example 7 6

 Production of 8-chloro-2-phenyl-1-H-purine

 Reference Example 75 A mixture of 7,9-dihydro-1-phenyl-8H-purine-1-on 6 g, N, N-getylaniline 6 m 1 and phosphorus oxychloride 30 O m 1 obtained in Reference Example 5 was used. The mixture was refluxed for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue is poured into ice water! ], Neutralized with aqueous sodium hydroxide solution, and extracted with black-mouthed form. The mouth layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from ethanol to obtain 2.3 g of the desired product.

Melting point:> 300

Reference Example 7 7

 2-Amino 6-Chloro-N-Methynole N-Feninole 9 H-Purine 9-acetamide

To a mixture of 5 g of 2-amino-6-chloropurine and 5 Om1 of dimethylformamide, 1.3 g of about 60% sodium hydride (oily) was added at 0 ° C, and the mixture was added at room temperature. Stirred for 0 minutes. The reaction mixture was cooled again on ice, and 2-bromo-N-methyl-1-N-phenyla 7.4 g of cetamide was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain 6.9 g of the desired product.

Melting point: 186-188 ° C

Example A

 Preparation of 2-phenyl-9H-purine-9-ethyl acetate

 To a mixture of 19 g of 2-phenyl 9H-purine obtained in Reference Example 72 and 190 ml of dimethylformamide, 4.3 g of sodium hydride (oil-based) was added at about 60%, and the mixture was stirred at room temperature for 30 minutes. did. The reaction mixture was ice-cooled again, and 17.8 g of ethyl bromoacetate was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain 15 g of the desired product.

Melting point: 129-13

Example B

 Preparation of 6-chloro-1-8-phenyl-9H-purine-9-methyl acetate 6-chloro-8-methyl-2-phenyl-1-H-purine obtained in Reference Example 73メ チ ル Using methyl bromoacetate, the reaction was performed in the same manner as in Reference Example 77, Recrystallization from knol gave the desired product.

Melting point: 136-137

Example.

 Production of 2-Hueneru 9 H-Purine 9-Acetic Acid

 A mixture of 1-2.8 g of 2-phenyl 9H-purine 9-ethyl acetate obtained in Example A, 72 ml of aqueous sodium hydroxide (1 mo 1ZL) and 72 ml of ethanol was stirred at room temperature for 1 hour. . After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and washed with ethanol to obtain 11 g of the desired product.

Melting point: 295-296 ° C

Example D

Production of 8-Methyl-1-pheninole-9H-Purine-9-Acetic Acid 6-methyl-1-methyl-2-phenyl-1-H-9-purine-1-methyl acetate monomethyl acetate 20 g obtained in Example B, 10% palladium on carbon 2 g, sodium hydroxide (1 mo1 / L) aqueous solution A mixture of 19 Oml and 16 Om1 of ethanol was stirred at 30 ° C for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was made 4 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and then washed with ethanol to obtain 15 g of the desired product.

Melting point: 288-292

Example E

 Production of N- (2-funerolopheni / re) -1-2-pheninole 9 H-purine 9-acetoamide

 0.8 g of 2-phenyl-l9H-purine-l-monoacetic acid, 0.6 g of 2-fluoroaline, 0.6 g of N-methyl-14-chloroaline, 1 g of benzotriazole-l-fluoro-tris (dimethylamino) phosphonium A mixture of 1.5 g of xafluorophosphate (BOP reagent), 0.35 g of triethylamine and 10 ml of dimethylformamide was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the precipitate was collected by filtration, washed with water, and dried to obtain 0.76 g of crude N- (2-fluorophenyl) -12-phenyl-9H-purine-9-acetoamide.

Examples F to L

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example E to obtain the compounds shown in Table A.

Table A

Example R ¹⁰ R ⁴

 F 3-F-Ph H

 G 4-F-Ph H

 H sBu Me

 J cPr Me

K CH ₂ -cPr Me

 L iBu Me

Example 1

N-Methinole N-Fenilou 2-Feninole 9 H-Purine-1 9-acetoamide

 A mixture of 16 g of 2- (5-amino-12-phenyl-14-pyrimidinylamino) -1-N-methyl-1N-phenylacetamide and 32 ml of formamide was stirred at 180 ° C. for 2 hours. The reaction mixture was added to ice water, and the precipitate was collected by filtration, washed with water, and then subjected to silica gel column chromatography, eluting with chlorophonorem, and then with a mixed solvent of chlorophonolem and methanol (ratio 100: 1). Recrystallization from isopropanol gave 10 g of the desired product.

Melting point: 130-132

Examples 2 to 2 2

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds shown in Table 8. Table 8

Example R ¹ R ² R ⁸ A Recrystallization solvent Melting point c)

2 Me Ph H 4-F-Ph IP 168-170

3 Me Ph H 4-Cl-Ph IP 189-191

4 Me Ph H 4-OMe-Ph IP-AN 177-179

5 Me Ph H 4-CFg-Ph IP-AN 222-224

6 Me Ph H 3-Cl-Ph IP 135-136

7 Me 4-OMe-Ph H Ph IP 166-167

8 Me 4-CN-Ph H Ph IP 205-206

9 Me Ph (S) -Me * Ph HX-EA 124-127

10 Me Ph (R) -Me * Ph HX-EA 172-173

11 Me Ph (S) -iPr * Ph HX-EA 99-102

12 Me Ph (S) -iBu * Ph HX 48-52

13 Me Ph (S) -CH ₂ OBzl * Ph HX 112-115

14 Et Ph H Ph IP 143-144

15 Et Ph H 4-F-Ph IP 154-156

16 Et Ph H 4-Cl-Ph IP 192-193

17 Et Ph H 4-OMe-Ph IP-AN 189-191

18 Me Bzl H Ph IP 170-171

19 Et Bzl H Ph IP 165-167

20 Pr Pr H Ph HX-EA 98-99

21 Pr Pr H 4-CFg-Ph IP 159-161

22 Me Me H 4-CF ₃ -Ph A 248-249

It means S or R optically active substance. Example 23

 Preparation of 2- (4-hydroxyphenyl) -1-N-methyl-1-N-phenyl-1-9H-purine-19-acetoamide

 A mixture of 1.4 g of 2- (4-methoxyphenyl) -1-N-methinole-N-phenyl—9H-purine-9-acetoamide obtained in Example 4 and 2 mL of methylene chloride at 0 ° C. was added with 1M triodor at 0 ° C. 11.2 ml of a borohydride / methylene chloride solution was added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from a mixed solution of methanol and chloroform to obtain 0.5 g of the desired dihydrate.

Melting point: 291-293 ° C

Example 24

 2— (4—Mouth phenol) 1—8—Methoxy N—Methinole N—Feninole 9 H—Purine—9-Acetoamide

 2- [5-amino-1 2_ (4-chlorophenol) -14-pyrimidinylamino] N-methyl-1-N-phenylacetamide 3.0 g, sodium acetate 0.7 g, tetramethoxymethane 3.1 g and 17 ml of acetic acid were stirred at 60 for 5 hours. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, and the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 1.0 g of the desired product.

Melting point: 185-187 ° C

Example 25

 8-Methoxy-1- (4-Methoxyphenyl) -1-N-methyl-1-N-phenyl 9H-Purine-9-acetoamide

 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 24, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point: 183 ~; I 85 ° C

Example 26

(S) — 3-Hydroxy-1-N—Methyl-1-N—Feninole 2— (2-Phenyl-1-H —Purine 1) Manufacturing of propane amide

 0.34 g of (S) -3-benzyloxy-1-N-methynole-1-N-phenyl-2- (2-phenyl-1-H-purine-1-yl) propanamide obtained in Example 13 After stirring a mixture of 0.1 g of 0% palladium on carbon and 3 ml of acetic acid at 40 ° C. for 8 hours under a hydrogen atmosphere, the reaction mixture was filtered. The filtrate is concentrated under reduced pressure, water and chloroform are added to the residue, the pore-form layer is separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from isopropanol and acetonitrile for the purpose. 0.1 g was obtained.

Melting point: 2 18 to 220

Example 2 7

 8-Ethoxycanoleponinoleamino-1N-methinole-1 N-pheninole-1 2-Feninole 9 H-Purine-1 9-acetoamide

 (1) 2- (5-Amino-2-pheninoleic 4-pyrimidinoleamino) -1-N-methinole-1-N-pheninoleacetamide A mixture of 3 g and acetonitrile 30 ml was mixed with ethoxycarbonylisothiosia. 1.8 g of the nitrate was added dropwise at room temperature. After completion of the dropwise addition, the mixture was heated under reflux for 4 hours. The reaction mixture was returned to room temperature, and 2 g of Ν, Ν'-dicyclohexylcarbodiimide and 30 ml of acetonitrile were added dropwise at the same temperature. After the addition was completed, the mixture was refluxed again for 4 hours. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain two kinds of mixtures.

 (2) The above mixture was subjected to silica gel flash column chromatography, and eluted with a silica gel form. The less polar fraction was collected and concentrated under reduced pressure. Recrystallization from a mixture of ethanol and acetonitrile yielded 0.8 g of the desired 1/2 hydrate.

Melting point: 1 28-130 ° C

Example 2 8

 Preparation of 8-amino-1-N-methyl-1-N-phenyl-2-phenyl-1-H-9-purine 9-acetoamide

Example 27 The mixture obtained in (1) of 7 was subjected to silica gel flash column chromatography. The mixture was applied to a raffle, eluted with chloroform, collected with high polarity, concentrated under reduced pressure, and recrystallized from isopropanol to obtain 0.35 g of the desired product.

Melting point: 237-240 ° C

Example 29

 8—Methinole amino 1 N—Methinole 1 N—Feninole 1 2—Feninole 9H—Purine 1

9—Manufacture of acetoamide

 The reaction was carried out in the same manner as in Example 27, except that methylethoxythiocyanate was used in place of ethoxycarbonylisothionate in (1) of Example 27, and the target product was obtained by recrystallization from isopropanol.

Melting point: 200-202 ° C

Example 30

 Production of 8-methylamino-1-N, N-dipropyl-1- (4- trifluoromethylphenyl) -1-H-purine-9-acetamide

 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 29, and the target product was obtained by recrystallization from isopropanol.

Melting point: 181 ~ 182 ° C

Example 31

 Production of N, N-dimethyl-1-methylamino-2- (4-trifluoromethylphenyl) -9H-purine-9-acetamide

 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 29, and the target product was obtained by recrystallization from ethanol.

Melting point: 258-261 ° C

Example 32

 Production of N, N-Dimethyl-18-dimethinoleamino-12- (4-trifluoromethylpheninole) -19H-Purine-19-acetoamide

1.0 g of Ν, Ν-dimethyl-18-methylamino-2- (4-trifluoromethylphenyl) -19-purine-19-acetoamide obtained in Example 31 and 10 ml of Ν, Ν-dimethylformamide were obtained. 0.12 g of about 60% sodium hydride (oil-based) is added to the mixture little by little at 0 ~ 5 ^, and the mixture is stirred at room temperature for 1 hour, and then methyl iodide is added at the same temperature. 0.41 g of toluene was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol and acetonitrile to give 0.56 g of the desired product.

Melting point: 262-263 ° C

Example 33

 8—Methinole N—Methinole N—Feninole 21—Feninole 9 H—Purine 9—Acetamide

 (1) A mixture of 4 g of 2- (5-amino-1-phenyl-1-41-pyrimidinylamino) -N-methyl-1-N-phenylacetamide, 1 Oml of acetic anhydride and 7 ml of pyridine was stirred at room temperature for 4 hours. did. Water and chloroform are added to the reaction mixture, the chloroform layer is separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude 2- (5-acetylamino-2-phenyl-1-4-pyrimidene is concentrated. 4.2 g of gelamino) methyl-1-phenylenoleacetamide was obtained.

 (2) After stirring 1.5 g of the above product at 200 ° C for 2 hours, the mixture was cooled to room temperature, water and chloroform were added, and the pore form layer was separated.After drying over anhydrous sodium sulfate, the pressure was reduced. Concentrated. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from ethanol to obtain 1.0 g of the desired product. Melting point: 175-176 ° C

Examples 34 to 56

Using the compounds of Reference Examples 44 to 66, the reaction was carried out in the same manner as in Example 33 (2) to obtain the compounds shown in Table 9.

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96 、 ΐ- Dimensions-Dimensions- Example 57

 2— (4—Hydroxyphene) 1 8-Methinole N—Methinole 1 N—Feninole 1 9 H-Purine 1 9-Acetamide

 The same reaction as in Example 23 was carried out using 2- (4-methoxyphenyl) -8-methyl-1-N-methyl-N-phenyl-19H-purine-19-acetoamide obtained in Example 35. Treated and recrystallized from a mixture of methanol and porcine form to obtain the desired product.

Example 58

 8—Hydroxymethinol N-Methynole 1 N—Feninole 2 —Feninole 1 9 H—Prinine 9—Acetamide Production

 Of 7.8 g of 8-acetoxymethyl-N-methyl-N-phenyl-2-H-phenyl-9H-purine-9-acetoamide obtained in Example 39, 3.2 g of potassium carbonate and 80 ml of methanol The mixture was stirred at room temperature for 3 hours. Water and chloroform are added to the reaction mixture, the chloroform layer is separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from a mixed solution of isopropanol and acetonitrile to obtain the desired 1Z dihydrate. 6.6 g of the product were obtained.

Melting point: 182 ~: I 84 ° C

Example 59

 8-Honoleminolay N-Methinolay N-Feninole 1 2-Feninole 9H-Purine 91 Manufacture of acetoamide

 6-g of 8-hydroxymethyl-N-methinole-2-N-phenyl-2-H-purine-9H-purine-9-acetoamide obtained in Example 58, 14 g of manganese dioxide, and 60 ml of mouth form The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and recrystallized from a mixture of dimethylformamide and acetonitrile to obtain 3 g of the desired product.

Melting point: 209-21 1¾

Example 60

8-Hydroxymethyl-1-N, N-dipropyl-1-2-phenyl-9 H-Purine 9 —Manufacture of acetoamide

 Using 8-acetoxymethyl-N, N-dipropyl-12-phenyl-9H-purine-19-acetoamide obtained in Example 51, the reaction was carried out in the same manner as in Example 58, followed by isopropanol. To give the desired product.

Melting point: 144-146 ° C

Example 6 1

 8-Honoremil 1 N, N-dipropyl 1- 2-phenyl 9 H-Purine 9-Acetamide

 Using 8-hydroxyhydroxy-1,2-dipropyl-12-phenyl-19-purine-19-acetoamide obtained in Example 60, the reaction was carried out in the same manner as in Example 59, and η- Recrystallization from a mixture of hexane and ethyl acetate gave the desired product.

Melting point: 109-110 ° C

Example 6 2

 Production of N-methyl-1-N- (4-nitrophenyl) -1-2-phenyl 9 H-purine 9-acetamide

 0.5 g of about 60% sodium hydride (oil-based) is added little by little to 0 to 5Ό to a mixture of 2.3 g of 2-Fe 9-purine 9 H-purine and 2 Om 1 of dimethylformamide at room temperature. After stirring for 1 hour at the same temperature, 3.4 g of 2-bromo-N-ethyl-N- (4-nitrophenyl) acetoamide and 3.4 g of dimethylformamide were added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours and then at 70 for 1 hour. Water and chloroform were added to the reaction mixture, and the pore form layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from a mixed solution of isopropanol and acetonitrile to obtain 2.6 g of the desired product.

Melting point: 188 ~ 190 ° C

Example 6 3 to 6 9

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 62 to obtain the compounds shown in Table 10. Table 10

Example R ¹ R ² R ⁴ W recrystallization solvent melting point)

 63 cPr Ph H H IP 155-157

 64 iPr Ph H H IP 160-162

65 CH ₂ CF ₃ Ph HH IP 163-165

 66 Me Ph Me CI IP 209-210

 67 Et Ph Me CI IP 196-198

 68 Me Ph CI H IP 132-134

 69 Pr Pr CI H IP 116-118 Example 7 0

 6-Chloro-N, N-dimethyl-8-methinole 2- (4-trifluoromethylphenyl) -9H-purine-9-acetamide

 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 62, and the target product was obtained by recrystallization from acetonitrile.

Melting point: 2 28 to 230

Example Ί 1

 Preparation of N- (4-aminophenyl) -1-N-methyl-1-2-phenyl-1 9H-purine 9-acetoamide

Example 6 0.3 g of N-methyl-1-N- (4-ditrophenyl) -12-phenyl-9H-purine-9-acetoamide obtained in 2, a Raney nickel monoethanol suspension 1 Om After a mixture of 1 and 5 ml of ethanol was stirred at 40 under a hydrogen atmosphere for 5 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, water and chloroform were added to the residue, the pore form layer was separated, dried over anhydrous sodium sulfate, and then dried under reduced pressure. Concentrated in WO 00/73306 _ PCT / JPOO / 03374 and recrystallized from isopropanol to obtain the desired product o.lg.

Melting point: 212-214 ° C

Example 72

 6-Jetinole amino-1 8-Methinole N-Methinole N-Feninole 1 2-Feninole 9 H-Purine-1 9-Acetamide

 6-chloro-1-8-methyl-1N-methyl-1N-phenyl-12-phenyl-2- 9H-purine-9-acetoamide obtained in Example 66 1.3 g, getinoleamine 0.3 g, A mixture of 0.4 g of triethi / reamine and 2Om1 of isopropanol was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added water and porcine form, the porcelain form layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 0.4 g of the desired product.

Melting point: 164-166

Example 73

 6- [2- (N ', N'-Dimethylamino) ethylamino] 18-methyl-1-N-methyl-1-N-phenylen-2-phenyl-19H-purine-9-acetamide Preparation of Example 72 The reaction was carried out in the same manner as in Example 72, except that N, N-dimethylethylenediamine was used instead of getylamine, and recrystallization from isopropanol gave the desired product.

Melting point: 169-171 ° C

Example 74

 N-Echinole-1-6-methoxy-8-Metinole N-Feninole 2-Fenix 9H-Purine-9-Acetamide

6-chloro-1-N-ethyl-1-8-methyl-1-N-phenyl-9H-purine-9-acetoamide obtained in Example 67 1.7 g, 28% sodium methoxide / methanol solution A mixture of 1.0 g and 20 ml of methanol was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, and the chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated with mi £. The residue was subjected to silica gel column chromatography, and eluted with The product was recrystallized from isopropanol to obtain 1.2 g of the desired product.

Melting point: 144-145 ° C

Example 7 5

 Production of N-ethyl-8-methyl-6-dimethylamino N-phenyl-2-phenyl-19H-purine-19-acetoamide

 The reaction was carried out in the same manner as in Example 72 using 6-chloro-N-ethyl-8-methinole N-phenyl-2-ethyl 9H-purine-9-acetoamide and dimethylamine obtained in Example 67. · Treatment and recrystallization from isopropanol to obtain the desired product c

Melting point: 16-8 ~ 170

Example 7 6

 Production of N, N-dimethyl-8-methyl-1-6-dimethylamino2_ (trifluoromethylphenyl) -19H-purine-19-acetamide

 Using 6_chloro-N, N-dimethyl-18-methyl-N-phenyl-2- (trifluoromethylphenyl) -19H-purine-19acetamide obtained in Example 70 and dimethylamine, The reaction and treatment were carried out in the same manner as in Example 72, and the target product was obtained by recrystallization from acetonitrile.

Melting point: 154-15-156. C

Example 7 7

Production of N-ethyl-8-methyl-1-N-phenyl-1-phenyl-1-9H-purine-9-acetamide

 Example 6 7-Chloro-1-N-ethyl-8-methyl-1-N-phenyl-2-ethyl 9H-purine-9-acetoamide 2.0 g, 5% palladium on carbon 0. After stirring a mixture of 5 g, 5 ml of 1 N sodium hydroxide and 2 O ml of ethanol at room temperature under a hydrogen atmosphere for 2 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, water and chloroform were added to the residue, the chloroform layer was separated, dried over anhydrous sodium sulfate, concentrated with, and recrystallized from isopropanol to give 1. 4 g were obtained.

Melting point: 156-158 ° C Example 78

 8-Methoxy N-methyl N-phenyl 2-N-phenyl 9 H-Purine 91 Production of acetoamide

 Using 8-chloro-N-methyl-1-N-phenyl-12-phenyl-19H-purine-19-acetoamide obtained in Example 68, the reaction was carried out in the same manner as in Example 74, followed by recrystallization from isopropanol. To obtain the desired product.

Melting point: 187-189 ° C

Example 79

 N-Methinolay 8-Methinorecho N-Feninole 2-Heninolay 9 H-Purine-9-1 Production of acetoamide

 The reaction was carried out in the same manner as in Example 78, except that sodium methoxide was used in place of sodium methoxide in Example 78, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point: 127-129 ° C

Example 80

 N— (4-—Feninole) 1 N—Methinole 2—Feninole 9 H—Purine 9—Acetamide

 0.8 g of 2-phenylen-9H-purine-9-diacid, 0.6 g of N-methynole-4-chloroaniline, 0.6 g of benzotriazole-11-yloxy-tris (dimethylamino) phosphonium A mixture of 1.5 g of xafluorophosphate (BOP reagent), 0.35 g of triethylamine and 10 ml of dimethylformamide was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water and chloroform were added to the residue. The foam-form layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 1.1 g of the desired product.

Melting point: 183-185 ° C

Examples 81 to 86

Using the corresponding starting compounds, the reaction was carried out in the same manner as in Example 80 to obtain the compounds shown in Table 11.

Example R ¹ R ² R ⁴ Recrystallization solvent Melting point C)

 81 Me 3-Cl-Ph H IP 169-170

82 Me 4-OH-Ph H IP-AN 237-238

83 Me 4-Me-Ph H IP 138-140

84 Me 4-C0 ₂ Me-Ph H IP 164-165

85 Et Pr Me HX-EA 130-132

86 CH ₂ CH ₂ CN cPr Me IP 201-203 Examples 87-89

 The corresponding compounds were reacted and treated in the same manner as in Example 80 to obtain the following compounds.

 (Example 87)

 1- (2-Phenyl-1H-purine-1-inole) acetyl-1,2,3-dihydro-1H-indole; melting point: 21 7-218 ° C (recrystallized from a mixture of ethanol and acetonitrile)

(Example 88)

 1- (2-Phenyl-9H-purine-9-yl) acetyl-1,2,3,4-tetrahydroquinoline; melting point: 157-159 ° C (recrystallized from isopropanol) (Example 89) ——

2- (2-phenyl-1-9H-purine-1-inole) acetyl-1,2,3,4-tetrahydroisoquinoline; melting point: 210-212 ° C (recrystallized from a mixture of ethanol and acetonitrile) Example 90

 Production of N- (2-fluorophenyl) -1-N-methynole-1-H-purinole-9H-purine-1-acetoamide

(1) 2-phenyl one 9 H- purine one 9-齚酸0. 8 g, 2 Funoreoroa diphosphate 0. 6 g, 80? Reagent 1.5 _8, the Toryechiruamin 0.35 g and mixtures dimethylformamide § bromide 10 m 1 The mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the precipitate was collected by filtration, washed with water, and dried to obtain 0.76 g of crude N- (2-fluorophenyl) -12-phenyl-19H-purine-19-acetoamide.

 (2) To a mixture of 0.1 g of about 60% sodium hydride (oily) and 10 ml of dimethylformamide, 0.7 g of the above product was added little by little at 0 to 5 ° C, and the mixture was stirred at room temperature for 1 hour. Thereafter, 0.3 g of methyl iodide was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 0.5 g of the desired product.

Melting point: 164-166 ° C

Example 91-: L 04

Using the corresponding starting compounds, the reaction and treatment were conducted in the same manner as in Example 90 to obtain the compounds shown in Table 12.

 twenty four

 Fushi Example> Recrystallization solvent Melting point C)

91 Me 3-F-Ph H IP 158-159

92 Me 4-F-Ph H IP 181-182

93 Et 4-F-Ph H IP 195-196

94 Me sBu Me HX-EA 123-126

95 Et sBu Me HX-EA 109-111

96 Me cPr Me EA 156-158

97 Et cPr Me EA 144-146

98 Pr cPr Me EA 148-150

99 Me CH ₂ -cPr Me HX-EA 124-126

100 Et CH ₂ -cPr Me HX-EA 122-123

101 Pr CH ₂ -cPr Me HX-EA 135-137

102 Me iBu Me HX-EA 123-125

103 Et iBu Me HX-EA 137-139

104 Pr iBu Me HX-EA 143-144 Example 1 0 5

 6-Chloro-N-methinole N-Feninole 1 2-Feninole 9 H-Purine 9-acetamide

2-amino-6-chloro-N-methyl-1-N-phenyl 9H-purine-9-acetoamide 3 g, cuprous oxide 1.4 g, isoaminoyl nitrite 5.3 m1 and Benze The mixture of 200 ml was heated to reflux for 1 hour. After the reaction mixture was filtered and concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, Elution with lume was followed by purification and recrystallization from isopropanol to obtain 1.Og of the desired product. Melting point: 1 73-175 ° C

Example 106

 6-Black N-Methinole 2- (5-Methinole 2-Frisle) -1 N-Feninole 1 H-Purine 1-Acetoamide

 The reaction and treatment were carried out in the same manner as in Example 105, except that 2-methylfuran was used in place of benzene in Example 105, and the product was recrystallized from a mixed solution of isopropanol and acetonitrile to obtain the desired product.

Melting point: 179-182 ° C

Example 107

 6-Chloro-N-methino-N-Feninole 2- (2-Cheninole) -19H-Purine-9-acetoamide

 The reaction and treatment were carried out in the same manner as in Example 105 except that thiophene was used in place of benzene in Example 105, and the target product was obtained by recrystallization from a mixed solution of isopropanol and acetonitrile.

Melting point: 191-193 ° C

Example 108

 6-Methoxy N-Methinole N-Feninole 1 2-Feninole 9 H-Purine 9-Acetamide production

 Using 6-chloro-1-N-methyl-1-N-phenyl-12-phenyl-9H-purine-19-acetoamide obtained in Example 105, the reaction and treatment were carried out in the same manner as in Example 74, and isopropanol was used. Recrystallization afforded the desired monomonohydrate.

Melting point: 90-93 ° C

Example 109

N-methyl-1-6-dimethylamino-N-phenyl-1-phenyl-1-9H-purine

—9—Manufacture of acetoamide

6-chloro-N-methyl-1N-phenyl-2-phenyl-19H-purine-9-acetoamide obtained in Example 105 and dimethylamine in place of getylamine in Example 72, Reaction and treatment in the same manner 7

 Recrystallization from 60 panol gave the desired product.

Melting point: 178-181 ° C

 Example 1 10

 Production of N-methyl-1-N-phenyl-2-phenyl-1-6- (1-pyrrolidinyl) -1 9H-purine-9-acetoamide

 Reaction was performed in the same manner as in Example 72, except that 6-chloro-N-methyl-N-phenyl-12-phenyl-9H-purine-19-acetoamide obtained in Example 105 and pyrrolidine were used instead of getylamine in Example 72. · Treatment and recrystallization from isopropanol gave the desired product.

Melting point: 162-165

Example 1 1 1

 N-Methinole 6-Methinole 1 N-Feninole 2 9-Feninole 9 H-Purine 1 9-Acetamide

 Using 6-chloro-N-methyl-N-phenyl-2-Huline 9 H-purine-19-acetoamide obtained in Example 105 and sodium thiomethoxide in place of sodium methoxide in Example 74, The reaction and treatment were conducted in the same manner as in Example 74, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point: 172-173 ° C

Example 112

 6- (1-ethoxyvininole) -1-N-methinole N-pheninole 2-Heninole 9 H-purine 9-acetoamide

 1.5 g of 6-chloro-1-N-methyl-1-N-phenyl-9-phenyl-9H-purine-9-acetoamide obtained in Example 105, bis (triphenylphosphine) palladium dichloride (I 1 ) 0. lg, a mixture of 1.9 g of tributyl (1-ethoxybininole) tin and 24 ml of dimethylformamide in an argon gas atmosphere was used for 10 g.

The mixture was stirred at 0 ° C for 7 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with silica gel column form, and recrystallized from isopropanol to obtain 1.0 g of the desired product.

Melting point: 157-158 ° C Example 1 1 3

 6- (1-Ethoxyvul) -1-N, N-dimethyl-1-8-methyl-1-2- (4_trifluoromethylphenyl) -19H-purine-1-9-acetamide

 Example 11 Using 6-chloro-N, N-dimethyl-18-methyl-2- (4-trifluoromethylphenyl) -19H-purine-19-acetoamide obtained in Example 70, Example 11 The reaction and treatment were carried out in the same manner as in 2, and the desired product was obtained by recrystallization from acetonitrile and ethanol.

Melting point: 198 ~ 200 ° C

Example 1 1 4

 6-Acetinole N-Methinole 1 N-Feninole 2 -Feninole 1 9 H-Purine 1 9-Acetamide

 Example 11 6- (1-Ethoxyvul) -1-N-methyl-1-N-phenyl-1-H-purine 9H-purine-9-acetoamide obtained in 12 0.7 g, 5% hydrochloric acid lm A mixture of 1 and 10 ml of ethanol was stirred at 50 ° C for 1 hour. To the reaction mixture were added water and black form, and the black form layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 0.4 g of the desired product.

Melting point: 17-9 ~: L 8 1 ° C

Example 1 1 5

 6-Acetyl-1-N, N-dimethyl-1-8-methinole-2- (4-trifluoromethylinophenyl) -9H-purine-9-acetoamide

 Example 11 13- (1-ethoxyvinyl) -1-N, N-dimethyl-8-methyl-1- (4-trifluoromethylpheninole) -19H-purine-19-acetamide obtained in 13 The reaction and treatment were carried out in the same manner as in Example 11-14, and the desired product was obtained by recrystallization from acetonitrile and ethanol.

Melting point: 2 27-2 28 ¾

Example 1 1 6

N-Methyl-N-Phenyl-2-Heninole 6-Vininole 9 H-Purine 9- Manufacturing of setamide

 Reaction and treatment were carried out in the same manner as in Example 112, except that tributyl (1-ethoxybutyl) tin was used in place of tributyl (1-ethoxybutyl) tin in Example 112 to obtain the desired product. Example 1 17

 6-Echinole N-Methylenole N-Feninole 1 2-Heninole 9 H-Purine 9-Acetamide

 Example 1 N-methyl-1-N-phenyl-12-phenyl-16-vinyl-19H-purine-9-acetoamide obtained in Example 16 0.5 g, 0.1 g of 10% palladium on carbon, and ethanol 1 Om 1 This mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours, and then the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and recrystallized from isopropanol to obtain 0.2 g of the intended product.

Melting point: 145 ~ 147 ° C

Formulation Example 1: Tablet production

 ■ N—Methinole N—Feninole 1—Feninole 9 H—

 Pudding one 9—acetamide lg

• Lactose 84g

'' Corn Starch 3 Og

'' 25g crystalline cellulose

'' Hydroxypropinoresenolerose 3 g After mixing and granulating the above ingredients by a conventional method, adding light caffeic anhydride (0.7 g) and magnesium stearate (1.3 g), and tableting at 145 mg per tablet. To make 1000 tablets.

Formulation Example 2: Production of capsules

 • N—Methinole N—Feninole 1—Feninole 9H—

 Pudding 91 Acetamide 2g

'Lactose 165 g

• 25g corn starch

'' Hydroxypropinoresenolerose 3.5g

'' 1.8 g of light caffeic anhydride • Magnesium stearate 2.7 g The above ingredients are mixed and granulated by a conventional method, and 20 Omg of granules are filled into capsules to produce 1000 capsules.

Formulation Example 3: Production of powder

 • N-methyl-1-N-phenyl-2-phenyl-1-H

 Pudding 9-acetamide 10g

'Lactose 960g

• Hydroxypropinoresenolerose 25g

• 5 g of light caffeic anhydride Mix the above ingredients by a conventional method to make a powder.

Industrial applicability

As described above, the compounds and pharmaceutically biological acceptable acid addition salts of the present invention represented by the formula (I) are selective and significant parent on peripheral-type BZ omega ₃ receptors As well as being compatible with anxiety-related diseases (neurosis, psychosomatic disorders, anxiety disorders, and others), central illnesses such as depression and epilepsy, It is useful as a therapeutic and prophylactic agent for cardiovascular diseases such as heart disease and hypertension. Further, the compound of the present invention represented by the formula (IXa) is useful as an intermediate of the compound represented by the formula (I).

Claims

The scope of the claims

1. A 2-arylpurine-9-acetoamide derivative represented by the following formula (I) or a pharmaceutically acceptable acid addition salt thereof.

-Country,

()

[In the formula, R ¹ is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a hydroxy (lower) alkyl group, a halogeno (lower) alkyl group or a lower alkyl group substituted with cyano. Means

R ² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted phenyl (lower) alkyl group, or R ¹ and R ² Piberidine ring, pyrrolidine ring, morpholine ring or piperazine ring, 2,3-dihydroindole which may be substituted with one or two lower alkyl groups together with the nitrogen atom to which they are attached A ring, a 1,2,3,4-tetrahydroquinoline ring or a 1,2,3,4-tetrahydroisoquinoline ring,

R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy (lower) alkyl group or a protected hydroxy (lower) alkyl group,

R ⁴ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, an amino group, a mono or di (lower) alkylamino group, a lower alkoxycarbonylamino group, a hydroxy (lower) Alkyl group, protected hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, halogeno (lower) alkyl group, unsubstituted or substituted phenyl group, formyl group, carboxyl group, protected carboxyl group, canolebamoyl Group or mono or di (lower) alkyl radical

A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group, DO w is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, an amino group, a mono or di (lower) alkylamino group, a mono or di (lower) alkylamino (lower) alkylamino Group, pyrrolidinyl group, piperidinyl group, butyl group, butyl group substituted with lower alkoxy or unsubstituted or substituted phenyl group.)

2. A is the following formula [Α ']

(Wherein, R ⁵ is a hydrogen atom, a halogen atom, a C ₁ -C ₃ alkyl group, a Ci Cg alkoxy group, a trifluoromethyl group, a hydroxy group, a carboxyl group, a Ci CgT alkoxycarbonyl group, an amino group, a mono group. or di (Cj Cg) alkylamino group means an Shiano group or a nitro group, R ⁶ is a hydrogen atom, a halogen atom, with C ~ C ₃ alkyl group means a C ₁ -C ₃ alkoxy or hydroxy group) or a group represented by the respective C i to C ₃ alkyl optionally pyridyl group optionally substituted with a group, the compound in the range first claim of claim is thienyl group or furyl group.

3. R ¹ is 〇 ~. An alkyl group or a C _{3 to} C ₆ cycloalkyl group, wherein R ² is a C to C ₄ alkyl group or the following formula [B]

(Wherein, R ⁷ is a hydrogen atom, a halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy groups, trifluoperazine Ruo Russia methyl, human Dorokishi group, carboxyl group, C ₁ -C ₃ 7 Turkey R ⁸ represents a hydrogen atom, a halogen atom, a di-C ₃ alkyl group, a Ci Cg alkoxy group, or a xycarbonyl group, an amino group, a mono- or di- (alkyl-amino group, a cyano group, or a nitro group) And R ¹ and R ² are each substituted with one or two C to C ₃ alkyl groups together with the bonding nitrogen atom. May form a piperidine ring, a pyrrolidine ring, a morpholine ring or a piperazine ring. 3. The compound according to claim 1 or claim 2, wherein

4. A is the following formula [A "]

(Wherein, R ⁵¹ represents a hydrogen atom, a halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy groups, trifluoperazine Ruo Russia methyl group, hydroxy group, amino group, refers to a Shiano group or a nitro port group And R ⁶¹ represents a hydrogen atom, a halogen atom or a Ci Cg alkoxy group)

In a represented by group, R ¹ is a C i to C ₄ alkyl group or a C ₃ ~ C ₆ cycloalkyl group, 1¾ ² is represented by the following formula [8 ']

(Wherein, R ⁷¹ is a hydrogen atom, a halogen atom, C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy groups, trifluoperazine Ruo Russia methyl group, hydroxy group, amino group, refers to a Shiano group or a nitro port group and, R ⁸¹ is a hydrogen atom, a halogen atom, 〇 ₁ ～〇 ₃ Arukiru group or Ji ₁ -C ₃ alkoxy group)

2. The compound according to claim 1, which is a group represented by the formula:

5. R ⁴ is a hydrogen atom, a C ₁ -C ₃ alkyl group, a C ₃ -C ₆ cycloalkyl group, a nitrogen atom, a Ci Cg alkoxy group, a Ci Cg alkylthio group or a halogeno (C _3. ) Alkyl group. The compound according to any one of claims 1 to 4, wherein the compound is:

6. The compound according to claim 5, wherein W is a hydrogen atom or a C ₃ -C ₃ alkyl group.

7. 2-Arylrubrin-9-acetoamide derivative represented by the following formula (Ia) or a pharmaceutically acceptable acid addition thereof: io

(Wherein, R ¹¹ represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a cyclopropyl group,

R ⁵² represents a hydrogen atom, a halogen atom, a methoxy group, a hydroxy group or a trifluoromethyl group,

R ⁷² represents a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or an amino group)

 8. N-methyl-1-N-phenyl-1-phenyl 9H-purine-9-acetamide or its pharmaceutically acceptable acidity B¾o

 9. By the method shown in (a), (b), (c), (d) or (e) below, the following formula (I)

[In the formula, R ¹ is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a hydroxy (lower) alkyl group, a halogeno (lower) alkyl group or a lower alkyl substituted with cyano. Means the group

R ² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted phenyl (lower) alkyl group, or R ¹ and R ² are Piberidine ring, pyrrolidine ring, morpholine ring or piperazine ring, 2,3-dihydroindole which may be substituted with one or two lower alkyl groups together with the nitrogen atom to which they are attached A ring, a 1,2,3,4-tetrahydroquinoline ring or a 1,2,3,4-tetrahydroisoquinoline ring, R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy (lower) alkyl group or a protected hydroxy (lower) alkyl group;

R ⁴ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, an amino group, a mono or di (lower) alkylamino group, a lower alkoxycarbonylamino group, a hydroxy (lower) Alkyl groups, protected hydroxy (lower) alkyl groups, lower alkoxy (lower) alkyl groups, halogeno (lower) alkyl groups, unsubstituted or substituted phenyl groups, formyl groups, carboxyl groups, protected carboxyl groups A radical, a labamoyl group or a mono- or di- (lower) alkyl levamoyl group;

 A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group,

 W is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkyl group, an amino group, a mono or di (lower) alkylamino group, a mono or di (lower) alkylamino (lower) An alkylamino group, a pyrrolidinyl group, a piperidinyl group, a butyl group, a butyl group substituted with a lower alkoxy, or an unsubstituted or substituted phenyl group.)

A method for producing a 2-arylpurine-9-acetoamide derivative represented by the following formula, or a pharmaceutically acceptable acid addition salt thereof:

(a) In the formula (I), the compound wherein R ⁴ is a hydrogen atom is represented by the following formula (II)

(Where RR ² , R ³ , A and IV mean the same as above)

Is cyclized in the presence of a formic acid derivative,

(b) In the formula (I), R ⁴ is a lower alkyl group, a cycloalkyl group, a lower alkoxy (lower) alkyl group, a halogeno (lower) alkyl group, a hydroxy (lower) alkyl group, a protected hydroxy ( Compounds which are a (lower) alkyl group, a formyl group or an unsubstituted or substituted phenyl group are represented by the following formula (III)

(Wherein, RR ² , R ³ , RA and the same as those described above) are cyclized by heating,

 (.) The compound of the formula (1) is represented by the following formula (V)

(Where A, W and R ⁴ mean the same as above)

And a compound represented by the following formula (VI)

Z ^J — CH (R ³ ) — CON R ¹ ) (R ² ) (VI)

(Wherein, Z ¹ represents a leaving atom or a leaving group, and RR ² and R ³ have the same meanings as described above.)

With a compound represented by

(The compound of the formula (1) is represented by the following formula (IX)

(Where A, RR ⁴ and IV mean the same as above)

Or a reactive derivative thereof represented by the following formula (X)

HN (R ¹³ ) (R ²³ ) (X)

(Wherein, R ¹³ and R ²³ represent a hydrogen atom or the same as defined above for R ¹ and R ² respectively)

When one of R ¹³ and R ²³ is a hydrogen atom, the compound represented by the following formula (XIa) or (XIb) R ² -Z ¹ (XI a)

R ¹⁴ — Z ¹ (XI b)

(Wherein, R ²⁴ represents a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group or an unsubstituted or substituted phenyl (lower) alkyl group, and R ¹⁴ represents a lower alkyl group, a lower alkenyl group, alkyl group means a cycloalkyl (lower) alkyl, hydroxy (lower) alkyl, halogeno (lower) lower alkyl group substituted with an alkyl group or § Bruno, Z ¹ is the same as defined above. However, when R ¹³ is a hydrogen atom, the compound of the above formula (XIa) is reacted, and when R ²³ is a hydrogen atom, the compound of the above formula (XI b) is reacted. Reacts with the compound

 (6) The compound of the formula (1) is represented by the following formula (XII I)

(Where RR ² , R ³ , R ⁴ and * W mean the same as above)

In the presence of a diazotizing agent and a catalyst, a compound represented by the following formula (XIV)

 A-H (X I V)

 (Where A means the same as above)

Reacting a compound represented by

Deprotect if necessary, and further convert to a pharmaceutically acceptable acid addition salt as necessary.

 10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 as an active ingredient.

 1 1. A therapeutic drug for anxiety-related diseases, comprising the compound according to any one of claims 1 to 8 as an active ingredient.

1 2. Treatment of anxiety-related diseases by administering an effective amount of the compound according to any one of claims 1 to 8 to a patient with anxiety-related diseases such as neurosis, psychosomatic disorder, and anxiety disorder. Treatment method.

13. Use of the compound according to any one of claims 1 to 8 for the treatment of patients with anxiety-related diseases such as neurosis, psychosomatic disorder, and anxiety disorder.

 14. An anxiolytic drug comprising the compound according to any one of claims 1 to 8 as an active ingredient.

 15. An intermediate represented by the following formula (I Xa) or a salt thereof.

[Wherein R ⁹ is a hydroxy group, a lower alkoxy group or the following formula [C]

One ^{NH (R 1 0) [C} ]

(Wherein R ¹⁰ is a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, a lower alkenyl group, (Means lower alkyl group substituted with (lower) alkyl group, nodogeno (lower) alkyl group or cyano)

 Means a group represented by

R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy (lower) alkyl group or a protected hydroxy (lower) alkyl group;

R ⁴ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, an amino group, a mono or di (lower) alkylamino group, a lower alkoxycarbonylamino group, a hydroxy (lower) Alkyl group, protected hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, halogeno (lower) alkyl group, unsubstituted or substituted phenyl group, formyl group, carboxyl group, protected carboxyl group, A rubamoyl group or a mono- or di- (lower) alkyl-powered lubamoyl group;

 A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group,

W is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkanol group, an amino group, a mono- or di- (lower) alkylamino A mono- or di- (lower) alkylamino (lower) alkylamino group, a pyrrolidinyl group, a piperidinyl group, a butyl group, a butyl group substituted with a lower alkoxy or an unsubstituted or substituted phenyl group]