EP0991639A1 - 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilid derivate, ihre herstellung und verwendung als arzneimittel - Google Patents

4-[(1h-imidazol-4-yl)piperidin-1-yl]anilid derivate, ihre herstellung und verwendung als arzneimittel

Info

Publication number
EP0991639A1
EP0991639A1 EP98932237A EP98932237A EP0991639A1 EP 0991639 A1 EP0991639 A1 EP 0991639A1 EP 98932237 A EP98932237 A EP 98932237A EP 98932237 A EP98932237 A EP 98932237A EP 0991639 A1 EP0991639 A1 EP 0991639A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
straight
cyclo
branched alkyl
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.)
Withdrawn
Application number
EP98932237A
Other languages
English (en)
French (fr)
Inventor
Gérard Cremer
Marc Daumas
Marie-Angèle ADLER
Geneviève DELLAC
Véronique ROUANNET
Christian Hoornaert
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.)
Sanofi Aventis France
Original Assignee
Sanofi Synthelabo SA
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 Sanofi Synthelabo SA filed Critical Sanofi Synthelabo SA
Publication of EP0991639A1 publication Critical patent/EP0991639A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the subject of the present invention is derivatives of 4- [(1H-imidazol-4-yl) piperidin-1-yl] anilide, their preparation and their therapeutic application.
  • R- L represents either a hydrogen atom or a group
  • R 2 represents either a (C ⁇ Cg) straight or branched alkyl group, or a cyclo (C 3 -C 7 ) alkyl group, or a cyclo (C 3 -C 7 ) (C j ⁇ -Cg) alkyl and
  • R 3 represents either a group -OR 4 or a group
  • the preferred compounds are those for which
  • R x represents a (C- L -C ⁇ straight or branched alkyl group
  • R 2 represents either a (C ⁇ C) straight or branched alkyl group, or a cyclo (C 3 -C 7 ) alkyl group
  • R 3 represents either a group -OR 4 , or a group -O (CH 2 ) n NR 5 R 6 , or a group -NHC (NH) NH 2 , or a group -NHC (NH) N (CH 3 ) 2 , or a group -NR 5 R 6 , i.e. a group
  • the oxygen atom and the groups -CHR 8 , -NR 8 , R 4 , R 5 , R 6 , R 7 and R 8 being independently of each other, a hydrogen atom, a group (C- L -Cg) straight or branched alkyl, a phenyl group, a phenyl (C ⁇ Cg) alkyl group or a heteroaryl group of 5 to 6 sides, the heteroatom being a nitrogen atom, m is equal to 1 or 2 and n is 2, 3 or 4, in the form of free bases or of addition salts with pharmaceutically acceptable acids.
  • R- ⁇ represents a (C- L -C J ) straight or branched alkyl group
  • R 2 represents either a (C ⁇ Cg) straight or branched alkyl group, or a cyclo group (C 3 -C 7 ) alkyl
  • R 3 represents either a group -NHC (NH) NH 2 , or a group
  • the compounds of choice are chosen from 3- [(cyclopropylcarbonyl) amino] -N- [2- (dimethylamino) ethyl] -4- [4- (5-methyl-1H-imidazol-4-yl) piperidin- 1-yl] benzamide, the
  • the compounds of formula (I) can be prepared according to the methods illustrated in schemes 1 and 2; in these diagrams the group -C (C 6 H 5 ) 3 represents a triphenylmethyl protective group (trityl group).
  • the compounds of formula (Ie) can be prepared by reacting the corresponding compounds of formula (Ia) in which R 3 represents a group -0R 4 , R 4 being a hydrogen atom, with a compound of formula R 3 H in an aprotic solvent such as dimethylformamide in the presence of a base such as N, N-diisopropylethylamine and of 1,1 '-carbonyldiimidazole then by carrying out deprotection of the imidazole nucleus under known conventional conditions of the skilled person.
  • aprotic solvent such as dimethylformamide
  • the dimethylformamide is evaporated, the residue is taken up in ether and it is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (90:10). The appropriate fractions are combined, evaporated to dryness and recrystallized from a water: methanol mixture (1: 1). It is filtered and dried under vacuum over phosphorus pentoxide.
  • R -c (C 3 H 7 ) represents a cyclopropyl group, in the column” Salt “,” fum. “represents a fumarate and” chlor. "a hydrochloride; the parenthesis ratios represent the ratio (acid: base ); the absence of any mention means that the co is in base form, in the column "Melting point or M + H", (d) corresponds to a melting with decomposition; melting point for compounds 1 to 14 and M + H for compounds 15 to 23
  • the compounds of the invention have been the subject of pharmacological studies which have demonstrated their inhibitory properties of the sodium / proton exchanger and their advantage as substances with therapeutic activity.
  • the compounds of the invention were subjected to a test for inhibiting the swelling of rabbit blood platelets in an acid medium according to the method of Grinstein et al. (In Methods in Enzymology, Fleisher S. And Flusher B., Vol 173, pp 777-790, Académie Press Inc., 1984).
  • Platelet-rich plasma is obtained by centrifugation at 1200 rpm for 20 minutes at room temperature. After measuring the initial average platelet volume, an aliquot of PRP is incubated for 20 minutes in a sodium propionate / propionic acid medium (140 mM) containing potassium chloride (1 mM), magnesium chloride (1 mM), glucose (10 mM), all buffered with Hepes (20 mM) at pH 6.7 and the osmolarity of which is approximately 300 mosm / 1.
  • Propionic acid diffuses into the platelets where it dissociates, causing intra-cellular acidification and activation of the sodium / proton antiport.
  • the influx of sodium ions is accompanied by a capture of water which causes the swelling of the platelets.
  • the measurement of. mean platelet volume at the end of the incubation, minus the initial mean platelet volume, makes it possible to estimate the maximum swelling of the platelets.
  • the products to be tested are added to the propionic acid incubation medium at the desired concentrations, before the addition of PRP. The results are expressed as a percentage of inhibition of maximum swelling making it possible to calculate the IC 50 or concentration inhibiting by 50% the maximum swelling.
  • the IC 50 of the most interesting compounds of the invention are less than 10 ⁇ M.
  • the compounds of the invention can be used alone or in combination with other substances such as nitrates, calcium antagonists, beta-blockers, antithrombotics, thrombolytics, salicylates.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP98932237A 1997-06-25 1998-06-19 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilid derivate, ihre herstellung und verwendung als arzneimittel Withdrawn EP0991639A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9707900 1997-06-25
FR9707900A FR2765221B1 (fr) 1997-06-25 1997-06-25 Derives de 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilide, leur preparation et leur application en therapeutique
PCT/FR1998/001288 WO1999000379A1 (fr) 1997-06-25 1998-06-19 Derives de 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilide, leur preparation et leur application en therapeutique

Publications (1)

Publication Number Publication Date
EP0991639A1 true EP0991639A1 (de) 2000-04-12

Family

ID=9508386

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98932237A Withdrawn EP0991639A1 (de) 1997-06-25 1998-06-19 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilid derivate, ihre herstellung und verwendung als arzneimittel

Country Status (7)

Country Link
EP (1) EP0991639A1 (de)
JP (1) JP2002506458A (de)
AR (1) AR013127A1 (de)
AU (1) AU8220698A (de)
FR (1) FR2765221B1 (de)
WO (1) WO1999000379A1 (de)
ZA (1) ZA985518B (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6887870B1 (en) 1999-10-12 2005-05-03 Bristol-Myers Squibb Company Heterocyclic sodium/proton exchange inhibitors and method
US7501889B2 (en) 2004-04-26 2009-03-10 Rgb Systems, Inc. Method and apparatus for implementing soft switching in a class D amplifier
EP2734517B1 (de) * 2011-07-18 2017-08-30 Merck Patent GmbH Benzamide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2579596B1 (fr) * 1985-03-26 1987-11-20 Inst Nat Sante Rech Med (imidazolyl-4) piperidines, leur preparation et leur application en therapeutique
FR2671083B1 (fr) * 1990-12-31 1994-12-23 Inst Nat Sante Rech Med Nouvelles 4-(4-imidazolyl) piperidines substituees en 1, leur preparation ainsi que leurs applications therapeutiques.
FR2674855B1 (fr) * 1991-04-03 1994-01-14 Synthelabo Derives de piperidine, leur preparation et leur application en therapeutique.
FR2696177B1 (fr) * 1992-09-28 1995-05-12 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique.
DE4325822A1 (de) * 1993-07-31 1995-02-02 Hoechst Ag Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9900379A1 *

Also Published As

Publication number Publication date
FR2765221A1 (fr) 1998-12-31
FR2765221B1 (fr) 1999-07-30
ZA985518B (en) 1999-01-28
WO1999000379A1 (fr) 1999-01-07
AU8220698A (en) 1999-01-19
AR013127A1 (es) 2000-12-13
JP2002506458A (ja) 2002-02-26

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