WO1997017349A1 - Derives heterocycliques fusionnes pentagonaux d'azepine et leur emploi pharmaceutique - Google Patents

Derives heterocycliques fusionnes pentagonaux d'azepine et leur emploi pharmaceutique Download PDF

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Publication number
WO1997017349A1
WO1997017349A1 PCT/JP1996/003186 JP9603186W WO9717349A1 WO 1997017349 A1 WO1997017349 A1 WO 1997017349A1 JP 9603186 W JP9603186 W JP 9603186W WO 9717349 A1 WO9717349 A1 WO 9717349A1
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carbonyl
thieno
biphenyl
phenyl
tetrahydro
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PCT/JP1996/003186
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English (en)
Japanese (ja)
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Hidetsura Cho
Korekiyo Wakitani
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Japan Tobacco Inc.
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Priority to AU73387/96A priority Critical patent/AU7338796A/en
Publication of WO1997017349A1 publication Critical patent/WO1997017349A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel fused 5-membered heterocyclic azepine compound, and more particularly, to a novel fused 5-membered heterocyclic azepine compound having excellent vasopressin antagonism and its pharmaceutical use.
  • Vasobretsin is one of the posterior pituitary hormones, and has an antidiuretic effect by promoting the reabsorption of water in the collecting tubules of the kidney, thereby maintaining body fluid homeostasis. Some also act on the central nervous system as paracrine hormones. In addition, vasopressin exerts a vasopressor effect due to vascular smooth muscle contraction, vasoconstriction related to the circulatory system, cardiac depression, body temperature regulation, blood coagulation, hepatic protein release, mesangial mucous cell proliferation, etc. There is.
  • V Receptors Basoburetsushin
  • V receptors are distributed in a group of cells, including vascular smooth muscle and hepatocytes, and cause vasoconstriction and glycogenolysis via inositol phospholipid metabolism (MJ Berridge, RF Irrine, Nature, 212, 315 ( 1984).
  • V 2 receptors are distributed in the renal tubules, express activity through c AMP production system (J. Bockart et al .. J. Biol . Chem., 248, 5922
  • vasobretsin having such an effect may be caused by various pathological conditions, such as depressive 'deficiency (Pharmacological Reviews, 43, P73-108 (1991)), cerebral edema [ Stroke, 23, p 1767-1773 (1992), Life Sciences, 43, p3 991-403, (1988), cranial nerve, 44 (1), p43 ( 1992), neurosurgery, 21 (12), p 1103 (1993)), arginine vasopletsusin hypersecretion syndrome [Journal of Cardio Vascular Pharmacology] (Journal of Cardiovascular Pharmacology), 8 (Suppl. 7), pS36-S43 (19986)], hypertension and the like.
  • pathological conditions such as depressive 'deficiency (Pharmacological Reviews, 43, P73-108 (1991)), cerebral edema [ Stroke, 23, p 1767-1773 (1992), Life Sciences, 43, p3 991-403, (1988), cranial nerve, 44 (1),
  • vasopletusin antagonist if a superior vasopletusin antagonist is developed, these diseases caused by excess vasobrethsin, such as cardiac insufficiency, edema, arginine vasobrethsin hypersecretion syndrome, renal failure, high blood pressure, ascites, cirrhosis, and low sodium
  • vasobrethsin such as cardiac insufficiency, edema, arginine vasobrethsin hypersecretion syndrome, renal failure, high blood pressure, ascites, cirrhosis, and low sodium
  • vasobrethsin such as cardiac insufficiency, edema, arginine vasobrethsin hypersecretion syndrome, renal failure, high blood pressure, ascites, cirrhosis, and low sodium
  • thoremia hypokalemia
  • diabetes circulatory failure
  • pulmonary edema Meniere's syndrome
  • okintocin-related disease etc.
  • diuretic
  • An object of the present invention is to provide a novel compound that antagonizes vasobretsin.
  • the present invention relates to a novel 5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azepine derivative or an analog thereof, and a novel 5,6,7,8-tetrahydro-4H-fluoro [3 , 2-b] azepine derivatives or analogs thereof, and new 4,5,6,7,8-hexahydropyrro [3,2-b] azepine derivatives or analogs thereof, and containing these compounds
  • nasobusetsushinshin antagonist The details are as shown in the following (1) to (18),
  • R 1 represents a hydrogen atom, a hydroxyl group, a lowly treated alkyl group, a halogen atom, a formyl group or a carboxy group,
  • R 2 represents a hydrogen atom or a lower alkyl group
  • R 3 and R 4 may be the same or different and each represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, an acyl group, a cyano group or a halogen atom;
  • R 5 represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted radical
  • R 6 represents a hydrogen atom or a lower alkyl group
  • a 1 represents an oxygen atom, a sulfur atom or —NR 7 — (wherein R 7 represents a hydrogen atom or a lower alkyl group);
  • a 2 is one of CR 8 R 9 (wherein, one of R 8 and R 9 represents a hydrogen atom, and the other is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted or represents lower pole alkoxy group or an optionally substituted amino group, or an Okiso group becomes R 8 and R 9 gar cord) or one NR ie - (wherein, R 1 () is a hydrogen atom, Which may be substituted (representing an alkyl group or an acyl group);
  • a 3 represents an oxygen atom, a sulfur atom or one NR 11 — (wherein, R 11 represents a hydrogen atom or a lower alkyl group) or a single bond;
  • Z is a halogen atom, an optionally substituted heteroaryl group, one NR 12 R 13 (wherein R 12 and R 13 are the same or different and represent a hydrogen atom or a lower alkyl group),
  • R 14 is a hydrogen atom, a low-handed alkyl group which may be substituted with a hydroxyl group, a lower alkoxycarbonyl group, a phenyl group (the phenyl group may be substituted with a hydroxyl group or a halogen atom.
  • R 15 represents a hydrogen atom or a lower alkyl group.
  • R 15 has the same meaning as described above, s represents 0 or an integer of 1 to 6) or a single bond, and is a nitrogen atom or CH Represents a nitrogen atom or a CH group or represents an oxygen atom by W 2 —R 14 , and n represents 1 to 3 Represents an integer, and p represents an integer of 0 or 1 to 3.
  • Y—X ⁇ Y is an oxygen atom, a sulfur atom, — NR 15 — (wherein, R 15 has the same meaning as described above.), —COO— or one NHCO—, and X is a hydrogen atom
  • a lower alkyl group ⁇ the lower alkyl group may be substituted with a halogen atom or one NR 12 R 13 (wherein, R 12 and R 13 have the same meanings as described above).
  • R 12 and R 13 have the same meanings as described above.
  • an optionally substituted heteroaryl group Represents
  • n 0 or an integer of ⁇ to 6. However, when A 3 is a single bond, m represents an integer of 1 to 6.
  • Alpha ' is a sulfur atom
  • Alpha 2 the salts are CH 2
  • a 3 is (1), wherein the hetero 5-membered to fused ring Azepin derivative or a pharmacologically oxygen atom acceptable.
  • a pharmaceutical composition comprising the condensed hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (5), and a carrier.
  • a vasopressin antagonist comprising the condensed a 5-membered azepine derivative or the pharmacologically acceptable salt thereof according to any one of the above (1) to (5).
  • a therapeutic drug for depressive heart failure comprising the condensed hetero 5-membered ring azevin derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (5).
  • a therapeutic agent for cerebral edema comprising the condensed hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a diuretic comprising the body or a pharmacologically acceptable salt thereof.
  • a therapeutic agent for renal failure comprising a heterozygous 5-membered ring azepine derivative or a pharmacologically acceptable salt thereof according to any one of the above (1) to (5).
  • a therapeutic agent for pulmonary edema comprising the condensed hetero 5-membered ring azepine derivative or the pharmacologically acceptable salt thereof according to any of (1) to (5).
  • a therapeutic drug for Meniere's syndrome comprising the condensed hetero 5-membered ring azepine derivative or the pharmacologically acceptable salt thereof according to any one of the above (1) to (5).
  • R 16 ′ represents a hydrogen atom or a lower alkyl group
  • R 18 represents a nitro group or an amino group
  • R ′, R 2 , R 3 , R 4 , A 1 , A 2 , A 3 or And A 4 has the same meaning as described above.
  • lower refers to a hydrocarbon chain having 1 to 6 carbon atoms.
  • the “lower alkyl group” may be straight-chain or branched, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1 — (2— or 3—) Methylpentyl group, 1,1— (1,2—, 2,2-, 1,3-, 2,3- or 3,3-) dimethylbutyl group, 1- (or 2-) ethylbutyl group, I, and 2- (or 2,2-) trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like.
  • Methyl group, Echiru group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl groups, C such as tert- butyl group, - 4 alkyl group, a Riwake methyl group, Echiru group and propyl Groups are particularly preferred.
  • halogen atom examples include fluorine, chlorine, bromine and iodine, and chlorine and bromine are preferred.
  • lower alkoxy group examples include a methoxy group, an ethoxyquin group, a proboxyl group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a benzyloxy group and an isopentyloxy group Tert-pentyloxy, neopentyloxy, 2-methylbutyne, 2-dimethylpropoxy, 11-ethylpropoxy, hexyloxy and the like.
  • main butoxy group Etokin group, Purobokishi group, Isopurobokishi group, but-Kin group, such as tert- butoxy - 4 alkoxy groups, especially main butoxy group, is Etokin group particularly preferred.
  • the "aryl group” preferably has 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a biphenyl group, a fluorenyl group, an anthryl group and a phenanthryl group.
  • heteroaryl group contains at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring, and may be a fused ring.
  • the heteroaryl group include, for example, a pyridyl group, a fluorimido group, a tetrabryl group, a quinolyl group, an isoquinolyl group, an indolyl group, a chenyl group, a benzothenyl group, a furyl group and a benzofuryl group.
  • a pyridyl group, a quinolyl group, an isoquinolyl group, a phthalimid group, a tetrazolyl group, and the like are preferable, and an indolyl group, a pyridyl group, a phthalimid group, and a tetrabryl group are particularly preferable.
  • the terminating silyl group may include an aroyl group. And the like.
  • alkenyl groups such as an acetyl group, a formyl group, a propionyl group and a butyryl group, and a benzoyl group are preferable, and an acetyl group, a formyl group, and a propylion group are particularly preferable.
  • lower alkenyl group examples include, for example, ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group Nyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-hexenyl, 2-hexenyl, 3- Xenenyl group, 4-hexenyl group, 5-hexenyl A 2-methyl-1-pentenyl group, a 3-methyl-1-pentenyl group, a 4-methyl-1-pentenyl group, a 2,3-dimethyl-1-butenyl group, a 3,3-dimethyl-1-butenyl group, etc. I can do it.
  • ethenyl group having 2 to 4 carbon atoms 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-bromo group And the like, and particularly preferably an ethenyl group.
  • alkoxy moiety of the “alkoxycarbonyl group” examples include those mentioned above as the low alkoxy group. Of these, methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like are preferable, and methoxy and ethoxyquin are particularly preferable.
  • the above-mentioned lower alkyl groups are mono- or di-substituted with an amino group, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group.
  • methylamino group, ethylamino group, propylamino group, isopropylamine Preferred are a lumino group, a dimethylamino group, a getylamino group, a diaminopropylamino group, a diisopropylamino group and the like, and particularly preferred are a dimethylamino group and a dimethylamino group.
  • Examples of the substituent of the phenyl group or the aryl group include a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a methylamino group, a dimethylamino group, a hydroxyl group, a carboxy group, a phenoxy group, and an acyloxy group.
  • a lower alkyl group, a halogen atom, an amino group, a methylamino group, a dimethylamino group and the like are preferable, and a methyl group, a dimethylamino group and an amino group are particularly preferable.
  • the substitution position is not particularly limited.
  • Examples of the substituent of the heteroaryl group include the aryl group and those described as the substituent of the aryl group.
  • a lower alkyl group, an aryl group, a halogen atom, a dimethylamino group, a phenoxy group and the like are preferable, and a methyl group, a phenyl group and a phenoxy group are particularly preferable.
  • the substitution position is not particularly limited.
  • any protecting group may be used as long as it is generally used.
  • Preferred R 2 includes a hydrogen atom and a C,-* alkyl group, and particularly preferred is a hydrogen atom.
  • R 3 and R 4 each include a hydrogen atom, a lower alkyl group and the like, and a hydrogen atom is particularly preferred.
  • Preferred R 5, a hydrogen atom, is substitution with an alkyl group and a lower alkyl group include good Fuyuniru group, especially a hydrogen atom, a phenyl group which may be substituted with a methyl group or a methyl group is preferable.
  • Preferred R 6 is a hydrogen atom or a methyl group, and a hydrogen atom is particularly preferred.
  • Preferred substituents for the lower alkyl group or lower alkoxy group in R 8 , R 9 or Rie include an amino group, a lower alkylamino group, a di-lower alkylamino group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, and a 4-lower.
  • the substitution position and number are not particularly limited, but the terminal is preferable.
  • di-lower alkylamino, pyrrolidinyl, piperidino, 4 lower-alkylpiperazinyl, pyridyl and carbonyl are preferred, and dimethylamino, pyrrolidinyl and 4-methylbiperazinyl are particularly preferred. And a pyridyl group are particularly preferred.
  • W 1 is preferably a CH group.
  • the pharmacologically acceptable salts of compound (I) include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid) in a conventional manner.
  • Linoleic acid Linoleic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.
  • inorganic bases sodium hydroxide, potassium hydroxide, calcium hydroxide
  • organic bases methylamine, getylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethyl) Methane, quinine, guanidine, cinchonine, etc.
  • amino acids lysine, ol Ditin, arginine, alanine, etc.
  • it may be a hydrate or a hydrate. It may also be a prodrug.
  • the feature of the compound (I) of the present invention is that benzozepines, which are the basic skeleton of a conventionally known vasopressin antagonist compound, are converted into condensed 5-membered heterocyclic azepines, and the side chain from the central benzene ring is converted. It is a point that we succeeded in improving the activity.
  • the compound (I) of the present invention is expected not only to have an excellent vasobrethsin antagonism but also to reduce side effects such as central toxicity.
  • R 16 represents a protecting group for a lower alkyl group or a hydroxyl group
  • Ha represents a halogen atom, and other symbols are as defined above.
  • pyridine 2,6-lutidine, triethylamine, sodium acetate and the like are used, and pyridine is particularly preferable.
  • the solvent methanol or a base can be used as it is.
  • the reaction is usually carried out at about O'C to room temperature, and the reaction time is about 30 minutes to 24 hours.
  • the reaction for obtaining compound 3 from compound 2 is a Beckmann rearrangement reaction.
  • Compound 2 is carried out in a suitable solvent in the presence of an acid catalyst used in a usual Beckmann rearrangement reaction, or a tosyl mouth ride, a mesyl mouth ride and a basic solvent such as pyridine, lutidine, etc. Is performed by converting tosylate or mesylate by using and then transposing by heating.
  • the acid catalyst for example, sulfuric acid, sulfonic acid, phosphoric anhydride, phosphorus pentachloride, sulfuryl chloride, methylsulfonic acid Z phosphorus pentoxide and the like can be used.
  • Any solvent can be used as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene.
  • the reaction is preferably carried out at about 100 to 140 ° C., and is generally completed in about 30 minutes to 15 hours.
  • Compound 3 is reduced using a hydride reducing agent in a suitable solvent.
  • Examples of the hydrogenation-reducing agent include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diborane, and the like.
  • the molar amount is from 10 to 10 times the molar amount.
  • Examples of the solvent include ethers such as tetrahydrofuran, getyl ether and diisopropyl ether (these may be used as a mixture).
  • the reaction is usually completed in about 0 to 7 (TC, about 10 minutes to 15 hours).
  • lithium aluminum hydride When lithium aluminum hydride is used as the reducing agent, use of an anhydrous solvent is preferred.
  • Compound 4 can also be manufactured by the method of Yamamoto et al. Described in Tet rahedron Letters, 24 (43), p4711-7112, (1983). The method can be performed more efficiently than the two-stage reaction.
  • compound 2 is dissolved in a suitable organic solvent, preferably toluene or methylene chloride, and diisobutylaluminum hydride (DIBAH) is added thereto, whereby a rearrangement reaction occurs one-dimensionally, whereby compound 4 can be obtained. it can.
  • DIBAH diisobutylaluminum hydride
  • the compound 4 (amine compound) and a suitable carboxylic acid are benzoylated by a usual amide bond formation reaction.
  • Known conditions for amide bond formation reaction can be appropriately applied to the amide bond formation reaction.
  • the carboxylic acid is reacted with an alkyl halocarbonate to form a mixed acid anhydride, which is then reacted with an amine (compound 4).
  • the carboxylic acid is converted into an active ester such as ⁇ -ditrophenyl ester, N-hydroxysuccinic acid imidoester, 1-hydroxybenbutriabule ester, etc., and reacted with amine (compound 4).
  • active ester such as ⁇ -ditrophenyl ester, N-hydroxysuccinic acid imidoester, 1-hydroxybenbutriabule ester, etc.
  • An amine (compound 4) is condensed with a carboxylic acid in the presence of an activator such as dicyclohexylcarpoimide or carbodimidazole.
  • the lower alcohol ester of the carboxylic acid is reacted with the amine (compound 4) at high temperature and high pressure.
  • the mixed acid anhydride used in the mixed acid anhydride method is obtained by a known method, and the compound 5 is obtained by reacting the mixed acid anhydride with an amine (compound 4) without isolation, for example. ⁇ Basic and Experimental Peptide Synthesis ”, written by Nobuo Izumiya, published by Maruzen Co., Ltd.).
  • the mixed acid anhydride method is performed in one step in a solvent.
  • the solvent to be used any of the solvents used in the ordinary mixed acid anhydride method can be used.
  • halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and quinylene
  • ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxetane
  • Esters such as methyl acetate and ethyl acetate, non-protonic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitril, hexamethyl phosphoric acid triamide, or mixed solvents thereof Is mentioned.
  • the mixed acid anhydride method is usually performed in the presence of a base compound.
  • a base compound examples include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, and 5-diazavinclo [4.3.0] nonene-5 (DBN), 1, 8-Diazavincro [5.4.0] Pendene-1 7 (DBU) 1,4 Diazabicyclo [2.2.2]
  • Organic bases such as octane (DABCO), inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate
  • DABCO octane
  • alkyl halocarbonate used in the mixed acid anhydride include methyl chloroformate, ethyl ethyl chloroformate, isobutyl chloroformate and the like.
  • the use ratio of the carboxylic acid and the amine (compound 4) is usually preferably equimolar, but both the alkylhalocarbonate and the carboxylic acid are used in an amount of about 1 to 1.5 times the mol of the amine (compound 4). Can be used within IS enclosures.
  • the reaction is usually carried out at about 20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. .
  • the basic compound for example, known basic compounds such as a basic compound used in the mixed acid anhydride method, sodium hydroxide, lithium hydroxide, sodium hydride, and lithium hydrogen hydride are used. You.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and kynene; ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; Is exemplified.
  • aromatic hydrocarbons such as benzene, toluene, and kynene
  • ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether
  • halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride
  • the solvents exemplified in the mixed acid anhydride method can also be used.
  • the proportions of the amine (compound 4) and the carboxylic acid halide are not particularly limited and can be determined as appropriate.
  • the carboxylic acid halide is used in an amount of at least an equimolar amount of the amide (compound 4), preferably about an equimolar to 5 times the molar amount.
  • the reaction is carried out at about 120 to 180 ° C., preferably at about 0 to 150 ° C., and is generally completed in about 5 minutes to 30 hours.
  • Examples of the condensing agent for a phosphorus compound used in the condensation reaction between a carboxylic acid and an amine include, for example, triphenylphosphine, diphenylphosphinylchloride, getylchlorophosphate, and cyanophosphoric acid. Examples include getyl, diphenylphosphoric azide, N, N-bis (2-oxo-13-oxazolidinyl) phosphinic chloride.
  • the basic compound the same basic compound as used in the method for reacting a carboxylic acid halide can be used.
  • the same solvent as used in the method for reacting the carboxylic acid halide with the amine (compound 4) can be used.
  • the reaction is carried out at about 150 ° C., preferably about 0 to 100 e C, and the reaction is completed in 5 minutes to 30 hours at a time.
  • the amount of the condensing agent and the amount of the carboxylic acid to be used are both equimolar or more, preferably about equimolar to about 2 times the molar amount of the amine (compound 4).
  • the reduction of the nitro group of compound 5 to the amino group can be performed, for example, by (i) a method using a catalytic reduction catalyst in a suitable solvent, or (ii) a metal or metal salt and an acid, or It is carried out by a method using a mixture of a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt or the like as a reducing agent.
  • Examples of the solvent used in the method (i) include alcohols such as water, acetic acid, methanol, ethanol, and 2-propanol; hydrocarbons such as hexane and cyclohexane; dioxane; tetrahydrofuran; Ethers such as getyl ether diethylene glycol and dimethyl ether; esters such as methyl acetate and ethyl acetate; non-protonic polar solvents such as N, N-dimethylformamide; and mixed solvents thereof.
  • alcohols such as water, acetic acid, methanol, ethanol, and 2-propanol
  • hydrocarbons such as hexane and cyclohexane
  • dioxane dioxane
  • tetrahydrofuran Ethers such as getyl ether diethylene glycol and dimethyl ether
  • esters such as methyl acetate and ethyl acetate
  • the reduction catalyst to be used examples include palladium, palladium black, palladium carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like.
  • the catalyst is preferably used in an amount of about 0.02 to 1 mol per mol of Compound 5.
  • the reaction temperature is usually about 120 to 150, preferably about 0 to 100, and the hydrogen E is usually 1 to 10 atm.
  • the reaction is generally completed in about 30 minutes to 10 hours.
  • An acid such as hydrochloric acid may be added to the reaction.
  • the reducing agent in the reaction (ii) is iron, zinc, tin or stannous chloride and hydrochloric acid,
  • Examples include a mixture with ammonium salt, or a combination of chlorazine and hydrazine.
  • the inert solvent used includes, for example, water, acetic acid, methanol, ethanol, dioxane and the like, and is preferably methanol.
  • the conditions of the reduction reaction are appropriately selected depending on the reducing agent used.For example, when a mixture of iron and salt S $ is used as the reducing agent, the reaction is performed at about 0 to 10 O'C for 30 minutes to 1 minute. It is preferable to perform the reaction at about 0 hours.
  • the reducing agent is used in an amount of at least equimolar to compound 5, preferably about equimolar to 20-fold molar.
  • This reaction is a benzoylation reaction of compound 6.
  • the benzoylation reaction can be carried out in the same manner as in the reaction from compound 4 to compound 5.
  • Compound 8 can be obtained by deprotecting the hydroxyl-protecting group (OR 16 ) on the benzene ring of compound 7.
  • 'If 6 is a lower alkyl group
  • a reagent to be used for deprotection for example, boron tribromide, boron trichloride, bis one Ibburopiruchio bromide boron (: (' R as a protecting group P r S ) 2 BB r] (Tetorahi Delon Letters, ⁇ _, 3, (1 9 84) compounds), iodine Kaboku Rimechirushiran (T MS- I) or aluminum chloride and the like by EJ Corey, etc. that are described.
  • the solvent examples include methylene chloride and cetonitrile.
  • the reaction is carried out at 2 to 5 equivalents, preferably 3.5 equivalents, by reacting the solvent at room temperature or at room temperature using methylene chloride or the like. I can.
  • aluminum chloride sodium iodide or the like may be added.
  • a method usually used for removing the protecting group may be used.
  • solvent used examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, chloroform, halogenated compounds such as dichloromethane, dichloroethane and carbon tetrachloride. Hydrocarbons, alcohols such as methanol, ethanol, n-propanol, and 2-propanol, acetone, acetonitril, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphate triamide or these Can be exemplified.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether
  • chloroform halogenated compounds
  • halogenated compounds such as dichloromethane, dichloroethan
  • Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium hydride and the like.
  • Organic bases such as DBU and DABCO can be mentioned.
  • the ratio of the compound 8 and the halogen-substituted alkane derivative to be used is not particularly limited and may be appropriately selected.
  • the compound [H a1-(CH 2 ) n- Z] (wherein each symbol in the formula is as defined above) Equimolar or more, preferably equimolar to 10-fold molar amount, relative to compound 8.
  • the alkylation reaction is carried out under O'C to reflux, preferably under reflux, and the reaction is completed in about 2 to 5 hours.
  • Z is Z ' ⁇ ' is — NR n R 12 ,
  • I represents 0-X (when Y is an oxygen atom), _S—X (when Y is a sulfur atom), and other symbols are as defined above.
  • ⁇ The compound 9 ′ where Z is a halogen atom is used, and HNR H R l2 , (CH 2 ),
  • the reaction can be carried out by subjecting H ⁇ —X, HS—X or an alkali metal salt thereof to a nucleophilic substitution reaction.
  • reaction solvent examples include N, N-dimethylformamide, dioxane, tetrahydrofuran, dimethylsulfokind, acetone, and the like, and preferably N, N-dimethylformamide.
  • the reaction is usually performed at room temperature or under reflux with heating, and the reaction is completed in about 30 minutes to 24 hours.
  • a base for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium hydride and the like
  • metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium hydride and the like
  • Metal hydrides, metal amides such as sodium amide
  • gold alcohols such as sodium methylate, sodium ethylate, pyridine, N-ethyldiisopropylamine, dimethylamino pyridine, triethylamine
  • Organic bases such as DBN, DBU and DABCO can be mentioned.
  • the iodide force Agrobacterium In this reaction may be added iodide Natoriumu like ⁇ Manufacturing method (3)
  • R 17 represents a lower alkyl group, and other symbols are as defined above.
  • Y is -C 00-, X is a hydrogen atom or Z is
  • W5 can be produced by the following method S using compound 11 in which Y is —C 00 — and X is a hydrogen atom.
  • the alkyl group can be eliminated by hydrolyzing compound 11 o
  • the hydrolysis of compound 11 can be carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound.
  • the solvent examples include water, low-end alcohols such as methanol, ethanol, n-propanol and 2-propanol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether.
  • Octanoic acids such as acetic acid, formic acid and the like, or a mixed solution thereof and the like can be used.
  • the acid for example, mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acid, and aromatic sulfonic acid can be used.
  • Examples of the basic compound include metal carbonates such as sodium carbonate and potassium carbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide.
  • the hydrolysis proceeds favorably at room temperature to about 200 ° C., preferably at room temperature to about 150 ° C.
  • the reaction is generally completed in about 10 minutes to 25 hours.
  • Compound 13 is obtained by a condensation reaction of the amine derivative represented by the following formula.
  • Examples of the compounding agent include dicyclohexylcarbodiimide (DCC), carbonylylimidabyl, N, N-bis (2-oxo-3--3-oxazolidinyl) phosphinic chloride (B0P— Examples include C 1), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HC 1), and ethyl ethyl carbonate.
  • DCC dicyclohexylcarbodiimide
  • B0P 2-bis (2-oxo-3--3-oxazolidinyl) phosphinic chloride
  • Examples include C 1), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HC 1), and ethyl ethyl carbonate.
  • the reaction is performed in the presence or absence of a basic compound.
  • Examples of the basic compound include known basic compounds used in the mixed acid anhydride method described above, such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium hydroxide, triethylamine, and the like. Compounds can be used.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; Is exemplified.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether
  • halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride
  • the solvents exemplified in the mixed acid anhydride method can also be used.
  • the proportions of the amine derivative and compound 12 used are not particularly limited, and can be determined as appropriate.
  • the amount of the amide derivative used is at least an equimolar amount of the compound 12, preferably about an equimolar to about 5 times the molar amount.
  • the amount of the condensing agent to be used is at least equimolar to the amide derivative, and preferably about equimolar to about twice the molar amount.
  • the reaction is carried out at about ⁇ 20 to 15 O′C, preferably about 0 to 10O′C, and is generally completed in about 5 minutes to 30 hours.
  • compound 12 is converted into a carboxylic acid halide with a reagent such as oxalyl chloride or thionyl chloride, the amine derivative is dissolved in an organic solvent such as chloroform or acetonitrile.
  • Compound 13 can also be obtained by performing the reaction in a medium in the presence of a base such as triethylamine for about 30 minutes to about 24 hours at 0 ° C. or room temperature.
  • R ′ and R ′ ′ are the same or different and represent a lower alkyl group such as a methyl group or an ethyl group or an aralkyl group such as a benzyl group, and other symbols are as defined above.
  • Compound 4 is represented by A 1 Is a sulfur atom, a method known in the literature [Kunick. Arch.
  • the conversion of compound 14 to compound 16 is carried out by reacting the acyl compound (compound 15) in an appropriate solvent in the presence or absence of a basic compound.
  • a basic compound include organic bases such as triethylamine, trimethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, DBN, DBU, and DBACO, potassium carbonate, sodium carbonate, calcium carbonate, and carbonate.
  • organic bases such as triethylamine, trimethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, DBN, DBU, and DBACO
  • potassium carbonate sodium carbonate, calcium carbonate, and carbonate.
  • Inorganic bases such as hydrogen hydrogen and sodium hydrogen carbonate;
  • the solvent examples include halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, getyl ether, dibutyl pill ether, tetrahydrofuran, and dimethoxyethane.
  • halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • getyl ether dibutyl pill ether
  • tetrahydrofuran tetrahydrofuran
  • dimethoxyethane dimethoxyethane
  • Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoric acid triamide, or a mixed solution thereof.
  • Compound 15 is preferably used in an equimolar to 10-fold molar amount with respect to compound 14.
  • the reaction is preferably carried out under ice-cooling to 20 ° C., and is completed in about 1 to 50 hours.
  • Compound 16 is converted to compound 17 by heating 2 to 3 equivalents of metal hydride or base to compound 16 in an organic solvent such as toluene, benzene, N, N-dimethylformamide, etc. The mixture is stirred to obtain a Dieckmann condensate, which is then heated under reflux in a water-containing organic solvent in the presence of sodium chloride, potassium chloride or the like to carry out decarboxylation to obtain compound 17.
  • organic solvent such as toluene, benzene, N, N-dimethylformamide, etc.
  • metal hydride examples include sodium hydride, potassium hydride and the like.
  • Examples of the base include potassium tert-butoxide, lithium disopropylamide and the like.
  • organic solvent examples include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, tetrahydrofuran, dioxane and the like.
  • the heating and stirring are carried out at 60 to 100 ° C., preferably at 70 ° C., and the reaction is completed in about 30 minutes to 48 hours.
  • Examples of the hydrogenation reducing agent include lithium aluminum hydride, diborane and the like.
  • the amount of the reducing agent to be used is 1 mol or more, preferably 1 mol to 15 mol, per 1 mol of compound 17.
  • the reaction is usually performed in a suitable solvent.
  • suitable solvent include ethers such as tetrahydrofuran, getyl ether, diisopropyl ether, ethylene glycol dimethyl ether, and diglyme, and mixtures thereof.
  • the reaction is usually carried out at 160-150'C, preferably at 130-100. C, about 10 minutes to 15 hours.
  • compound 18 (a compound in which m is 0 and Z is —C) NH 2 ) is obtained by reacting compound 8 with chlorosulfonyl isocyanate, generally in an inert solvent. .
  • inert solvent examples include, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether; chloroform; dichloromethane; Halogenated hydrocarbons such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, etc., esters such as methyl acetate, ethyl acetate, acetic acid, acetone, acetonitrile, pyridine , Dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric acid triamide or a mixed solution thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether
  • chloroform dichloromethane
  • the ratio of compound 8 and chlorosulfonyl isocyanate to be used is not particularly limited and may be appropriately selected, but chlorosulfonyl isocyanate is at least equimolar to compound 8, preferably at equimolar to 10-fold molar. Use the amount.
  • the desired compound 18 is obtained by reacting water under heating ( production method (6)).
  • the compound 1 9 (Z compound is a flow evening Louis Mi de), methanol, heat in an alcoholic solvent such as ethanol It can also be obtained by reacting drazine.
  • the hydrazine may be used in an amount of 1 to 10 equivalents to the compound 19.
  • the reaction is carried out under heating, preferably under reflux, and the reaction is completed in about 1 to 10 hours.
  • the following steps may be performed using a compound in which Z is an amino group.
  • the use ratio of Hal * CO (CH 2 ) and Ha 1 is preferably 1 to 2 equivalents to compound 20.
  • the reaction is carried out under heating to reflux, preferably at 0 ° C. to heating under reflux, and the reaction is completed in about 30 minutes to 24 hours.
  • the inert solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, acetone, tetrahydrofuran, N, N-dimethylformamide and the like. .
  • the base examples include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, such as triethylamine, and N, N-diisopropylethylamine.
  • Organic bases such as pyridine, 4-dimethylaminopyridine and the like can be used.
  • the compound 22 is obtained by reacting in an inert solvent in the presence or absence of a base.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples include dichloromethane, chloroform, acetone, tetrahydrofuran, N, N-dimethylformamide and the like.
  • the base examples include inorganic bases such as sodium hydride, potassium hydride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, such as triethylamine, N, N-diamine.
  • Organic bases such as isoprovirethylamine, pyridine and 4-dimethylaminoviridine can be used.
  • This step may be performed when a compound in which R 15 is a lower alkyl group is desired.
  • Compound 22 is used in a solvent such as tetrahydrofuran, N, N-dimethylformamide, or cetone, and a base such as sodium hydride, potassium hydride, sodium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc.
  • Compound 23 is obtained by reacting an alkylating agent such as an alkyl halide or dialkyl sulfate having a desired alkyl residue in the presence of
  • R 19 and R 2 ° may be the same or different and each represents an optionally substituted alkyl group or a cycloalkyl group, or represents a ring together with a nitrogen atom to which R 19 and R 2 bind. And the ring may further contain a nitrogen atom which may be substituted and an oxygen filant). If desired, the compound 17 is obtained by the following steps using compound 17 be able to.
  • R 21 represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group, and other symbols are as defined above
  • Compound 17 is converted to water, lower alcohols such as methanol, ethanol, isopropanol, tert-butanol, ethers such as tetrahydrofuran, getyl ether, diisopropyl ether, ethylene glycol, dimethyl ether, diglyme, or a mixed solvent thereof.
  • hydrogenation Compound 24 is obtained by performing a reduction reaction using a reducing agent such as sodium trimethoxyborohydride or lithium borohydride. The reaction is usually completed at about 160 to 150 ° C., preferably about 130 to 100 ° C., in about 10 minutes to 15 hours.
  • halogenate compound 24 with a halogenating agent such as hydrogen chloride, thionyl chloride, or oxalyl chloride in a solvent such as dichloromethane, chloroform, tetrahydrofuran, or methyl ether; triethylamine; Sulfonylating agents such as methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, anhydrous trifluoromethanesulfonyl, etc. in the presence of bases such as min, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.
  • Compound 25 is obtained by reacting
  • Compound 25 was converted to chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, getyl ether, diisopropyl ether, tetrahydrofuran, furan, dimethoxetane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, In a solvent such as xamethylphosphoric acid triamide, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • Mino compounds, preferably no R s
  • the solvent examples include alcohols such as methanol, ethanol, and 2-propanol; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as carbon form, dichloromethane, dichloroethane, and carbon tetrachloride; Non-protonic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, and mixtures thereof can be used.
  • alcohols such as methanol, ethanol, and 2-propanol
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • halogenated hydrocarbons such as carbon form, dichloromethane, dichloroethane, and carbon tetrachloride
  • Non-protonic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, and mixtures
  • dehydrating agent examples include desiccants used for drying ordinary solvents such as molecular sieves, mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, and organic acids such as p-toluenesulfonic acid. Mixtures and the like can be used.
  • the reaction is usually carried out at room temperature to 250'C, preferably at about 50 to 200'C, and is generally completed in about 1 to 48 hours.
  • Compound 26 is subjected to a reduction reaction using a reducing agent such as lithium aluminum hydride, diborane, or diisobutyl aluminum hydride in a solvent such as getyl ether, tetrahydrofuran, benzene, or toluene to obtain compound 27. Is obtained.
  • a reducing agent such as lithium aluminum hydride, diborane, or diisobutyl aluminum hydride in a solvent such as getyl ether, tetrahydrofuran, benzene, or toluene
  • each symbol in the formula is as defined above, is obtained.
  • the target compound is separated from the anti-mixture and produced by a means known in the art, such as solvent extraction, column chromatography, recrystallization, etc., as appropriate. It can be done by doing. In addition, the target compound can be produced even if it proceeds to the next step without isolation and purification of the target compound.
  • a protecting group When synthesizing the final target compound represented by the general formula (I), a protecting group may be introduced at an appropriate stage as necessary, and the protecting group may be removed at an appropriate stage.
  • the compound When converting the acid addition salt of the compound represented by the general formula (I), the compound is converted into sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydroxide, potassium hydroxide or water. Dissolve or suspend in an aqueous solution of a base such as lithium oxide and extract with ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof.
  • a base such as lithium oxide and extract with ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof.
  • the residue is then treated with water, methanol, ethanol, n-propanol, 2-propanol, getylether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane or chloroform, or
  • the above-mentioned solvent in which the desired acid is dissolved in these mixed solvents and the like is added, and the precipitated crystals are collected by filtration or reduced E and concentrated to obtain the desired salt represented by the general formula (I).
  • An acid addition salt of the represented compound is obtained.
  • various isomers may exist.
  • cis-form and trans-form as geometric isomers can exist.
  • an asymmetric carbon atom is present, an enantiomer as a stereoisomer based on these, Diastereomers can be r-present.
  • tautomers may exist. Therefore, the scope of the present invention includes all these isomers and mixtures thereof.
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof antagonize vasobretsin. It can be expected to have various effects such as an inhibitory effect and an oxytocin antagonistic effect.
  • hypertension, heart failure, renal failure, edema, ascites, arginine vasobretsin hypersecretion syndrome, cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, pulmonary edema, Meniere's syndrome, okintocin It is considered to be useful for treatment and prevention or prevention of diseases and the like.
  • it is expected to be useful as a therapeutic agent for cerebral edema, congestive heart failure, arginine vasopressin hypersecretion syndrome, hypertension, renal failure, pulmonary edema, Meniere's syndrome, and the like.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used in the form of a general pharmaceutical preparation.
  • the preparations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants.
  • diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants.
  • Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, Injection (solution, suspension) and the like.
  • various carriers known in the art can be used as carriers.
  • carriers include excipients such as milk, white, sodium chloride, grape, urea, calcium carbonate, kaolin, crystalline cellulose, gay acid, water, ethanol, propanol, simple syrup, grape, Binders such as starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene ethylene sorbitan fatty acid ester , Sodium lauryl sulfate, stearic acid monoglyceride, dampening agents, demulsifying agents such as milk, lactic acid, encouragement, stearin, cocoa butter, degrading agents such as hydrogenated oil, quaternary ammonium base, lauryl sulfate Promotion of absorption of sodium, etc.
  • excipients such as milk, white, sodium chloride, grape, ure
  • Moisturizers such as glycerin and starch; adsorbents such as starch, lactose, lactose, bentonite, and colloidal gay acid; lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol, etc.
  • the preparation can be a preparation coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated, enteric-coated, a film-coated tablet or a double tablet or a multilayer tablet.
  • various carriers known in the art can be used as the carrier.
  • carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc, binders such as gum arabic, tragacanth, gelatin, ethanol, and disintegrants such as laminaran and agar. Etc. can be used
  • various carriers known in the art can be used as the carrier.
  • examples thereof include polyethylene glycol, cocoa butter, higher alcohols, highly alcoholic esters, gelatin, and semi-synthetic glycerides.
  • Capsules are usually prepared by mixing the active ingredient compound with the various carriers described above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.
  • liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood and blood, and are commonly used as diluents in this field when shaping into these forms.
  • Everything can be used.
  • ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, boroxylated isostearyl alcohol, and polyoxetylene rubine fatty acid esters can be used.
  • a sufficient amount of salt, fluid, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and ordinary dissolution aids, buffers, soothing agents, etc. may be used. It may be added.
  • a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent or the like and other pharmaceuticals may be contained in the pharmaceutical preparation, if necessary.
  • the amount of the salt is not particularly limited and may be appropriately selected, but is usually 1 to 70 times in the pharmaceutical composition. %, Preferably about 5 to 50% by weight.
  • vasobretsin antagonist of the present invention there is no particular limitation on the method of administration of the vasobretsin antagonist of the present invention, and it is administered according to the formulation, age, sex and other conditions of the patient, degree of disease, and the like.
  • tablets, pills, solutions, suspensions, emulsions, contraceptives and capsules are orally administered.
  • they are administered intravenously, alone or in combination with ordinary fluid replacements such as voodoo and amino acids, and if necessary, intramuscularly, intradermally, subcutaneously, or intraperitoneally.
  • Suppositories are administered rectally.
  • the dosage is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, etc.
  • the amount of the active ingredient compound is about 0.6 to 5 Omg per kg of body weight per day. Is good. It is preferable that the active ingredient compound is contained in the dosage unit form in the range of about 10 to 100 mg.
  • step c 4- (3-Methoxy-412-trobenzyl) -1-5,6,7,8-tetrahydro-14-thieno [3,2-b] azepine obtained in step c (430 mg) was dissolved in ethanol (30 ml), 10% palladium on carbon (43 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere of ffl for 10 hours.
  • the reaction solution was passed through celite, the residue on the celite was washed with ethanol, the filtrate and the washing were combined, and the solvent was distilled off under reduced pressure.
  • Example 2 N- [2-hydroxy-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-14-yl) carbonyl] carbonyl obtained in Example 2
  • the title compound (921 mg) was prepared in the same manner as in Example 3 by using 1- [1'-biphenyl] -12-carboxamide (1.0 g) and 4-ethylbutyrate ethyl ester (1.2 g). Obtained.
  • Example 40 Etyl obtained in 40 [2 — [[[[1,1'-biphenyl] —2—carbonyl] amino] -1 5 — [(5,6,7,8-tetrahydrodraw The title compound (6H mg) was obtained in the same manner as in Example 6 using 4H-cheno [3,2-b] azepin-14-yl) carbonyl] phenoxy] petiteate (820 mg). .
  • Example 41 4- [2 — [[[1,1, '-biphenyl] -12-carbonyl] amino] -1-5 — [(5,6,7,8-tetrahydro-4H— Using thieno [3,2-b] azepine-14-yl) carbonyl] phenoxy] butyric acid (180 mg) and N-methylbiperazine (43 ⁇ 1) in the same manner as in Example 7, the title compound (131 mg ) was obtained.
  • Example 41 4- [2-[[[Shibibiphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4 4-thieno [3, 2-b] azepine-41-yl) carbonyl] phenoxy] severe acid (180 mg) and N-methyl homopyrazine (481) were used to give the title compound (171 mg) in the same manner as in Example 7. Obtained.
  • Example 4 4- [2-[[[1,1'-biphenyl] -2-carbonyl] Rmino] obtained in Example 1—5 — [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenoxy] butyric acid (180 mg) and 4-dimethylaminopiperidine dihydrochloride (89 mg) were prepared in the same manner as in Example 7 to give the title compound ( 98 mg).
  • Example 2 N- [2-Hydroxy-41-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-1-4-yl) carbonyl] carbonyl obtained in Example 2
  • the title compound (201 mg) was prepared in the same manner as in Example 3 using [1,2] -biphenyl-1-2-carboxamide (180 mg) and 4-chloromethylpyridine hydrochloride (158 mg). ).
  • Example 12 N— [2- (3-Chlorobromoxoxy) 1-4 [(5,6,7,8-tetrahydrido) 4 H—thieno [3,2-b] azepine 1-41 obtained in Example 12
  • the title compound (260 mg) was prepared in the same manner as in Example 15 using luponyl] phenyl] -1- [bi-biphenyl] -12-carboxamide (280 mg) and N-methylbiperazine (0.09 ml). ).

Abstract

La présente invention concerne des dérivés hétérocycliques fusionnés pentagonaux d'azépine, représentés par la formule générale (I), ou des sels de ces dérivés acceptables en pharmacie. Dans ladite formule, R?1, R2, R3, R4 et R6¿ représentent chacun hydrogène ou alkyle inférieur; R5 représente hydrogène, alkyle inférieur ou phényle; A1 représente oxygène, soufre ou -NR7-; A2 représente -CR?8R9- (R8 ou R9¿ représente hydrogène, l'autre représentant hydrogène, hydroxyle ou alkyle inférieur); A3 représente oxygène, soufre, -NR11- ou une liaison simple, et Z représente halogéno, un groupe hétérocyclique ou analogue. Ces composés sont excellents comme agents prophylactiques ou thérapeutiques pour les maladies liées à la vasopressine, par exemple l'insuffisance cardiaque congestive, l'÷dème, en particulier l'÷dème cérébral, le syndrome de sécrétion inappropriée d'ADH, l'hypertension, etc., et comme diurétiques.
PCT/JP1996/003186 1995-11-09 1996-11-05 Derives heterocycliques fusionnes pentagonaux d'azepine et leur emploi pharmaceutique WO1997017349A1 (fr)

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US6828460B2 (en) 1999-03-22 2004-12-07 Pfizer Inc. Resorcinol derivatives

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JPH04154765A (ja) * 1989-10-20 1992-05-27 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物
JPH04321669A (ja) * 1991-04-19 1992-11-11 Otsuka Pharmaceut Co Ltd バソプレシン拮抗剤
JPH08143565A (ja) * 1994-11-16 1996-06-04 Fujisawa Pharmaceut Co Ltd ベンズアミド化合物
US5532235A (en) * 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
WO1996022294A1 (fr) * 1995-01-17 1996-07-25 American Cyanamid Company Derives de benzazepine bicyclique antagoniste de la vasopressine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04154765A (ja) * 1989-10-20 1992-05-27 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物
JPH04321669A (ja) * 1991-04-19 1992-11-11 Otsuka Pharmaceut Co Ltd バソプレシン拮抗剤
JPH08143565A (ja) * 1994-11-16 1996-06-04 Fujisawa Pharmaceut Co Ltd ベンズアミド化合物
US5532235A (en) * 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
WO1996022294A1 (fr) * 1995-01-17 1996-07-25 American Cyanamid Company Derives de benzazepine bicyclique antagoniste de la vasopressine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6828460B2 (en) 1999-03-22 2004-12-07 Pfizer Inc. Resorcinol derivatives
US6933319B2 (en) 1999-03-22 2005-08-23 Pfizer Inc. Resorcinol derivatives

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