WO2000073306A1 - Derives de 2-arylpurine-9-acetamide, leur procede de preparation, compositions medicinales les contenant et intermediaires des derives - Google Patents

Derives de 2-arylpurine-9-acetamide, leur procede de preparation, compositions medicinales les contenant et intermediaires des derives Download PDF

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WO2000073306A1
WO2000073306A1 PCT/JP2000/003374 JP0003374W WO0073306A1 WO 2000073306 A1 WO2000073306 A1 WO 2000073306A1 JP 0003374 W JP0003374 W JP 0003374W WO 0073306 A1 WO0073306 A1 WO 0073306A1
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group
alkyl group
alkyl
compound
hydrogen atom
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PCT/JP2000/003374
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Japanese (ja)
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Teruya Murata
Katsunori Kondo
Kaoru Masumoto
Hitoshi Kohayakawa
Kiyoshi Furukawa
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Dainippon Pharmaceutical Co., Ltd.
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Priority to AU49498/00A priority Critical patent/AU4949800A/en
Publication of WO2000073306A1 publication Critical patent/WO2000073306A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • 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.
  • BZ benzodiazepine
  • central ( ⁇ ⁇ , ⁇ 2 ) and “peripheral ( omega 3) "Benzojiazepin is referred to as receptor (hereinafter, respectively” ⁇ ⁇ ⁇ receptor ", also referred to as” 8 ⁇ 0 ⁇ 2 receptor "and” Betazetaomega 3 receptor ").
  • the central type ⁇ receptor is ⁇ -aminobutyric acid of the central nervous system (hereinafter sometimes referred to as “GABA”).
  • GABA ⁇ -aminobutyric acid of the central nervous system
  • peripheral BZ receptors are widely distributed in central and peripheral tissues and organs (brain, kidney, liver, heart, etc.).
  • 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.
  • 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.
  • peripheral BZ receptors stimulate 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)].
  • recognition sites different from benzodiazepine receptors
  • C1 ion channel opening process [Roraeo, E. et al., J. Pharmacol. Exp. Ther., 262, 971 -978 (1992)].
  • the following compounds are known as compounds having a non-BZ skeleton and exhibiting selective affinity for peripheral BZ receptors.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • R 9 is a hydroxy group, a lower alkoxy group or the following formula [C]
  • 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)
  • 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.
  • 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.
  • the acid addition salt include those described in the above “Pharmaceutically acceptable acid addition salt of the compound represented by the formula (I)”.
  • the alkali metal salt include inorganic alkali salts such as a sodium salt and a potassium salt.
  • 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.
  • the compounds of formula (I) may optionally exist in more than one stereoisomeric form.
  • 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.
  • the lower alkyl group and the lower alkyl moiety have 1 to 1 carbon atoms unless otherwise specified.
  • lower alkyl group 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.
  • Lower alkoxy group means an alkoxy group having 1 to 6 carbon atoms, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentyloxy.
  • 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.
  • 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.
  • lower alkylthio group examples include methylthio and ethylthio.
  • Hydro (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.
  • 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, ⁇ 1 Ji 3 Arukiru Oyobi ⁇ 1 ⁇ 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.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • 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,
  • “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.
  • 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-
  • “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;
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • R 1 is a C i to C 4 alkyl group or a C 3 ⁇ C 6 cycloalkyl group
  • 13 ⁇ 4 2 is represented by the following formula [8 ']
  • 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
  • R 81 represents a hydrogen atom, a halogen atom, a C Cg alkyl group or a ⁇ C 3 alkoxy group
  • 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.
  • 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.
  • 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)
  • particularly suitable compounds include, for example, the following compounds.
  • 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.
  • 3--Ph represents a 3-chlorophenyl group
  • 2-F-Ph represents a 2-fluorophenyl group
  • 2-Thi represents a 2-phenyl group.
  • R 9 is a hydroxy group or the following formula [C]
  • R 10 represents a ⁇ - ⁇ 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.
  • R 9 is the following formula [C]
  • 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).
  • 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.
  • 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.
  • a formic acid derivative include formamide, formic acid, and ethyl formate.
  • 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.
  • deprotection performed as necessary is usually performed by hydrolysis or hydrogenation shown 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.
  • a suitable solvent for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used.
  • 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.
  • a catalyst such as palladium carbon or Raney nickel.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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 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.
  • a solvent include halogenated hydrocarbons such as chloroform and methylene chloride, and aromatic hydrocarbons such as benzene, toluene and xylene.
  • 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.
  • 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.
  • 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.
  • a base examples include toluene, xylene, dimethoxyethane, 1,2-dichloroethane, acetone, methylethylketone, dioxane, diglyme, ethylethyl acetate, dimethylformamide, and dimethylsulfoxide.
  • 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 (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.
  • a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide or the like in a conventional manner.
  • 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).
  • a halogenating agent for example, phosphorus oxychloride, phosphorus tribromide.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • This reaction can be carried out by reacting a compound of the formula (D) with an azide compound.
  • 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.
  • the solvent to be used include tonoleene, xylene, dimethoxetane, 1,2-dichloroethane, acetone, methylethylketone, dioxane, diglyme, ethinoleate, dimethylformamide, and dimethylsulfoxide.
  • 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.
  • 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)
  • R 13 and R 23 represent a hydrogen atom or the same as defined above for R 1 and R 2 respectively.
  • R 24 represents a lower alkyl group, a cycloalkynole group, a cycloalkyl (lower) alkyl group or an unsubstituted or substituted phenyl (lower) alkyl group
  • 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.
  • R 1 3 is a hydrogen atom reacting a compound of formula (XI a)
  • 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
  • methyl esters especially methyl esters
  • active esters include p-nitrophenylester, 2,4,5-trichlorophenol enoester, and N-hydroxyconodic acid imido ester.
  • acid anhydride a symmetric acid anhydride or a mixed acid anhydride is used.
  • 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.
  • alnic acid such as sovalic acid and bivalic acid can be mentioned.
  • 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.
  • the base include sodium hydroxide, aluminum hydroxide such as potassium hydroxide, sodium carbonate, and carbonate such as potassium carbonate.
  • 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.
  • 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.
  • 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.
  • 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 can be produced by reacting with a compound represented by the formula and deprotecting if necessary.
  • 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.
  • 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.
  • 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).
  • W is a lower alkoxybutyl group or a butyl group
  • 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.
  • 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 ( ⁇ ⁇ 2 ) and peripheral ( ⁇ 3 ) benzodiazepine receptor binding test
  • ⁇ 1 ⁇ 2 and ⁇ 3 receptor membrane preparations were prepared from the cerebellum ( ⁇ i), spinal cord ( ⁇ 2 ), or kidney ( ⁇ 3 ) of 7-8 week old male Wistar rats, respectively, by the following procedure. .
  • 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.
  • 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.
  • 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 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 ⁇ 3 receptor binding. The values are shown in Table 2.
  • 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.
  • Test Example 2 Light / dark box test (Anxiolytic effect)
  • 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.
  • rodents such as mice and rats
  • 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.
  • mice 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
  • the compounds of the present invention shown in Table 3 showed an anxiolytic effect at a dose of 0.1 mg / kg or less.
  • anxiety-related diseases neurosomatic disorder, anxiety disorder and others
  • central diseases such as depression and epilepsy
  • immune neurological diseases such as multiple sclerosis
  • angina 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.
  • 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.
  • a preparation 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.
  • lactose 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
  • 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.
  • 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.
  • Example 122 of WO96 / 32383 the compounds shown in Table 5 were obtained using the corresponding raw material compounds.
  • 4-chloro-5-two-row 2-phenylpyrimidine 40 g, ammonium chloride 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.
  • 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.
  • 75 g of N-acetyl-2-cyanoglycineethyl ester was added at the same temperature, and the mixture was heated under reflux for 6 hours.
  • the reaction mixture was concentrated with, water was added to the residue, and concentrated hydrochloric acid was added dropwise until ⁇ 4. The precipitate was collected by filtration, washed with water, and then with ethanol to obtain 40 g of the desired product.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 27 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.
  • Example 23 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 39 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.
  • Example 51 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.
  • Example 60 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 ⁇ - Recrystallization from a mixture of hexane and ethyl acetate gave the desired product.
  • 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.
  • Example 66 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.
  • Example 72 6- [2- (N ', N'-Dimethylamino) ethylamino] 18-methyl-1-N-methyl-1-N-phenylen-2-phenyl-19H-purine-9-acetamide
  • N, N-dimethylethylenediamine was used instead of getylamine, and recrystallization from isopropanol gave the desired product.
  • Example 70 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.
  • 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.
  • Example 68 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.
  • Example 78 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.
  • Example 105 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.
  • Example 105 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.
  • Example 105 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.
  • Example 72 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.
  • Example 74 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.
  • 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.
  • 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.
  • Example 11 (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.
  • 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.
  • Example 1 17 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
  • 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.
  • 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).

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Abstract

L'invention concerne des dérivés de 2-arylpurine-9-acétamide représentés par la formule générale (I) ou leurs sels d'addition d'acide acceptables sur le plan pharmaceutique, lesquels agissent sur le récepteur BZφ3 et sont utiles en tant que médicaments thérapeutiques et préventifs contre des maladies centrales telles que les maladies apparentées à l'anxiété, la dépression et l'épilepsie, formule dans laquelle R1 représente alkyle inférieur, cycloalkyle, alkyle inférieur cycloalcoylé ou analogue; R2 représente alkyle inférieur, phényle substitué ou non substitué ou analogue; R3 représente hydrogène ou analogue; R4 représente hydrogène, alkyle inférieur, cycloalkyle, halogéno, alcoxy inférieur ou analogue; A représente phényle substitué ou non substitué ou analogue; W représente hydrogène, alkyle inférieur, halogéno, alcoxy inférieur, alkylthio inférieur, alcanoyle inférieur ou analogue.
PCT/JP2000/003374 1999-05-31 2000-05-26 Derives de 2-arylpurine-9-acetamide, leur procede de preparation, compositions medicinales les contenant et intermediaires des derives WO2000073306A1 (fr)

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EP2009003A1 (fr) * 2007-06-27 2008-12-31 Ajinomoto Co., Inc. Procédé de production de composés de diaminopyrimidine
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