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WO2003066626A1 - Benzimidazoles deuterises biphenyle-substitues et medicaments contenant ces composes pour le traitement de l'hypertonie - Google Patents

Benzimidazoles deuterises biphenyle-substitues et medicaments contenant ces composes pour le traitement de l'hypertonie Download PDF

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Publication number
WO2003066626A1
WO2003066626A1 PCT/DE2003/000365 DE0300365W WO03066626A1 WO 2003066626 A1 WO2003066626 A1 WO 2003066626A1 DE 0300365 W DE0300365 W DE 0300365W WO 03066626 A1 WO03066626 A1 WO 03066626A1
Authority
WO
WIPO (PCT)
Prior art keywords
biphenyl
ethoxy
dideuteromethyl
carboxylic acid
tetrazol
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/DE2003/000365
Other languages
German (de)
English (en)
Inventor
Rudolf-Giesbert Alken
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TURICUM DRUG DEVELOPMENT AG
Original Assignee
TURICUM DRUG DEVELOPMENT AG
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 TURICUM DRUG DEVELOPMENT AG filed Critical TURICUM DRUG DEVELOPMENT AG
Priority to AU2003208288A priority Critical patent/AU2003208288A1/en
Publication of WO2003066626A1 publication Critical patent/WO2003066626A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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 invention relates to deuterated biphenyl-substituted benzimidazoles and medicaments containing these compounds.
  • the object of the present invention is to provide biphenyl-substituted benzimidazoles which have improved pharmacokinetic and / or pharmacodynamic properties compared to the already known compounds.
  • the object is therefore achieved by providing deuterated biphenyl-substituted benzimidazoles of the general formula I:
  • R 1 is H, D or partially or completely deuterated alkyl or substituted alkyl having 1-5 carbon atoms
  • R 2 independently represents H or D
  • R 3 is partially or completely deuterated alkoxy with 1-5 carbon atoms
  • R 4 represents H or D
  • R 5 is independently H or D and at least one of the radicals R 2 to R 5 is deuterium or contains deuterium.
  • R 2 is independently H or D
  • R 3 is ethoxy or partially or completely deuterated ethoxy
  • RH or D means and R 5 is independently H or D and at least one of the radicals R 2 to R 5 is deuterium or contains deuterium.
  • deuterated biphenyl-substituted benzimidazoles of the general formula I, in which R 1 is ethyl or partially or completely deuterated ethyl, R 2 independently of one another represents H or D, R 3 is H or D,
  • R 4 is H or D
  • R 5 is independently H or D and at least one of the radicals R 2 to R 5 is deuterium or contains deuterium.
  • Deuterated biphenyl-substituted benzimidazoles of the general formula I in which R 1 is 1- (cyclohexyloxycarbonyloxy) ethyl or partially or completely deuterated 1- (cyclohexyloxycarbonyloxy) ethyl are particularly preferred,
  • R 2 independently of one another represents H or D
  • R 3 denotes H or D
  • R 4 is H or D
  • R 5 is independently H or D and at least one of the radicals R 2 to R 5 is deuterium or contains deuterium.
  • deuterated biphenyl-substituted benzimidazoles according to the invention and their physiologically tolerable salts for the manufacture of medicaments for vasodilation, in particular for the treatment of hypertension.
  • compositions which contain the deuterated biphenyl-substituted benzimidazoles according to the invention and their physiologically tolerable salts for vasodilation, in particular for Treatment of hypertension, in addition to pharmaceutically acceptable auxiliaries and / or additives.
  • a suitably substituted benzimidazole derivative is alkylated with a (bromomethyl) biphenyl building block or a deuterated (bromomethyl) biphenyl building block.
  • the deuterated acid chloride is generated and this is reacted with 2-amino-2-methyl-l-propanol to give the deuterated 4,4-dimethyl-2- (2-methoxyphenyl) oxazoline.
  • This oxazoline is further processed with deuterated 4-methylphenyl-Grignard reagent, obtained from deuterated 4-bromotoluene, to give deuterated 2- (4 '-methylbiphenyl-2-yl) -4, 4-dimethyl-oxazoline.
  • deuterated 4'-methyl-2-biphenylcarboxylic acid is obtained from this by heating in deuterium chloride solution.
  • the deuterated 4 '-methyl-2-biphenylcarboxylic acid is over the acid amide, which with ammonium hydroxide solution from the
  • Acid chloride is obtained, converted to deuterated 4'-methyl-2-biphenylnitrile.
  • the deuterated 4'-methyl-2-biphenylnitrile with trimethyltin azide is now used to obtain the deuterated N-trimethylstannyl-5- (4'-methylbiphenyl-2-yl) tetrazole.
  • the tetrazole group is subsequently protected by reaction with trityl chloride and the deuterated N-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) tetrazole obtained is converted into the deuterated (bromomethyl) biphenyl derivative with N-bromosuccinimide.
  • the benzimidazole derivatives suitable as starting material can be prepared analogously to known production processes, such as by P.N. Preston [The Chemistry of Heterocyclic Compounds, Vol. 40, 1-286 (1981)] or N.J. Leonhard, D.Y. Curtin and K.M. Beck [J. At the. Che. Soc. 69, 2459 (1947)].
  • the two regioisomers formed in this alkylation are separated from one another by known separation and purification processes.
  • the deuterated starting materials used in the syntheses have a degree of deuteration above 98%.
  • customary physiologically compatible inorganic and organic acids can be, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid,
  • the acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or their solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, or n-propanol Isopropanol or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition.
  • physiologically compatible aqueous solutions of acid addition salts of the compounds used according to the invention can be prepared in an aqueous acid solution.
  • the acid addition salts of the compounds according to the invention can be carried out in a manner known per se, e.g. with alkalis or ion exchangers, are converted into the free base. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, in particular those which are suitable for forming therapeutically usable salts. These or other salts of the new compound, e.g. the picrate can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.
  • the present invention also relates to pharmaceuticals for oral, sublingual, buccal, rectal, subcutaneous, intravenous, intramuscular, topical, intratracheal, intranasal, transdermal or rectal application, which, in addition to conventional carriers and diluents, contain a compound of the general formula I o which contain their acid addition salt as an active ingredient.
  • the medicaments of the invention are mixed with the usual solid or liquid carriers or diluents. teln and the commonly used pharmaceutical technical auxiliaries according to the desired type of application with a suitable dosage in a known manner.
  • the preferred preparations are in a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
  • parenteral preparations such as injection solutions are also suitable.
  • Suppositories may also be mentioned as preparations.
  • Corresponding tablets can be prepared, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents Achieving a depot effect such as carboxyl polymethylene, carboxyl ethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the active ingredient used according to the invention can additionally contain taste-improving agents such as saccharin, cyclaat or sugar and, for example, flavoring agents such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with suitable carriers such as neutral fats or polyethylene glycol or their derivatives.
  • Topical application can take place, for example, in the form of ointments, creams, gels, solutions or by plasters.
  • the compounds according to the invention have a comparison with those in the prior art.
  • Known compounds which contain deuterium only in the natural distribution, have a number of advantages. On the one hand, deuteration slows down metabolism in the organism. This makes it possible to create preparations with a longer effect and thus to reduce the dose.
  • the pharmacodynamics have also changed, since the deuterated compounds according to the invention form other hydration shells, so that their distribution in the organism differs from that of the undeuterated compounds.
  • the d7-4-methylphenyl Grignard reagent is prepared from 10 g of d7-4-bromotoluene in a manner known per se by reaction with magnesium in anhydrous tetrahydrofuran. This is added to 5.3 g of 4,4-dimethyl-2- (2-methoxy-d4-phenyl) oxazoline in anhydrous tetrahydrofuran and the reaction mixture is stirred at room temperature for 2 hours. After working up, 5.7 g of 2- (dll-4 '-methylbiphenyl-2-yl) -4, -dimethyloxazoline are obtained as a colorless liquid. Yield: 81% calculated: C: 78.21%; H: 10.93%; N: 5.07% found:
  • the product is prepared by dissolving 33 g of N-trimethylstannyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole in a mixture of toluene and tetrahydrofuran and so long dry deuterium chloride at room temperature through the solution is blown until a clear solution is obtained.
  • the product crystallizes out of the solution and, after recrystallization, 16.8 g of 5- (dll-4 '-methylbiphenyl-2-yl) - ID-tetrazole are obtained. Yield: 82%
  • the preparation is carried out in a manner known per se by reacting 0.93 g of 2-ethoxy-7-carbethoxy-1H-benzimidazole in DMF with ice cooling with sodium hydride and 2.5 g of l-triphenylmethyl-5- [dlO- 4 '- (Bromomethyl) biphenyl-2-yl] 1H tetrazole can be added.
  • the reaction mixture is stirred for 5 hours at room temperature and then mixed with ice water and ethyl acetate.
  • the organic phase is washed with water and then the solvent is removed.
  • the residue is dissolved in methanol and, in a variation of the literature specification, deuterium chloride solution is added and the mixture is stirred at 60 ° C. for 2 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des benzimidazoles deutérisés biphényle-substitués et des médicaments contenant ces composés. L'invention concerne en outre l'utilisation de benzimidazoles deutérisés biphényle-substitués pour la vasodilatation, en particulier pour le traitement de l'hypertonie, ainsi que pour la production de médicaments correspondants. Sont également décrites des compositions pharmaceutiques qui contiennent des benzimidazoles deutérisés biphényle-substitués ainsi que leurs sels physiologiquement compatibles, en plus de produits auxiliaires et/ou additifs pharmaceutiquement compatibles, pour la vasodilatation, en particulier pour le traitement de l'hypertonie.
PCT/DE2003/000365 2002-02-07 2003-02-06 Benzimidazoles deuterises biphenyle-substitues et medicaments contenant ces composes pour le traitement de l'hypertonie Ceased WO2003066626A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003208288A AU2003208288A1 (en) 2002-02-07 2003-02-06 Deuterated biphenyl-substituted benzimidazoles and medicament containing said compounds for the treatment of hypertonia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10205335A DE10205335A1 (de) 2002-02-07 2002-02-07 Deuterierte biphenylsubstituierte Benzimidazole sowie diese Verbindungen enthaltende Arzneimittel
DE10205335.9 2002-02-07

Publications (1)

Publication Number Publication Date
WO2003066626A1 true WO2003066626A1 (fr) 2003-08-14

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PCT/DE2003/000365 Ceased WO2003066626A1 (fr) 2002-02-07 2003-02-06 Benzimidazoles deuterises biphenyle-substitues et medicaments contenant ces composes pour le traitement de l'hypertonie

Country Status (3)

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AU (1) AU2003208288A1 (fr)
DE (1) DE10205335A1 (fr)
WO (1) WO2003066626A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008067378A3 (fr) * 2006-11-28 2009-05-14 Auspex Pharmaceuticals Inc Préparation et utilité de phényltétrazoles substitués

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUBO K ET AL: "NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS. SYNTHESIS AND BIOLOGICAL ACTIVITY OF BENZIMIDAZOLECARBOXYLIC ACIDS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 36, 1993, pages 2182 - 2195, XP001018907, ISSN: 0022-2623 *
KUBO K ET AL: "NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS. SYNTHESIS AND BIOLOGICAL ACTIVITY OF POTENTIAL PRODRUGS OF BENZIMIDAZOLE-7-CARBOXYLIC ACIDS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 36, no. 16, 1993, pages 2343 - 2349, XP001008066, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008067378A3 (fr) * 2006-11-28 2009-05-14 Auspex Pharmaceuticals Inc Préparation et utilité de phényltétrazoles substitués

Also Published As

Publication number Publication date
DE10205335A1 (de) 2003-08-21
AU2003208288A1 (en) 2003-09-02

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