WO2005061508A1 - Tricyclic heterocyclic compound and medicine containing the compound as active ingredient - Google Patents

Abstract

A compound represented by the general formula (I): (I) (wherein R1 and R2 each independently represents optionally protected hydroxy; R3 and R4 each independently represents optionally protected hydroxy or oxo; R5 represents optionally oxidized methyl; and n, m, and p each independently is an integer of 0 to 3), a salt, solvate, or N-oxide of the compound, or a prodrug of any of these. They have CRF antagonistic activity and are useful for the prevention of and/or treatments for psychoneurotic diseases or digestive diseases.

Description

Tricyclic heterocyclic compound and drug containing the compound as active ingredient

Technical field

 The present invention relates to a tricyclic heterocyclic compound, a salt thereof, an N-oxide thereof, a solvate thereof, a prodrug thereof, and a composition comprising the same as an active ingredient.

Related to a medicament having.

 Rice field

 More specifically, the general formula (I)

 book

(Wherein all symbols have the same meanings as described below), a salt thereof, an N-oxide thereof, a solvate thereof, a prodrug thereof, And a medicament containing them as an active ingredient.

Background art

 Corticotropin Releasing Factor (CRF) is a 41 amino acid peptide isolated from the hypothalamus of ovine in 1981. This CRF was released from the hypothalamus and was suggested to play a role in regulating the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland [Science, 218, 377-379 (1982)].

ACTH secreted by CRF stimulation is cortizoone from the adrenal cortex. CRF is thought to act as a regulator of these functions, stimulating the secretion of glycerol, and related to systemic effects on reproduction, growth, gastrointestinal function, inflammation, immune system, nervous system, etc. For these reasons, attention has been paid to the involvement of CRF in neuropsychiatric disorders or diseases of peripheral organs.

 On the other hand, the number of depressed patients and anxiety disorders is increasing, and the number of mildly depressed patients is increasing recently. Elderly patients account for the majority of depression patients. Under such circumstances, there is a growing demand for easy-to-use drugs for treating neuropsychiatric disorders in view of the rapid onset of effects and side effects.

 Currently, for the treatment of neuropsychiatric disorders, for example, antidepressants include tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase (ΜΑ Ο) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRI), serotonin selective reuptake inhibitor (SSRI) and the like have been used. However, the therapeutic effect is not sufficient, it takes a long time for the effect to appear, and side effects such as drowsiness, mouth openness, constipation, and feeling of difficulty urinating are often observed. Benzodiazepines, chenozazepines, non-benzodiazepines, etc. are used as anxiolytics. However, this treatment is not effective enough, and side effects include decreased psychomotor function, reduced concentration and attention, drowsiness, lightheadedness, dizziness, headache, amnesia, and the like.

 Compounds having a CRF antagonistic activity are expected to be used as therapeutic agents for depression and anxiety disorders. For example, WO2O02 / 53565 describes the general formula (Α)

(A)

(Wherein X ^A and Y ^{A each} independently represent a carbon atom or a nitrogen atom (However, two do not represent a nitrogen atom at the same time), W ^A represents a carbon atom or a nitrogen atom, u ^A and z ^{A each} independently represent C: R ^2A , NR ^13A , a nitrogen atom, Oxygen atom, sulfur atom, 〇 = 〇 or 〇 = 3, and is Cl-4 alkyl, C

1-4 alkoxy, at least one content or is substituted with a group 1-3 pieces selected from halogen atoms and CF _3, or unsubstituted C4 ~ 6 carbocyclic or Nozomimoto atom, a SansoHara child or a sulfur atom to 4 represents a 6-membered heterocyclic ring, R ^{1 a} is either substituted by ①. 1 to 5 amino ^R 14Α, or unsubstituted C. 1 to 8 alkyl, (ii) 1~ 5 amino R ¹⁴ a in either substituted or unsubstituted C 2 to 8 alkenyl, (iii) :! ~ 5 amino or substituted with R ^14A, or unsubstituted C2~8 ^{alkynyl, v) NR 4A R 5A,} ( v) OR ^6A , (vi) SH, (vii) S (0) _nA R ^7A , (viii) COR ⁶ \ Gx) CO) R ^6A , (x) CON ^4A R ⁵ ^ ^0d ) NR ^{8A COR} R ^6aA , (Xii) NR ^8A COOR ^6A , (xiii) NR ^8A CONR ^4A R ⁵ \ (xiv) 1 to 5 R ^{15 A} substituted or unsubstituted C 3 to C 15 monocyclic or bicyclic carbocyclic, or (xv) or substituted with l~5 one R ^15A, Or an unsubstituted 3- to 15-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms. ,

R ^3A is (1-5's properly be monocyclic C5～ 10 substituted by R ^16A bicyclic carbocyclic or) :! To five R ^16A 1 to 4 nitrogen atoms substituted by from 1 to 2 oxygen atoms and Z or from 1 to 2 sulfur atoms and having free. 5 to: L 0-membered monocyclic or bicyclic Represents a cyclic heterocyclic ring. Compounds indicated by) are described. Disclosure of the invention

For prevention and / or treatment of neuropsychiatric disorders or diseases of peripheral organs Therefore, there is a need for drugs that are easy to use and have a strong prophylactic and / or therapeutic effect.

 Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above problems, and as a result, have found that a tricyclic heterocyclic compound achieves the object.

 That is, the present invention

 (1) General formula (I)

(In the formula, R ¹ and R ^{2 each} independently represent a hydroxyl group which may be protected, and R ³ and R ^{4 each} represent a hydroxyl group or an oxo group which may be independently protected. R ⁵ represents a methyl group which may be oxidized, and n, m, and p each independently represent 0 or an integer of 1 to 3.) A compound represented by the formula: Its N-year-old oxide form, their solvates, or their prodrugs,

 (2) General formula (la)

(Wherein, R ¹ represents a hydroxyl group or a methoxy group, R ² represents a hydroxyl group, R ³ and R ⁴ each independently represent a hydroxyl group or an oxo group, and R ⁵ represents a methyl group. Represents a tyl group, and na, ma and pa each independently represent 0 or an integer of 1 to 3. However, when ma and pa are 0, na represents an integer of 1 to 3. The compound according to the above (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

(3) Manufactured by chemical synthesis (i) 8-[(1-Ethylpropyl) amino] -12-methyl-3- (2-chloro-4-methoxyphenyl) 1,6,7-dihydro-5H-cyclopentene d] pyrazo mouth [1, 5-a] pyrimidin-1-ol, (ii) 3- (2-chloro-1-methoxyphenyl) -18-[(1-ethylpropyl) amino] -12-methyl-6 , 7-dihydro- 1 5H-cyclo-pentyl [d] pyrazo [1,5-a] pyrimidine-15-one, (iii) 3- (2-chloro-4-methoxyphenyl) 18- [( 1-Ethylpropyl) amino] _2-methyl-5,6-dihydro-1 7H-cyclopentyl [d] pyrazo mouth [1,5-a] pyrimidin-1 7-one, (iv) 3— (2-chloro-1-4 —Methoxyphenyl) 1 8— [(1-Ethylpropyl) amino] —2-Methyl-6,7-dihydro-5 H-cyclopentene [d] Pyrazo mouth [1,5— a] pyrimidine _7-ol, (V) 3— (2-chloro-4-methoxyphenyl) _8-[(1-ethyl-2-oxopropyl) amino] —2-methyl-1,6-dihydro-7H— Cyclopene [d] pyrazo mouth [1, 5-a] pyrimidine-1-7-one, (vi) 3- (2-chloro-1--4-methoxyphenyl) -18-[(1-ethyl-2-hydroxypropyl) amino] — 2-Methyl-6,7-dihidro 5H-Cyclopentyl [d] Pyrazo mouth [1, 5-a] Pyrimidin-7-ol, (vii) 3— (2-Chloro-1-methoxyphenyl) 1 8 — [(1-Ethyl-2-hydroxypropyl) amino] 1—2-Methyl-6,7—dihydrone 1H—Cyclopentyl [d] Pyrazo mouth [1, 5—a] pyrimidine 1—5 , (Viii) 3- (2-chloro-5-hydroxy-4-methoxyphenyl) — 8 — [(1-Ethylpropyl) amino] —2 Methyl-5, 6-dihydro —7H—Cyclopene [d] pyrazo [1,5—a] pyrimidin-7-one, (ix) 3- (2-chloro-4-hydroxyphenyl) 18-[(1-ethylpropyl) amino] 1-Methyl-5,6-dihydro-7H-cyclopentyl [d] pyrazo opening [1,5-a] pyrimidine-17-one, (X) 3- (2-chloro-5-hydroxy-14-methoxyf Enyl) 18-[(1-Ethynolepropyl) amino] 12-methyl-6,7-dihydro-15H-cyclopenta [d] pyrazo opening [1,5-a] pyrimidin-7-ol, (xi) 3— (2-Cross mouth —4-hydroxyphenyl) 18-[(1-Ethylpropyl) amino] —2 —Methyl-6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1,5-a] pyrimidine One 7-ol, (xii) 3- (2-Chloro-4-methoxyphenyl) One 8 — [(1-Ethyl-3-hydroxypropyl) amino] —2 — Methyl-6,7-dihydro- 1 H-cyclopentene [d] pyrazo [1,5-a] pyrimidin-7-ol, (xiii) 3-{[3- (2-chloro-1--4-methoxyphenyl) 1) 7-Hydroxy-2-methyl-6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1,5-a] Pyrimidin-8-yl] amino} pentan-1-one, (xiv) 3- (2-Chloro-4-methoxyphenyl) -18-[(1-ethylpropyl) .amino] _2-Methyl-6,7-dihydro-5H-cyclopentyl [d] Pyrazo mouth [1,5-a ] Pyrimidine-1-6- or (XV) 3- (2-chloro-4-hydroxyphenyl) -18-[(1-ethylpropyl) amino] 1-2-Methyl-6,7-dihydro-5 The compound according to the above (2), which is H-cyclopentene [d] pyrazo-mouth [1,5-a] pyrimidin-5-ol, a salt thereof, an N-year-old oxide form thereof, Et solvates or their Purodoradzugu,

(4) Manufactured by chemical synthesis (i) 3-chloro-1-4- (8-[(1-ethylpropyl) amino] —2-methyl-1,6,7-dihydro-5H-cyclobenzene [d ] Pyrazo mouth [1, 5-a] pyrimidine-1-3-yl} phenol 3-{[3- (2-Chloro-4-methoxyphenyl) -1-2-methyl-6,7-dihydro-5H-cyclopentyl [d] pyrazo [1,5-a] pyrimidine-18-yl] amino} -2-pentanol, (iii) 3-{[3- (2-chloro-4-methoxyphenyl) 1-2-methyl-6,7-dihydro-5H-sic 5 _a] pyrimidine-1-8-inole] amino} pentan-2-one, (iv) 3-{[3- (2-chloro-4-methoxyphenyl) 1-2-methyl-6,7-dihydro-5H-cyclopen Evening [d] Pyrazo mouth [1,5-a] pyrimidine-18-yl] amino} pentane-12-ol, (V) 3-{[3- (2-chloro-4-methoxyphenyl) 1-2 —Methyl-6,7—dihydro-5 H-cyclopentene [d] pyrazo-mouth [1,5-a] pyrimidine —8-yl] amino} pentane-1-ol or (vi) 4-octane Rollo 5-{8-[(1-Ethylpropyl) amino] —2-Methyl-1,6,7-dihide Mouth 5H—Cyclopene [d] Pyrazo Mouth [1,5-a] Pyrimidine-1-3-yl} The compound according to the above (1), which is 2-methoxyphenol, a salt thereof, an N-hydroxylated compound thereof, a solvate thereof, or a prodrug thereof,

(5) a pharmaceutical composition comprising the compound according to (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as an active ingredient;

 (6) The pharmaceutical composition according to (5), which is a CRF antagonist,

 (7) The pharmaceutical composition according to the above (6), which is an agent for preventing and / or treating a CRF-mediated disease,

 (8) the CRF-mediated disease is a nervous system disease or digestive system disease

(7) The pharmaceutical composition according to,

(9) If the psychiatric nervous system disorder is mood disorder, anxiety disorder, adaptation disorder, stress-related disorder, eating disorder, symptom or dependence due to use of a psychoactive substance, organic mental disorder, schizophrenia, or caution The doctor according to the above (8), which is a deficient hyperactivity disorder. Drug composition,

 (10) The pharmaceutical composition according to (8), wherein the digestive system disease is irritable bowel syndrome or gastrointestinal dysfunction due to stress.

 (11) Mood disorders include depression, single episode depression, recurrent depression, postpartum depression, child abuse-induced depression, bipolar affective disorder, indefinite complaints, premenstrual dysphoric mood disorder, peri-menopause Or the pharmaceutical composition according to the above (9), which is a mood disorder during menopause,

(12) The compound according to the above (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, a tricyclic antidepressant, a tetracyclic antidepressant, a monoamine Oxidase inhibitor, serotonin and noradrenaline reuptake inhibitor, serotonin selective reuptake inhibitor, serotonin reuptake inhibitor, psychostimulant, anxiolytic, antipsychotic, mitochondrial benzodiazepine receptor ligand, NK 1 antagonists, gastrointestinal function adjusting agents, 5-HT ₃掊抗drugs, 5-HTJ乍動agents, anticholinergics, made in conjunction with antidiarrheal, laxatives and autonomic adjustment agents or al least one selected Medicine,

 (13) A CRF-mediated method comprising administering to a mammal an effective amount of the compound according to (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. Disease prevention and Z or treatment methods, and

(14) Use of the compound according to the above (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for producing a CRF antagonist.

In the present invention, the optionally protected hydroxyl group includes a hydroxyl group which may be protected by a protecting group having an elimination ability. Examples of the protective group capable of leaving include, for example, a methyl group, an isopropyl group, a trityl group, a methoxymethyl (MOM) group, an 11-ethoxyxyl (EE) group, a methoxyethoxymethyl (MEM) group, Tetrahydroviranyl (THP) group, trimethylsi Ryl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, bivaloyl group, benzoyl group, benzyl (Bn ) Group, p-methoxybenzyl group, aryloxycarbonyl (Alloc) 2,2,2-trichloromouth ethoxycarbonyl (Troc) group.

 In the present invention, the preferred optionally protected hydroxyl group includes a hydroxyl group or a hydroxyl group protected by a methyl group, an isopropyl group, a MOM group, an EE group, a TBDMS group or an acetyl group. Particularly preferred is a hydroxyl group protected by a hydroxyl group or a methyl group.

In the present invention, when n represents 2 or 3, each R ² group may be the same or different, and when m represents 2 or 3, each R ³ group may be the same or different. And when p represents 2 or 3, each R ⁴ group may be the same or different.

In the present invention, preferred R ¹ is a hydroxyl group (methoxy group) protected by a hydroxyl group or a methyl group. Desirable R ² is 0 to 1 hydroxyl group, or a hydroxyl group protected by a methyl group or an isopropyl group (methoxy group, isopropoxy group). Desirable R ³ is one or two groups selected from a hydroxyl group (methoxy group) and an oxo group protected by a hydroxyl group, a methyl group, and particularly one hydroxyl group and a hydroxyl group protected by a methyl group (a methoxy group). Or oxo groups are preferred. Further, the substitution position is preferably any of the 5-, 6-, and 7-positions of the following tricyclic heterocycle, and particularly preferably the 5- or 7-position.

Preferred: R ⁴ is protected by a hydroxyl, methyl or TBDMS group One or two groups selected from a hydroxyl group (methoxy group, t-butyldimethylsilyloxy group) and an oxo group, and one hydroxyl group or oxo group is particularly preferred. The substitution position is preferably the 1- or 2-position of a pentane-3-yl group in the case of a hydroxyl group, and the 2-position in the case of an oxo group.

Desirable R ⁵ is a group selected from a methyl group, a hydroxymethyl group, a formyl group, and a carboxy group, and a methyl group is particularly preferable.

 In the present invention, the compound represented by the general formula (I) is a compound produced by chemical synthesis.

 In the present invention, preferred compounds are those represented by the general formula (la)

(Wherein, R ¹ represents a hydroxyl group or a methoxy group, R ² represents a hydroxyl group, R ³ and R ^{4 each} independently represent a hydroxyl group or an oxo group, R ⁵ represents a methyl group, na , Ma and pa each independently represent 0 or an integer of 1-3, provided that when ma and pa are 0, na represents an integer of 1-3. , Its N-oxide, its solvates, or their prodrugs, and chemically synthesized (i) 3-chloro41- {8-[((1-ethylpropyl) amino] 1-2-methyl-16,7 -Dihydro-5H-cyclopentene [d] pyrazo-mouth [1, 5_a] pyrimidine-131- ^ fur] "phenol, (ϋ) 3— {[3- (2-chloro-mouth _4-methoxyphenyl) one 2— Methyl-6,7-dihydro-5-cyclopentene [d] pyrazo mouth [1,5-a] pyrimidine-1 8— Le] amino} - 2-pen evening Nord, (iii) 3-{[3- (2-Chloro-4-methoxyphenyl) _2-Methyl-6,7-dihydro-5H-cyclopentene [d] Pyrazo-mouth [1,5-a] pyrimidine-18-yl] amino} Pentane-2-one, (iv) 3-{[3- (2-chloro-1-4-methoxyphenyl) -1-methyl-6,7-dihydro-1-5H-cyclopen [d] pyrazo [1 , 5 _a] pyrimidine-18-yl] amino} pentan-2-ol, (V) 3-{[3- (2-chloro-4-methoxyphenyl) 1-2-methyl-6,7-dihydro-1 5 H—cyclopentyl [d] pyrazo [1, 5-a] pyrimidin-1-yl] amino} pentan-1-ol, or (vi) 4-chloro-5— {8-[(1-1 Ethylpropyl) amino] -2-Methyl-6,7-dihydro-15H-cyclopentyl [d] pyrazo [1,5-a] pyrimidine-13-yl} -12-methoxyphenol Among the compounds represented by the general formula (la), a more preferable compound is a chemically synthesized (i) 8-[(1-ethylpropyl) amino] -12-methyl-3-((2-chloro-1--4-methoxyphene) Nyl) 1,6,7-dihydro_5H-cyclopentene [d] Pyrazo mouth [1, 5—a] Pyrimidin-5-ol, (ii) 3- (2-chloro-1--4-methoxyphenyl) 1) 8-[[(1-Ethylpropyl) amino] 1-methyl-6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1,5-a] pyrimidin-5-one, (iii) 3— 2-chloro-1-4-methoxyphenyl) -1-8-[(1-ethylpropyl) amino] —2-methyl-5,6-dihydro-7H-cyclopentene [d] pyrazo-mouth [1,5-a] pyrimidine-1 7 -On, (iv) 3- (2-chloro-1-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] -12-methyl-6,7-dihi Draw 5 H—Sik Mouth Pen Pen [d] Pyrazo Mouth [1,5-a] Pyrimidin-1-7-ol, (V) 3-(2-Chloro-4-methoxyphenyl) 1 8— [(1Ethyl _2— Oxopropyl) amino] 1-Methyl-5,6-dihydro-17H-cyclopentene [d] Pyrazo mouth [1, 5—a] pyrimidine-1 7-one, (vi) 3- (2- 1-Methoxy-1-yl) 8-([1-Ethyl-2-hydroxypropyl) amino] 1-2-Methyl-6,7-dihydro-5H-cyclopentene [d] Pyrazo [1,5-a] pyrimidine 1 7-ol, (νϋ) 3— (2-chloro 1-4-methoxyphenyl) 1 8 — [(1-ethyl-2-hydroxypropyl) amino] —2-methyl-1,6,7-dihydro-15- Cyclopene [d] bilazolo [1,5-a] pyrimidin-5-ol, (viii) 3- (2-chloro-5-hydroxy-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] — 2-Methyl-5,6-dihydro-7H-cyclopentene [d] Pyrazo mouth [1,5-a] Pyrimidine-17_one, (ix) 3- (2-Chloro-1-hydroxyhydroxyphenyl) -18 — [(1-Ethylpropyl) amino] _ 2-Methyl-1,5,6-dihydro-17H-cyclopentyl [d] pyra Zoguchi [1, 5_a] pyrimidine-1 7-one, (X) 3-(2-chloro-1-5-hydroxy-4-methoxyphenyl) 18-[(1-ethylpropyl) amino] —2-methyl-16 , 7-Dihydro-5H-cyclopentyl [d] pyrazo [1,5-a] pyrimidin-1 7-ol, (xi) 3— (2-chloro-4-hydroxyphenyl) 1 8 1 [(1 —Ethylpropyl) amino] 1-Methyl-6,7-dihydro-5H-cyclopentyl [d] pyrazo [1,5-a] pyrimidin-7-ol, (xii) 3- (2-chloro-1) 4-Methoxyphenyl) 1-8 — [(1-Ethyl-1-hydroxypropyl) amino] _ 2-Methyl-1,6,7-dihydro-5Ηcyclopentene [d] Pyrazo mouth [1,5-a] pyrimidine 17-ol, (xiii) 3- {[3- (2-chloro-4-methoxyphenyl) 17-hydroxy-2 monomethyl-1,6,7-dihydro-5H-cyclopen [d] Pyrazo mouth [1,5 — a] pyrimidine-18fl] amino} pentan-2-one, (iv) 3- (2-chloro-1-4-methoxyphenyl) -18-[(1-ethylpropyl) [Amino] 12-methyl-1, 6,7-dihydro-5H-cyclopentene [d] pyrazo [1,5-a] pyrimidin-1-6-ol, and (XV) 3- (2-chloro-4- 4- (Droxyphenyl) -1-[(1-ethylpropyl) amino] -12-methyl_6,7-dihydro-5H-cyclopentene [d] pyrazo opening [5-a] pyrimidin-1-ol.

 Further, specific compounds of the present invention include the following compounds produced by chemical synthesis.

 (a) N- (1-Ethylpropyl) -1-5-methoxy-2-methyl-3- (2-chloro-1-methoxyphenyl) -1,6,7-dihydro-15H-cyclopentene [d] Pyrazo mouth [1, 5—a] pyrimidine-1 8-amine, (b) 3— (2-chloro-5-isopropoxy-1-methoxyphenyl) 1-N- (1-ethylpropyl) 1-2-methyl-6,7-dihydro-1 5H-cyclopentene [d] pyrazo [1,5—a] pyrimidine-18-amine, (c) 3- (2-chloro-1-5-propoxy-1-methoxyphenyl) 18- [ (1—Ethylpropyl) amino] 1—2—Methyl-5,6-dihydro-17H—cyclopentene [d] Pyrazo mouth [1, 5-1 a] Pyrimidin—7—one, (d) N— (3— {[ tert-butyl (dimethyl) silyl] oxy} — 1-ethylpropyl) 1-3- (2-chloro-4-methoxyphenyl) 1-2-methyl-6, 7-dihydro-5H-cyclopentyl [d] pyrazo opening [1, 5-a] pyrimidine-18-amine, (e) 8— [(3-{[tert-butyl (dimethyl) silyl] oxy} 1-11 Ethylpropyl) Amino] 1 3— (2-chloro-1-4-methoxyphenyl) 1-2-Methyl-5,6-dihydrido 7H-Cyclopentyl [d] Pyrazo [1,5—a] pyrimidine 7-one, and (08 _ [(3-{[tert-butyl (dimethyl) silyl] oxy] -111-ethylpropyl) amino] -1 3_ (2-chloro-port 4-methoxyphenyl) 1-2-methyl-16 , 7-Dihydro-5H-cyclopentyl [d] Pyrazo mouth [1, 5-a] Pyrimidin-7-ol.

In the present invention, all isomers are included unless otherwise indicated. For example, alkyl groups include straight and branched ones. further, Isomers in double bonds, rings and condensed rings (E, Z, cis, trans), isomers due to the presence of asymmetric carbon (R, S, a,? Configuration, enantiomer, diastereomer), Optically active forms with optical activity (D, L, d, 1 form), polar forms by chromatographic separation (high-polarity, low-polarity), equilibrium compounds, rotamers, any ratio of these And racemic mixtures are all included in the present invention. In the present invention, the notation of asymmetric carbon is obvious to those skilled in the art unless otherwise specified... Indicates that the bond is on the other side of the page (that is, one arrangement), and Z indicates the point on the page. On the side (that is,? -Configuration), ^ indicates a single configuration or /?-Configuration, and Ζ indicates a mixture of a-configuration and β-configuration.

 In the present invention, non-toxic, water-soluble salts are preferred.

 Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salt, tetrabutylammonium salt). Salt, etc.), organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxylmethyl) methylamine, lysine, arginine , Ν-methyl-D-glucamine, etc.), acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acids Salt (acetate, trifluoroacetate, lactate, tartrate, oxalate, Malate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.) Etc.).

In addition, the pentoxide compound is obtained by oxidizing a nitrogen atom of the compound represented by the general formula (I). The compound of the present invention can be converted into a pendoxide by any method. Can.

 The compounds of the present invention, their salts and N-oxides also include solvates and solvates of the alkali (earth) metal salts, ammonium salts, organic amine salts, and acid addition salts of the compounds of the present invention. .

 Preferably, the solvate is non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water and alcoholic solvents (e.g., ethanol). Prodrugs of the compound represented by the general formula (I) are produced in vivo by enzymes or stomach acids. A compound which is converted into a compound represented by the general formula (I) by a reaction. Examples of the prodrug of the compound represented by the general formula (I) include, when the compound represented by the general formula (I) has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, a compound represented by the general formula Compounds in which the hydroxyl group of the compound represented by formula (I) is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, and the like. These compounds can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate.

 [Method for producing compound of the present invention]

 The compounds of the present invention can be produced, for example, by the following methods or the methods described in the Examples below.

 For example, the general formula (I)

(Wherein all symbols have the same meanings as described above.) Are represented by the general formula (VIII)

(Wherein all symbols have the same meanings as described above).

(Wherein the symbols have the same meanings as described above.).

 The above reaction is carried out in an organic solvent (eg, toluene, xylene, 1,2-dimethoxetane, dimethylformamide, dimethylamine, dimethylsulfoxide, 2-propanol, isopropanol, acetonitrile) or without a solvent, in a base (eg, triethylamine, trimethylamine). , Di-so-propylethylamine, N-methylmorpholine, N-ethylmorpholine, tri-n-butylpyramine, tri-n-butylamine, etc.) at 80 to 150 ° C.

When R ^{5 of the} compound represented by the general formula (VHI) is a methyl group, it can be produced, for example, by a method represented by the following reaction scheme. Reaction formula

In the reaction scheme, X represents a halogen atom, specifically, chlorine, bromine, fluorine, or iodine, particularly preferably chlorine or bromine; M represents a metal; specifically, sodium or potassium And lithium, with sodium being preferred. R ⁶ represents methyl or ethyl.

Step [1] is performed in an organic solvent (eg, 1,2-dimethoxyethane, diglyme, toluene, xylene, dimethylformamide, cyclopentylmethyl ether, tetrahydrofuran, dioxane, dimethylacetamide, or dimethylimidazolidinone) Using a homogeneous catalyst in the presence of a base (eg, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, sodium hydride, sodium carbonate, potassium carbonate, lithium carbonate, potassium phosphate, sodium phosphate) At 70 to 120 ° C. As the homogeneous catalyst, a palladium-based homogeneous catalyst is preferable, and examples thereof include tetrakistriphenylphosphine palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium, and palladium chloride. The amount used is a catalytic amount, preferably 0.1 to 2 O mo 1%, more preferably 0.25 to: LO mo 1%, particularly preferably 0.25 to 5 mo 1% based on the raw material. Quantity.

The homogeneous catalyst may be a homogeneous catalyst alone or a combination of a homogeneous catalyst and a ligand. As ligands, triphenylphosphine, 2,2,1-bis (diphenylphosphino) 1-1,1,1-binaphthyl, 9,9,1-dimethyl-4,5-bis (diphenylphosphino) xanthene 1,1,1-bis (diphenylphosphino) phenyl, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenyl) Phosphino) butane, tree 2-m-tolylphosphine, tri-p-tolylphosphine, tree o-tolylphosphine, tris (2-methoxyphenyl) phosphine, tris (3-methoxyphenyl) phosphine, tris (4 —Methoxyphenyl) phosphine, 1,2-bis (diphenylphosphino) benzene, trimethylsilylphosphine, tris (4-fluoro) Phenyl) phosphine, tris (pentafluorophenyl) phosphine, cyclohexyldiphenylphosphine, dicyclohexylphenyl phosphine, tris (3-sulfophenyl) phosphine trihydrochloride, bis (2-diphenylphosphinophenenyl) ether Cis-1,2-bis (diphenylphosphino) ethylene, diphenyl pentafluorophenylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2 —Dicyclohexylphosphino 2 ′ — (Ν, Ν-dimethylamino) biphenyl. Preferred ligands are 1,2-bis (diphenylphosphino) ethane, tree 2-m-tolylphosphine, Tri-p-tolylphosphine, 2,2'-bis (diphenylphosphino) 1-1,1, -binaphthyl.

Examples of the homogeneous catalyst or the combination of the homogeneous catalyst and the ligand used in the present invention include tetrakistriphenylphosphine palladium alone, palladium acetate, 1,2-bis (diphenylphosphino) ethane, and palladium acetate. Application Benefits one 2-m-tolylphosphine, palladium acetate and tri-one p- Toriruhosufu Inn, palladium acetate and 2, 2, single-bis (diphenyl phosphine Ino) over 1, 1 ^J - binaphthyl, tris (dibenzylideneacetone) Palladium and 1,2-bis (diphenylphosphino) ethane, tris (dibenzylideneacetone) dipalladium and tri-1 2-m-tolylphosphine, tris (dibenzylideneacetone) dipalladium and tri-p-tolylphosphine, tris (Dibenzylideneacetone) dipalladium and 2,2,1-bis (Diphenylphosphino) _1, -binaphthyl is preferred.

 Step [2] is performed in an organic solvent (eg, toluene, methanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, aceto nitrile, dimethylformamide, dimethyl sulfoxide) in an acid (eg, acetic acid, propionic acid, p-toluene). Hydrazine, hydrazine monohydrate, or a solution of hydrazine or hydrazine monohydrate at 60 to 80% by mass in the presence of sulfonic acid, methanesulfonic acid) at 10 to 60 ° C or It is performed under heat reflux.

Step [3] is performed using an acid (eg, acetic acid, sulfuric acid, methanesulfonic acid) as a solvent at 50 to 1 ° C. or under reflux with heating. Or in the presence of an acid (eg, acetic acid, sulfuric acid, methanesulfonic acid, tosylic acid) in an organic solvent (eg, methanol, ethanol, toluene, dimethylformamide, 1-propanol, 2-propanol, acetonitrile, etc.) Methyl 3-methoxy-2-oxocyclopentenecarboxylate or 3-methoxy-2-oxo The reaction is carried out at 50 to 100 ° C or under reflux using ethyl chloropentanecarboxylate.

 In the above reaction, when an organic solvent is used, the amount of acid used is smaller than the amount used when reacting with an acid as a solvent, so that the reaction can be carried out in a smaller amount, so that its removal is simple and safe. Can react to

Step [4] is carried out in an organic solvent (eg, toluene, 1,2-dimethoxyethane, acetonitrile, tetrahydrofuran) in a base (eg, pyridine, triethylamine, dimethylaniline, getylaniline, dimethylaminopyridine, diisopropylamine). In the presence of thiolamine, 2,6-lutidine, 2-picoline, N-methylmorpholine, N-ethylmorpholine, tri-n-propylamine, tri-n-butylamine), use Performed at ~ 120 ° C. The reaction can also be carried out by using tetrahydrocarbon in the presence of triphenylphosphine (Ph ₃ P) in an organic solvent (specific examples are the same as those described above). In the compounds of the present invention, compounds in which I ¹ , R ² , R ³ , and / or R ⁴ are a hydroxyl group or an oxo group can be obtained by deprotecting, demethylating, or oxidizing the corresponding compound. It can also be produced by making full use of a reaction or reduction reaction. For example, general formula (1-1)

(Wherein all symbols have the same meanings as described above.) The compound represented by the general formula (I-12)

(Wherein all symbols have the same meanings as described above.) The compound can be produced by subjecting the compound to a demethylation reaction. Further, by subjecting the compound represented by the general formula (I-11) to an acid reaction, the compound represented by the general formula (1-3)

(Wherein all symbols have the same meanings as described above.). The deprotection reaction, demethylation reaction, oxidation reaction and reduction reaction are selected from known methods according to the compound to be reacted and the target compound.

 The other starting materials and each reagent in the present invention are known per se or can be produced according to a known method.

 In each reaction in the present specification, a reaction involving heating can be performed using a water bath, an oil bath, a sand bath, or a microwave, as will be apparent to those skilled in the art.

In each reaction in the present specification, a reaction product is obtained by a usual purification means, for example, Purification by distillation under pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion-exchange resin, scavenger resin or column chromatography or washing, recrystallization, etc. can do. Purification may be performed for each reaction, or may be performed after completion of several reactions. The toxicity of the compound of the present invention represented by the general formula (I) is sufficiently low, and is considered to be sufficiently safe for use as a medicament.

 [Application to pharmaceutical products]

 Since the compound of the present invention represented by the general formula (I) binds to a CRF receptor and exhibits an antagonistic effect, the compound of the present invention exhibits a CRF-mediated disease such as a psychiatric nervous system disease, a digestive system disease, a respiratory system disease, an endocrine system. It is considered to be useful as a prophylactic and / or therapeutic agent for sexual diseases, metabolic diseases, cardiovascular diseases, skin diseases, urinary tract diseases, eye diseases, and musculoskeletal diseases. '

More specifically, neuropsychiatric disorders include, for example, mood disorders (eg, depression, single episode depression, recurrent depression, postpartum depression, child abuse-induced depression, bipolar affective disorder) , Indefinite complaints, premenstrual dysphoric disorder, perimenopause or perimenopausal mood disorder, anxiety disorders (general anxiety disorder, panic disorder, obsessive-compulsive disorder, phobic anxiety disorder (altitude phobia, claustrophobia) Illness, agoraphobia, social phobia etc.)), Adaptation disorder (emotional disorder, behavioral disorder, disability with both of them, physical complaints, social withdrawal, occupational or academic stagnation, etc.) , Stress-related disorders (eg, post-traumatic stress disorder (PTSD), stress-induced immune suppression, stress-induced headache, stress-induced fever, stress-induced pain, surgical assault stress, stress Gastrointestinal dysfunction, irritable bowel syndrome), eating disorders (eg, anorexia nervosa, bulimia, vomiting nervous), symptoms caused by the use of psychoactive substances or their dependence (eg, withdrawal symptoms of alcohol, Al Cole addiction, drug addiction, drug addiction), organic mental disorders (eg, Alzheimer's disease type 1 senile dementia, polyinfarct dementia), schizophrenia, attention deficit hyperactivity disorder, neurodegenerative disease ( For example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), pain, convulsive disorders (eg, convulsions, muscle spasms), paroxysmal disorders (eg, epilepsy, seizures, migraine) or Sleep disorders (eg, non-organic sleep disorders, fibromyalgia sleep disorders); and digestive disorders include, for example, peptic ulcers, inflammatory bowel diseases (eg, ulcerative colitis, Crohn's disease). Irritable bowel syndrome, gastrointestinal dysfunction due to stress, diarrhea or constipation, and respiratory diseases such as asthma, bronchitis, chronic obstructive pulmonary disease or Endocrine disorders include, for example, thyroid dysfunction syndrome, Cushing's disease or antidiuretic hormone incompatible secretion syndrome; and metabolic disorders include, for example, obesity or hypoglycemia. Organ diseases include, for example, hypertension, ischemic heart disease, tachycardia, depressive heart failure or cerebrovascular disease, and skin diseases include, for example, atopic dermatitis, allergic contact dermatitis or psoriasis, Urinary genital disorders include, for example, dysuria, pollakiuria or urinary incontinence; ophthalmic disorders, for example, uveitis; or musculoskeletal disorders, for example, rheumatoid arthritis, osteoarthritis Disease or osteoporosis.

 The compound of the present invention represented by the general formula (I)

 (1) complement and / or enhance the preventive and / or therapeutic effects of the compound,

(2) the kinetics of the compound'improved absorption, reduced dosage, and

 (3) The compound may be administered as a concomitant drug in combination with other drugs to reduce side effects of the compound.

The concomitant drug of the compound of the present invention represented by the general formula (I) and another drug may be administered in the form of a combination preparation in which both components are combined in one preparation, or in the form of a separate preparation. May be taken. When administered in this separate formulation, Simultaneous administration and administration with a time difference are included. In addition, administration with a time difference may be performed by administering the compound of the present invention represented by the general formula (I) first and then administering another drug later, or administering the other drug first and then administering the compound represented by the general formula (I) The compound of the present invention represented by may be administered later. Each administration method may be the same or different. Diseases which exert the preventive and / or therapeutic effects by the above concomitant drug are not particularly limited, as long as they complement and / or enhance the preventive and / or therapeutic effects of the compound of the present invention represented by the general formula (I). Good.

 Other agents for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention represented by the general formula (I) on mood disorders include, for example, antidepressants (for example, tricyclic anticancer drugs). Depressants, tetracyclic antidepressants, monoamine oxidase (MAO) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors , Psychostimulants, anxiolytics, antipsychotics, mitochondrial benzodiazepine receptor (MBR) ligands, NK1 antagonists and the like.

 Other agents for the prevention of the anxiety disorder and the complementation of Z or therapeutic effect and the Z or enhancement of the anxiety disorder of the compound of the present invention represented by the general formula (I) include, for example, anxiolytics (eg, benzodiazepines, chenodiazepines). System, non-benzodiazepine system), and MBR ligand.

Other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention represented by the general formula (I) on irritable bowel syndrome include, for example, a gastrointestinal function regulator, HT ₃ antagonists, 5-HT ₄ agonists, anticholinergics, antidiarrheals, laxatives, autonomic modulators, antidepressants, anxiolytics. Examples of antidepressants include tricyclic antidepressants (eg, amitriptyline hydrochloride, imibramine hydrochloride, clomipramine hydrochloride, doslevin hydrochloride, nortriplipline hydrochloride, mouth uebramine, trimibramine maleate, amoxapi ), Tetracyclic antidepressants (for example, maprotiline hydrochloride, mianserin hydrochloride, setiptiline maleate), MAOP and harmful drugs (saflazine hydrochloride), SNRI (for example, milnacipran hydrochloride, benrafaxin hydrochloride), SSRIs (eg, fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, ciyulopram hydrochloride), and serotonin reuptake inhibitors (eg, trazodone hydrochloride).

 As anxiolytics, for example, benzodiazepines (eg, alprazolam, oxazepam, oxazolam, cloxazolam, dipotassium chlorazepate, chlordazepoxide, diazepam, tofisopam, triazolam, plazepam, fluzazepam, fluzazepam, fluzazelam, fluzazelam, fluzazelam) Examples thereof include bromazepam, mexazolam, medazepam, oral ethyl frazepate, lorazepam), chenodiazepines (eg, etizolam, clotiazepam), and non-benzodiazepines (eg, tandospirone quenate, hydroxylzine hydrochloride).

 As psychostimulants, for example, methyl fenidate hydrochloride and emorin can be mentioned.

 Antipsychotics include sulpiride, trazodone hydrochloride, serotonin 'dopamine antagonists (eg, risperidone, perspirone hydrochloride hydrate, quetiapine fumarate, olanzapine).

 Gastrointestinal function regulators include, for example, trimebutine maleate and polycarbophil calcium.

Examples of 5-HT ₃ antagonists include arosetron.

The 5 _ HT ₄ agonists, e.g. Tegase port de, cisapride, include 'Kuen acid deaf Purido.

The mass ratio of the compound represented by the general formula (e) to another drug is not particularly limited. Other drugs may be administered in any combination of two or more. Further, other drugs that supplement and / or enhance the preventive and / or therapeutic effects of the compound represented by the general formula (I) include, based on the above-mentioned mechanism, only those that have been found so far. And those found in the future. In order to use the compound represented by the general formula (I) or a non-toxic salt thereof or a combination drug of the compound represented by the general formula (I) and another drug for the above-mentioned purpose in the present invention, generally a systemic It is administered orally or parenterally, either topically or topically.

 Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually, per adult, in the range of lmg to 100mg, once orally several times a day Dosage or parenteral once to several times daily, from O.lmg to 100 mg per adult per day, or 1 hour to 2 times daily It is continuously administered intravenously for a period of 4 hours.

 Of course, as described above, the dose varies depending on various conditions, so a smaller dose than the above-mentioned dose may be sufficient, or may be required beyond the range.

 When administering the compound of the present invention represented by the general formula (I) or the combination drug of the compound represented by the general formula (I) and another drug, a solid preparation for oral administration, a solid preparation for oral administration, It is used as liquids, parenteral injections, external preparations, suppositories, eye drops, inhalants and the like.

 Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. Tablets include sublingual tablets, buccal patches, and buccally disintegrating tablets.

3 o

In such solid dosage forms, one or more of the active substances may be intact or excipients (such as lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (such as hydroxylpropyl cellulose, Polyvinylpyrrolidose mixed with magnesium aluminate metasilicate, disintegrant (calcium fiber glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, dissolution aid (glutamic acid, aspartic acid, etc.) It is used after being formulated according to a conventional method. Further, if necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethyl cell mouth perfume rate, etc.), or may be coated with two or more layers. In addition, capsules made of an absorbable substance such as gelatin are included.

 Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such solutions, one or more active substances are dissolved, suspended, or emulsified in a commonly used diluent (such as purified water, ethanol, or a mixture thereof). Further, this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

 Topical dosage forms for parenteral administration include, for example, ointments, gels, creams, compresses, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops And nasal drops. They contain one or more active substances and are prepared by known methods or commonly used formulations.

 Propellants, inhalants and sprays may be formulated with buffering agents other than commonly used diluents, such as sodium chloride, sodium citrate or citric acid, to give isotonicity with stabilizers such as sodium bisulfite. Such an isotonic agent may be contained. Methods for producing sprays are described in detail, for example, in U.S. Pat. Nos. 2,868,691 and 3,095,355.

Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use. One injection Alternatively, more active substances are used by dissolving, suspending or emulsifying the same in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and a combination thereof are used. Further, the injection includes a stabilizer, a solubilizing agent (glucamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative. Etc. may be included. They are prepared by sterilization or aseptic processing in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be manufactured and then used after dissolving in sterilized or sterile distilled water for injection or other solvents before use.

 Other compositions for parenteral administration include one or more active substances, including suppositories for rectal administration and saliva for vaginal administration, formulated in a conventional manner. . BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

 The solvent in the kakkou indicated by the place of separation by chromatography and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

 The solvent in the parenthesis shown in the NMR section indicates the solvent used for the measurement.

 The nomenclature used in this specification has been completed based on ACD / Name (registered trademark) (version 6.00, Advanced Chemistry Development Inc., Chido).

Example 1: 3- (2-chloro-4-methoxyphenyl) -1-5-methoxy-2-monomethyl-1,6,7-dihydro-5-cyclopentene [d] pyrazo-mouth [1,5-a] pyrimidine-18- One liter

4- (2-chloro-4-methoxyphenyl) 1-3-methyl-1H-pyrazo -To a solution of 5-ruamine (5.0 g) in ethanol (25 mL), add acetic acid (3.61 mL) and methyl 3- (methoxymethoxy) -2-cyclopentanecarboxylate (4.35 g). Stirred for hours. After cooling the reaction mixture, toluene (50 mL) was added, and the mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration to give the title compound (6.0 g) having the following physical data.

 TLC: Rf 0.67 (black form: methanol = 10: 1);

CDCla): δ 8.53, 7.10, 7.04, 6.87, 4.87, 3.86, 3.40, 2.95,

Example 2: 8-chloro-3- (2-chloro-4-methoxyphenyl) -1,5-methoxy-2-methyl-6,7-dihydro-1.5-cyclopentene [d] villazolo [1,5-a ] Pyrimidine

 Carbon tetrachloride (18 mL) and triphenylphosphine (13.1 g) were added to a suspension of the compound prepared in Example 1 (6.0 g) in tetrahydrofuran (144 mL), and the mixture was heated under reflux for 8 hours. After cooling the reaction mixture, the insolubles were filtered off and the filtrate was concentrated, followed by silica gel column chromatography (hexane: ethyl acetate = 3:

Purification by 1) afforded the title compound (5.07 g) having the following physical data.

 TLC: Rf0.36 (hexane: ethyl acetate = 3: 1);

iH-NMR (300 MHz, CDCI3): δ 7.29, 7.08, 6.90, 4.65, 3.85, 3.52, 3.20, 2.94,

Example 3: Ν— (1-Ethylpropyl) _5-methoxy-2-methyl-13- (2-chloro-4-methoxyphenyl) -1,6,7-dihydro-5Ηcyclopentene [d] pyrazo port [1] , 5—a] pyrimidine-1—amine

To a solution of the compound (2.0) prepared in Example 2 in isopropanol (1 OmL) was added 3-aminopentane (1.85 mL), and 90. The mixture was stirred at C for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column residue 08

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8S96l0 / fr00Cdf / X3d 80S190 / S00J OAV 1,2-methyl-1,6,7-dihydro-5H-cyclopentene [d] pyrazo mouth [1,

5—a] Pyrimidine was obtained.

An 80% aqueous acetic acid solution of the obtained compound (42 lmg) was stirred at 60 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give the title compound (1

63 mg).

 TLC: Rf0.32 (cloth form: methanol = 20: 1);

_{Ή-ΝΜβ (300ΜΗζ, CDC1 3} ): δ 1.02 (m, 3H) 1.25 (m, 3H) 1.75 (m, 2H) 2.01 (m, IH) 2.35 (m, J = 3.30Hz, 3H) 2.49 (m, 2H) 2.95 (m, IH) 3.13 (m, IH) 3.47 (m, IH) 3.73 (m, IH) 3.83 (s, 3H) 3.91 (m, J = 10.71, 10.71Hz, IH) 4.95 (m, IH ) 6.61 (m, IH) 6.88 (dd, J = 8.51, 2.65Hz, IH) 7.06 (d, J = 2.56Hz, IH)

Example 4: 3-amino-2-pentanol

3-Nitro-2-pentanol (40 g) was dissolved in a mixed solution of methanol (200 mL) and tetrahydrofuran (200 mL), the inside of the reaction vessel was degassed, and then replaced with argon. _{10% PdZC (H 2 0:} 60.66%, 4 g) was added, after degassing the reaction vessel was replaced with argon. Ammonium formate (95 g) was added, and the mixture was stirred at room temperature for 4 days. The reaction solution was filtered through celite, and the solvent was distilled off. The residue was dried with a vacuum pump to give the title compound (36.7 g) having the following physical data.

! H-NMRi ^ OMHz, CDC1 3): δ 5.46, 4.02-3.58, 2.96-2.61, 1.75-1.34, 1.22,

Example 5: 8-[(1-Ethylpropyl) amino] 1-2-methyl-3- (2-1,4-methylphenyl) -1,6,7-dihydro-5-cyclopentene Evening [d] Pyrazo mouth [1,5-a] pyrimidin-5-ol To the compound (2.03 g) produced in Example 3 was added pyridine hydrochloride (9.0 g), and the mixture was stirred at 150 ° C for 3 hours. After cooling, the reaction mixture was dissolved in ethyl acetate and water, and separated. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain a crude product (69 Omg). Further recrystallization from hexane Z ethyl acetate (1Z1) (4.0 mL) gave the title compound (363 mg and 96 mg as a secondary crystal) having the following physical data. TLC: Rf0.38 (hexane: ethyl acetate = 1: 1);

_{iH-NMR (300MHz CDC1 3?} ): δ 7.31, 7.07, 6.88, 6.35, 4.95, 3.84, 3.81, 3.30, 3.14, 2.94, 2.48, 2.36, 2.00, 1.66, 1.03, 1.00ο

 Example 6: 3- (2-chloro-4-methoxyphenyl) -18 _ [(1-ethylpropyl) amino] -12-methyl-6,7-dihydro-5Η-cyclobenzene [d] pyrazo [1 , 5_a] Pyrimidine-1 5-one

 To a solution of the compound prepared in Example 5 (28 Omg) in methylene chloride (3.0 mL) was added dimethylsulfoxide (192 L), triethylamine (377 L) and pyridine triacid-sulfide sulfur complex (323 mg) in that order. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (11 lmg) having the following physical data.

TLC: Rf 0.38 (toluene: ethyl acetate = 2: 1);

iH-NMR (300 MHz, CDCI3): δ 7.31, 7.04, 6.78, 6.68, 3.97, 3.84, 3.30, 2.81, 2.41, 1.92-1.66, 1.06.

Example 7: 3-Chloro-4- {8-[(1-ethylpropyl) amino] 1-2-methyl-6,7-dihydro-15-cyclopentyl [d] pyrazo [1,5 A) pyrimidine-3-yl} phenol

 Anhydrous aluminum chloride (1.67 g) was added to dodecanethiol (1 OmL), and the mixture was stirred for 5 minutes under ice cooling. 8 — [(1-Ethylpropyl) amino] —2-methyl-3— (2-chloro-4-methoxyphenyl) -1,6,7-dihydro-5H—cyclopentyl [d] pyrazo port [1, 5-a] Pyrimidine (l.Og) was added, and the mixture was stirred at the same temperature for about 1 hour. Water (1 OmL) was slowly added to the reaction solution, and the mixture was stirred for 10 minutes. After adding water (2 OmL), the mixture was extracted twice with methylene chloride (3 OmL). The organic layer was washed with saturated saline (2 OmL) and dried over anhydrous sodium sulfate, and the solvent was distilled off. Hexane (20 OmL) was added to the residue, and the mixture was stirred for 30 minutes under ice cooling. The obtained crystals were collected by filtration and dried under reduced pressure. The crystals were dissolved in chloroform and purified by silica gel column chromatography (cloform: ethyl acetate = 3: 1). The solvent was distilled off to give the title compound (78 Omg) having the following physical data.

TLC: Rf 0.53 (hexane: ethyl acetate = 1: 1);

iH-NMR (400 MHz, CDCls): δ 11.43, 7.02, 6.65, 6.50, 6.42, 3.86, 3.12, 3.00, 2.30, 2.20, 1.71, 1.04.

Example 8: 3- (2-chloro-1-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] -2-methyl-5,6-dihydro_7-cyclopentene [d] Pyrazo mouth [1, 5_a] Pyrimidine-1 7-one

8-[(1-Ethylpropyl) amino] —2-methyl-3- (2-chloro- mouth —4-methoxyphenyl) 1,6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1,5-a] To a solution of the pyrimidine (15 g) in benzene (375 mL) were added celite (95 g) and pyridinum bromide chromate (40.5 g) ground in a mortar, and the mixture was heated and stirred under reflux with heating. After 1 hour, the mixture was cooled to room temperature, diluted with methylene chloride (40 OmL), and filtered through celite. After distilling off the solvent, the residue was subjected to silica gel column chromatography (hexane: vinegar). Purification by ethyl acetate = 2: 1-1: 1) gave the title compound (2.98 g) having the following physical data.

 TLC: Rf 0.50 (hexane: ethyl acetate = 1: 1);

iH-NMR (400 MHz, DMSO-d ₆ , 100 ° C.): δ 8.22, 7.30, 7.13, 6.99, 5.31, 3.85, 2.89, 2.65, 2.26, 1.71, 0.95.

Example 8 (1): 3- (2-chloro-5-isopropoxy-1-methoxyphenyl) _8-[(1-ethylpropyl) amino] —2-methyl-5,6-dihydro-17-cyclopentyl [d] pyrazo Mouth [1, 5—a] pyrimidine-1 7-one

 The same operation as in Example 8 was performed using the compound (5.7 g) produced in Example 3 (1) to give the title compound (1.1 g) having the following physical data.

TLC: Rf 0.36 (hexane: ethyl acetate = 2: 1);

1H), 6.99 (s, IH), 6.86 (s, 1H), 5.44 and 5.32 (m, 1H), 4.48 (sept, J = 6.3Hz, IH), 3.88 (s, 3H), 3.06 and 2.99 (m , 2H), 2.73 (m, 2H), 2.33 (s, 3H), 1.89-1.55 (m, 4H), 1.37 (d, J = 6.3Hz, 6H), 1.02 (t, J = 7.5Hz, 6H) .

Example 9: 3- (2-Chloro-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] -12-methyl-1,6,7-dihydro-5H-cyclopene [d] pyrazo port [1] , 5—a] pyrimidine-1 7-ol

The compound (1.5 g) produced in Example 8 was dissolved in a mixed solution of ethanol (3 OmL) and tetrahydrofuran (5 mL), and the mixture was stirred under ice-cooling. After sodium borohydride (550 mg) was slowly added, the mixture was stirred at room temperature. After 14 hours, the reaction solution was ice-cooled and acetic acid was added until pH 4-5. Water (5 OmL) was added to the reaction solution, and extracted twice with ethyl acetate (20 OmL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and brine (5 OmL), and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is silica gel Purification by column chromatography (hexane: ethyl acetate = 1: 1) gave the title compound (1.23 g) having the following physical data.

TLC: Kf 0.30 (hexane: ethyl acetate = 1: 1);

iH-NMR (400 MHz, CDCla): δ 7.29, 7.05, 6.88, 6.51, 5.36, 4.14, 3.83, 3.16, 2.83, 2.43, 2.14, 1.73, 1.05, 1.01ο

Example 10: 3-{[3- (2-chloro-4-methoxyphenyl) -12-methyl-1-6,7-dihydro-5-cyclopentene [d] pyrazo-mouth [1,5-a] pyrimidine-1 8—yl] amino} 1—2-pentanol

 8-Clot mouth _3— (2-Chloro-4-methoxyphenyl) 1,2-methyl-6,7-dihydro-5H-cyclopenta [d] virazol [1,5-a] pyrimidine (30 g) to 2-propanol Was suspended. Triethylamine (26.2 g) and the compound prepared in Example 4 (I5.7 g) were added, and the mixture was heated at 85 °. For 22 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. Water (100 mL) was added to the residue, and extracted three times with ethyl acetate (20 OmL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate (10 OmL) and brine (10 OmL), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and toluene (6 OmL) was added to the obtained residue, followed by stirring under ice cooling for 30 minutes. The crystals were collected by filtration and dried under reduced pressure to give the title compound (21.5 g) having the following physical data.

Diastereomer ratio = 7: 1;

TLC: Rf0.33 (hexane: ethyl acetate = 1: 1);

¹ H-NMR (400 MHz, CDCI3): δ 7.30, 7.05, 6.88, 6.49, 4.01-3.90, 3.82, 3.80-3.70, 3.18-2.99, 2.90, 2.34, 2.20-2.08, 1.88-1.60, 1.29, 1.02.

Example 10 (1): Ν— (3-{[tert-butyl (dimethyl) silyl] oxy} -11-ethylpropyl) -13- (2-chloro-4-methoxyphenyl) -12-methyl-6,7-dihydro _ 5 H—Cyclopentyl [d] Pyrazo mouth [1, 5 1 a] Pyrimidine 18-amine 98

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After 15 hours, the reaction solution was ice-cooled, and acetic acid was added until pH5. The solvent was distilled off under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (20 mL) and brine (2

OmL) and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (form: methanol = 1: 1) to give the title compound (377 mg) having the following physical data.

TLC: Rf 0.20 (hexane: ethyl acetate = 1: 1);

^{1 H-NMR (400MHz, CDC1} 3): δ 7.28, 7.05, 6.88, 5.59-5.40, 4.40-4.22, 4.06-3.92, 3.83, 3.19-3.40, 2.84-2.70, 2.50-2.22, 2.20-2.02, 1.91- 1.49, 1.33-1.16, 1.13-1.00.

Example 13: 3- (2-chloro-5-hydroxy-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] -2-methyl-5,6-dihydro-17-cyclopentene [d] pyrazo Mouth [1,5-a] pyrimidin-1 7-one To a solution of the compound (99 Omg) prepared in Example 8 (1) in methylene chloride (10 mL) was added boron tribromide (5.06 mL) for 20 °. C, and the mixture was stirred at the same temperature for 6 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 81: 19 ^ 60: 40) to give the title compound (148 mg) having the following physical data.

TLC: Rf0.47 (hexane: ethyl acetate = 1: 2);

! H-NMRCSOOMHz, CDCla): δ 1.02 (t, J = 7.4Hz, 6H), 1.60-1.88 (m, 4H), 2.29-2.35 (m, 3H), 2.68-2.76 (m, 2H ), 2.94-3.13 (m, 2 H), 3.89 (s, 3 H), 88

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8S96 Fuji 00idfA13d 80SI90 / S003 OAV -2-Methyl-5,6-dihydro_7H-cyclopentene [d] pyrazo mouth [1,5-a] pyrimidine-1 7-year-old

 The title compound having the following physical properties was obtained by performing the same operations as in Example 8 using the compound produced in Example 10 (1).

TLC: Rf0.30 (hexane: ethyl acetate = 2: 1);

¹ H-NMR (400 MHz, DMSO_d ₆ ): δ -0.07 (s, 3H), -0.05 (s, 3H), 0.80 (s, 9H), 0.95 (t, J = 7.6 Hz, 3H), 1.62-2.00 (m, 4H), 2.25 (s, 3H), 2.64 (t, J = 6.8Hz, 2H), 2.88 (t, J = 6.8Hz, 2H), 3.74 (t, J = 6.0Hz, 2H), 3.84 (s, 3Ή), 5.52 (brs, IH), 6.99 (dd, J = 8.4, 2.4Hz, IH), 7.13 (d, J = 2.4Hz), 7.28 (d, J = 8.4Hz, 1H). Example 17 (1) to 17 (4)

 The compounds obtained in Example 13, Example 14, Example 15 or Example 16 were each subjected to the same operation as in Example 12 to obtain the following compounds.

Example 17 (1): 3- (2-chloro-5-hydroxy-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] -12-methyl-6,7-dihydro-5H-cyclopentene [ d] Pyrazo mouth [1, 5-a] pyrimidine-one monol

 TLC: I ぱ 0.40 (hexane: ethyl acetate = 1: 3);

iH-NMRGOO image z, CDCla): δ 1.01 (t, J = 7.5Hz, 3H), 1.04 (t, J = 7.4Hz, 3H), 1.56-1.89 (m, 4H), 2.08-2.19 (m, IH ), 2.33 (s, 3H), 2.35-2.50 (m, IH), 2.76-2.92 (m, IH), 3.05-3.23 (m, 1H), 3.85 (s, 3H), 4.07-4.19 (m, IH ), 5.36 (t, J = 6.6Hz, IH), 6.55 (d, J = 10.4Hz, IH), 6.88 (s, IH), 6.92 (s, 1H).

Example 17 (2): 3- (2-Chloro-4-hydroxyphenyl) -1-8-[(1-ethylpropyl) amino] —2-methyl-1,6,7-dihydro-5H—sic ] Pyrazo [1,5-a] pyrimidine-1 7-ol

TLC: Rf0.41 (hexane: ethyl acetate = 1: 2);

Ή-ΝΜΙΚΒΟΟΜΗΖ, DMSO-d ₆ ): δ 0.86-0.96 (m, 6H), 1.58-1.76 (m, 4H), 1.88-2.02 (m, IH), 2.20-2.32 (m, 4H), 2.52-2.61 (m, IH), 2.89-3.06 (m, IH), 4.04-4.23 (m, IH), 5.19 (s, IH ), 5.20 (s, 113), 6.79 (dd, J = 8.3, 2.5Hz, IH), 6.93 (d, J = 2.4Hz, IH), 7.03 (d, J = 10.2Hz, IH), 7.15 (d , J = 8.4Hz, IH), 9.88 (s, 1H).

Example 17 (3): 3-({3- (2-chloro-1--4-methoxyphenyl) -1-2-methyl-6,7-dihydro-5H-cyclopentene [d] pyrazo [1,5 — A] pyrimidine-1-yl] amino} pentane-2-ol

Diastereomer ratio = 3: 7;

 TLC: Rf0.76 (methylene chloride: ethyl acetate = 3: 1);

1H-N (200MHz, CDCla): δ 1.04 (t, J = 7.33Hz, 3H) 1.29 (d, J = 5.68Hz, 3H) 1.69 (m, 2H) 2.14 (m, 2H) 2.34 ( s, 3 H) 3.01 (m, 4 H) 3.82 (m, 2 H) 3.82 (s, 3 H) 6.42 (m, 1 H) 6.88 (dd, J = 8.42, 2.56 Hz, 1 H) 7.05 (d , J = 2.75Hz, 1H) 7.30 (d, J = 8.42Hz, 1H).

Example 17 (4): 8 — [(3-{[tert-butyl (dimethyl) silyl] oxy} -11-ethylpropyl) amino ”13— (2-chloro-4-methoxyphenyl) _2-methyl_ 6,7-dihydro-5H-cyclopentene [d] bilazolo [1,5—a] pyrimidin-1 7-ol

TLC: Rf 0.48 (hexane: ethyl acetate = 1: 1);

_{Ή-ΝΜΚ (400ΜΗζ, CDC1 3} ): δ 0.04-0.10 m, 6H), 0.84-0.92 (m, 9H), 1.00-1.08 (m, 3H), 1.60-2.00 (m, 4H), 2.06-2.22 ( m, IH), 2.30-2.44 (m, 4H),

2.74-2.88 (m, IH), 3.10-3.24 (m, 1H), 3.72-3.88 (m, 2H), 3.83 (s, 3H),

4.20-4.52 (m, IH), 5.40-5.66 (m, IH), 6.48-6.62 (m, 1H), 6.88 (dd, J = 8.4,

2.4Hz, IH), 7.05 (d, J = 2.4Hz, IH), 7.26-7.34 (m, 1H).

Implementation ^ II 8: 3— {[3— (2-chloro-1-4-methoxyphenyl) -12-methyl-1-6,7-dihydro-1-5H-cyclopentyl [d] Pyrazo [1,5— a] pyrimidine-1-yl] amino} pentane-1_ol In a solution of the compound (50 Omg) prepared in Example 10 (1) in tetrahydrofuran (THF; 1 OmL), tetrabutylammonium fluoride (1.13 mL; 1.0 mol ZL in THF) was added with ice cooling. The mixture was added dropwise, and stirred at room temperature for 30 minutes. Water was added to the reaction solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (337 mg) having the following physical data.

TLC: Rf0.33 (hexane: ethyl acetate = 1: 1);

! H-NMR (200MHz, CDC1 3): 61.01 (t, J = 7.00Hz, 3H), 1.79 (m, 6H), 2.12 (m, 2H), 2.33 (s, 3H), 2.90 (t, J = 7.87Hz, 2H), 3.11 (m, 2H), 3.82 (s, 3H), 4.18 (m, IH), 6.23 (d, J = 10.99Hz, IH), 6.87 (dd, J = 8.52, 2.66Hz, 1H), 7.05 (d, J = 2.56Hz, IH), 7.30 (d, J = 8.61Hz, 1H).

Example 18 (1): 3- (2-chloro-4-methoxyphenyl) -18-[(1-ethyl-3-hydroxypropyl) amino] -12-methyl-6,7-dihidro 5H-cyclopentene [d] Birazolo [1,5-a] pyrimidine-1 7-ol

 The title compound (225 mg) having the following physical data was obtained by the same procedures as in Example 18 using the compound (35 Omg) produced in Example 17 (4).

Diastereomeric ratio = 1: 1;

 TLC: Rf 0.46, 0.54 (black mouth form: ethyl acetate = 10: 1);

1H-NMR (400MHz, CDCls): δ 1.00-1.08 (m, 3H), 1.62-2.20 (m, 6H), 2.30-2.36 (m, 3H), 2.36-2.50 (m, 1H), 2.74-2.86 ( m, 1H), 3.08-3.36 (m, 2H), 3.64-3.80 (m, 2H), 3.83 (s, 3H), 4.22-4.62 (m, 1H), 5.50-5.62 (m, IH), 6.34- 6.44 (m, 1H), 6.84-6.92 (m, 1H), 7.04-7.08 (m, IH), 7.26-7.32 (m, 1H). Example 19: 3-{[3- (2-chloro-1--4-methoxyphenyl) _7-h Dodroloxixi 11 ---- Memethytyl-l-66, 77-Digihydrodrolo 1-l 55 HH-Sisik-Chloropepene evening [[dd]] Vibirara Zozorolo [[11 ,, 55- aa]] pipyrimimididine 88 ---- Illyl]] Aminaminon}} Pepentantatan 22 ---- Onthone TTHHFF of the compound ((8800 OOmmgg)) produced in Example 11-11 ((11 66 mmLL)) In a solution, under ice-cooling and ice-cooling, 99-11 bobora rabibivic chloro [[33..33..11]] nononananane ((1111..77 mmLL ;; 00 ..44 LL solution of 55 LL in TTHHFF)) was added dropwise. . The mixed solution was stirred and stirred for half an hour and a half for 22 hours. . To the reaction solution was added a saturated aqueous solution of saturated sodium bicarbonate aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate acetate. . The organic layer is successively washed and washed with water and saturated saturated saline water, dried and dried over anhydrous sodium sulfate, and then dried. It was concentrated and concentrated. . The remaining residue was refined and purified using a silylic lizard, gerum, karalaram, chloromamatotoguraraffy ((cuchlorooral mouth phorholumum :: metamethanol) == 33 00 :: 11). The title compound having the following physical property values ((4400 OOmmgg :: jijia 1100 sterelereomama ratio 11 :: 11)) Was obtained. .

 TTLLCC :: KKff 00..5599 ((chlorochlorophorforum :: ethylethyl acetate acetate == 11 00 :: 11)) ;;

 ΉΉ--ΝΝStorm storm ((440000MMHHzz ,, CCDDCCllaa)) :: δδ 11..0000--11..1188 ((mm ,, 33HH)) ,, 11..7744--11..8844 ((mm ,, 11HH)) ,, 11..8844--22..0022 ((mm ,, 44HH)) ,, 22..2266--22..3366 ((mm ,, 66HH)) ,, 22 .. 3388--22..5566 ((mm ,, llHH)) ,, 22..7788--22..8800 ((mm ,, 11HH)) ,, 33..0066--33..2200 ((mm ,, 11HH)), 33..8833 ((ss ,, 33HH)) ,, 44..9966--55..4422 ((mm ,, 22HH)) ,, 66..8822--77 .. 4400 ((mm, 44HH)). .

 1155

 The present invention is characterized in that the compound of the present invention represented by the general formula ((II)) has CCRRFF receptor antagonist antagonist activity. Was confirmed in the following experimental tests. .

 [Membrane preparation]

20 A human CRF receptor type 1 forced expression cell line (CH 0 _ K 1 cells) was cultured until confluent, and then collected using a scraper. After the collected cells were washed twice with PBS, and ice-cold binding mediation Si buffer (Tris-HC 1 (5 0mM , pH7.0), EDTA (2 mM, pH8.0), Mg C l 2 (1 OmM)). The suspended cells were disrupted using a dounce-type homogenizer, and then centrifuged at 10,000 g to collect a membrane fraction. After resuspending the collected membrane fraction with a small amount of BindingAssy buffer, the concentration was 1 mg. / mL was diluted with Binding Atsushi buffer. The above is a membrane fraction

 125I-CRF was diluted with Bindingase buffer to 0.5 nM, and 50 zL was added to a 1.5 mL siliconized tube. The test drug, DMSO (for total binding), or 100 M CRF (for non-specific), diluted appropriately, was then added to the 1 L tube. Finally, the membrane fraction of 5 O ^ L was added to start the reaction (final concentration of 125I-CRF was 0.25 nM). The tubes were incubated at room temperature for 2 hours. After the reaction was completed, the membrane fraction was centrifuged at 15,000 g to collect the supernatant, the supernatant was discarded, and the membrane was washed twice with ice-cold PBS / 0.01% Triton X—100. Membrane binding counts were measured using a gamma counter.

Specific binding was determined by subtracting the non-specific binding count from the measured count. As a result, it was confirmed that the compounds of the present invention include those having strong receptor binding activity (IC ₅ Jit <lzM). Example 21: Receptor antagonist activity (cyclic AMPase)

Human CRF receptor type 1 forced expression cell line was cultured at 37 ° C using Ham's F-12 medium (F-12 nutrient mixture) containing 10% fetal serum and 1% antibiotics and antifungals. C. The cells were cultured under the conditions of carbon dioxide 5% and air 95%. One day before the measurement of cyclic AMP, the cells were seeded on a 96-well plate so as to have 1 × 10 ⁴ cells. On the day of the measurement, after washing twice with Ham F-12 medium, Ham F-1

2 Medium ZlmM's 3-isobutyl-1-methylxanthine (Atzey medium) (178 / L) was added to each well. 3 7. After incubation for 10 minutes at C, DMSO (2 zL) was added to the test drug solution (2 L) at various concentrations or to the CRF group and blank group. Further, an Atsey medium (20 juh) containing 1 OnM human / rat CRF was added to the wells of the I-Danied compound group and the CRF group. The blank group was supplemented with Atsey medium (20 L) containing 0.00001% acetic acid and incubated at 37 ° C for 15 minutes. The supernatant was removed and the reaction was stopped by cooling on ice. All reactions were performed in 2 μl steps. The amount of intracellular cyclic AMP accumulation was measured using a cyclic AMP Biotrak enzyme immunoassay system (Amersham Biosciences). Cyclic AMP accumulation was calculated by subtracting the mean of the corresponding 2-well blank group from the mean of the 2-well. IC _S0 values were calculated by non-linear regression analysis using the log concentration of the compound as an independent variable and the amount of accumulated cyclic AMP as a dependent variable.

As a result, it was confirmed that the compounds of the present invention include those having a strong antagonistic activity against CRF (IC ₅₀ i6 <1 μ.Μ). Formulation Example 1:

 The following components were mixed in a conventional manner and then tableted to give 10,000 tablets each containing 1 Omg of the active ingredient.

 · 3- (2-Chloro-4-methoxyphenyl) _8— [(1-Ethylpropyl) amino] —2-Methyl-1,6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1, 5-a ] Pyrimidine one 5—one …… 100 g

'Carboxymethylcellulose calcium (disintegrant) …… 20 g

• Magnesium stearate (lubricant …… 10 g 'microcrystalline cellulose …… 870 g Formulation example 2:

 After mixing the following components in the usual manner, filter through a dust-repelling filter, fill each 5 ml into an ampoule, and heat-sterilize with an autoclave to obtain an ampoule containing 20 mg of active ingredient in 1 ampoule. I got ten thousand.

· 3- (2-chloro-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] -12-methyl-1,6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1, 5—a] pyrimidine _5—one …… 200 g

• Manni! ^ 20 g per liter

'Distilled water… 50L Industrial applicability

 Since the compound of the present invention has a CRF antagonistic effect, it is useful for the prevention and / or treatment of CRF-mediated diseases, for example, psychiatric and digestive diseases.

Claims

Scope of claim General formula (I)

(Wherein, R ¹ and R ² each independently represent a hydroxyl group which may be protected, and R ³ and R ⁴ each independently represent a hydroxyl group or an oxo group which may be protected. , Represents a methyl group which may be oxidized, and n, m and p each independently represents 0 or an integer of 1 to 3.) A compound represented by the following formula: Oxidized form, their solvates, or their prodrugs.

2General formula (la)

(Wherein, R ¹ represents a hydroxyl group or a methoxy group, R ² represents a hydroxyl group, R ³ and R ⁴ each independently represent a hydroxyl group or an oxo group, R ⁵ represents a methyl group, na, ma and pa each independently represent 0 or an integer of 1 to 3. However, when ma and pa are 0, na is an integer of 1 to 3. Represents 3. The compound according to claim 1, wherein the salt, the N-oxide, the solvate, or the prodrug thereof.

3. (i) 8-[(1-Ethylpropyl) amino] —2-methyl-1- (2-chloro-4-methoxyphenyl) -1,6,7-dihydro-5H-cyclopentyl produced by chemical synthesis [d] Pyrazo mouth [1, 5—a] pyrimidine _5—ol, (ii) 3— (2 _black mouth _4-methoxyphenyl) 18 — [(1-ethylpropyl) amino] 1-2—methyl-6 , 7-Dihydro-5H-cyclobenzene [d] Pyrazo mouth [1, 5-a] Pyrimidin-5-one, (iii) 3- (2-chloro-4-methoxyphenyl) _8— [(1— Ethylpropyl) amino] -2-Methyl-5,6-dihydro-17H-cyclopentyl [d] pyrazo [1,5—a] pyrimidin-1 7-one, (iv) 3-(2-chloro-1-4 -Methoxyphenyl) — 8— [(1-Ethylpropyl) amino] 1-methyl-6,7-dihydro-5H-cyclopentene [d] Pyrazo mouth [1,5-a] Pyrimidine-1 7 —Ol, (V) 3— (2-Chloro-4-methoxyphenyl) 1 8— [(1 1-ethyl-2-oxopropyl) amino] 1-Methyl-5,6-dihydro — 7 H— Cyclopene [d] pyrazo mouth [1,5-a] pyrimidin-1 7-one, (vi) 3— (2-chloro mouth 1-4-methoxyphenyl) -18- [(1-ethylethyl)

2-Hydroxypropyl) amino] 1-methyl-6,7-dihydro-5H-cyclopentene [d] pyrazo-mouth [1,5-a] pyrimidin-1-7-ol, (vii)

3- (2-Chloro-4-methoxyphenyl) 18-[(1-Ethyl-2-hydroxypropyl) amino] 1-2-Methyl-6,7-dihydro_5H-Sic Mouth [1,5-a] pyrimidin-5-ol, (viii) 3- (2-chloro-5-hydroxy-4-methoxyphenyl) -18-[(1-ethylpropyl) amino] —2-methyl-5,6 —Dihydro_7H—cyclopentene “d” pyrazo mouth [1,5—a] pyrimidine-1- 7-one, (ix) 3-(2 1,4-hydroxyphenyl) 8-[[(1-ethylpropyl) amino] -2-methyl-5,6-dihydro-17H-cyclopentyl [d] Pyrazo [1,5-a] Pyrimidin-1 7-one, (X) 3— (2-chloro _5-hydroxy_4-methoxyphenyl) 18-[(1-Ethylpropyl) amino] 1-2-methyl-1,6-dihydro-5H— Cyclopentyl [d] pyrazo [1,5-a] pyrimidin-7-ol, (xi) 3- (2-chloro-1-hydroxyphenyl) -18 _ [(1-ethylpropyl) amino] -12-methyl- 6,7-dihydro-5H-cyclopentene [d] pyrazo opening [5-a] pyrimidin-1- 7-ol, (xii) 3--(2-chloro-4-methoxyphenyl) 18-[(1-ethyl 3-Hydroxypropyl) amino] _ 2-Methyl-6,7-dihydro_5H-Cyclopene [d] Pyrazo mouth [1, 5-a] Gin —7—ol, (xiii) 3— {[3- (2_chloro-1--4-methoxyphenyl) — 7-hydroxy_2-methyl-6,7-dihydro-1 5H-cyclopentyl [d] Pyrazo mouth [1, 5—a] pyrimidine-18-yl] amino} pentane-2-one, (xiv) 3_ (2-chloro-1--4-methoxyphenyl) -18 — [(1-ethylpropyl) amino] —2—Methyl-1,6,7-dihydro-5 H—six Mouth pen [d] Pyrazo mouth [1,5 _a] pyrimidin-16-ol or (XV) 3-(2-chloro-4-hydroxyphenyl) (8) [8-[(1-Ethylpropyl) amino] -2-methyl-6,7-dihydro-5H-cyclopentyl [d] pyrazo [1,5-a] pyrimidin-5-ol The compound of the above, a salt thereof, an N-hydroxylated form thereof, a solvate thereof, or a prodrug thereof.

4. (i) 3-Chloro-4- {8-[(1-ethylpropyl) amino] —2-methyl-1,6,7-dihydro-5H-cyclopene produced by chemical synthesis [d] Pyrazo [1 , 5—a] pyrimidine-3-yl} phenol, (ii) 3-{[3- (2-Chloro-4-methoxyphenyl) 1-2-methyl-1,6,7-dihydro-5H-cyclopentene [d] pyrazo opening [1,5-a] pyrimidine-18-yl] Amino} _2-pentanol, (iii) 3-{[3- (2-chloro-4-methoxyphenyl) -12-methyl-6,7-dihydro-1-5H-sic [d] pyrazo [ 1,5—a] pyrimidine-1 8— ^ Tl] amino} pentan-2-one, (iv) 3 — {[3- (2-chloro-4-methoxyphenyl) 1-2-methyl-6,7— Dihydro-5H-cyclopentyl [d] pyrazo [1,5—a] pyrimidin-18-yl] amino} pentan_2-ol, (V) 3 — {[3- (2-chloro-4-methoxy) Phenyl) 1-methyl-6,7-dihydro-5H-cyclopentene [d] pyrazo [1,5-a] pyrimidine _8_yl] amino} pentane-1-ol, or (vi) 4— Chloro 5- {8-[(1-Ethylpropyl) amino] 1-2-methyl-6,7-dihydro 5H-cyclopentyl [d] pyrazo [1,5-a] pyrimidin-3-yl} -2-methoxyphenol 2. The compound according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

5. A pharmaceutical composition comprising a compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof as an active ingredient. .

6. The pharmaceutical composition according to claim 5, which is a CRF antagonist.

7. The pharmaceutical composition according to claim 6, which is a prophylactic and / or therapeutic agent for a CRF-mediated disease.

8. The claim that the CRF-mediated disorder is a psychiatric disorder or a digestive disorder. The pharmaceutical composition according to range ⁷ ,

9.If the neuropsychiatric disorder is a mood disorder, anxiety disorder, adjustment disorder, stress-related disorder, eating disorder, symptom or dependence due to use of a psychoactive substance, organic mental disorder, schizophrenia, or attention deficit 9. The pharmaceutical composition according to claim 8, which is a kinetic disorder.

10. The pharmaceutical composition according to claim 8, wherein the digestive system disease is irritable bowel syndrome or gastrointestinal dysfunction associated with stress.

11. Mood disorders are depression, single episode depression, recurrent depression, postpartum depression, child abuse-induced depression, bipolar affective disorder, indefinite complaints, premenstrual dysphoric disorder, peri-menopause 10. The pharmaceutical composition according to claim 9, which is a menopausal mood disorder.

12. A compound represented by the general formula (I) according to claim 1, a salt thereof, a methoxide thereof, a solvate thereof, or a prodrug thereof, and a tricyclic antidepressant; Cyclic antidepressants, monoamine oxidase inhibitors, serotonin and noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors, serotonin reuptake inhibitors, psychostimulants, anxiolytics, antipsychotics, mitochondria Benzojiazepin receptor ligands, NK1 antagonists, gastrointestinal function adjustment agents, 5-ΗΤ ₃ antagonists, 5-ΗΤ ₄ agonists, anticholinergics, antidiarrheals, laxatives agent and autonomic adjustment agents A drug which is combined with at least one selected from the group consisting of:

13. The compound represented by the general formula (I) according to claim 1, a salt thereof, A method for preventing and / or treating a CRF-mediated disease, comprising administering to a mammal an effective amount of an N-year-old oxide, a solvate thereof, or a prodrug thereof.

14. A compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof for producing a CRF antagonist Use of.