WO1994020473A1 - Compose avec action antagoniste de la vasopressine - Google Patents

Compose avec action antagoniste de la vasopressine Download PDF

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Publication number
WO1994020473A1
WO1994020473A1 PCT/JP1994/000391 JP9400391W WO9420473A1 WO 1994020473 A1 WO1994020473 A1 WO 1994020473A1 JP 9400391 W JP9400391 W JP 9400391W WO 9420473 A1 WO9420473 A1 WO 9420473A1
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WIPO (PCT)
Prior art keywords
group
formula
tetrahydro
benzodiazepine
substituent
Prior art date
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PCT/JP1994/000391
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English (en)
Japanese (ja)
Inventor
Akira Matsuhisa
Akihiro Tanaka
Ken-Ichiro Sakamoto
Yuzo Matsumoto
Kazumi Kikuchi
Nobuaki Taniguchi
Takeyuki Yatsu
Isao Yanagisawa
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU62199/94A priority Critical patent/AU6219994A/en
Publication of WO1994020473A1 publication Critical patent/WO1994020473A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Arginine vasopressin is a peptide consisting of nine amino acids that are biosynthesized and secreted by the hypothalamus-pituitary system.
  • peptide-type compounds and non-peptide-type compounds have been developed as arginine vasopressin antagonists.
  • a peptide type compound for example, a compound described in JP-A-2-32098 is known.
  • non-peptide vasopressin antagonists related to the dihydrobenzazepine derivative of the present invention European Patent Application Publication No. 0 514 667, which discloses a compound represented by the following general formula, A 2,3,4,5-tetrahydro 1H-1-benzazepine derivative disclosed in Japanese Unexamined Patent Publication No. Hei 5-1332466 is known.
  • the present inventors have conducted intensive studies on compounds having an arginine vasopressin antagonistic activity.
  • the present invention has been completed by finding that a benzodiazepine derivative and a tetrahydrobenzazepine derivative represented by the general formula (I-C) have an excellent arginine vasopressin antagonistic action.
  • a pharmaceutically acceptable salt thereof selected from the group consisting of tetrahydrobenzazepine derivatives represented by the formula:
  • R 1 is a carboxy group or a group represented by the formula:
  • R 6 and R 7 are the same or different, and may be a hydrogen atom or a lower alkyl group which may be substituted with a pyridyl group.
  • a 3- to 10-membered nitrogen-containing saturated heterocyclic group which may contain two or more nitrogen atoms and may contain oxygen atoms.
  • R 8 hydrogen atom or lower alkyl group.
  • R 2 An optionally substituted phenyl group.
  • R 3 carboxy group, lower alkoxycarbonyl group, formula
  • Lower alkylamino group or 5- or 6-membered nitrogen-containing aromatic heterocycle R 9 and R 1Q the same or different, a hydrogen atom, or a lower alkyl group which may have an amino group, a mono- or di-lower alkylamino group or a pyridyl group as a substituent.
  • -NB a 3- to 10-membered nitrogen-containing saturated heterocyclic group which may contain two or more nitrogen atoms and may contain oxygen atoms.
  • R 11 hydrogen atom, lower alkyl group, formula 1 N (! ⁇ And 1 ;
  • 0 has the meaning described above. Or a group represented by —NB) or a pyridyl group.
  • Fuunyl group which may have a substituent.
  • a 5- or 6-membered nitrogen-containing heterocyclic group which may have an R 5 substituent; ].
  • the compound of the general formula (I-B) or a pharmaceutically acceptable salt thereof is a carboxylic acid (particularly carboxyamide) diamine group or a L-group having a ring at the 5-position is a heterocyclic ring. It has a chemical structural feature in that it has a 2,3,4,5-tetrahydro 1H-1,5-benzodiazepine structure linked via a lower alkylene chain, and arginine With the features of the pharmacology in that receptor antagonism and V 2 receptor antagonism is excellent in both.
  • the present invention relates to a compound selected from the group consisting of compounds represented by the general formulas (I-A), (I-B) and (I-C), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier is also included.
  • a methyl group, Echiru group, an isopropyl groups, C and butyl groups, -C 4 alkyl group, especially methyl group, Echiru group, d -C 3 alkyl groups such as propyl are preferred.
  • the “lower alkylene group” represented by L 1 and L 2 includes a methylene group, an ethylene group, a methylethylene group, a trimethylene group, a 1-methylethylene group, a 2-methylethylene group, a tetramethylene group, a 1-methyltrimethylene group, Methyltrimethylene, 3-methyltrimethylene, 1-ethylethylene, 2-ethylethylene, 1,2-dimethylethylene, propylmethylene, pentamethylene, 1-methyltetramethylene, 2-methyl Tetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1-ethyltrimethylene group, 2-ethyltrimethylene group, 3-ethyltrimethylene group, 1,1-dimethyltrimethylene group, 2,2 —Dimethyltrimethylene group, 3,3-dimethyltrimethylene group, hexamethylene group, 1 —methyl Pentamethylene group, 2-methylpentamethylene group, 3-methylpentamethylene group, 4-methyl
  • the “mono- or di-lower alkylamino group” means a group in which one or two hydrogen atoms of an amino group are substituted with the above “lower alkyl group”. Specifically, methylamino, ethylamino, propyl Monoalkylamino, dimethylamino, dimethylamino, dipropylamino, diisopropyl, monoalkylamino, substituted with linear or branched lower alkyl such as lumino, isopropylamino, butylamino, pentylamino, isopentylamino, etc.
  • Examples of the “lower alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group and a tert-butoxycarbonyl group.
  • (C! Cealkoxy) carbonyl groups such as pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, and hexyloxycarbonyl group.
  • a (C, -C 4 alkoxy) carbonyl group particularly a (d -C 2 alkoxy) carbonyl group, is preferable.
  • nodogen atom for example, F, C 1, Br
  • hydroxyl group hydroxyl group, mercapto group, lower alkoxy group (Eg, OCH 3 , OC 2 H 5 ), lower alkylthio group (eg, S CH 3 , SC 2 H 5 ), cycloalkyl lower alcohol, cycloalkyl
  • OCH2 CH 2 P h Ararukiruchio group (e.g. S CH 2 P h, S CH 2 CH 2 P h), Ariruokishi group (e.g. OP h), ⁇ Li one thio group (e.g., SP h), Ariruokishi lower alkoxy ( For example, OCH 2 OP h), aryloxy lower alkylthio group (eg, S CH 2 OPh), aryl thio lower alkoxy group (eg, OCH 2 SP h), aryl thio lower alkyl thio group (eg, S CH 2 SP h)), oxo Group (oxo group, thioxo group), carboxy group [carboxy group, lower alkoxycarbonyl group (eg, COOCHa, COOC 2 H 5 ), and acyl group (eg, COCH 3 , COC 2 H 5 , S 0 2 CH 3 , S0 2 C 2 H 5 )]
  • -A) or NB indicates that the ⁇ 3- to 10-membered nitrogen-containing saturated heterocyclic group which may contain two or more nitrogen atoms and which may contain an oxygen atom '' includes an aziridinyl group and an azetidinyl group.
  • Kisa A nitrogen-containing saturated heterocyclic group containing a nitrogen atom and an oxygen atom such as a droxazepinyl group; among others, a monocyclic 5- to 7-membered nitrogen-containing saturated heterocyclic group containing 1 or 2 nitrogen atoms, Bicyclic nitrogen-containing saturated heterocyclic group containing 2 or 5 to 6-membered nitrogen-containing heterocyclic group having 1 nitrogen atom and 1 oxygen atom, especially pyrrolidino group, piperidino group, 4-piperidinopiperidino group, piperazino group , A morpholino group and a hexahydrodiazepinyl group are preferred.
  • Each of these groups further has the aforementioned “substituent” at an arbitrary position. May have one or more substituents as specific examples of the substituents of the optionally substituted fuunyl group.
  • Examples of the "5- or 6-membered nitrogen-containing aromatic heterocyclic group" for R 3 include a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a virazinyl group, and a triazinyl group.
  • An aromatic 5- to 6-membered nitrogen-containing heterocyclic group having 1 to 4 nitrogen atoms is exemplified. Among them, a 5- or 6-membered nitrogen-containing aromatic heterocyclic group having 1 to 2 nitrogen atoms, particularly a pyridyl group.
  • An imidazolyl group is preferred.
  • each of these groups may further have a substituent
  • the substituents exemplified as specific examples of the substituent of the “fuunyl group optionally having a substituent” are 1 to You may have two or more.
  • Examples of the 5- or 6-membered nitrogen-containing heterocyclic group of the ⁇ 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent '' for R 5 include a pyrrolyl group, a pyrrolylyl group, a pyrrolidinyl group, a pyrazolyl group, Pyrazolinyl group, pyrazolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, triazolyl group, dihydrotriazolyl group, tetrahydrotriazolyl group, tetrazolyl group, dihydrotetrazolyl group, tetrahydrotetrazolyl group A saturated or unsaturated nitrogen-containing compound having 1 to 4 nitrogen atoms, such as 6-membered nitrogen-containing heterocyclic group, oxazolyl group, thiazolyl group, Xazolinyl group, thiazolinyl group,
  • a 5- or 6-membered nitrogen-containing saturated heterocyclic group or a 5- or 6-membered nitrogen-containing aromatic heterocyclic group which may contain an oxygen atom is preferable, especially a pyrrolidino group, a piperidino group , A piperazino group, a morpholino group, an imidazolyl group, a bilazolyl group, a triazolyl group, a tetrazolyl group and a pyridyl group are particularly preferred.
  • substituents which the “5- or 6-membered nitrogen-containing heterocyclic group” may have include the substituents exemplified as specific examples of the above-mentioned “phenyl which may have a substituent” And may have one or more substituents.
  • the compounds of the present invention represented by the general formulas (I-A), (I-B) and (I-C) may form salts.
  • the present invention includes pharmaceutically acceptable salts thereof.
  • examples of such salts include inorganic acids including mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propionic acid. Acids with organic acids such as, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, malic, tartaric, glutamic, aspartic, carbonic, methanesulfonic, ethanesulfonic, etc.
  • Inorganic bases such as addition salts, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, and trivalent metals such as aluminum etc.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as magnesium and calcium
  • trivalent metals such as aluminum etc.
  • Metals such as aluminum etc.
  • ethylamine, ethanolamine, and diethanolamine Salts and ammonium salts with organic bases such as triethanolamine, cyclohexylamine, lysine, orditin, imidazole, etc. And the like.
  • the compounds (I-A), (I-B) and (I-C) of the present invention each have a substituent Some compounds may contain an asymmetric carbon, and such compounds have optical isomers.
  • the compound (IA) of the present invention has geometric isomers.
  • the present invention includes an isolated form of each isomer and a mixture thereof.
  • the compound of the present invention may be isolated as a hydrate, various solvates, and polymorphic substances, and the present invention also includes these substances.
  • a phenyl group which may have the following.
  • Particularly preferred compounds include the following.
  • particularly preferred compounds (I-B) include those in which R 3 has the formula —CON, —CONB ′ /, or —NB
  • particularly excellent compounds (I-C) include compounds in which R 5 is a morpholinyl group, a pyrrolyl group or an imidazolyl group which may have a substituent, and in particular, a compound substituted with a lower alkyl group.
  • R 5 is a morpholinyl group, a pyrrolyl group or an imidazolyl group which may have a substituent, and in particular, a compound substituted with a lower alkyl group.
  • the compound which is a pyrrolyl group or an imidazolyl group is mentioned, and particularly, the following are exemplified as the most suitable compound.
  • the compound of the present invention can be synthesized by various methods. The typical production method is illustrated below.
  • the present invention provides a method for producing the compound (IA) of the present invention.
  • the reactive derivative of the compound ( ⁇ —A) include ordinary esters such as methyl ester, ethyl ester, isobutyl ester and tert-butyl ester; acid halides such as acid chloride and acid bromide; acid azide; Phenolic compounds such as ditropanol,
  • an acid chloride method a method of reacting in the presence of an active esterifying agent and a condensing agent, or a method of treating an ordinary ester with an amine can be easily and easily used as the compound of the present invention. It is advantageous.
  • the reaction varies depending on the reactive derivative used, the condensing agent, etc., but is usually halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ether, and tetrahydrofuran.
  • Ethers, etc. esters such as ethyl acetate, N, N-dimethylformamide ⁇ dimethylsulfo
  • an organic solvent inert to the reaction such as oxide
  • the reaction is carried out under cooling, under cooling to room temperature, or at room temperature to heating depending on the reactive derivative.
  • the compound (II-A) was used in excess, or N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) were used.
  • a base such as pyridine, picoline, lutidine, etc. In some cases, it is advantageous for the reaction to proceed smoothly.
  • Pyridine can also be used as a solvent.
  • This production method is a method for producing the compound (I-A-2) of the present invention having an amino group by reducing the compound of the present invention (I-A-1) having a nitro group.
  • alcohol such as methanol and ethanol
  • ethers such as ether, tetrahydrofuran and dioxane, acetic acid, N, N-dimethylformamide and the like are used in a solvent inert to the reaction, palladium carbon,
  • metal reagents such as stannic chloride and zinc chloride as esters such as ethyl acetate and propyl acetate
  • ethers such as ether, tetrahydrofuran and dioxane.
  • the reaction is carried out in an inert solvent such as acetic acid, acetic acid, acetonitrile, N, N-dimethylformamide and the like under ice-cooling or reflux conditions.
  • metals such as tin, zinc and iron and mineral acids such as hydrochloric acid are carried out in a solvent inert to the reaction such as water or alcohol under ice-cooling or reflux temperature conditions.
  • R 1 , R 2 , R E , R 7 , R 8 , L 1 and one NA are as defined above or
  • This process comprises reacting a compound of the present invention (I-III-3) with an amino compound (IV-III) and subjecting it to amiddig to obtain a compound (I-III-4). It is.
  • This production method can be carried out in substantially the same manner as the first production method, production method 41 A 1 C 0 2 R 13
  • R 2 and L 1 have the same meaning as described above, and R 13 represents an ester-forming group.
  • the free carboxylic acid compound represented by the general formula (I-A-3) can be easily produced by ester hydrolysis of the corresponding ester compound (I-A-3 ').
  • ester forming groups represented by R 13 is not particularly limited as long as it is an ester forming group which can be converted to a carboxylic acid that corresponds undergo hydrolysis, methyl group, Echiru group, butyl group, tert A monobutyl group, A benzyl group and the like are common.
  • This production method comprises the steps of reacting a carboxylic acid represented by the general formula (IE-B) or a reactive derivative thereof with an amino compound represented by the general formula ( ⁇ -B) or a derivative thereof.
  • This is a method for producing the compound (IB) of the present invention by amidating a salt with a conventional method and removing a protecting group when the compound has a protecting group.
  • dicyclohexylcarbodiimide carbonyldiimidazole, diphenylphosphotyl, rilamide, gelamide, etc.
  • a condensing agent such as tyl phosphoryl cyanide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
  • an acid chloride method a method of reacting in the presence of an active esterifying agent and a condensing agent, or a method of treating an ordinary ester with an amine can be easily and easily used as the compound of the present invention. It is advantageous.
  • the reaction varies depending on the reactive derivative used, the condensing agent, etc., but is usually halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ether, and tetrahydrofuran.
  • Ethers, etc., ethyl acetate In an organic solvent inert to the reaction of esters such as N, N-dimethylformamide and dimethylsulfoxide, etc., depending on the reactive derivative, the reaction is carried out under cooling, from cooling to room temperature, or from room temperature to heating .
  • the compound ( ⁇ -B) was used in excess, N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethyladiline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline
  • a base such as lutidine or the like may be advantageous in that the reaction proceeds smoothly.
  • Pyridine can also be used as a solvent.
  • the free carboxylic acid compound represented by the general formula (I-B-2) can be easily produced by ester hydrolysis of the corresponding ester compound (I-B-1).
  • the compound (I-B-3) of the present invention which is a carboxylic acid derivative, is reacted with an amino compound (IV-B) to amidate to obtain a compound (I-B-3).
  • This manufacturing method can be performed in substantially the same manner as the first manufacturing method. iii) Amidation reaction of ester
  • the carboxylic acid ester derivative represented by the general formula (I-B-1) and the amine derivative represented by the general formula (IV-B) are amide-treated by a conventional method.
  • esters with primary alcohols such as methyl ester, ethyl ester, propyl ester, n -butyl ester, and benzyl ester are preferable, and ethyl ester is particularly preferable.
  • the reaction does not need to use a solvent, but is usually performed in a solvent such as water, alcohols, glycols, acetonitrile, N, N-dimethylformamide at room temperature or under heating.
  • a solvent such as water, alcohols, glycols, acetonitrile, N, N-dimethylformamide at room temperature or under heating.
  • the amine is a gas or has a low boiling point, it is preferable to perform heating in a sealed tube.
  • This production method is a method for producing the present compound (IB-5) having an amino group by reducing the present compound (IB-4) having a two-mouth group.
  • the reduction treatment is carried out in an inert solvent such as alcohols such as methanol and ethanol, ethers such as ether, tetrahydrofuran and dioxane, acetic acid, N, N-dimethylformamide, and the like.
  • an inert solvent such as alcohols such as methanol and ethanol, ethers such as ether, tetrahydrofuran and dioxane, acetic acid, N, N-dimethylformamide, and the like.
  • the reaction is carried out in an inert solvent such as acetic acid, acetic acid, acetonitrile, N, N-dimethylformamide, etc.
  • tin, zinc, metals and mineral acids such as hydrochloric acid, such as iron water, alcohol chromatography in a solvent inert to the reaction, such as Le, ice-cooling to the line I-les at reflux under 0
  • a reducing agent such as sodium hydrosulfite is used in a solution of a solvent inactive to water, or a solvent such as water and an alcohol, or water and dimethylformamide, at a temperature of from ice-cooling to 10 ° C. It can also be done below.
  • R 4 HNB (the nitrogen-containing heterocyclic compound and its The substituent R 11 is a heterocyclic group represented by the following formula:
  • X is a halogen atom
  • R 15 and R 18 are the same or different, and are a hydrogen atom or a lower alkyl group
  • HNC is a 5-membered nitrogen-containing aromatic heterocyclic group.
  • a ring, R 18 is a formula
  • the compound represented by the formula (I-B-6) is produced by reacting a halide represented by the formula (V-B) with an amine represented by the formula (VI-B). can do.
  • This reaction is carried out at room temperature in a solvent such as dichloromethane, acetonitrile, dimethylformamide, dichloroethane, or acetone, if necessary, in the presence of a base such as sodium hydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, and the like. It is preferably carried out under heating (preferably under heating to reflux).
  • a solvent such as dichloromethane, acetonitrile, dimethylformamide, dichloroethane, or acetone
  • a base such as sodium hydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, and the like. It is preferably carried out under heating (preferably under heating to reflux).
  • a carboxylic acid represented by the general formula (III-C) or a reactive derivative thereof and a substituted aniline represented by the general formula (m-c) or a salt thereof are amidated by a conventional method to form a protective group.
  • the compound (Ic) of the present invention is produced by removing the protecting group when the compound has the formula (I).
  • Examples of the reactive derivative of the compound ( ⁇ -c) include ordinary esters such as methyl ester, ethyl ester, isobutyl ester and tert-butyl ester; acid halides such as acid chloride and acid bromide; acid azide; Phenolic compounds such as ditropanol, Active esters obtained by reacting with N-hydroxylamine compounds such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole; symmetric acid anhydrides; alkyl carbonate halides Organic acid-based mixed acid anhydrides obtained by reaction with halocarboxylic acid alkyl esters or bivaloyl halides, diphenylphosphoryl chloride, and phosphoric acid-based mixed acid anhydrides obtained by reaction with N-methylmorpholine. Mixed acid anhydrides;
  • an acid chloride method a method of reacting in the presence of an active esterifying agent and a condensing agent, and a method of subjecting an ordinary ester to amine treatment can be simply and easily used as the compound of the present invention. It is advantageous.
  • the reaction varies depending on the reactive derivative used, the condensing agent, etc., but usually, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, xylene, ether, and terephthalate Ethers such as trahydrofuran, esters such as ethyl acetate, and organic solvents inert to the reaction such as N, N-dimethylformamide and dimethyl sulfoxide.
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform
  • aromatic hydrocarbons such as benzene, toluene, xylene, ether, and terephthalate Ethers such as trahydrofuran, esters such as ethyl acetate
  • organic solvents inert to the reaction such as N, N-dimethylformamide and dimethyl sulfoxide.
  • R a , R b , R c and R d are the same or different and represent a hydrogen atom or a lower alkyl group.
  • the present production method comprises reacting a 1,4-dicarbonyl compound represented by the general formula (IV-C) with an amino compound represented by the formula (V-C) to produce a pyrrole derivative of the present compound (I — C— 1)
  • the reaction is usually carried out under heating, but a method in which glacial acetic acid is used as a solvent and the mixture is heated to reflux from room temperature is preferred.
  • R ′ represents an alkyl group or an aryl group.
  • the tetrazole derivative represented by (I-C-12) in the above formula is represented by the formula (VI-C) It can be obtained by reacting the nitrile compound shown with an equimolar mixture of sodium azide (or potassium azide) and ammonium chloride in a polar aprotic solvent such as dimethylformamide. The temperature at this time is from room temperature to the reflux temperature of the solvent (described in the above formula as method A).
  • the compound of the formula (I-C-12) is a compound represented by the formula (VI-C) And tolyl body, non-polar aprotic solvent such as toluene, (in the above formula, and R '3 S n N 3 Display) Bok Riaruki Ruchin'ajido or Bok Leary rutin azide is reacted with a, followed by acid or base It can also be obtained by performing hydrolysis.
  • the reaction temperature for the reaction with trialkyltin azide or triaryltin azide is from room temperature to the reflux temperature of the solvent. In particular, when the reaction is carried out with tri-n-butyltin azide and toluene, the reflux temperature is preferred.
  • the hydrolysis is usually carried out at room temperature to about 100 ° C. using an excess of an aqueous sodium hydroxide solution or aqueous hydrochloric acid solution (described as method B in the above formula).
  • the reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt thereof, a hydrate or various solvates.
  • the salt can be produced by subjecting it to a usual salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compound of the present invention has a single isomer, such as a racemate, an optically active substance, and a diastereomer, and L exists as a mixture.
  • the racemic compound can be prepared by using an appropriate starting compound, or By a simple racemic resolution method [for example, a diastereomeric salt with a general optically active acid (tartaric acid, etc.) and a method of optical resolution] can be led to stereochemically pure isomers.
  • the mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.
  • the compound (I - A) or a pharmaceutically salt that will be tolerated with respect to both the arginine vasopressin V, and V 2 receptors While both have excellent antagonism, a potent particularly antagonizing V 2 receptor.
  • the compound (I one B) or a pharmaceutically acceptable Ru salt, arginine vasopressin V, and V 2 receptor antagonism are potent co.
  • the compound (IC) or a pharmaceutically acceptable salt thereof is arginine vasopressin! It has selective and potent antagonism at the receptor.
  • the compound of the present invention has a profile based on these actions, which is an aquaretic action, a urea excretion promoting action, a factor I secretion suppressing action, a vasodilatory action, a cardiac function enhancing action, a mesangial cell contraction suppressing action, a mesangial cell proliferation.
  • Suppressive action hepatic gluconeogenesis inhibitory action, platelet aggregation inhibitory action, aldosterone secretion inhibitory action, endothelin production inhibitory action, central blood pressure regulation action, renin secretion regulation action, memory regulation action, body temperature regulation action, prostaglandin production regulation action, etc.
  • V receptor binding
  • the incubation solution is aspirated using a cell harvester and passed through a glass filter (GF / B) to remove free ligand and excess buffer, and the labeled ligand bound to the receptor is removed from the glass filter.
  • GF / B glass filter
  • the glass filter was taken out, dried sufficiently, mixed with a liquid scintillation capsule, and the amount of [H] 3 -vasopressin bound to the membrane was measured with a liquid scintillation counter.
  • KD dissociation constant obtained from scatch yard and plot The negative logarithm of K i calculated above was used as the p K i value.
  • the compounds of the present invention compounds excellent arginine having vasopressin antagonistic activity e.g. Example 1 one A is, V, but both have excellent antagonistic activity against both V 2 receptor, in particular antagonism of V 2 receptors It was confirmed that the activity was remarkably potent as compared with control compounds such as OPC-320260 currently being developed as arginine vasopressin antagonists (see Table 1).
  • compound (I-C) or a pharmaceutically acceptable salt thereof is represented by V! It was confirmed that the antagonist activity against the receptor was strong and excellent in selectivity (see Table 3).
  • Table 3 Arginine vasopressin and receptor antagonism
  • the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which the compound is applied. mg, which is administered once or in several divided doses. Since the dose varies under various conditions, a smaller dose than the above dose range may be sufficient.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone.
  • the metasilicate is mixed with magnesium aluminate.
  • the composition may, in a conventional manner, contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid.
  • a solubilizing or solubilizing agent such as aspartic acid may be contained.
  • the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Including ethanol.
  • This composition contains, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, suspending agents It may contain adjuvants such as agents, sweeteners, flavors, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous diluents and suspension diluents include distilled water for injection and physiological saline.
  • diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. Good.
  • Table 4 below shows the chemical structural formulas of the compounds obtained in the above Reference Examples and Examples.
  • Examples A-1 to 46 are shown below in the form of a table (Table 5), in addition to the compounds of the above-mentioned Examples. These compounds can be synthesized using the synthetic methods and methods described in the above Preparations and Examples, and modifications thereof known to those of ordinary skill in the art and require special experimentation. It does not mean that.
  • Reference example 26 1- (4-Methyl-1-piperazinyl) carbonylmethyl-4,5-dihydro 1H-1,5-benzodiazepine 1-2 (3H) one 7 3 From 0 mg, 600 mg of 1- [2-((4-methyl-1--1-piperazinyl) ethyl]]-2,3,4,5-tetrahydro 1H-1, 5-benzodiazepine was obtained.
  • One 960 mg of tetrahydrofuran solution (1 Om1) was added, and the mixture was refluxed for 24 hours. After cooling, methanol was added and the solvent was distilled off. A saturated aqueous solution of ammonium chloride was added to the residue, and the mixture was extracted with chloroform. The pore-form was washed with water, brine, and dried over anhydrous magnesium sulfate.
  • the mixture was added dropwise to 5 ml of a dichloromethane solution of 220 mg of triacetamide and 0.09 ml of triethylamine under ice-cooling, and stirred at room temperature for 3 hours.
  • the reaction solution was added to ice water and extracted with dichloromethane.
  • the dichloromethane was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography.
  • Example 8-B In the same manner as in Example 6-B (1), 5- [4-[[2- (4-methylphenyl) benzoyl] amino] benzoyl] -1,2,3,4,5-tetrahydro-1H-1 , 5 monobenzodiazepine-monoacetic acid 180 mg, 2-(aminomethyl) pyridine 45 from 5 mg 2- (4-methylphenyl)-4 'mono [[5-[N- (2- pyridylmethyl) carbamoylmethyl ] — 2,3,4,5-tetrahydro 1H-1,5-benzodiazepine-1-yl] carbonyl] benzanilide 16 Omg was obtained.
  • Example 4 In the same manner as in Example 1B, 5 [4-[[2- (412-phenyl) benzoyl] amino] benzoyl] -1,2,3,4,5-tetrahydro-1H-1,5 From 4 mg of 4 '-[[5- (N-methylcarbamoylmethyl)-1,2,3,4,5-tetrahydro- 1H- 1,5-benzodiazepine- 1-benzodiazepine-ethyl monoacetate [Carbyl] carbonyl] -2- (4-nitrophenyl) benzanilide (27 Omg) was obtained.
  • Example 1 In the same manner as in 6-B, 4 '-[[5-[(4-methyl-1-piperazinyl) carbonylmethyl]-1,2,3,4,5-tetrahydro 1H-1,5-benzodiazepine 1-yl] carbonyl]-2- (4-torophenyl) benzanilide From 300 mg, 21- (4-aminophenyl) -14 '-[[5-[(4-methyl-1-1piperazinyl) carbonylmethyl] 1,2,3,4,5-tetrahydro 1H-1,5-benzodiazepine- 11-yl] carbonyl] benzanilide 21 Omg was obtained.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à un dérivé de dihydrobenzazépine représenté par la formule générale (I-A), à un dérivé de tétrahydrobenzodiazépine représenté par la formule générale (I-B) ou à un dérivé de tétrahydrobenzazépine représenté par la formule générale (I-C), à un sel pharmaceutiquement acceptable de ces dérivés, ainsi qu'à une composition pharmaceutique de ces dérivés, qui sont utiles comme agent antagoniste de la vasopressine d'arginine.
PCT/JP1994/000391 1993-03-11 1994-03-10 Compose avec action antagoniste de la vasopressine WO1994020473A1 (fr)

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JP5/77705 1993-03-11
JP7770593 1993-03-11
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JP5/100321 1993-04-02
JP11095893 1993-04-13
JP5/110957 1993-04-13
JP11095793 1993-04-13
JP5/110958 1993-04-13
JP11229393 1993-04-15
JP5/112293 1993-04-15
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Cited By (26)

* Cited by examiner, † Cited by third party
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US5521170A (en) * 1993-04-13 1996-05-28 Fujisawa Pharmaceutical Co., Ltd. Benzamide derivatives and pharmaceutical composition comprising the same
US5521173A (en) * 1995-01-17 1996-05-28 American Home Products Corporation Tricyclic benzazepine vasopressin antagonists
US5532235A (en) * 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5536718A (en) * 1995-01-17 1996-07-16 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5654297A (en) * 1995-01-17 1997-08-05 American Cyanamid Company Tricyclic thieno-azepine vasopressin antagonists
US5700796A (en) * 1995-01-17 1997-12-23 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5753648A (en) * 1995-01-17 1998-05-19 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5849735A (en) * 1995-01-17 1998-12-15 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
EP0892797A1 (fr) * 1996-02-26 1999-01-27 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl-transferase
US5880122A (en) * 1996-11-01 1999-03-09 American Home Products Corporation 3-Carboxamide derivatives of 5H-pyrrolo 2,1-c! 1,4!-benzodiazepines
US6096736A (en) * 1995-12-15 2000-08-01 Otsuka Pharmaceutical Company, Limited Benzazepine derivatives with vasopressin agonistic activity
WO2001029005A1 (fr) * 1999-10-20 2001-04-26 Ferring Bv Agonistes de la vasopressine bicyclique
WO2001049682A1 (fr) * 2000-01-05 2001-07-12 Ferring Bv Azepines condensees en tant qu'agonistes de vasopressine
US6632814B1 (en) 1998-12-23 2003-10-14 Aventis Pharma Ltd. Dihydro-benzo(1,4)oxazines
JP2005507906A (ja) * 2001-10-12 2005-03-24 ノボ　ノルディスク　アクティーゼルスカブ 置換ピペリジン類、およびヒスタミンｈ３受容体関連疾患の治療のためのその使用
US6900200B2 (en) 2001-04-12 2005-05-31 Wyeth Tricyclic hydroxy carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US6977254B2 (en) 2001-04-12 2005-12-20 Wyeth Hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US7022699B2 (en) 2001-04-12 2006-04-04 Wyeth Cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
US7064120B2 (en) 2001-04-12 2006-06-20 Wyeth Tricyclic pyridyl carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US7109193B2 (en) 2001-04-12 2006-09-19 Wyeth Tricyclic diazepines tocolytic oxytocin receptor antagonists
US7202239B2 (en) 2001-04-12 2007-04-10 Wyeth Cyclohexylphenyl carboxamides tocolytic oxytocin receptor antagonists
US7326700B2 (en) 2001-04-12 2008-02-05 Wyeth Cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
CN111187227A (zh) * 2020-01-20 2020-05-22 河南农业大学 一种用于小麦全蚀病病菌抑制的2-(1,2,4-三氮唑)苯甲酰芳胺类活性化合物
CN115141153A (zh) * 2022-05-05 2022-10-04 徐州医科大学 一种苯并二氮杂䓬类化合物及其制备方法与应用

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JPH04321669A (ja) * 1991-04-19 1992-11-11 Otsuka Pharmaceut Co Ltd バソプレシン拮抗剤
JPH05132466A (ja) * 1991-04-19 1993-05-28 Otsuka Pharmaceut Co Ltd ベンゾヘテロ環化合物
JPH05320135A (ja) * 1992-05-19 1993-12-03 Yamanouchi Pharmaceut Co Ltd テトラヒドロベンズアゼピン誘導体
JPH0616643A (ja) * 1992-07-03 1994-01-25 Yamanouchi Pharmaceut Co Ltd ビフェニル誘導体
JPH0680641A (ja) * 1992-09-01 1994-03-22 Otsuka Pharmaceut Co Ltd 光学活性な５−ヒドロキシベンゾアゼピン誘導体の製造法

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521170A (en) * 1993-04-13 1996-05-28 Fujisawa Pharmaceutical Co., Ltd. Benzamide derivatives and pharmaceutical composition comprising the same
US5654297A (en) * 1995-01-17 1997-08-05 American Cyanamid Company Tricyclic thieno-azepine vasopressin antagonists
US5532235A (en) * 1995-01-17 1996-07-02 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5536718A (en) * 1995-01-17 1996-07-16 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5610156A (en) * 1995-01-17 1997-03-11 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5612334A (en) * 1995-01-17 1997-03-18 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5696112A (en) * 1995-01-17 1997-12-09 American Cyanamid Company Fused heterocyclic azepines as vasopressin antagonists
US5700796A (en) * 1995-01-17 1997-12-23 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5719278A (en) * 1995-01-17 1998-02-17 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5753648A (en) * 1995-01-17 1998-05-19 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5780471A (en) * 1995-01-17 1998-07-14 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5849735A (en) * 1995-01-17 1998-12-15 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5521173A (en) * 1995-01-17 1996-05-28 American Home Products Corporation Tricyclic benzazepine vasopressin antagonists
US6096736A (en) * 1995-12-15 2000-08-01 Otsuka Pharmaceutical Company, Limited Benzazepine derivatives with vasopressin agonistic activity
EP1481975A1 (fr) * 1996-02-26 2004-12-01 Bristol-Myers Squibb Company Inhibiteurs de la farnésyl protéine transférase
EP0892797A1 (fr) * 1996-02-26 1999-01-27 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl-transferase
EP0892797A4 (fr) * 1996-02-26 2004-10-20 Bristol Myers Squibb Co Inhibiteurs de la farnesyl-transferase
US5880122A (en) * 1996-11-01 1999-03-09 American Home Products Corporation 3-Carboxamide derivatives of 5H-pyrrolo 2,1-c! 1,4!-benzodiazepines
US6632814B1 (en) 1998-12-23 2003-10-14 Aventis Pharma Ltd. Dihydro-benzo(1,4)oxazines
JP4694747B2 (ja) * 1999-10-20 2011-06-08 バンテイア・リミテツド 二環式バソプレッシン・アゴニスト
JP2003512356A (ja) * 1999-10-20 2003-04-02 フェリング ベスローテン フェンノートシャップ 二環式バソプレッシン・アゴニスト
CZ304069B6 (cs) * 1999-10-20 2013-09-18 Vantia Limited Bicyklické agonisty vasopresinu
WO2001029005A1 (fr) * 1999-10-20 2001-04-26 Ferring Bv Agonistes de la vasopressine bicyclique
US6664249B1 (en) 1999-10-20 2003-12-16 Ferring Bv Bicyclic vasopressin agonists
US7074781B2 (en) 2000-01-05 2006-07-11 Ferring Bv Condensed azepines as vasopressin agonists
WO2001049682A1 (fr) * 2000-01-05 2001-07-12 Ferring Bv Azepines condensees en tant qu'agonistes de vasopressine
US7560454B2 (en) 2000-01-05 2009-07-14 Vantia Limited Condensed azepines as vasopressin agonists
HRP20020481B1 (en) * 2000-01-05 2009-03-31 Vantia Limited Condensed azepines as vasopressin agonists
US7326700B2 (en) 2001-04-12 2008-02-05 Wyeth Cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
US7064120B2 (en) 2001-04-12 2006-06-20 Wyeth Tricyclic pyridyl carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US7109193B2 (en) 2001-04-12 2006-09-19 Wyeth Tricyclic diazepines tocolytic oxytocin receptor antagonists
US7202239B2 (en) 2001-04-12 2007-04-10 Wyeth Cyclohexylphenyl carboxamides tocolytic oxytocin receptor antagonists
US6900200B2 (en) 2001-04-12 2005-05-31 Wyeth Tricyclic hydroxy carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists
US7022699B2 (en) 2001-04-12 2006-04-04 Wyeth Cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators
US6977254B2 (en) 2001-04-12 2005-12-20 Wyeth Hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
EP2243776A1 (fr) * 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Piperidines substituées et leur utilisation dans le traitement de maladies liées au recepteur histaminique H3
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
JP2005507906A (ja) * 2001-10-12 2005-03-24 ノボ　ノルディスク　アクティーゼルスカブ 置換ピペリジン類、およびヒスタミンｈ３受容体関連疾患の治療のためのその使用
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
CN111187227A (zh) * 2020-01-20 2020-05-22 河南农业大学 一种用于小麦全蚀病病菌抑制的2-(1,2,4-三氮唑)苯甲酰芳胺类活性化合物
CN115141153A (zh) * 2022-05-05 2022-10-04 徐州医科大学 一种苯并二氮杂䓬类化合物及其制备方法与应用
CN115141153B (zh) * 2022-05-05 2023-11-14 徐州医科大学 一种苯并二氮杂䓬类化合物及其制备方法与应用

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