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US 7,678,831 B2Granted
Butanoic acid derivatives, processes for the preparation thereof, pharmaceutical compositions comprising them, and therapeutic applications thereof
AssigneeMerck Patent GmbH
InventorsJean Jacques Zeiller, Hervè Dumas, Valérie Guyard-Dangremont, Isabelle Berard, Francis Contard, Daniel Guerrier, Gérard Ferrand, Yves Bonhomme
Life of this patent
Estimating the term…
Abstract
Compounds of the formula (I): in which R, R1 and R2 are as defined in the description, the use thereof for the treatment of dyslipidaemia, atherosclerosis and diabetes, pharmaceutical compositions comprising them, and . processes for the preparation of these compounds. Compounds of formula (I) are activators of PPARα and PPARα isoforms.
Claims11
Compound of the formula (I):
- in which:
- R is a hydrogen atom or a C1-C10 alkyl radical;
- R1 and R2, which may be identical or different, are:
- A.- either:
- R1 is:
- a (C6-C18)aryl radical bearing from two to five identical or different substituents G;
- a (C6-C18)aryl radical bearing a substituent G, itself comprising an optionally substituted (C6-C18)aryl radical and/or a saturated, unsaturated or aromatic, optionally substituted 5- to 8-membered monocyclic heterocyclic radical containing one or more O, N or S atoms;
- an optionally substituted (C6-C18)aryl radical, fused to a saturated or unsaturated 5- to 8-membered monocyclic or polycyclic nucleus optionally containing one or more hetero atoms chosen from oxygen and sulfur, the said nucleus itself being optionally substituted;
- an optionally substituted (C6-C18)aryl radical, fused to a saturated or unsaturated 6- to 8-membered monocyclic or polycyclic nucleus comprising at least one nitrogen atom as hetero atom, the said nucleus itself being optionally substituted;
- or
- a saturated, unsaturated or aromatic, 5- to 8-membered monocyclic heterocyclic radical containing one or more oxygen, nitrogen or sulphur atoms, optionally substituted by one or more of the following radicals;
- trifluoromethyl, a halogen atom, a C1-C6 alkylenediyl chain, a C1-C6 alkylenedioxy chain, nitro, cyano, (C1-C10)alkyl, (C2-C10)alkynyl, (C1-C10)alkylcarbonyl, (C1-C10)alkoxycarbonyl-A-, in which A represents (C1-C6)alkylene, (C2-C8)alkenylene or a bond, (C3-C10)cycloalkyl, trifluoromethoxy, di(C3-C10)alkylamino, (C1-C10)alkoxy(C3-C10)alkyl, (C1-C10)alkoxy, hydroxyl or oxo;
- and, in this case,
- R2 is:
- a phenyl, naphthyl, anthryl or phenanthryl radical;
- or
- an optionally substituted 5- to 8-membered monocyclic aromatic heterocyclic radical containing one or more O, N or S atoms;
- B.- or:
- R2 is:
- an optionally substituted biphenyl radical;
- or;
- an optionally substituted 5- to 8-membered monocyclic aromatic heterocyclic radical containing one or more O, N or S atoms;
- and, in this case,
- R1 is:
- an optionally substituted (C6-C18)aryl radical fused to a saturated or unsaturated 5- to 8-membered monocyclic or polycyclic nucleus optionally containing one or more hetero atoms chosen from oxygen and sulfur, the said nucleus itself being optionally substituted;
- an optionally substituted (C6-C18)aryl radical fused to a saturated or unsaturated 6- to 8-membered monocyclic or polycyclic nucleus bearing at least one nitrogen atom as hetero atom, the said nucleus itself being optionally substituted;
- or
- a saturated, unsaturated or aromatic, 5- to 8-membered monocyclic heterocyclic radical containing one or more hetero atoms chosen from oxygen, nitrogen or sulfur, optionally substituted by one or more of the following radicals:
- trifluoromethyl, a halogen atom, a C1-C8 alkylenediyl chain, a C1-C8 alkylenedioxy chain nitro, cyano, (C1-C10)alkyl, (C3-C10)alkynyl, (C1 -C10)alkylcarbonyl, (C1 -C10)alkoxycarbonyl-A-, in which A represents (C1-C8)alkylene, (C2-C8)alkenylene or a bond, (C3-C10)cycloalkyl, trifluoromethoxy, di(C1-C10)alkylamino, (C1 -C10)alkoxy(C3-C10)alkyl, (C1-C10)alkoxy, hydroxyl or oxo;
- G is trifluoromethyl;
- a halogen atom;
- styryl;
- a monocyclic or, bicyclic aromatic heterocyclic radical comprising one or more O, N or S atoms, wherein the monocyclic aromatic heterocyclic radical is thiophene, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole, thiadiazole, thianyl, triazine, pyran, thiopyran, morpholine, thiomorpholine, piperdine, thiazolidine, oxazolidine, tetrahydrothienyl, tetrahydrofuryl, pyrrolidine, isoxazolidine, imidazolidine and pyrazolidine, and wherein the bicyclic heteroaryls are indolizine, isoindole, indazole, benzimidazole, benzothiazole, benzoflurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pyrazolotriazine, pyrazolopyrimidine or pteridine, and optionally substituted by one or more radicals T as defined below;
- a group Het-CO—, in which Het represents an aromatic heterocyclic group, optionally substituted by one or more radicals T;
- a C1-C6 alkylenediyl chain;
- a C1-C6 alkylenedioxy chain;
- amino;
- nitro;
- cyano;
- (C1-C10)alkyl radical;
- (C2-C6)alkynyl radical;
- (C1-C10)alkylcarbonyl radical;
- (C1-C10)alkoxycarbonyl-A- radical, in which A represents (C1-C6)alkylene, (C2-C6)alkenylene radical or a bond;
- (C3-C10)cycloalkyl radical;
- trifluoromethoxy radical;
- di(C1-C10)alkylamino radical;
- (C1-C10)alkoxy(C1-C10)alkyl radical;
- (C1-C10)alkoxy radical;
- (C6-C18)aryloxy(CO)n—radical, in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryloxy(CO)n-(C2-C6)alkenyl radical, in which n is 0 or 1;
- (C6-C18)arylthio radical, in which aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryloxy(C1- C10)alkyl(CO)n, in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T;
- a saturated or unsaturated, monocyclic 5- to 8-membered heterocycle comprising one or more O, N or S atoms, optionally substituted by one or more radicals T;
- (C6-C18)arylcarbonyl radical optionally substituted by one or more radicals T;
- (C6-C18)arylcarbonyl-B-(CO)n- radical, in which n is 0 or 1, where B represents (C1-C6)alkylene or (C2-C6)alkenylene and the aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryl-C-(CO)n- radical, in which n is 0 or 1, C represents (C1-C6)alkylene or (C2-C6)alkenylene and aryl is optionally substituted by one or more radicals T;
- or a (C2-C10)alkynyl radical;
- and
- T is a halogen atom;
- (C1-C6)alkyl;
- (C1-C6)alkoxy;
- nitro;
- carboxyl;
- (C1-C6)alkoxy -carboxyl;
- and T may represent oxo in the case where it substitutes a saturated or unsaturated heterocycle;
- or alternatively T represents (C1-C6)alkoxycarbonyl(C1-C6)alkyl;
- or (C1-C6)alkylcarbonyl((C1-C6)alkyl)n-, in which n is 0 or 1;
- optical isomers thereof, or pharmaceutically acceptable addition salts thereof with acids or bases
- with the restriction that when R2 represents a phenyl radical not substituted by an aromatic or heteroaromatic radical, then R1 cannot represent a phenyl radical that is itself substituted by a phenyl or naphthyl radical.
66 more elements
A method for treating diabetes, dyslipidemia and/or atherosclerosis, comprising administering to a patient a compound of the formula (1):
- in which
- R is a hydrogen atom or a C1-C10 alkyl radical;
- R1 and R2, which may be identical or different, are:
- A.-either:
- R1 is:
- a (C6-C18)aryl radical bearing from two to five identical or different substituents G;
- a (C6-C18)aryl radical bearing a substituent G, itself comprising an optionally substituted (C6-C18)aryl radical and/or a saturated, unsaturated or aromatic, optionally substituted 5- to 8-membered monocyclic heterocyclic radical containing one or more hetero atoms chosen from O, N and S;
- an optionally substituted (C6-C18)aryl radical, fused to a saturated or unsaturated 5- to 8-membered monocyclic or polycyclic nucleus optionally containing one or more hetero atoms chosen from oxygen and sulfur, the said nucleus itself being optionally substituted;
- an optionally substituted (C6-C18)aryl radical, fused to a saturated or unsaturated 6- to 8-membered monocyclic or polycyclic nucleus comprising at least one nitrogen atom as hetero atom, the said nucleus itself being optionally substituted;
- or
- a saturated, unsaturated or aromatic, optionally substituted 5- to 8-membered monocyclic heterocyclic radical containing one or more oxygen, nitrogen or sulphur atoms;
- and, in this case,
- R2 is:
- a (C6-C18)aryl radical, which is optionally substituted and/or optionally fused to a saturated or unsaturated 5- to 8-membered monocyclic or polycyclic nucleus optionally containing one or more O, N or S atoms, said nucleus itself being optionally substituted;
- and
- an optionally substituted 5- to 8-membered monocyclic aromatic heterocyclic radical containing one or more O, N or S atoms;
- or
- B.-
- R2 is:
- a (C6-C18)aryl radical substituted by a (C6-C18)aryl radical, which is itself optionally substituted and/or optionally fused to a saturated or unsaturated 5- to 8-membered monocyclic or polycyclic nucleus optionally containing one or more O, N or S atoms, said nucleus itself being optionally substituted;
- and
- an optionally substituted 5- to 8-membered monocyclic aromatic heterocyclic radical containing one or more O, N or S atoms;
- and, in this case,
- R1 is:
- an optionally substituted (C6-C18)aryl radical fused to a saturated or unsaturated 5- to 8-membered monocyclic or polycyclic nucleus optionally containing one or more oxygen or sulphur atoms, said nucleus itself being optionally substituted;
- an optionally substituted (C6-C18)aryl radical fused to a saturated or unsaturated 6- to 8-membered monocyclic or polycyclic nucleus bearing at least one nitrogen atom, said nucleus itself being optionally substituted;
- and
- a saturated, unsaturated or aromatic, optionally substituted 5- to 8-membered monocyclic heterocyclic radical containing one or more oxygen, nitrogen or sulphur atoms;
- G is trifluoromethyl;
- a halogen atom;
- styryl;
- a monocyclic, bicyclic or tricyclic aromatic heterocyclic radical comprising one or more O, N or S atoms, and optionally substituted by one or more radicals T as defined below;
- a group Het-CO—, in which Het represents an aromatic heterocyclic group, optionally substituted by one or more radicals T;
- a C1-C6 alkylenediyl chain;
- a C1-C6 alkylenedioxy chain;
- amino;
- nitro;
- cyano;
- (C1-C10)alkyl radical;
- (C2-C6)alkynyl radical;
- (C1-C10) alkylcarbonyl radical;
- (C1-C10)alkoxycarbonyl-A- radical, in which A represents (C1-C6) alkylene, (C2-C6)alkenylene radical or a bond;
- (C3-C10)cycloalkyl radical;
- trifluoromethoxy radical;
- di(C1-C10)alkylamino radical;
- (C1-C10)alkoxy(C1-C10)alkyl radical;
- (C1-C10)alkoxy radical;
- (C6-C18)aryl radical optionally substituted by one or more radicals T;
- (C6-C18)aryl(C1-C10)alkoxy -(CO)n- radical, in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryloxy(CO)n- radical, in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryloxy(CO)n-(C2-C6)alkenyl radical, in which n is 0 or 1;
- (C6-C18)arylthio radical, in which aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryloxy(C1-C10)alkyl(CO)n, in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T;
- a saturated or unsaturated, monocyclic 5- to 8-membered heterocycle comprising one or more O, N or S atoms, optionally substituted by one or more radicals T;
- (C6-C18)arylcarbonyl radical optionally substituted by one or more radicals T;
- (C6-C18) arylcarbonyl-B-(CO)n- radical, in which n is 0 or 1, where B represents (C1-C6)alkylene or (C2-C6)alkenylene and the aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryl-C -(CO)n- radical, in which n is 0 or 1, C represents (C1-C6)alkylene or (C2-C6)alkenylene and aryl is optionally substituted by one or more radicals T;
- (C6-C18)aryl radical fused to a saturated or unsaturated heterocycle as defined above, optionally substituted by one or more radicals T;
- or a (C2-C10)alkynyl radical;
- and
- T is a halogen atom;
- (C6-C18)aryl;
- (C1-C6)alkyl;
- (C1-C6)alkoxy;
- nitro;
- carboxyl;
- or (C1-C6)alkoxycarboxyl;
- or T may represent oxo in the case where it substitutes a saturated or unsaturated heterocycle;
- or alternatively T represents (C1-C6)alkoxycarbonyl(C1-C6)alkyl;
- or (C1-C6)alkylcarbonyl((C1-C6)alkyl)n-, in which n is 0 or 1;
- optical isomers thereof, or pharmaceutically acceptable addition salts thereof with acids or bases
- with the restriction that when R2 represents a phenyl radical not substituted by an aromatic or heteroaromatic radical, then R1 cannot represent a phenyl radical that is itself substituted by a phenyl or naphthyl radical.
69 more elements
Dependencies are inferred from the claim text.