WO2005087775A1 - Composé hétérocyclique tricyclique et composition médicinale contenant le composé comme ingrédient actif - Google Patents

Composé hétérocyclique tricyclique et composition médicinale contenant le composé comme ingrédient actif Download PDF

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WO2005087775A1
WO2005087775A1 PCT/JP2005/004875 JP2005004875W WO2005087775A1 WO 2005087775 A1 WO2005087775 A1 WO 2005087775A1 JP 2005004875 W JP2005004875 W JP 2005004875W WO 2005087775 A1 WO2005087775 A1 WO 2005087775A1
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group
ring
alkyl
pyrimidine
compound
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PCT/JP2005/004875
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English (en)
Japanese (ja)
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Hisao Nakai
Tetsuji Saito
Seishi Katsumata
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Ono Pharmaceutical Co., Ltd.
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Publication of WO2005087775A1 publication Critical patent/WO2005087775A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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Definitions

  • the present invention relates to a tricyclic heterocyclic compound.
  • General formula (I) For details, see General formula (I)
  • the present invention relates to a pharmaceutical composition.
  • Corticotropin Releasing Factor is a 41 amino acid peptide isolated from the hypothalamus of Higgs in 1981. This CRF was released from the hypothalamus and was suggested to play a role in regulating secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland [Science, 218, 377-379 (1982)].
  • ACTH adrenocorticotropic hormone
  • type 1 and type 2 are known roughly [Receptors Channels, 8, 163-177 (2002)].
  • ACTH secreted by the stimulation of CRF stimulates the secretion of cortisol from the adrenal cortex and is related to systemic effects on reproduction, growth, gastrointestinal function, inflammation, the immune system, nervous system, etc. It is thought that they act as regulators of these functions. From these facts, attention has been paid to the involvement of CRF in neuropsychiatric disorders or peripheral JI-zoki disorders. On the other hand, the number of patients with depression and anxiety disorders is increasing, and the number of patients with mild depression is increasing recently. Elderly patients account for the majority of patients with depression. Under these circumstances, there is an increasing demand for remedies, easy-to-use drugs, and drugs for treating neuropsychiatric disorders due to the rapid onset of effects and side effects.
  • neuropsychiatric disorders includes, for example, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase (MAO) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNR I ), And selective serotonin reuptake inhibitors (SSR I) have been used.
  • 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.
  • 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.
  • WO02 / 53565 describes the general formula (A)
  • 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
  • a ⁇ I is C 1-4 alkyl, C 1-4 alcohol Alkoxy, C4 ⁇ 6 carbocycle or or unsubstituted substituted with group 1 to 3 or selected from a halogen atom
  • 1 is (1) substituted with 1 to 5 R 14A or unsubstituted C 1-8 alkyl, ii) substituted with 1 to 5 R 14A , or unsubsti
  • WO00 / 09506 describes a compound represented by the general formula (B)
  • R 1B represents a hydrogen atom, a hydroxyl group, an alkyl group optionally having one or more substituents, a cycloalkyl group optionally having a substituent, Having styryl groups or one or more substituents
  • R 2B represents a hydrogen atom, an alkyl group, a halogen atom, an amino group optionally having one or two substituents, and a cyclic amino group optionally having substituents A ring or a phenoxy group which may have a substituent;
  • ring A B represents a homo- or heterocyclic ring which may be substituted with one or more alkyl groups, alkoxy groups or halogen atoms;
  • R 3B represents a saturated nitrogen-containing heterocyclic group which may have a substituent, and mB represents an integer of 0 to 3.
  • R 3 B represents an unsubstituted piperidino group
  • at least one of R 1B and R 2B is not a hydrogen atom.
  • the 1H-imidazopyridine-derivatives or their salts have excellent inhibitory effects on the production of TNF and IL-1 and are useful as preventive or therapeutic agents for diseases caused by these sites. It is stated that there is.
  • WO03 / 013523 describes a compound represented by the general formula (C)
  • R 1C , R 2C , R 3C , R 4C , R 5C , and R 6 each independently represent a hydrogen atom, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a cyano group, a nitro group.
  • R 1G and R 2C are selected from the group consisting of a group, a halogen atom, a C12 alkyl group, a C12 alkenyl group, an aryl group, an allyl-oxy group, a heteroaryl group, and the like.
  • R 7G is a hydrogen atom, an amino group, a C12 alkyl group, a C12 alkenyl group, a C2 12 selected from the group consisting of alkynyl groups, aryl groups, aryl C1-6 alkyl groups, heteroaryl groups, heteroaryl C1-6 alkyl groups, and cycloalkyl groups.
  • Aminoisoki shown by) It is described that a norin derivative is used as an SH3 domain agonist or an SH3 domain antagonist.
  • An object of the present invention is to provide a drug which is easy to use and has a strong prophylactic and / or Z or therapeutic effect in the prevention and / or treatment of a psychiatric / neurological disorder or a disease of a peripheral organ.
  • R 1 is (1) optionally substituted (a) C 1-15 alkyl, (b) C 2 Alkenyl or (c) C2-15 alkynyl, (2) optionally protected amino, (3) optionally protected hydroxy, (4) optionally protected mercapto, (5) — S (O) n R 6 (wherein, n represents 1 or 2, R 6 represents (0 may be substituted (a) C 1-15 anolequinole, (b) C 2-15 Alkenyl or (c) C2-l5 alkiel, or Gi) an optionally substituted cyclic group.),, (6) —COR 7 (wherein R 7 is (hydrogen atom, ) Optionally substituted (a) C1-15 alkyl, (b) C2-15 alkaryl or (c) C2-15 alkynyl, ⁇ ⁇ ⁇ ⁇ optionally protected hydroxy, (Lv) protected Amino or (V) substitute
  • ring A represents a 5- or 6-membered monocyclic ring which may be substituted, and ring Ba may be a nitrogen atom, an oxygen atom and / or an oxidized atom other than W 1 and W 2
  • ring Ba may be a nitrogen atom, an oxygen atom and / or an oxidized atom other than W 1 and W 2
  • Represents an optionally substituted 5- to 6-membered monocyclic heterocyclic ring, W 1 and ⁇ W 2 each independently represent a carbon atom or a nitrogen atom, and other symbols have the same meanings as in the above 1
  • B a one 1 ring further represents a monocyclic unsaturated heterocyclic ring substituted 6 may be members, and the other symbols. As defined above 1 and 2) shown in The compound according to the above 2, which is a compound,
  • ring A a represents a 5- or 6-membered monocyclic ring which may be substituted, and when W 1 is a carbon atom,-represents a single bond or a double bond; represents a single bond, R w represents a substituent, y is 0, 1 or 2 represents the compound of the 3, wherein the compound represented by the other symbols have the same meanings as described above 1 and 2.
  • the B b ring further contains, in addition to W 1 and W 2 , one or two hetero atoms selected from a nitrogen atom, an oxygen atom and Z or a sulfur atom which may be oxidized.
  • ring E is an optionally substituted 5- or 6-membered monocyclic heterocyclic ring.
  • W 3 represents a carbon atom or a nitrogen atom
  • the other symbols have the same meanings as in 1 and 2.
  • a pharmaceutical composition comprising the compound according to 1 above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof as an active ingredient;
  • the mood disorder is depression, bipolar affective disorder, indefinite complaint, premenstrual dysphoric disorder, postpartum mood disorder, peri-menopausal or menopausal mood disorder, and the anxiety disorder is general anxiety disorder, panic disorder, Said obsessive-compulsive disorder, phobic anxiety disorder
  • Reuptake inhibitors selective serotoyun reuptake inhibitors, serotonin reuptake inhibitors, psychostimulants, anxiolytics, antipsychotics, mitochondrial benzodiazepine receptor ligands, neurokinin 1 antagonists, gastrointestinal function adjusting agents, 5-HT 3 antagonists, 5-HT 4 agonists, anticholinergic agents, antidiarrheal, comprising in combination with a laxative and at least one or more that are selected from the autonomic adjustment agents medicament,
  • An effective amount of a compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof according to the above 1 is administered to a mammal.
  • a salt thereof for the prevention of CRF-mediated disease and the production of a Z or therapeutic agent.
  • the optionally substituted 56-membered monocyclic ring means an optionally substituted 5- to 6-membered monocyclic carbocyclic ring or an optionally substituted monocyclic heterocyclic ring.
  • the monocyclic ring is selected from a halogen atom, CF 3 OCF 3 , hydroxy, mercapto, carboxyl, oxo, (Cl 6 alkoxy) carbonyl, carbamoyl, utro, cyano, and each is a halogen atom, CF 3 and hydroxy.
  • Substituted by 13 groups selected from C 16 alkyl, C 26 alkyl, C 26 alkyl, C 16 alkoxy and C 1,6 alkylthio It may be.
  • Examples of the 56-membered monocyclic carbocycle include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene ring.
  • a 5- to 6-membered monocyclic heterocycle is a 5- to 6-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom Z, and an optionally oxidized sulfur atom.
  • the 5- to 6-membered monocyclic heterocycle includes a halogen atom, CF 3 , OCF 3 , hydroxy, mercapto, carboxyl, oxo, (C1-6 alkoxy) carbonyl, carbamoyl, nitro , Shiano, Oyopi each halogen atom, it may also be substituted by one to three groups selected from CF 3 and hydroxy les, C L ⁇ 6 alkyl, C 2 to 6. alkenyl, C. 2 to It may be substituted by 1-3 groups selected from 6 alkyl, C1-6 alkoxy and C1-6 alkylthio.
  • a nitrogen atom, an oxygen atom and / or one or two hetero atoms selected from sulfur atoms which may be oxidized may be contained.
  • 5 to 7-membered monocyclic unsaturated heterocyclic ring which may be further substituted may be substituted with 1 to 2 groups selected from Substituent Group 2, other than W 1 and W 2
  • the monocyclic unsaturated heterocyclic ring includes a monocyclic aromatic heterocyclic ring or a monocyclic partially unsaturated heterocyclic ring.
  • pyrrol imidazole, triazole, pyridine, pyrimidine, pyridazine, triazine, azepine, diazepine, oxazine, oxazine, oxazepine, oxazineazepine, thiazine, thiadiazine, thiazepine, thiazipine ring, or a part thereof, And a partially unsaturated ring.
  • the sum of nitrogen atoms contained in the A ring and B a ring or ring A and B b ring is 5 or less, an oxygen atom and oxidized even if Yo Le, total sulfur atom with up to two is there.
  • the substituent group 2 comprises (1) an optionally substituted (a) C 1 to 15 alkyl, (b) a C 2 to 15 alkyl or (c) a C 2 to 15 alkynyl (2) optionally protected amino, (3) optionally protected hydroxy, (4) protected (5) —S (O) n R 6 (wherein n represents 1 or 2, R 6 is (0-substituted, (a) C 1-15 alkyl, (B) C 2-15 alkenyl or (c) C 2-15 alkynyl, or (ii) a cyclic group which may be substituted.), (6) —COR 7 (wherein R 7 is (0 hydrogen atom, (ii) optionally substituted (a) C1-15 alkyl, (b) C2-15 alcohol or (c) C2-15 alkyl, ( ⁇ ⁇ -protected A good hydroxy, ⁇ ) an optionally protected amino, or (V) an optionally substituted cyclic group.), (7) an optionally substituted cyclic
  • the optionally oxidized sulfur atom, S is meant SO or S o 2.
  • the optionally substituted C1-15 alkyl is a straight-chain or branched optionally substituted C1-15 alkyl, for example, optionally substituted methyl, Ethyl, n-propyl, isopropyl, n-butyl, i-zeptinole, sec-butynole, tert-butylinole, pentinole, hexinole, heptyl, octyl, noel, decyl, pendecyl, dodecyl, tridecyl, tetradecyl or pentadecyl. .
  • the optionally substituted C2-15 alkenyl is a C2-15 alkenyl having 1 to 3 double bonds which may be linear or branched, and
  • the optionally substituted C 2-15 alkyl means a linear or branched optionally substituted C 2-15 alkyl having 1 to 3 triple bonds.
  • 15 alkynyl for example, optionally substituted ethur, propynole, butininole, penchuren, hexenole, hexazininole, heptininole, heptazinyl, otachur, octadinil, noninyl, decinyl, dexinyl, decinyl And tridecynyl, tetradecynyl and pentadecyl groups.
  • optionally substituted C1-15 alkyl "optionally substituted C2-15 alkenyl", “optionally substituted C2-15 alkynyl” and “substituted C1-15 alkoxy which may be substituted are respectively a substituted or unsubstituted C1-15 alkyl, a substituted or unsubstituted C2-15 alkyl J, "Substituted or unsubstituted C2-15 alkynyl” and “substituted or unsubstituted C1-15 alkoxy", wherein the "substituent” includes the following substituents Group 3 is included.
  • Substituent group 3 includes (1) a halogen atom, (2) CF 3 , (3) OCF 3 s (4) cyano, (5) -toro, (6) C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, hydroxy optionally protected by a cyclic group or a protecting group capable of leaving, (7) C1-7 acyl, (8) C1-6 alkyl, C2-6 alkenyl A carbonyl optionally protected by a C2-6 alkyl or cyclic group, (9) a carbamoyl optionally protected by a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or cyclic group, (10) C 1 to 6 alkyl, C 2 to 3 Aruke - le, C 2 to 6 alkynyl or thiol which may be protected by a cyclic group, (11) NR 17 in R 18 (group, the R 17 (a ) hydrogen atom, (b) C l
  • 0-COOR 20 in the group, R 2 ° has the same meaning as described above.
  • R 17 is each independently Represents the same meaning.
  • (12) -S (O) n R 19 wherein, n represents the same meaning as described above, and R 19 represents (a) a hydrogen atom, (b) C 1-6 alkyl, C 2-6 alkenyl or represents a C. 2 to 6 Arukyuru or (c) a cyclic group.), (13) in -COR 20 (group, R 2 ° are as defined above.), and (14) substituted Represents a good cyclic group.
  • One to four of these substituents may be substituted at substitutable positions.
  • C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl in the substituent group 3 may be substituted with a group selected from the substituent group 5, and the cyclic group is a substituent group 4 And may be substituted by a group selected from In the present invention, the halogen atom is fluorine, chlorine, bromine and iodine.
  • C1-6 alkynole represents, for example, methyl, ethyl, n-propynole, isopropynole, n-butynole, isoptinole, sec-petitinole, tert-butyl, pentyl, hexyl.
  • the C 2-6 alcohol represents, for example, bier, propenil, buteninole, penteninole, hexeninole, hexeninole.
  • the C2-6 phenol is, for example, ethur, propiele, butininole, pentinole, hexyl, hexazinole.
  • hydroxy protected by C1-6 alkyl means C1-6 alkoxy.
  • the C1-6 alkoxy represents, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy.
  • C1-15 anoreoxy is, for example, straight-up or branched C1-15 alkoxy, such as methoxy, ethoxypropoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy.
  • C 1-6 alkylthio means, for example, methylthio, ethylthio, propylthio, isopropylthio, ⁇ -butylthio, isoptinolethio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.
  • C7-7 acyl refers to, for example, formyl, acetyl, propanoyl, vivaloyl, and benzoyl.
  • optionally protected amino refers to an amino acid protected by one or two protecting groups described below, or an unprotected amino.
  • the protecting group for amino include (a) optionally substituted C1-15 alkyl, (b) optionally substituted C2-15 alkenyl, and (c) optionally substituted C2-15.
  • R 21 is (aa) a hydrogen atom, (bb) optionally substituted C 1-15 anoquinone, C 2 to 15 alkenyl or C 2 to 15 alkynyl, or (cc) an optionally substituted cyclic group.), (0-COOR 21 (in the group, R 21 has the same meaning as described above)) And (g) —CON (R 22 ) 2 (wherein each R 22 independently represents (aa) a hydrogen atom or (bb) optionally substituted C 1-15 alkyl, C 2-15 alkenyl or C Represents 2 to 15 archiels.
  • the optionally protected hydroxy includes, for example, (a) optionally substituted C1-15 alkyl, (b) optionally substituted C2-15 alkenyl, (c) substituted Optionally substituted C 2-15 alkynyl, (d) substituted And (e) hydroxy protected by a leaving-capable protecting group, or unprotected hydroxy.
  • the protective group capable of leaving include, for example, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyshethyl (EE) group, a methoxyethoxymethyl (MEM) group, and a 2-tetrahydrovinylinole (THP) group.
  • Trimethylsilinole TMS
  • triethylsilyl TES
  • t-butyldimethylsilyl TDMS
  • t-butyldiphenylsilyl TBS
  • acetyl Ac
  • pivaloyl benzoyl
  • benzyl (Bn) group ⁇ -methoxybenzyl group
  • aryloxycarbonyl A1 oc
  • 2,2,2-trichloroethoxycarbonyl Troc
  • the hydroxy protected by an optionally substituted C15 alkyl means an optionally substituted C1-15 alkoxy.
  • the optionally protected mercapto includes: (a) optionally substituted C1-15 alkyl, (b) optionally substituted C2-15 alkenyl, (c) substituted Represents an optionally protected C2-15 alkynyl or (d) an optionally protected mercaptocap or unprotected mercapto by a cyclic group.
  • a cyclic group represents a carbocyclic group or a heterocyclic group.
  • the carbocyclic group represents a C3 to C12 monocyclic or bicyclic carbocyclic group, and includes, for example, cyclopronone, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentagen, Cyclohexadiene, cyclohexadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, heptalene, perhydroheptale , Bicyclo [3.1.1]-heptane ring group.
  • a heterocyclic group is a 3- to 12-membered monocyclic or bicyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and Z or a sulfur atom which may be oxidized.
  • Represents a heterocyclic group for example, oxylane, thiirane, aziridine, oxetane, titan, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, dihydropyridine, dihydropyridine Lysine, dihydrovirazine, tetrahydrovirazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine,
  • the optionally substituted cyclic group means a carbocyclic group or a heterocyclic group which may be substituted with the substituent group 4.
  • the carbocyclic group and the heterocyclic group include the aforementioned ring groups.
  • Substituent group 4 includes (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) C1-6 alkyl, C2-6 alkenyl A C 2-6 alcohol, a cyclic group or a hydroxy group which may be protected by a protecting group having a leaving ability; (6) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and a cyclic group which may be protected by 1 to 2 groups Amino, (7) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a group of labamoyl optionally protected by one or two groups selected from a cyclic group, (8) C1 From 1 to 2 alkyl, C2 to 6 alkenyl, C2 to 6 alkynyl or a cyclic group.
  • Substituent group 5 includes (1) C1-6 alkoxy, (2) C1-6 alkylthio, (3) halogen atom, (4) C1-6 alkyl, C2-6 alcohol, C2-6 Arukieru, cyclic group, the cyclic group (C l ⁇ 6) alkyl or hydroxy may be protected by a protecting group having a leaving Hanareno, (5) CF 3, ( 6) OCF 3, (7) nitro, (8 ) Siano, (9) carboxyl, (10) (Cl-6 alkoxy) carbonyl, (11) benzyloxycarbonyl, (12) mercapto, (13) amino, (14) C1-6 alkylamino, (15) Di (Cl-6 bulkyl) amino, (16) Lubamoyl, (17) N— (C1-6 alkyl) Lubamoyl, (18) N, N—di (C1-6 alkyl) carbamoyl (19) Sulfamoyl, (20) N— (C1-6 alkyl) sulfamoyl, (2
  • Substituent group 6 includes (1) C1-6 alkyl, (2) C2-6 alkyl, (3) C2-6 alkynyl, (4) C1-6 alkoxy, (5) C1-6 6 alkylthio, (6) halogen atom, (7) CF 3 , (8) OCF 3 , (9) tutro, (10) cyano, (11) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyl- , Cyclic group, cyclic group (Cl-6) hydroxy optionally protected by alkyl or elimination-protecting group, (12) carboxyl, (13) (Cl-6 alkoxy) (14) benzyloxycarbonyl, (15) mercapto, (16) amino, (17) C1-6 alkylamino, (18) di (C1-6 alkyl) amino, (19) dirubamoyl, (20) N— (C 1-6 alkyl) dirubamoyl, (2l) N, N—di (C 1-6 alkyl) cal Bamoyl
  • (Cl-6 alkoxy) carbonyl means, for example, methoxycarbol, ethoxycarbonyl, propynolecarbonyl, isopropylcarbol, putoxycarbol, isoptoxoxycarbonyl, sec-butoxycanoleboninsul, tert-butoxycanol Represents levenolen, pentynoleoxycanolebohenole, hexinoleoxycarbonyl.
  • the cyclic group (C 1-6) alkyl means a carbocyclic group (C 1-6) alkyl or an alkyl group (C 1-6) alkyl, each of which is substituted by one carbon ring group.
  • Carbocyclic group, heterocyclic group and C1-6 alkyl have the same meaning as described above.
  • the optionally substituted unsaturated cyclic group means an unsaturated carbocyclic group or an unsaturated heterocyclic group which may be substituted with 1 to 5 groups selected from Substituent Group 7.
  • Unsaturated carbocyclic group means a C 5 to C 12 monocyclic or bicyclic unsaturated carbocyclic group, for example, benzene, pentalene, indene, indane, naphthalene, 'dihydronaphthalene, tetrahydronaphthalene, azulene ring group Is mentioned.
  • the benzene ring of those rings bonds to the Z group.
  • An unsaturated heterocyclic group is a 5- to 12-membered monocyclic or bicyclic ring containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and / or a sulfur atom which may be oxidized. Represents an unsaturated heterocyclic group.
  • indone isoindone, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, phthalazine, quinoxaline, quinazoline, cinnoline, benzoxazono, benzothiazonole, benzoimidazonole
  • chromene, benzofurazan, benzothiadiazole and benzotriazole ring groups the benzene ring of those rings bonds to the z group.
  • substituent group 7 examples include: (1) optionally substituted C 1-15 alkynole, (2) optionally substituted C 2-15 alkenyl, (3) optionally substituted Good C2-15 archiel, (4) optionally protected hydroxy, (5) optionally protected mercapto, (6) optionally protected amino, (7) optionally protected good force Rubamoiru, (8) an optionally protected Surupuamoiru, (9) optionally protected carboxyl, (10) optionally protected sulfo (one SO 3 H), and is protected (11) Sulfino (1 S 0 2 H), (12) utro, (13) cyano, (14) amidino, (15) imino, (16) halogen atom, ( ⁇ 7) optionally substituted cyclic And (18) C1-7 acyl, (19) oxo and (20) thioxo. One to five of these substituents may be substituted at substitutable positions.
  • the “protecting group” in “optionally protected sulfo” and “optionally protected sulfino” includes (a) optionally substituted C 1-15 alkyl, and (b) optionally substituted And optionally substituted C 2-15 alkenyl, (c) optionally substituted C 2-15 alkyl and (d) optionally substituted cyclic group.
  • the C2-5 alkylene in which one carbon atom may be replaced with one oxygen atom, nitrogen atom or sulfur atom includes ethylene, propylene, isopropylene, butylene, isobutylene, pentylene group and the like.
  • the remaining bond of the nitrogen atom is a hydrogen atom, C1-6 alkyl, C2-6 acyl, or C1-6 alkoxycarbyl (for example, methoxycarbyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.) ).
  • the C 2-5 alkylene may be substituted with a substituent.
  • examples of the substituent include C1-8 alkyl (for example, methyl, ethyl, n-propynole, isopropinole, n-butynole, isobutynole, sec-butynole, tert-butyl, pentyl, hexyl, heptyl, Octyl group, etc.), hydroxyl group, amino, carboxyl, utro, mono- or di-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, getylamino, etc.), Cl-6 alkoxy (for example, methoxy, ethoxy) , Propoxy, hexyloxy, etc.), C 1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1-6 alkylcarboxyloxy (e
  • C 2-5 alkylene examples include: 1 (CH 2 ) 2 —,-(CH 2 ) 3 -,-(CH 2 ) 4 1, 1 (CH 2 ) 5 —, — O—CH 2 -, -O- (CH 2) 2- , - O - (CH 2) 3 -, -O- (CH 2) 4 one, -CH 2 -0- CH 2 -, -CH 2 -0- (CH 2) 2 -, one CH 2 - ⁇ - (CH 2) 3 -, - (CH 2) 2 -0- (CH 2) 2 -, one NH-CH 2 -, one ⁇ chromatography (CH 2) 2 - , ⁇ NH— (CH 2 ) 3 —, one NH— (CH 2 ) 4 —, one CH 2 — NH—CH 2 —, one CH.
  • one carbon atom is Alkylene which may be replaced by one oxygen atom, nitrogen atom or sulfur atom includes C 2-5 alkylene such as burene, propylenylene, isopropylidene, putenylene, isoptenylene, penteurene group, etc.
  • One carbon atom in a linear or branched alkenylene, or biene, propylene, isopropylenylene, butenylene, isobutenylene, pentenurene group is placed on an oxygen, nitrogen, or sulfur atom And substituted C 2-5 alkenylene and the like.
  • the remaining bond of the nitrogen atom is a hydrogen atom, C1-6 alkyl, C2-6 acyl, or C1-6 alkoxy carbyl (for example, methoxycarbonyl, ethoxycarbyl, tert-butoxycarbonyl, etc.) ).
  • C 2-5 alkenylene may be substituted by a substituent.
  • C1-8 alkyl for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoprene
  • Tyl sec-butynole, tert-butynole, pentynole, hexinole, heptinole, octyl, etc.
  • hydroxyl amino, carboxyl, nitro, mono, or di-C1-6 alkylamino.
  • C1-6 alkoxy for example, methoxy, ethoxy, propoxy, hexoxy, etc.
  • C1-6 alkoxyl power e.g., methoxycarpoenole, ethoxycanolepo
  • C1-6 alkylcarbonyloxy e.g, acetoxyl, ethylcarponyloxy, etc.
  • C1-4 alkylthio eg, methylthio, ethylthio, propylthio, butylthio, etc.
  • halogen atoms fluorine, chlorine, bromine, iodine
  • examples of the C1-6 alkylidene in the "optionally substituted C1-6 alkylidene” include methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene group and the like.
  • the substituent of the "optionally substituted C1-6 alkylidene” includes a hydroxyl group, an amino, a carboxyl, a nitro, an azide, a mono or a C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, Dimethylamino, dimethylamino, etc., N-aromatic ring amino (for example, N-phenylamino group), N-aromatic ring-N-alkylamino (for example, N-phenyl-2-amino-N-methylamino, N-phenylamino) I-N-ethynoleamino, N-fenolene N-propynoleamino, N-bueninole N-butynoleamino, N-phenylen-N-pentylamino, N-phenyl-1-N-hexylamino, etc., Cl-6 alkoxy
  • R 1 is preferably an optionally substituted C 1-15 alkyl, an optionally substituted C 2-15 alkenyl, an optionally substituted C 2-15 alkyl, S (O) n R 6 , one COR 7 , or an optionally substituted cyclic group, more preferably an optionally substituted C 1 to 15 alkyl, an optionally substituted C 2 to 15 arcules, substituted Also a C 2 to 15 alkyl, one S (0) is a n R 6 or a COR 7,, is et to preferably optionally substituted C 1 to 15 alkyl, a C substituted 2 to 15 alkenyl, or C 2 to 15 alkynyl which may be substituted.
  • the C 1-15 alkyl, C 2-15 alkenyl and C 2-15 alkyl are each independently unsubstituted or have the following substituents: (1) halogen atom, (2) 2 3 , (3) OCF 3 , (4) cyano, (5) nitro, (6) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or hydroxy which may be protected by a protecting group capable of leaving.
  • Z is preferably one NR 3 —, one O— or one CR 4 R 5 —, and more preferably one NR 3 —.
  • R 3 is preferably a hydrogen atom or an optionally substituted C 1-15 alkyl, more preferably a hydrogen atom or a C 1-6 alkyl, further preferably a hydrogen atom, methyl, ethyl, Or propyl.
  • the group represented by R 4 and R 5 together is preferably a C 2-5 alkylene group in which one carbon atom may be replaced by one oxygen atom, nitrogen atom or sulfur atom, more preferably , One (C, H 2 ) 2 —, one (CH 2 ) 3 —, one (CH 2 ) 4 one, one (CH 2 ) 5- , —0— CH 2- , -0- (CH 2 ) 2 -, One O— (CH 2 ) 3 —, -0- (CH 2 ) 4 one, — GH 2 — 0— CH 2 —, -CH 2 — O— (CH 2 ) 2 —, -CH 2 -0 -(CH 2 ) 3—, one (CH 2 ) 2 — 0— (CH 2 ) 2 —, — NH—CH?
  • R 2 is preferably a C 5 to C 12 monocyclic or bicyclic unsaturated carbocyclic group or a nitrogen atom, an oxygen atom and Z or 1 to 4 carbon atoms which may be oxidized, A 5- to 12-membered monocyclic or bicyclic unsaturated heterocyclic group containing more than one hetero atom, more preferably benzene, pentalene, indene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, Azulene, pyrrole, imidazole, triazole, tetrazole, pyrazonole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, '' Orchids, pyran, oxepin, thiophene, thiopyran, chepin, oxazole, isoxazole, thiazole, isothiazole, brazan,
  • R 2 is substituted with 1 to 5 groups selected from the substituent group 7. More preferred substituents include (1) an optionally substituted C1-15 alkanoquinole, (2) an optionally substituted C1-15 alkenyl, and (3) an optionally protected hydroxyl. (4) optionally protected mercapto, (5) optionally protected amino, (6) optionally protected rubamoyl, (7) optionally protected carboxyl, (8) protected And (9) a sulfino which may be protected, (10) a cyano, (11) a halogen atom, and (12) a cyclic group which may be substituted.
  • substituents include (1) an optionally substituted C1-15 alkanoquinole, (2) an optionally substituted C1-15 alkenyl, and (3) an optionally protected hydroxyl. (4) optionally protected mercapto, (5) optionally protected amino, (6) optionally protected rubamoyl, (7) optionally protected carboxyl, (8) protected And (9) a sulfino which may be protected, (10)
  • C1-6 alkyl Particularly preferred are (1) C1-6 alkyl, (2) C2-6 alkyl, (3) unsubstituted hydroxy, or optionally substituted C1-6 alkyl or protection having elimination ability. Hydroxyl protected by a group (in particular, Cl-6 alkoxy and trifluoromethoxy are preferable), (4) unsubstituted mercapto, or optionally substituted C1-6 alkyl or leaving ability. (In particular, C 1-6 alkylthio is preferable.) (5) Carboxyl protected with C 1-6 alkyl or benzyl, and (6) Cano (7) a halogen atom, and (8) a cyclic group which may be substituted.
  • R 2 is a 6-membered monocyclic ring, specifically a benzene or pyridine ring, its (1) 2-position, (2) 3-position, (3) 4-position, (4) 2-position and 4-position And (5) 2-, 4- and 5-positions, or (5) 2-, 4- and 6-positions.
  • the preferred ring A is an unsubstituted ring, a halogen atom, CF 3 , O CF 3 , hydroxy, mercapto, carboxyl, oxo, (C 1-6 alkoxy) carbonyl, carbamoyl, nitro, cyano, and each halogen atom as a substituent, CF 3 and 1-3 amino optionally C 1 to 6 alkyl optionally substituted by a group selected from hydroxy, C2-6 Arukeeru, C 2 to 6 alkyl Interview le, It is preferably a ring substituted by 1-3 groups selected from C1-6 alkoxy or C1-6 alkylthio.
  • B a ⁇ is preferably pipal, imidazole, triazole, pyridin, pyrimidine, pyridazine, triazine, azepi, diazepine, oxazine, oxaziazine, oxazepine, oxazezepine, thiazine, thiaziazine, thiazepine, and thiadiazepine.
  • D ring pyrrole, imidazole, dihydroimidazole, pyrazozole, dihydropyrazonolle, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydrovirazine, tetrahydrovirazine, Piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidin), dihydro Thiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, Tetra
  • B 3 —1 ring preferably 2,3,4,5-tetrahydropyridine, 34-dihydropyridine, 2,5-dihydropyridine, 2,3-dihydropyridine, pyridine, 1,2,5,6-tetrahydropyrimidine , 1,2-dihydropyrimidine, 1,4,5,6-tetrahydropyrimidine, 1,6-dihydropyrimidine, 1,4-dihydropyrimidine; /, 1,4,5,6-tetrahydropyrimidine, '1,4-dihydropyridazine, 1,6-dihydropyridazine ⁇ 1,2,3-tetrahydro-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine ring, more preferably , Pyridine, 1,
  • the ring b is preferably pyrrole, imidazole, triazole, pyridin, pyrimidine, pyridazine, triazine, azepine, diazepine, oxazine, oxaziazine, oxazepine, oxazedazepine.
  • pyrrol imidazole, 'triazole, pyridine, pyrimidine, pyridazine, .triazine, azepine, diazepine, 2,3,4,5-tetrahydropyridine, 3,4-dihydropyridine, 2,5-dihydropyridine, 2,5-dihydropyridine, 3-dihydropyridine, pyridine, 1,2,5,6-tetrahydropyrimidine, 1,2-dihydropyrimidine, 1, '4,5,6-tetrahydropyrimidine, 1,6-dihydropyrimidine, 1,4-dihydropyrimidine 1,4,5,6-tetrahydropyridazine, 1,4-dihydropyridazine, ⁇ , 6-dihydropyridazine, 1,2,5,6-tetrahydro-1,2,3-triazine, 1,2-dihydro-1 1, .2,3-Triazine, 1,4,5,
  • 2,5,6-tetrahydro-1,2,3,5-tetraazine or 1,2-dihydro—1,2,3,5-tetraazine ring more preferably pyrrole, imidazole, pyridine, pyrimidine, pyridazine, They are 1,2-dihydropyrimidine and 1,2-dihydro-1,3,5-triazine rings.
  • Preferred as the ring are pyrrole, pyrazole, pyrroline, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazoline, virazoly Gin, dihydropyridine, tetrahydropyridine, piperidine, tetrahydrid Mouth pyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine.
  • B b - as preferably 2 rings, 1, 4, 5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 1, 4-dihydro-pyrimidine, 4, 5-dihydro-pyrimidine, pyrimidine, 1, 2, 5, 6 —Tetrahydropyrimidine, 2,5-dihydropyrimidine, 1,2-dihydropyrimidine, 1,2,3,4-tetrahydro-1,3,5-triazine, 1,2-dihydro-1,3,5-triazine, 1,4-dihydro-1,3,5-triazine, 1,4,5,6-tetrahydro-1,2,4-triazine, 1,4-dihydro-1,2,4-triazine, 1,6-dihydro-1 , 2, 4-triazine, 1, 2, 5, 6-tetrahydro-1,2,3,5-tetraazine or 1,2-dihydro 1,2,3,5-tetraazine ring, more preferably pyrimidine,
  • Z is one of R—R 2 , wherein Z is one of NR 3 —, an oxygen atom, an optionally oxidized sulfur atom or —CR 4 R 5 —, and R 2 is an optionally substituted unsaturated More preferably, Z represents —NR 3 —, an oxygen atom or one CR 4 R 5 —, and R 2 represents an optionally substituted unsaturated cyclic group. More preferably, Z represents —NR 3 —, and R 2 represents an optionally substituted unsaturated cyclic group. In this case, preferred R 2 is as described above.
  • the compound represented by the general formula (I) is preferably a compound represented by the general formula (I-A)
  • the compound represented by the general formula (IA) is preferably a compound represented by the general formula (IA-1), and more specifically, a compound shown below.
  • R w is a force representing a substituent.
  • each is independently a halogen atom, CF 3 , OCF 3 , hydroxy, mercapto, carboxyl, oxo, (C 1-6 alkoxy) carbol, power Rubamoiru, nitro, Shiano, and each halogen atom, CF 3 and 1-3 good C 1 to 6 alkyl optionally substituted with a group Ru is selected from hydroxy as substituents, C 2 to 6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy or C 1-6 alkylthio, and other symbols have the same meanings as described above.
  • preferred compounds represented by the general formula (IA-1) include compounds represented by the general formula (IA-1a)
  • Preferred compounds include the compounds described in the examples, N- (2-chloro-4-methoxyphenyl) -18- (11-ethylpropy) -18H-pyrazo port [1,5-a] pyro port [3 , 2— e] pyrimidine-5-amine, N— (2-chloro-14-methoxyphenyl) 18- (1-ethylpropyl) 1-6-methyl-18 H-pyrazo [1,5-a ] Pyro mouth [3,2-e] Pyrimidine-15-amine, N- (2-chloro-4-methoxyphenyl) -18_.
  • the alkyl group, the alkenyl group, the alkyl group, the alkoxy group, the alkylthio group, the alkylene group, the alkenylene group and the alkynylene group include straight-chain and branched-chain ones.
  • differences in double bonds, rings, and fused rings Isomers (E, Z, cis, trans), isomers due to the presence of asymmetric carbon (R, S, HI,] 3 configuration, enantiomers, diastereomers), optically active compounds with optical activity (D,. L, d, 1), polar compounds (highly polar, low polar) by chromatographic separation, equilibrium compounds, rotamers, mixtures of these in any proportion, and racemic mixtures include.
  • 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.), and ammonium salts (tetramethylammonium, tetrabutyl, etc.).
  • Ammonium salts, etc. organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine / reamine, piperidine, monoethanolanolamine, diethananolamine, trisamine Salts of methylamine, lysine, algin, N-methyl-D-glucamine, etc., acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide) , Sulfates, phosphates, nitrates, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, salt) Borate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, Dalcon Acid salt)
  • the salt of the compound of the present invention also includes a solvate or a solvate of the above-mentioned compound of the present invention with an alkaline metal (earth) metal, an ammonium salt, an organic amine salt, or an acid addition salt.
  • the solvate is non-toxic and water-soluble.
  • Suitable solvates include, for example, solvates such as water and alcoholic solvents (such as ethanol).
  • the prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) in a living body by a reaction with an enzyme, gastric acid, or the like.
  • a prodrug of the compound represented by the general formula (I) when the compound represented by the general formula (I) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (eg, a compound represented by the general formula:
  • the amino group of the compound represented by (I) is an eicosanoyl compound, an aryl compound, a pentylaminocarbonate compound, (5-methyl-2-oxo-1,3-dioxolene 41-yl) methoxy Carbonylation, tetrahydrofuranylation, pyrrolidylmethylation, viva propyloxymethylation, acetoxymethylation, tert-butylylated compound, etc.); when the
  • the carboxy group of the compound represented by ' is converted to ethyl ester, isopropyl ester, phenol ester, carboxymethyl ester, dimethylamino methinole ester, pivaloynoleoxymethinole ester, ethoxy canole resin, ethoxy canole resin Oxyshetyl esterification, phthalidyl esterification, (5-methyl-12-oxo-1, 3-dioxolen-14-inole) methinoleestenolide, cyclohexyloxycarbonylethyl ester,
  • the compound represented by the formula (I) has a carboxy group
  • examples thereof include a compound in which the carboxy group is replaced with a hydroxymethyl group. 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. Oh good.
  • the compound of the present invention represented by the general formula (I) can be produced, for example, by the method shown below, a method analogous thereto, or a method shown in Examples.
  • the compound used as a raw material may be used as a salt.
  • the salt those described as the salt of the aforementioned general formula (I) are used.
  • X is a leaving group (eg, a halogen atom, a tosyloxy group, a mesyloxy group, a trifuryl group (a trifluoromethanesulfonyloxy group), an alkoxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group, an aryl group) a sulfonyl group, etc.), R, a p ring, 8 "ring Oyobi 0 15 ring, each R ⁇ a ring, B a represents the same meaning as ring and D ring, the other symbols are same as the means represent.
  • a leaving group eg, a halogen atom, a tosyloxy group, a mesyloxy group, a trifuryl group (a trifluoromethanesulfonyloxy group), an alkoxy group, an alkylthio group, an arylthio group, an al
  • the addition reaction may be performed, for example, using an organic solvent (eg, N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-1-2- ⁇ f midazolidinone, tetrahydrofuran, isopropanol, etc. )
  • organic solvent eg, N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-1-2- ⁇ f midazolidinone, tetrahydrofuran, isopropanol, etc.
  • alkali metal or alkaline earth metal salts of hydrogen carboxylic acid such as sodium hydrogencarbonate and potassium hydrogencarbonate
  • alkali metal or alkaline earth metal carbonate such as sodium carbonate and calcium carbonate
  • Alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, etc.
  • alkali metals such as phenyllithium, alkyls such as butyllithium, etc.
  • Lithiums for example, alkali metal hydrides such as sodium hydride and hydrogenation hydride, or alkali metal hydrides, for example, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, for example, metal sodium, metal power Alkali metals such as lime Inorganic bases such as triethylamine, triptylamine, etc., alkylamines such as N, N-dimethylaerine, pyridine, norethidine, collidine, aromatic amines such as 4- (dimethylamino) pyridine, DBU (1,8-diamine) Organic bases such as azabicyclo [5,4,0] indene-1) are used. Deprotection reactions of carboxyl, hydroxyl, amino, or thiol protecting groups are well known and include, for example,
  • the deprotection reaction by alkali hydrolysis is performed, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkali
  • the reaction is performed at a temperature of 0 to 80 ° C using an earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution or a mixture thereof. .
  • the deprotection reaction under acid conditions is performed, for example, by using an organic acid (acetic acid, acetic acid, etc.) in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisol, 2,2,2-trifluoroethanol, etc.).
  • the reaction is carried out in trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc., or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) at a temperature of 0 to 100 ° C.
  • the deprotection reaction by hydrogenolysis is carried out, for example, by using a solvent (ether (tetrahydrofuran, dioxane, dimethyloxetane, getinoleethenol, etc.)) Alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.), ketones (acetone, methylethylketone, etc.), nitriles (acetutrile, etc.), amides (dimethylformamide, etc.), In the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) in water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof, at normal pressure or under pressure The reaction is performed at a temperature of 0 to 200 ° C. in a hydrogen atmosphere or in the presence of ammonium formate.
  • a solvent ether (tetra
  • the deprotection reaction of the silyl group is carried out, for example, by using tetrabutylammonium fluoride in a water-miscible organic solvent (tetrahydrofuran, aceto-tolyl, etc.) at a temperature of 0 to 40 ° C. It is performed in.
  • a water-miscible organic solvent tetrahydrofuran, aceto-tolyl, etc.
  • the deprotection reaction using a metal is performed, for example, in the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran). It is carried out at a temperature of 0 to 40 ° C while applying ultrasonic waves if necessary.
  • an acidic solvent acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran.
  • the deprotection reaction using a metal complex may be performed, for example, in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitril, dioxane, ethanol, etc.), water or a mixed solvent thereof.
  • organic solvent dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitril, dioxane, ethanol, etc.
  • Trap reagents triptyltin hydride, triethylsilane, dimedone, morpholine, getylamine, pyrrolidine, etc.
  • organic acids acetic acid, formic acid, 2-ethylhexanoic acid, etc.
  • organic acid salts (2-ethylhexanoic acid)
  • Metal complex tetrakistriphenylphosphine palladium (0), bis (2) chloride
  • a phosphine-based reagent such as triphenyl-phosphine
  • Triphenylphosphine palladium (II), palladium acetate (I I), tris (triphenylphosphine) rhodium (I), etc.
  • the deprotection reaction can be carried out, for example, by the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
  • Examples of the carboxyl-protecting group include a methyl group, an ethyl group, an aryl group, a t-butyl group, a trichloroethyl group, a benzyl (Bn) group, a phenacyl group, a p-methoxybenzyl group, a trityl group and a 2-chloro group.
  • Examples include a solid carrier to which a trityl group or a structure thereof is bonded.
  • hydroxyl-protecting group examples include a methyl group, a trityl group, a methoxymethyl group (MOM) group, a 1-ethoxyshethyl (EE) group, a methoxyethoxymethyl (MEM) group, and a 2-tetrahydrovinyl (THP) group.
  • MOM methoxymethyl group
  • EE 1-ethoxyshethyl
  • MEM methoxyethoxymethyl
  • TPP 2-tetrahydrovinyl
  • TMS Trimethylsilyl
  • TES triethylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • acetinol (Ac) group bivaloyl group
  • benzoyl go benzyl (Bn ) Group: — — methoxybenzyl group, aryloxycarbone / (Al 1 oc) group, 2,2,2,1-trichloromouth ethoxycarbinole (Tr oc) group, and the like.
  • Examples of the protecting group for the amino group include benzyloxycarbonyl group, butoxycarbonyl group, aryloxycarbonyl (Al 1 oc) group, and 1-methylphenol (4-biphenyl).
  • Ethoxy canolepo-nore (B poc) group trifluorophenol acetyl group, 9-fluorene methoxycarbonyl group, benzyl (Bn) group, p-methoxybenzinole group, benzyloxymethyl (BOM) group, 2- (to (Methylmethylsilyl) ethoxymethyl (SEM) group.
  • thiol-protecting group examples include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydropyranyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.
  • the protecting group for the carboxyl group, hydroxyl group, amino group, or thiol group is not particularly limited as long as it is a group that can be easily and selectively eliminated in addition to those described above. Yes. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.
  • the intended compound of the present invention can be easily produced by properly using these deprotection reactions.
  • the compounds represented by the general formulas (II) and (III) are known per se or can be easily produced by known methods.
  • the compound in which the Bap ring is a 1,2-dihydropyrimidine that is, the compound represented by the general formula (II-11) is represented by the following reaction scheme 1 Can be produced.
  • R (In the formula, Zn represents zinc, ha 1 o represents a halogen atom, and other symbols have the same meanings as described above). It can also be manufactured by attaching.
  • This reaction is known.
  • a palladium catalyst tetrakistriphenylphosphine palladium, palladium acetate-triphenylphosphine, etc.
  • an organic solvent tetrahydrofuran, dimethylformamide, etc.
  • the deprotection reaction can be performed in the same manner as described above.
  • the compound represented by the general formula (III-11) is known per se or can be easily produced by a known method.
  • X is a leaving group (for example, a halogen atom, a tosyloxy group, a mesyloxy group, a trifuryl group (a trifluoromethanesulfonyloxy group), an alkoxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group, an aryl group)
  • a leaving group for example, a halogen atom, a tosyloxy group, a mesyloxy group, a trifuryl group (a trifluoromethanesulfonyloxy group), an alkoxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group, an aryl group
  • a p ring, B ap ring and force Rupokishiru group contained in the substituents of the ring represented by E p ring, a hydroxyl group, if necessary protecting the amino group or thiol group is protected by a protective group Shall be When the carboxyl group, hydroxyl group, amino group or thiol group contained in the substituent represented by is required to be protected, it shall be protected by a protecting group. ) And the compound represented by the general formula (III) are subjected to an addition reaction, and if necessary, a deprotection reaction.
  • the addition reaction can be performed in the same manner as described above.
  • the deprotection reaction of the carboxyl group, hydroxyl group, amino group or thiol group can be carried out in the same manner as described above.
  • the compound represented by the general formula (XXI) is known per se or can be easily produced by a known method.
  • 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.
  • a solid-phase-supported reagent supported on a high-molecular polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like
  • a high-molecular polymer eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like
  • the reaction product is purified by conventional purification means, for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion-exchange chromatography. It can be purified by a method such as scavenger resin or column chromatography or washing, and recrystallization. Purification may be performed for each reaction or may be performed after several reactions are completed.
  • conventional purification means for example, distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion-exchange chromatography. It can be purified by a method such as scavenger resin or column chromatography or washing, and recrystallization. Purification may be performed for each reaction or may be performed after several reactions are completed.
  • the toxicity of the compound of the present invention represented by the general formula (I) ′ was sufficiently low, and it was confirmed that the compound was sufficiently safe for use as a medicament.
  • 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 Sexual diseases, metabolic diseases, cardiovascular diseases, skin diseases, urinary tract It is considered to be useful as a prophylactic and / or therapeutic agent for genital, ocular and musculoskeletal disorders.
  • neuropsychiatric disorders include, for example, mood disorders (eg, depression (single episode depression, recurrent depression, postpartum depression, child abuse-induced depression, senile depression) , Masked depression, seasonal depression, etc.), bipolar affective disorder, indefinite complaints, premenstrual dysphoric disorder, postpartum mood disorder, perimenopause or perimenopausal mood disorder), anxiety disorder (eg, generalized anxiety disorder, Panic disorder, obsessive-compulsive disorder, phobic anxiety disorder (altitude phobia, claustrophobia, agoraphobia, social phobia etc.)), adaptation disorders (eg, emotional disorders, behavioral disorders, both of them) Accompanying disabilities, physical complaints, social withdrawal, occupational or academic stagnation, stress-related disorders (eg, post-traumatic stress disorder (PTSD), stress-induced immune suppression) Inducing stress sexual headache, stress-induced fever, stress-induced pain, surgical assault stress, stress-associated gastrointestinal dysfunction, irritable bowel syndrome), eating disorders (eg,
  • Examples of skin diseases include atopic dermatitis, allergic contact dermatitis and psoriasis.
  • urinary tract diseases include dysuria, pollakiuria and urinary incontinence.
  • Pseudomeningitis, or musculoskeletal disorders include, for example, rheumatoid arthritis, osteoarthritis or osteoporosis.
  • the compound of the present invention represented by the general formula (I) includes 1) complementation and Z or enhancement of the preventive and Z or therapeutic effects of the compound, 2) improvement of kinetics and absorption of the compound, reduction of the dose, and Z or 3)
  • the compound may be administered as a concomitant drug in combination with other drugs to reduce side effects of the compound.
  • the combination 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.
  • simultaneous administration and administration at different times are included.
  • the administration by the 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, 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.
  • the disease in which the above-mentioned concomitant drug exerts a prophylactic and / or therapeutic effect is not particularly limited as long as the disease complements and / or enhances the prophylactic and / or therapeutic effects of the compound of the present invention represented by the general formula (I).
  • drugs for the prevention of mood disorders and the supplementation and / or enhancement of the Z or therapeutic effect of the compound of the present invention represented by the general formula (I) include, for example, antidepressants (for example, tricyclic anticancer drugs).
  • antidepressants for example, tricyclic anticancer drugs.
  • agents for preventing and / or supplementing and / or enhancing the effect of the compound of the present invention represented by the general formula (I) on anxiety disorders include, for example, anxiolytics (for example, benzodiazepines, chenodiazepines). System, non-benzodiazepine system), MBR ligand (MBR antagonist, MBR agonist).
  • agents for preventing and / or enhancing and / or enhancing the 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 nervous regulators, antidepressants, anxiolytics.
  • antidepressants examples include tricyclic antidepressants (eg, amitriptyline hydrochloride, imibramine hydrochloride, clomipramine hydrochloride, doslevin hydrochloride, nortriplipline hydrochloride, mouth uebramine, trimipramine maleate, amoxapine), tetracyclic antidepressants Drugs (eg, maprotiline hydrochloride, mianserin hydrochloride, setiptiline maleate), MAO inhibitors (saflazine hydrochloride), SNRI '(eg, milnacipran hydrochloride, benlafaxine hydrochloride), SSRIs (eg, flupoxamine maleate, Paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride), and serotonin reuptake inhibitors (eg, trazodone hydrochloride).
  • tricyclic antidepressants eg, ami
  • anti-drugs examples include benzodiazepines (e.g., alprazolam, oxazepam, oxazolam, cloxazolam, dipotassium chlorazepate, chlordazepoxide, diazepam, tofisopam, triazolam, plazepam, fuzorezepam, fuzoreazepam, fuzoreazepam, fuzorezepam, fuzoreazepam, fuzoreazepam, fluzoazepam) Mexazolam, medazepam, mouth ethyl frazepate, lorazepam), chenozazepine (eg etizolam, clotiazepam), non-benzodiazepine Systems (eg, tandospirone quenate, hydroxyludine hydrochloride).
  • benzodiazepines e.g., alprazolam, oxaze
  • 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 polypotency / repofilcalcium.
  • Examples of 5-HT 3 antagonists include arosetron.
  • Examples of the 5-HT 4 agonist include tegase mouth, cisapride, and mosapride citrate.
  • the mass ratio of the compound represented by the general formula (I) to the other drug is not particularly limited. Any two or more other drugs may be administered in combination.
  • agents that supplement and / or enhance the prophylactic or therapeutic effects of the compounds of general formula (I) include those that have been discovered to date based on the mechanism described above. Not only those that will be discovered in the future, but also those that will be discovered in the future. .
  • 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 lOOmg, once orally once to several times Parenteral administration once or several times a day, in a range of 0.1 mg to 100 mg per adult per dose (preferably, Nasal drops, eye drops or ointments) or continuous administration intravenously for 1 hour to 24 hours.
  • 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.
  • the solid preparation for oral administration When administering the compound of the present invention represented by the general formula (I) or the combination of the compound represented by the general formula (I) and another drug, the solid preparation for oral administration, the 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 also include sublingual tablets, buccal patches, buccally disintegrating tablets and the like.
  • one or more of the active ingredients may be intact or excipients (such as lactose, manitol, g / recose, microcrystalline cellulose, starch, etc.), binders (hydroxylpropyl). Cellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants (such as calcium fiber dalicholate), lubricants (such as magnesium stearate), stabilizers, dissolution aids (glutamic acid, aspartic acid) Etc.), and used in the form of a formulation according to the usual methods.
  • excipients such as lactose, manitol, g / recose, microcrystalline cellulose, starch, etc.
  • binders hydroxylpropyl
  • disintegrants such as calcium fiber dalicholate
  • lubricants such as magnesium stearate
  • a coating agent sucrose, gelatin, hydroxylinolepropinoresenolylose, hydroxylinolepropinolemethinole cellulose phthalate, etc.
  • a coating agent sucrose, gelatin, hydroxylinolepropinoresenolylose, hydroxylinolepropinolemethinole cellulose phthalate, etc.
  • capsules of absorbable materials such as gelatin.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such liquids, Or more active substance is dissolved, suspended or emulsified in commonly used diluents (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.
  • Dosage forms for parenteral administration include, for example, ointments, gels, creams, patches, patches, liniments, sprays, inhalants, sprays, aerosols , Eye drops, nasal drops and the like. These contain one or more active substances and are manufactured by known methods or commonly used formulations.
  • Propellants, inhalants and sprays may be used in addition to commonly used diluents, buffers which provide isotonicity with stabilizers such as sodium bisulfite, for example, sodium chloride sodium, sodium citrate or It may contain an isotonic agent such as citric acid.
  • stabilizers such as sodium bisulfite, for example, sodium chloride sodium, sodium citrate or It may contain an isotonic agent such as citric acid.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent when used. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used.
  • this injection contains a stabilizer, a solubilizing agent (daltamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Is also good. They are manufactured 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 suppositories for rectal administration and pessaries for intravaginal administration which contain one or more active substances and are formulated in a conventional manner. Is included.
  • the compounds of the present invention bind to the CRF receptor and show strong antagonism.
  • the solvent in kakkou indicated by the chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • the solvent in kakkoko shown in the NMR section indicates the solvent used for the measurement.
  • Example 1 6-arylpyrazo mouth [1,5-a] pyrimidine mono 5,7-diol Sodium ethoxide was prepared by adding sodium metal (2.77 g) to ethanol (60 mL). To this mixture, a solution of getylarylmalonate (12.1 g ) in ethanol (2 OmL) and a solution of 1 H-pyrazole-13-amine (5.0 g ) in ethanol (2 OmL) were sequentially added at room temperature, and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled, and the precipitate was collected by filtration. Dissolve the resulting solid in water and add 2N Acidified with hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure at 60 ° C. for 8 hours to obtain the title compound (7.11 g).
  • Pentane-13-amine (1.54 mL) was added to a solution of the compound (l.Og) produced in Example 2 in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 7 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.
  • ⁇ -NMRCGDCls ⁇ 8.58, 7.86, 7.07, 7.00, 6.92, 6.84, 6.48, 6.31, 5,91, 3.82, 2.05-1.74, 0.84.
  • Example 9 4- (2-chloro-1-methoxyphenyl) -13-methyl-1H-pyrazole-15-amine
  • Acetic acid (3.66 mL) and hydrazine monohydrate (2.07 mL) were added to a toluene (50 mL) solution of the compound (4.19 g) produced in Example 8, and the reaction mixture was heated under reflux for 3 hours.
  • the reaction mixture was concentrated after cooling, and 6 N hydrochloric acid was added.
  • the aqueous layer was washed with a mixed solvent of hexane monoether (1: 1).
  • the aqueous layer was made basic with ammonia water and extracted with ethyl acetate.
  • the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.97 g) having the following physical data.
  • Example 12 N— (1-Ethylpropyl) -13- (4-Methoxy-12-methylphenyl) -1,2,7-dimethyl-6,7-dihydro-5H-cyclopenta [d] pyrazo [1, 5—a] pyrimidine 8—amine
  • ⁇ -NMRCCDCla ⁇ 7.15, 6.85, 6.77, 6.27, 3.82, 3.72, 3.42, 3.03, 2.79, 2.30, 2.20, 1.83, 1.65, 1.22, 1.11, 0.96.
  • Example 12 (3) .: 3— (2-chloro-4-methoxyphenyl) _2—methyl-1-N— (1-methinoleptinole) 1,6,7-dihydro 5 H-cyclopenta [d] pyrazo [ 1,5—a] pyrimidine-1-amine hydrochloride
  • Example 12 3- (2-chloro-4-methoxytoluene) 1-2-methyl ⁇ — [(1R) —1-methylpropyl] —6,7-dihydro-5-cyclopentane [d] Pyrazo mouth [1, 5—a] pyrimidine-1 8-amine
  • Example 12 3- (2-chloro-1-4-methoxyphenyl) -1-2-methyl-1-[(1S) -1-methylpropyl] —5 ⁇ , 7 ⁇ —flow [3,4— d] pyrazo mouth [1, 5—a] pyrimidine-1 8-amine
  • Example 12 (7) 3- (2-chloro-1--4-methoxyphenyl) -1-isopropyl-1--2-methyl-6,7-dihydro_5 ⁇ ⁇ ⁇ -cyclopenta [d] virazolo [1,5- a] Pyrimidine _ 8—amine
  • Example 13 (1): ⁇ — (2-ethyl 4-methoxyphenyl) 18- (1—ethylpropyl) —8 ⁇ -pyrazo port [1, 5—a] pyro port [3, 2—e] pyrimidine-1 5 —Amin
  • Example 13 (2) ⁇ - (4-chloro-1-2-ethylfuryl) -18- (1-ethylpropyl) -18-pyrazo [1,5-a] Pyro [3,2-e] Pyrimidine-1 5-amine
  • Example 13 (4): ⁇ - (2-Echinolene 4-methinolefeninole) -18- (1-ethylpropyl) -18-pyrazo mouth [1, 5-a] Pyro mouth [3, 2-e] 'Pyrimidine-1 5-amine
  • Example 13 8- (1-ethylpropyl) 1-mesityl-1 8-pyrazolo [1,5-a] pyro-mouth [3,2-e] pyrimidine-1-5-amine
  • Example 13 (8) .: ⁇ — (2,4-dimethyl-6-bulphenyl) -18- (1-ethylpropyl) -18 ⁇ -pyrazo mouth [1, 5_a] Pyro mouth [3,2-e] pyrimidine-1 5 —Amin
  • Example 14 8-((1-Ethylpropyl) -15- (mesitylmethyl) -18- ⁇ pyrazo mouth [1,5-a] Pyro mouth [3,2-e] pyrimidine Under an argon atmosphere, tetrakis (triphenylphosphine) palladium (22 mg) was added to a solution of the compound (10 Omg) produced in Example 4 in tetrahydrofuran (2 mL). To the mixed solution, bromo (mesitinolemethy / re) zinc (0.95 mL) was added dropwise, and the mixture was stirred at 60 ° C overnight.
  • a human CRF receptor type 1 forced expression cell line (parent cell line was CHO-K1 cell) was cultured until it became confluent, and then collected using a scraper. After the collected cells were washed twice with PBS, and binding ⁇ Tsu Si ice-cold buffer (T ris -HC 1 (5 OmM , pH7. 0), EDTA (2m M, pH8. 0), Mg C 1 2 (10-mM)). The suspended cells were crushed using a dance-type homogenizer, and then centrifuged at 10,000 g to collect a membrane fraction. The collected membrane fraction was resuspended with a small amount of binding assay buffer, and then diluted with binding assay buffer to a concentration of Img / mL. The above was used as a membrane fraction in a binding assay.
  • 125 I-CRF was diluted to 0.5 nM with binding Atsushi buffer, and 50 // L calories were added to a siliconized 1.5 mL tube.
  • 50 ⁇ L of the membrane fraction was caloried to start the reaction, and the final concentration of 25 I-CRF was 0.25 ⁇ ). Tubes' were incubated at room temperature for 2 hours. After completion of the reaction, centrifuge at 15000 g to collect the membrane fraction, discard the supernatant, and cool with ice-cold PB.
  • test drug solution 2 ⁇ or DMSO (2 ⁇ L) to CRF group and blank group
  • 10 nM human Z rat CRF 10 nM human Z rat CRF.
  • the blank group was supplemented with 20 liters of assay medium containing 0.00001% acetic acid (20 L), and incubated at 37 ° C for 15 minutes. The reaction was stopped by ice-cooling, and all reactions were performed in two-well increments.
  • the measurement of intracellular cytosolic AMP accumulation was performed using the Cytaric AMP Biotrak enzyme immunoassay system (Amersham Biosciences). Cyclic AMP accumulation was calculated by subtracting the mean of the corresponding 2 ⁇ blank blank group from the mean of the 2 ⁇ well IC 5. The values were calculated using the logarithmic concentration of the compound as an independent variable, and the italic AMP accumulation. With the quantity as the dependent variable Was calculated.
  • the present compound was found to have a strong antagonistic activity (1.2 50 values ⁇ 1 M) relative to the CRF.
  • the following components were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 5 Omg of the active ingredient.
  • the compound of the present invention has a CRF antagonistic effect, it is effective for the prevention and / or treatment of a CRF-mediated disease, for example, a psychiatric or digestive disease.

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Abstract

Composé représenté par la formule générale (I) (dans laquelle le cycle représente un hétérocycle tricyclique qui peut avoir un ou plusieurs autres substituants ; R1 représente (1) (a) un alkyle en C1-15, (b) un alcényle en C2-15 ou (c) un alcynyle en C2-15 facultativement substitués, (2) un amino facultativement protégé, (3) un hydroxy facultativement protégé, (4) un mercapto facultativement protégé, (5) -S(O)nR6, (6) -COR7 ou (7) un groupe cyclique facultativement substitué ; Z représente -NR3-, un oxygène, un soufre facultativement oxydé ou -CR4R5- ; et R2 représente un groupe cyclique insaturé facultativement substitué), sel, N-oxyde ou solvate du composé ou bien promédicament de l'un quelconque de ceux-ci ; et composition médicinale contenant l'un quelconque de ceux-ci comme ingrédient actif.
PCT/JP2005/004875 2004-03-15 2005-03-14 Composé hétérocyclique tricyclique et composition médicinale contenant le composé comme ingrédient actif WO2005087775A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007116708A1 (fr) 2006-03-31 2007-10-18 Mitsui Chemicals, Inc. Composition de polymère thermoplastique, procédé servant à produire la composition de polymère thermoplastique, corps moulé obtenu à partir de la composition de polymère thermoplastique et fil électrique
US8518933B2 (en) 2009-04-23 2013-08-27 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8546377B2 (en) 2009-04-23 2013-10-01 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8546368B2 (en) 2006-02-15 2013-10-01 Abbvie Inc. Pyrazoloquinolones are potent PARP inhibitors
CN111961047A (zh) * 2020-08-19 2020-11-20 南通大学 一种6-乙氧基-3,4-二氢-2,7-萘啶-1（2h）-酮及其合成方法

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8546368B2 (en) 2006-02-15 2013-10-01 Abbvie Inc. Pyrazoloquinolones are potent PARP inhibitors
WO2007116708A1 (fr) 2006-03-31 2007-10-18 Mitsui Chemicals, Inc. Composition de polymère thermoplastique, procédé servant à produire la composition de polymère thermoplastique, corps moulé obtenu à partir de la composition de polymère thermoplastique et fil électrique
US8518933B2 (en) 2009-04-23 2013-08-27 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8546377B2 (en) 2009-04-23 2013-10-01 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8846663B2 (en) 2009-04-23 2014-09-30 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US9701679B2 (en) 2009-04-23 2017-07-11 Abb Vie Deutschland GmbH & Co. KG Modulators of 5-HT receptors and methods of use thereof
CN111961047A (zh) * 2020-08-19 2020-11-20 南通大学 一种6-乙氧基-3,4-二氢-2,7-萘啶-1（2h）-酮及其合成方法

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