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WO2005061508A1 - Compose tricyclique heterocyclique, et medicament dont il est le principe actif - Google Patents

Compose tricyclique heterocyclique, et medicament dont il est le principe actif Download PDF

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Publication number
WO2005061508A1
WO2005061508A1 PCT/JP2004/019658 JP2004019658W WO2005061508A1 WO 2005061508 A1 WO2005061508 A1 WO 2005061508A1 JP 2004019658 W JP2004019658 W JP 2004019658W WO 2005061508 A1 WO2005061508 A1 WO 2005061508A1
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Prior art keywords
methyl
dihydro
amino
chloro
pyrazo
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English (en)
Japanese (ja)
Inventor
Kenichi Nunoya
Naoya Matsumura
Makiko Sugioka
Hideki Moriguchi
Seishi Katsumata
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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Priority to JP2005516533A priority Critical patent/JPWO2005061508A1/ja
Publication of WO2005061508A1 publication Critical patent/WO2005061508A1/fr
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a 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.
  • Corticotropin Releasing Factor 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 adrenocorticotropic hormone
  • CRF 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.
  • antidepressants include tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase ( ⁇ ⁇ ) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRI), serotonin selective reuptake inhibitor (SSRI) and the like have been used.
  • SNRI noradrenaline reuptake inhibitors
  • SSRI serotonin selective reuptake inhibitor
  • 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.
  • WO2O02 / 53565 describes the general formula ( ⁇ )
  • W A represents a carbon atom or a nitrogen atom
  • R 1 a is either substituted by 1. 1 to 5 amino R 14 ⁇ , 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) :!
  • 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
  • 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.
  • 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.
  • na represents an integer of 1 to 3.
  • 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;
  • composition according to the above (6) which is an agent for preventing and / or treating a CRF-mediated disease
  • the CRF-mediated disease is a nervous system disease or digestive system disease
  • 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.
  • 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,
  • 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.
  • the optionally protected hydroxyl group includes a hydroxyl group which may be protected by a protecting group having an elimination ability.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • R 4 is protected by a hydroxyl, methyl or TBDMS group
  • 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.
  • the compound represented by the general formula (I) is a compound produced by chemical synthesis.
  • preferred compounds are those represented by the general formula (la)
  • 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.
  • specific compounds of the present invention include the following compounds produced by chemical synthesis.
  • alkyl groups include straight and branched ones.
  • 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.
  • the notation of asymmetric carbon is obvious to those skilled in the art unless otherwise specified...
  • 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).
  • organic amines triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxylmethyl) methylamine, lysine, arginine , ⁇ -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.).
  • organic amines triethylamine,
  • 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 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. .
  • 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.
  • the compounds of the present invention can be produced, for example, by the following methods or the methods described in the Examples below.
  • 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.
  • an organic solvent eg, toluene, xylene, 1,2-dimethoxetane, dimethylformamide, dimethylamine, dimethylsulfoxide, 2-propanol, isopropanol, acetonitrile
  • a base eg, triethylamine, trimethylamine.
  • 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
  • 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)
  • an organic solvent eg, 1,2-dimethoxyethane, diglyme, toluene, xylene, dimethylformamide, cyclopentylmethyl ether, tetrahydrofuran, dioxane, dimethylacetamide, or dimethylimidazolidinone
  • a base eg, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, sodium hydride, sodium carbonate, potassium carbonate, lithium carbonate, potassium phosphate, sodium phosphate
  • 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.
  • 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 —
  • 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.
  • 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).
  • an organic solvent eg, toluene, methanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, aceto nitrile, dimethylformamide, dimethyl sulfoxide
  • an acid eg, acetic acid, propionic acid, p-toluene.
  • 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.
  • an acid eg, acetic acid, sulfuric acid, methanesulfonic acid, tosylic acid
  • 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.
  • 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.
  • 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).
  • a base eg, pyridine, triethylamine, dimethylaniline, getylaniline, dimethylaminopyridine, diisopropylamine.
  • 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).
  • Ph 3 P triphenylphosphine
  • 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.
  • general formula (1-1) for example, general formula (1-1)
  • 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)
  • 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.
  • 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 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.
  • 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. '
  • 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
  • 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 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.
  • Simultaneous administration and administration with a time difference are included.
  • 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.
  • 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).
  • antidepressants for example, tricyclic anticancer drugs.
  • SNRIs monoamine oxidase
  • SNRIs serotonin and noradrenaline reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • NK1 antagonists and the like.
  • 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.
  • 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.
  • antidepressants examples 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).
  • tricyclic antidepressants eg, amitript
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a solid preparation for oral administration 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.
  • 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.
  • 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
  • a coating agent sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethyl cell mouth perfume rate, etc.
  • a coating agent sucrose, gelatin, hydroxylpropylcellulose, hydroxylpropylmethyl cell mouth perfume rate, etc.
  • 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.
  • one or more active substances are dissolved, suspended, or emulsified in a commonly used diluent (such as purified water, ethanol, or a mixture thereof).
  • 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.
  • 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.
  • stabilizers such as sodium bisulfite.
  • Such an isotonic agent may be contained.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use.
  • a 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.
  • 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.
  • 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. .
  • 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.
  • 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
  • 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.
  • 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
  • pyridine hydrochloride 9.0 g
  • 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.
  • 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
  • Example 8 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
  • Example 8 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.
  • Example 10 (1): ⁇ — (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
  • 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
  • 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
  • methylene chloride 10 mL
  • boron tribromide 5.06 mL
  • Water was added to the reaction mixture, which was extracted with ethyl acetate.
  • 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 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
  • Example 17 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
  • Example 17 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
  • 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
  • Example 18 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
  • 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.
  • ⁇ -- ⁇ Storm storm ((440000MMHHzz ,, CCDDCCllaa)) :: ⁇ 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 ..
  • 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. .
  • 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 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.
  • 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
  • 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.

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Abstract

L'invention porte sur un composé de formule générale (I) dans laquelle: R1 et R2 représentent chacun indépendamment hydroxy facultativement protégé, R3 et R4 représentent chacun indépendamment hydroxy ou oxo facultativement protégé; R5 représente méthyle facultativement oxydé; et n, m et p représentent chacun indépendamment un entier de 0 à 3. L'invention porte également sur leurs sels, solvates, N-oxydes, ou une prodrogue de chacun d'eux. Ils présentent une activité antagoniste du CRF et s'avèrent utiles pour prévenir et/ou traiter les troubles psychoneurotiques ou digestifs.
PCT/JP2004/019658 2003-12-22 2004-12-21 Compose tricyclique heterocyclique, et medicament dont il est le principe actif Ceased WO2005061508A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009515899A (ja) * 2005-11-10 2009-04-16 ボード オブ スーパーバイザーズ オブ ルイジアナ ステイト ユニバーシティー アンド アグリカルチュラル アンド メカニカル カレッジ 依存症及び他の精神神経疾患の治療のための組成物及び方法
US9078886B2 (en) 2010-06-16 2015-07-14 Embera Neurotherapeutics, Inc. Compositions for the treatment of addiction, psychiatric disorders, and neurodegenerative disease
US11179377B2 (en) 2017-03-10 2021-11-23 Embera Neurotherapeutics, Inc. Pharmaceutical compositions and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053565A1 (fr) * 2000-12-28 2002-07-11 Ono Pharmaceutical Co., Ltd. Composes de derives tricycliques et heterocycliques et medicaments renfermant ces composes comme principe actif
WO2004113344A1 (fr) * 2003-06-25 2004-12-29 Ono Pharmaceutical Co., Ltd. Sel methanesulfonique acide d'un compose pyrazolopyrimidinique, cristal de ce sel, et procede de production correspondant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053565A1 (fr) * 2000-12-28 2002-07-11 Ono Pharmaceutical Co., Ltd. Composes de derives tricycliques et heterocycliques et medicaments renfermant ces composes comme principe actif
WO2004113344A1 (fr) * 2003-06-25 2004-12-29 Ono Pharmaceutical Co., Ltd. Sel methanesulfonique acide d'un compose pyrazolopyrimidinique, cristal de ce sel, et procede de production correspondant

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009515899A (ja) * 2005-11-10 2009-04-16 ボード オブ スーパーバイザーズ オブ ルイジアナ ステイト ユニバーシティー アンド アグリカルチュラル アンド メカニカル カレッジ 依存症及び他の精神神経疾患の治療のための組成物及び方法
US9415107B2 (en) 2005-11-10 2016-08-16 Board Of Supervisors Of Louisiana State University & Agricultural & Mechanical College Compositions and methods for the treatment of addiction and other neuropsychiatric disorders
US9078886B2 (en) 2010-06-16 2015-07-14 Embera Neurotherapeutics, Inc. Compositions for the treatment of addiction, psychiatric disorders, and neurodegenerative disease
US9987286B2 (en) 2010-06-16 2018-06-05 Embera Neurotherapeutics, Inc. Compositions and methods for the treatment of addiction, psychiatric disorders, and neurodegenerative disease
US11179377B2 (en) 2017-03-10 2021-11-23 Embera Neurotherapeutics, Inc. Pharmaceutical compositions and uses thereof

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