WO1994021641A1 - Procede de production d'un derive d'imidazole - Google Patents

Procede de production d'un derive d'imidazole Download PDF

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Publication number
WO1994021641A1
WO1994021641A1 PCT/US1994/001949 US9401949W WO9421641A1 WO 1994021641 A1 WO1994021641 A1 WO 1994021641A1 US 9401949 W US9401949 W US 9401949W WO 9421641 A1 WO9421641 A1 WO 9421641A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
hydrogen atom
alkyl group
formula
Prior art date
Application number
PCT/US1994/001949
Other languages
English (en)
Inventor
Hiroyoshi Yamada
Kiyotaka Munesada
Keiko Koh
Mikio Taniguchi
Yoshiji Fujita
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Priority to AU63519/94A priority Critical patent/AU6351994A/en
Priority to EP94910736A priority patent/EP0689544A1/fr
Priority to JP6521039A priority patent/JPH08508468A/ja
Publication of WO1994021641A1 publication Critical patent/WO1994021641A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a process for producing an imidazole derivative. More particularly, the present invention relates to a process for producing an imidazole derivative useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like and an intermediate therefor.
  • the present inventors have aimed at angiotensin II antagonist as an agent for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid manifestation of action upon intravenous injection, good absorbability into the body upon oral administration, lower toxicity and long-lasting action.
  • angiotensin II antagonist as an agent for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid manifestation of action upon intravenous injection, good absorbability into the body upon oral administration, lower toxicity and long-lasting action.
  • novel imidazole derivatives having the hydrazine cross-linking structure represented by the formula:
  • the object of the present invention is to improve the selectivity on the reduction of C ring double bond of the above imidazole derivative in order to achieve the high yield even in mass production and exclude the necessity of complicated purification steps.
  • the Means to Solve the Problems In order to solve the above problems, the present inventors have studied intensively and, as a result, found that C ring double bond can be reduced selectively without the C ring cleavage reaction.
  • the present invention provides a process for producing an imidazole derivative represented by the formula (II):
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are as defined below, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula (I):
  • R 1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF 3 group, aryl group or aralkyl group;
  • R is hydrogen atom, or a group selected from the group consisting of
  • X is -CH 2 -, -NR'-, oxygen atom or -S(0) n -, wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2; wherein X , X 2 and X are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, lH-tetrazol-5-yl group or alkali metal salt thereof, -C0 2 R 7 group, -CONR'R" group, -C0NHS0 2 R 8 group, amino group, -NHS0 2 CF 3 group or -S0 3 H group, or a group selected from the group consisting of
  • Y is lH-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, n methoxyethoxymethyl group or trimethylsilylethoxymethyl group, -C0 2 R group, -CONR'R" group, -CONHS0 2 R 8 group, amino group, -NHS0 2 CF 3 group or -S0 3 H group;
  • R 6 is hydrogen atom, halogen atom, lower alkyl group, -CF 3 group or -CF 2 CF 3 group;
  • R 7 is hydrogen atom, alkali metal atom or lower alkyl group
  • R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" are taken together to form the alicyclic structure;
  • R 8 is lower alkyl group, cycloalkyl group or aryl group
  • R 9 is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl group or aryloxy group;
  • R , R 11 and R are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, -C0 2 R 7 group or -CONR'R" group;
  • R there are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
  • R 1 As the lower alkoxy group represented by R 1 , there are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isoamyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like.
  • R 1 As the lower alkylthio group represented by R 1 , there are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n- pentylthio, n-hexylthio, n-heptylthio, n-octylthio and the like.
  • R 1 there are methylamino, dimethylamino, ethylamino, diethylamino, n- propylamino, di(n-propyl)amino, isopropylamino, n-butylamino, n-pentylamino, pyrrolidino, piperidino, piperazino, morpholino and the like.
  • R As the lower alkenyl group represented by R , there are vinyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl and the like.
  • R 1 As the lower alkynyl group represented by R 1 , there are acetylene group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl and the like.
  • aryl group or aralkyl group represented by R 1 there are aryl or aralkyl group having 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like. These aryl and aralkyl groups are optionally substituted with the substituent(s) such as the above described lower alkyl group, or lower alkoxy group, halogen atom, nitro group, cyano group and the like.
  • R is substituted or unsubstituted phenylmethyl group
  • halogen atom defined by X 1 , X and X 3
  • fluorine atom chlorine atom, bromine atom and iodine atom.
  • lower alkyl group and lower alkoxy group there are above defined lower alkyl group and alkoxy group.
  • X 1 , X 2 and X 3 are lH-tetrazol-5-yl group, as the alkali metal salt thereof, there are sodium salt, potassium salt and the like.
  • R 7 when X 1 , X 2 and X 3 are -C0 2 R 7 group, as the examples of R 7 in the group, there are hydrogen atom, alkali metal atom such as lithium, sodium, potassium and the like, alcohol ester of the above defined lower alkyl group.
  • R 7 alkali metal atom
  • X 1 , X 2 and X 3 are -CONR'R"
  • the examples of -NR'R" in the group there are amino, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, diisopropylamino, dibutylamino, pyrrolidyl, piperazino, morpholino and the like.
  • R 8 in -CONHS0 2 R group there are methyl, trifluoromethyl, ethyl, n-propyl, n- butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like.
  • X 1 , X 2 and X 3 are the group selected from the following:
  • R 9 is cycloalkyl group or cycloalkoxy group
  • the examples are 5 to 7 membered cyclic compounds such as cyclopentyl, cyclohexyl, cyclopentyl and the like.
  • aryl group or aryloxy group represented by R 9 there are substituted or unsubstituted phenyl compounds such as phenyl, p-hydroxyphenyl, p- carboxyphenyl, o-nitrophenyl and the like.
  • the example of halogen and lower alkyl group represented by R 6 the examples of alkali metal salts of lH-tetrazol-5-yl represented by Y, and the examples of R 7 , NR'R" and R 8 in -C0 2 R 7 group, -CONR'R" group or -CONHS0 2 R 8 group represented by Y are as defined above.
  • R 2 , R , R 4 and R 5 are lower alkyl group
  • the examples of them are the alkyl groups having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl; isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
  • R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are lower alkyl group
  • the example of them are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
  • R , R , R , R , R and R are lower fiuoroalkyl group, the examples of them are trifluoromethyl, 2,2,2,-trifluoroethyl, pentafluoroethyl and the like.
  • R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are -(CH 2 )j-C0 2 R 7 , -C(R')(R")-OR 19 , or -(CH 2 )j-CONR'R'"
  • the examples of R 7 , R' and R" are as defined above.
  • the diimide used in the process of the present invention can be generated by various methods, for example, by oxidation of hydrazine, decomposition of the dipotassium salt of azodicarboxylic acid by an acid, the decomposition of arylsulfohydrazide by a base, the hydroxylamine-acetic acid ester method, and the like (Organic Reactions, 40, 91-155 (1991)).
  • the use of decomposition of p-toluenesulfohydrazide by sodium acetate is suitable in view of simplicity of the operations and high safety.
  • the reaction between the diimide and the compound of the general formula (I) proceeds effectively at room temperature to 120 °C.
  • the reaction is carried out in a solvent.
  • a solvent there are the alcoholic solvents such as methanol, ethanol, propanol and the like, and the etheric solvent such as tetrahydrofuran, dimethoxyethane and the like.
  • the alcoholic solvents such as methanol, ethanol, propanol and the like
  • the etheric solvent such as tetrahydrofuran, dimethoxyethane and the like.
  • R is a protecting group such as benzyl group and the like
  • the reduced product is reacted in methanol in the presence of the catalytic amount of 20 % palladium hydroxide-carbon under 1 to 3 atmospheric pressure hydrogen by a conventional method to easily effect the deprotection such as debenzylation and the like. Therefore, a process of the present invention is also useful for preparing an intermediate (4) for synthesis (see the above Reaction Scheme).
  • the end imidazole derivative (5) can be obtained as crystals almost without side products by attaching the biphenyltetrazole part to the intermediate according to the method described in JP- A 3-277537, JP-A 3-323474, JP-A 4-095191 and JP-A 4-216809 and WO 93/08193 (see the above Reaction Scheme).
  • the purification by column chromatography which was indispensable to the previous process becomes unnecessary, and it was found that the present process can be applied to the mass production in the good reproductivity.
  • the compounds produced by the present process can be converted into the ester or salt thereof by a conventional method.
  • the esters or salts are pharmacologically acceptable and non-toxic ones.
  • Suitable esters include esters of lower alcohol having a straight or branched chain such as methanol, ethanol and the like.
  • Suitable salts include alkali metal salts such as sodium salt, potassium salt and the like, and alkaline earth metal salts, hydrogen halide salts such as hydrogen fluoride, hydrogen chloride and the like, inorganic acid salts such as nitrate, sulfate and the like, lower alkylsulfonate salts such as methanesulfonate and the like, organic acid salts such as maleate, fumarate and the like, and amino acid salts such as aspartate and the like.
  • the mixture was cooled to room temperature, further cooled to 0 °C, and the precipitated crystals were filtered.
  • the crystals were dissolved in methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'objectif de cette invention est d'améliorer la sélectivité de la réduction de la liaison double du cycle C d'un dérivé d'imidazole ayant la structure de réticulation d'hydrazine représentée par la formule (I). Le dérivé d'imidazole est soumis à une réaction avec un diimide (HN=NH).
PCT/US1994/001949 1993-03-19 1994-03-04 Procede de production d'un derive d'imidazole WO1994021641A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU63519/94A AU6351994A (en) 1993-03-19 1994-03-04 Process for production of an imidazole derivative
EP94910736A EP0689544A1 (fr) 1993-03-19 1994-03-04 Procede de production d'un derive d'imidazole
JP6521039A JPH08508468A (ja) 1993-03-19 1994-03-04 イミダゾール誘導体の製法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5060067A JPH06271576A (ja) 1993-03-19 1993-03-19 イミダゾール誘導体の製法
JP5/60067 1993-03-19

Publications (1)

Publication Number Publication Date
WO1994021641A1 true WO1994021641A1 (fr) 1994-09-29

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Application Number Title Priority Date Filing Date
PCT/US1994/001949 WO1994021641A1 (fr) 1993-03-19 1994-03-04 Procede de production d'un derive d'imidazole

Country Status (7)

Country Link
EP (1) EP0689544A1 (fr)
JP (2) JPH06271576A (fr)
CN (1) CN1120337A (fr)
AU (1) AU6351994A (fr)
CA (1) CA2155573A1 (fr)
NZ (1) NZ263008A (fr)
WO (1) WO1994021641A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0531876A2 (fr) * 1991-09-10 1993-03-17 Tanabe Seiyaku Co., Ltd. Dérivés de l'imidazoindolizine à activité inhibitrice de l'angiotensine II
WO1993008193A1 (fr) * 1991-10-24 1993-04-29 The Upjohn Company Derives d'imidazole et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0531876A2 (fr) * 1991-09-10 1993-03-17 Tanabe Seiyaku Co., Ltd. Dérivés de l'imidazoindolizine à activité inhibitrice de l'angiotensine II
WO1993008193A1 (fr) * 1991-10-24 1993-04-29 The Upjohn Company Derives d'imidazole et compositions pharmaceutiques les contenant

Also Published As

Publication number Publication date
JPH08508468A (ja) 1996-09-10
AU6351994A (en) 1994-10-11
CA2155573A1 (fr) 1994-09-29
JPH06271576A (ja) 1994-09-27
CN1120337A (zh) 1996-04-10
EP0689544A1 (fr) 1996-01-03
NZ263008A (en) 1996-12-20

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