WO1999001435A1 - Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique - Google Patents

Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique Download PDF

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Publication number
WO1999001435A1
WO1999001435A1 PCT/FR1998/001287 FR9801287W WO9901435A1 WO 1999001435 A1 WO1999001435 A1 WO 1999001435A1 FR 9801287 W FR9801287 W FR 9801287W WO 9901435 A1 WO9901435 A1 WO 9901435A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
alkyl group
phenyl
Prior art date
Application number
PCT/FR1998/001287
Other languages
English (en)
French (fr)
Inventor
Gérard Cremer
Christian Hoornaert
Original Assignee
Sanofi-Synthelabo
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 filed Critical Sanofi-Synthelabo
Priority to JP50651199A priority Critical patent/JP2002507983A/ja
Priority to AU82205/98A priority patent/AU8220598A/en
Priority to EP98932236A priority patent/EP0994857A1/fr
Publication of WO1999001435A1 publication Critical patent/WO1999001435A1/fr

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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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 present invention relates to derivatives of (1H-imidazol -4 -yl) piperidine, their preparation and their therapeutic use.
  • the compounds of the invention correspond to formula (I)
  • R 1 and R 2 each independently of one another represent either a hydrogen atom or a (0 2 -0) straight or branched alkyl group
  • R 2 forms a cycle of type - (CH 2 ) n CO- where n can take a value between 2 and 6, in the form of free bases or of addition salts with pharmaceutically acceptable acids.
  • the preferred compounds are those for which R 2 represents a (C 2 -C 4 ) straight or branched alkyl group, R 2 represents either a hydrogen atom or a (C 2 -C 4 ) alkyl group straight or branched, R 3 represents either a hydrogen atom, a halogen atom, or a (C 1 -C) alkyl group, or a trifluoromethyl group, or a (C 2 -C 4 ) alkoxy group, R 4 represents either a hydrogen atom or a halogen atom, and A represents either a hydrogen atom, or a (C 1 -C 6 ) straight or branched alkyl group, or a phenyl (C 2 -C) group 4 ) alkyl, either a group -
  • R x , R 3 and R 4 being as defined above, A and R 2 form a cycle of type - (CH 2 ) n C0- where n can take a value between 2 and 6, in the state of free bases or addition salts with pharmaceutically acceptable acids.
  • the compounds of formula (I) can be prepared according to the process illustrated in scheme 1 in which the group -C (C 6 H 5 ) 3 represents a triphenylmethyl protective group (trityl group).
  • a compound of formula (II) in which Hal represents a halogen atom and R 3 and R 4 are as defined above is reacted with a compound of formula (III) in which R x is as defined above, in an aprotic solvent such as dimethylformamide in the presence Diagram 1
  • N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] -3-phenylprop-2-enamide This compound is obtained from N- [2- [ 4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] phenyl] - 3-phenylprop-2-enamide according to the method described in 1 example 1. 5.
  • N- 2 - [4- [5-methyl- (1-triphenylmethyl) - IH- imidazol -4- yl] piperidin- 1 -yl] phenyl] benzenemethane A 0.5 g (1 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H- imidazol-4-yl] piperidin-1-yl] benzeneamine, in solution in 7 ml of toluene, 0.102 ml (1 mmol) of benzaldehyde and 0.05 g are added para-toluene sulfonic acid. The mixture is brought to reflux temperature, the solvent is evaporated and a gum is obtained.
  • N-2 - [4- (5-methyl-1H-imidazol-4 -yl) piperidin-1-yl] phenyl] benzenemethane This compound is obtained from N-2 - [4- [5-methyl- ( 1- triphenylmethyl) -IH- imidazol -4 -y1] piperidin-1-yl] phenyl] benzenemethanamine described in Example 1.5.
  • -cC 3 H 7 represents a cyclopropyl group, cCgl ⁇ a cyclohex group and -C 6 H 5 a phenyl group
  • (x: y) means x moles of acid for y moles of base, the absence of any mention means that the compound is in the basic state, fum. represents a fumarate, HC1 a hydrochloride
  • 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 m), 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 the 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/FR1998/001287 1997-07-01 1998-06-19 Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique WO1999001435A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP50651199A JP2002507983A (ja) 1997-07-01 1998-06-19 （１ｈ−イミダゾール−４−イル）ピペリジン誘導体、それらの製造およびそれらの治療における応用
AU82205/98A AU8220598A (en) 1997-07-01 1998-06-19 (1h-imidazol-4-yl)piperidine derivatives, preparation and application in therapy
EP98932236A EP0994857A1 (fr) 1997-07-01 1998-06-19 DERIVES DE (1$i(H)-IMIDAZOL-4-YL)PIPERIDINE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9708256A FR2765580B1 (fr) 1997-07-01 1997-07-01 Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique
FR97/08256 1997-07-01

Publications (1)

Publication Number Publication Date
WO1999001435A1 true WO1999001435A1 (fr) 1999-01-14

Family

ID=9508676

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1998/001287 WO1999001435A1 (fr) 1997-07-01 1998-06-19 Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique

Country Status (7)

Country Link
EP (1) EP0994857A1 (xx)
JP (1) JP2002507983A (xx)
AR (1) AR013149A1 (xx)
AU (1) AU8220598A (xx)
FR (1) FR2765580B1 (xx)
WO (1) WO1999001435A1 (xx)
ZA (1) ZA985727B (xx)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085723A1 (en) * 2000-05-08 2001-11-15 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands (ii)
US6887870B1 (en) 1999-10-12 2005-05-03 Bristol-Myers Squibb Company Heterocyclic sodium/proton exchange inhibitors and method
US7834001B2 (en) 2004-11-10 2010-11-16 Piramal Life Sciences Limited Tricyclic guanidine derivatives as sodium-proton exchange inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4357341A (en) * 1981-05-22 1982-11-02 The United States Of America As Represented By The Department Of Health And Human Services Specific irreversible antagonism of histamine receptors by photoaffinity actuated compounds
EP0507650A1 (fr) * 1991-04-03 1992-10-07 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4357341A (en) * 1981-05-22 1982-11-02 The United States Of America As Represented By The Department Of Health And Human Services Specific irreversible antagonism of histamine receptors by photoaffinity actuated compounds
EP0507650A1 (fr) * 1991-04-03 1992-10-07 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique

Cited By (7)

* 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
WO2001085723A1 (en) * 2000-05-08 2001-11-15 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands (ii)
GB2379443A (en) * 2000-05-08 2003-03-12 Black James Foundation Gastrin and cholecystokinin receptor ligands (ii)
GB2379443B (en) * 2000-05-08 2004-08-04 Black James Foundation Gastrin and cholecystokinin receptor ligands (II)
US6878734B2 (en) 2000-05-08 2005-04-12 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands(II)
US7834001B2 (en) 2004-11-10 2010-11-16 Piramal Life Sciences Limited Tricyclic guanidine derivatives as sodium-proton exchange inhibitors
US8183234B2 (en) 2004-11-10 2012-05-22 Piramal Life Sciences Limited Tricyclic guanidine derivatives as sodium-proton exchange inhibitors

Also Published As

Publication number Publication date
EP0994857A1 (fr) 2000-04-26
FR2765580A1 (fr) 1999-01-08
AR013149A1 (es) 2000-12-13
JP2002507983A (ja) 2002-03-12
FR2765580B1 (fr) 1999-08-06
AU8220598A (en) 1999-01-25
ZA985727B (en) 1999-01-27

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