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WO2003066627A1 - Spirocyclopentanimida zolinones deuterisees et leur utili sation pour le traitement de maladies cardio-vasculaires - Google Patents

Spirocyclopentanimida zolinones deuterisees et leur utili sation pour le traitement de maladies cardio-vasculaires Download PDF

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Publication number
WO2003066627A1
WO2003066627A1 PCT/DE2003/000366 DE0300366W WO03066627A1 WO 2003066627 A1 WO2003066627 A1 WO 2003066627A1 DE 0300366 W DE0300366 W DE 0300366W WO 03066627 A1 WO03066627 A1 WO 03066627A1
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WIPO (PCT)
Prior art keywords
biphenyl
deuterated
alkyl
substituted
independently
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/DE2003/000366
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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
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Priority to AU2003208289A priority Critical patent/AU2003208289A1/en
Publication of WO2003066627A1 publication Critical patent/WO2003066627A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to deuterated biphenyl-substituted spirocyclopentanimidazolinones and medicaments containing these compounds.
  • irbesartan (US 5270317, EP 454511), which is used for the treatment of cardiovascular diseases such as high blood pressure and heart failure, the treatment of disorders of the central nervous system and for the treatment
  • the object of the present invention is to provide biphenyl-substituted spirocyclopentanimidazolinones which have improved pharmacokinetic and / or pharmacodynamic properties compared to the already known compounds.
  • the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the invention have significantly better pharmacokinetic and / or pharmacodynamic properties than the undeuterated compounds.
  • R 1 is independently D or H
  • R 2 Ci-e-alkyl or partially or completely deuterated
  • C 6 alkyl or substituted C 6 alkyl means
  • R 3 independently represents D or H
  • R 4 is independently D or H and
  • R 5 is D or H and at least one of the radicals R 1 to R 5 is deuterium or contains deuterium.
  • Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I where R 1 is D, R 2 is C 6 alkyl or partially or fully deuterated C 6 alkyl or substituted C 6 alkyl, R 3 is independently D or H R 4 is independently D or H and R 5 is D or H.
  • Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I are particularly preferred, where
  • R 1 is independently D or H, R 2 is fully deuterated C 6 alkyl,
  • R 3 is independently D or H
  • R 4 is independently D or H
  • R 5 is D or H
  • R 1 is independently D or H
  • R 2 is C 6 alkyl or partially or fully deuterated C 6 alkyl or substituted C 6 alkyl
  • R 3 is D
  • R 4 is independently D or H and R 5 is D or H and at least one of the radicals R 1 to R 5 is deuterium or contains deuterium.
  • R 2 is C 6 alkyl or partially or completely deuterated C 6 alkyl or substituted C 6 alkyl
  • R 3 is independently H or D
  • R 4 is D
  • R 5 is H or D and at least one the radicals R 1 to R 5 are deuterium or contain deuterium.
  • R 2 denotes alkyl, deuteroalkyl or perdeuteroalkyl
  • R 3 is independently H or D
  • R 4 independently of one another denotes H or D
  • R 5 is D and at least one of the radicals R 1 to R 5 is deuterium or contains deuterium.
  • deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the invention and their physiologically tolerable salts is particularly preferred for the production of medicaments for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and Treatment of glaucoma, diabetic nephropathy and retinopathy.
  • compositions which contain the deuterated biphenyl-substituted spirocyclopentane imidazolinones according to the invention and their physiologically tolerable salts for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and for the treatment of glaucoma as well as diabetic nephropathy and auxiliary and retinopathy / or additives.
  • the preparation of the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the invention is carried out on the basis of the production processes of analogous non-deuterated compounds using deuterated starting materials with a degree of deuteration above 98%.
  • the ethyl ester of 1-aminocyclopentane carboxylic acid is produced via the acid chloride in aqueous ethanol.
  • This optionally deuterated ester is then reacted with an optionally deuterated ethyl pentanimide as in US 532788, at least one of the starting materials containing deuterium.
  • the optionally deuterated ethyl pentanimide is prepared according to Suydam et al. [J. Org. Chem., Vol. 34, No. 2, 292-296 (1969)] by reacting the carboxamide with ethyl chloroformate.
  • the resulting pentanimidic acid ethyl ester hydrochloride is converted analogously to US 5411980 by treatment with a base into the free acid, which is then immediately reacted with the 1-aminocyclopentanecarboxylic acid ethyl ester.
  • An embodiment of the invention describes the use of 2, 2, 3, 3, 4, 4, 5, 5, 5-nonadeuteropentane carboxamide, which is derived from 2,2,3,3,4,4,5,5,5 - Nonadeuteropentanecarboxylic acid was obtained via the corresponding acid chloride and its reaction with ammonium hydroxide [Tsuzuki et al., J. Chem. Research (S), 144-145 (1993)].
  • N-alkylation of the deuterated 2-butyl-l, 3-diaza-spiro [4.4] non-l-en-4-one is carried out using 2'-substituted and optionally deuterated (bromomethyl) biphenyl derivatives.
  • the 4, 2'-disubstituted biphenyl derivatives are synthesized by known processes.
  • the Ullmann reaction can be used to produce symmetrically and asymmetrically substituted biphenyls. Halogenaryl compounds are preferred for this Iodine compounds reacted with each other in the presence of copper at high temperatures.
  • the review article "Modern Methods Of Aryl-Aryl Bond Formation" by M. Sainsbury [Tetrahedron, 36, 3327-3359 (1980)] provides an overview of methods for forming aryl-aryl bonds.
  • EP 733366 is described, adapted to the production of deuterated compounds, using deuterated starting materials with a degree of deuteration above 98%.
  • 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-di ethyloxazoline.
  • deuterated 4'-methyl-2-biphenylcarboxylic acid is obtained from this by heating in deuterium chloride solution.
  • the deuterated 4'-methyl-2-biphenylcarboxylic acid is converted to deuterated 4'-methyl-2-biphenylnitrile via the acid amide which is obtained from the acid chloride with ammonium hydroxide solution.
  • the deuterated 4'-methyl-2-biphenylnitrile with trimethyltin azide is now used to obtain the deuterated N-trimethylstannyl-5- (4'-methylbiphenyl-2-yl) tetrazole. In a modification of the known regulation, this is with
  • Deuterium chloride is converted into the deuterated 5- (4 '-methylbiphenyl-2-yl) tetrazole.
  • the latter is used in one embodiment of the invention for the synthesis of a spirocyclopentanimidazolinone, which is also deuterated in the biphenyl radical.
  • physiologically acceptable inorganic and organic acids can be used to prepare physiologically acceptable salts of the spirocyclopentanimidazolinones according to the invention. These are, 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 its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or 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 in a manner known per se, for. B. 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 medicaments for oral, sublingual, buccal, rectal, subcutaneous, intravenous, intramuscular, topical, intratracheal, intranasal, transdermal or rectal application, which in addition to conventional carriers and diluents agents contain a compound of general formula I or its acid addition salt as active ingredient.
  • the medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage.
  • the preferred preparations are in a dosage form which is suitable for oral administration.
  • 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 found, 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 to achieve a depot effect such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • 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 to achieve a depot effect such as carboxyl poly
  • 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. It can the coated tablet also consists of several layers, it being possible to use the auxiliaries mentioned above for the tablets.
  • agents conventionally used in tablet coatings for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. It can the coated tablet also consists of several layers, it being possible to use the auxiliaries mentioned above for the tablets.
  • Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and e.g. Contain flavorings 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 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 preparation of the pharmaceutical preparations according to the invention is known per se and is described in the manuals known to the person skilled in the art, for example Hager's Handbuch (5.) 2, 622-1045; List et al. , Drug form theory, Stuttgart: Wiss. Publishing company , 1985; Sucker et al. , Pharmaceutical Technology, Stuttgart: Thie e 1991; Ullmann's Encyclopedia (5th) A 19, 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995.
  • the compounds according to the invention, specifically substituted with deuterium have a number of advantages over the compounds known in the prior art which contain deuterium only in the natural distribution. 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 is 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.
  • Deuterium chloride is blown through the solution at room temperature until a clear solution is formed. The product crystallizes out of the solution and is obtained
  • Methylbiphenyl-2-yl) -ID-tetrazole in dichloroethane reacted with 25 g of trityl chloride with the addition of triethylamine at room temperature.
  • the reaction mixture is heated to reflux for 2 hours and then cooled to room temperature. It is washed with water, the organic phase is dried and the solvent removed in a vacuum. After recrystallization, 28.8 g of product are obtained.
  • Nonadeuteropentanimidic acid ethyl ester hydrochloride In a 250 ml three-necked flask equipped with a cooler, 11 ml of 2, 2, 3, 3, 4, 4, 5, 5, 5, 5-nonadeuteropentanecarboxamide are added with stirring with 0.1 ml of ethyl chloroformate from a dropping funnel. The reaction mixture is achieved with a 40-45 ° C water bath. warms. The beginning of the reaction is visible through the development of C0 2 which is discharged via the cooler into a barium hydroxide solution. After stirring for 2.5 hours while maintaining the water bath temperature, the CO 2 evolution is complete. The reaction product is washed several times with anhydrous ether and then dried. 12.4 g of imidate hydrochloride are obtained in the form of a syrup. Yield: 71% calculated:
  • reaction mixture is stirred for 3 hours at room temperature and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and water is carefully added. The organic phase is washed with water and dried and the solvent is distilled off in vacuo.
  • the aqueous phase is extracted with ether, toluene and ether and then brought to pH 2 by adding hydrochloric acid.
  • the aqueous phase is shaken out with ethyl acetate and the organic phase is separated off and dried.
  • the solvent is removed in vacuo and the residue is dried. 0.87 g of product is obtained as a white solid. Yield 64% melting point: 179-181 ° C calculated:

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des spirocyclopentanimidazolinones biphényle-substituées déutérisées correspondant à la formule (I) et leur utilisation pour le traitement de maladies cardio-vasculaires telles que l'hypertension et l'insuffisance cardiaque, de troubles du système nerveux central, du glaucome, ainsi que de la néphropathie et de la rétinopathie diabétiques.
PCT/DE2003/000366 2002-02-07 2003-02-06 Spirocyclopentanimida zolinones deuterisees et leur utili sation pour le traitement de maladies cardio-vasculaires Ceased WO2003066627A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003208289A AU2003208289A1 (en) 2002-02-07 2003-02-06 Deuterated spirocyclopentanimidazolinones and the use thereof in the treatment of cardiovascular diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10205432A DE10205432A1 (de) 2002-02-07 2002-02-07 Deuterierte biphenylsubstituierte Spirocyclopentanimidazoline sowie diese Verbindungen enthaltende Arzneimittel
DE10205432.0 2002-02-07

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Publication Number Publication Date
WO2003066627A1 true WO2003066627A1 (fr) 2003-08-14

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Country Status (3)

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AU (1) AU2003208289A1 (fr)
DE (1) DE10205432A1 (fr)
WO (1) WO2003066627A1 (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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223269A (en) * 1989-08-31 1993-06-29 Andrejs Liepins Methods and composition for the treatment of hypertension
US5270317A (en) * 1990-03-20 1993-12-14 Elf Sanofi N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present
WO1995026325A2 (fr) * 1994-03-25 1995-10-05 Isotechnika Inc. Potentialisation de medicaments par deuteration_______________

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223269A (en) * 1989-08-31 1993-06-29 Andrejs Liepins Methods and composition for the treatment of hypertension
US5270317A (en) * 1990-03-20 1993-12-14 Elf Sanofi N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present
WO1995026325A2 (fr) * 1994-03-25 1995-10-05 Isotechnika Inc. Potentialisation de medicaments par deuteration_______________

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

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AU2003208289A1 (en) 2003-09-02
DE10205432A1 (de) 2003-08-21

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