FR2829766A1 - Composition useful in the treatment of pathologies associated with e.g. hyperglycemia, diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, and nephropathies, comprises oxamate derivatives - Google Patents
Composition useful in the treatment of pathologies associated with e.g. hyperglycemia, diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, and nephropathies, comprises oxamate derivatives Download PDFInfo
- Publication number
- FR2829766A1 FR2829766A1 FR0111950A FR0111950A FR2829766A1 FR 2829766 A1 FR2829766 A1 FR 2829766A1 FR 0111950 A FR0111950 A FR 0111950A FR 0111950 A FR0111950 A FR 0111950A FR 2829766 A1 FR2829766 A1 FR 2829766A1
- Authority
- FR
- France
- Prior art keywords
- radical
- optionally substituted
- aryl
- alkyl
- hydrogen atom
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Description
-I o RoO R2:,wNr,R3-I o RoO R2:, wNr, R3
R1 X^R4R1 X ^ R4
1 28297661 2829766
La présente invention concerne des dérivés d'oxamates comportant un hétérocycle azoté diversement substitué utiles dans le traitement de pathologies The present invention relates to oxamate derivatives comprising a nitrogenous heterocycle variously substituted useful in the treatment of pathologies.
associées au syndrome d'insulinorésistance. associated with insulin resistance syndrome.
Une demande de brevet W099462-37 de Novo Nordisk décrit des composés possédant un groupement de type oxamate utilisables dans le A patent application WO99462-37 of Novo Nordisk describes compounds having an oxamate type group which can be used in the
traitement du diabète.treatment of diabetes.
La présente invention vise à fournir de nouveaux composés ayant des The present invention aims to provide novel compounds having
propriétés améliorées.improved properties.
La présente invention a ainsi pour objet des composés de formule 1 0 générale (I): o RoO R2yN:R3 A subject of the present invention is thus compounds of general formula (I): o RoO R2yN: R3
R1:\X R4R1: \ X R4
(1) dans laquelle: R représente un atome d'hydrogène, un radical alkyle (Cl-C3), X représente un atome O ou S ou un radical -CR5R5'- ou -NR6-; R1, R2, R3 et R4 pouvant être indépendamment un atome d'hydrogène ou un radical alkyle (C1-C3); R5 et R5', indépendamment l'un de l'autre, représentent: un atome d'hydrogène, un radical hydroxyle, un radical alkyle (C1-C5), un radical de formule -CO-R7 ou un groupe aryle (C6-C14) éventuellement substitué; R6 pouvant être choisi parmi: un atome d'hydrogène; un radical alkyle (C1-C10) éventuellement substitué, un radical alkène (C2-C10) éventuellement substitué; un radical de formule: (1) in which: R represents a hydrogen atom, an alkyl radical (C1-C3), X represents an O or S atom or a -CR5R5'- or -NR6- radical; R1, R2, R3 and R4 possibly being independently a hydrogen atom or an alkyl radical (C1-C3); R5 and R5 ', independently of one another, represent: a hydrogen atom, a hydroxyl radical, an alkyl radical (C1-C5), a radical of formula -CO-R7 or an aryl group (C6- C14) optionally substituted; R6 may be chosen from: a hydrogen atom; an optionally substituted (C1-C10) alkyl radical, an optionally substituted (C2-C10) alkene radical; a radical of formula:
2 28297662 2829766
o R8 R8, m et n étant tels que définis ci-dessous; un radical aryle (C6C14) éventuellement substitué; un radical hétérocycle de 5 à 8 chainons comportant un ou plusieurs hétéroatomes (O. N. S) et éventuellement substitué; un radical sulfonyle substitué ou non par au moins un groupe choisi parmi: un radical alkyle (C1-C20) éventuellement substitué, perfluoroalkyle éventuellement substitué, aryle (C6-C14) éventuellement substitué, cycloalkyle de 5 à 8 chainons éventuellement substitué ou un hétérocycle de 5 à 8 chainons éventuellement substitué et comportant un ou plusieurs hétéroatomes O. N ou S et styryle éventuellement substitué, m et n, identiques ou différents, représentent 0 ou 1; R7 représente un radical hydroxyle, un radical alkyle (C1-C5), alkoxy (C1-C5), aryle (C6- C14), aryl(C6-C1 4)oxy; R8 pouvant être un atome d'hydrogène, un radical hydroxyle, alkoxy (C1-C5), alkyle (C1-C5), aikène (C2-C5) éventuellement substitué, cycloalkyle ou o R8 R8, m and n being as defined below; an optionally substituted (C6C14) aryl radical; a 5 to 8 membered heterocycle radical comprising one or more heteroatoms (O. N. S) and optionally substituted; a sulfonyl radical substituted or not with at least one group chosen from: an optionally substituted (C1-C20) alkyl radical, optionally substituted perfluoroalkyl, optionally substituted (C6-C14) aryl, optionally substituted 5 to 8-membered cycloalkyl or a heterocycle of 5 to 8 chain links optionally substituted and comprising one or more heteroatoms O. N or S and optionally substituted styryl, m and n, identical or different, represent 0 or 1; R7 represents a hydroxyl radical, an alkyl (C1-C5), alkoxy (C1-C5), aryl (C6-C14), aryl (C6-C1 4) oxy radical; R8 possibly being a hydrogen atom, a hydroxyl, alkoxy (C1-C5), alkyl (C1-C5), aikene (C2-C5) radical optionally substituted, cycloalkyl or
cycloalkoxy de 5 à 8 chainons éventuellement substitué, un radical aryle (C6- optionally substituted 5 to 8-membered cycloalkoxy, an aryl radical (C6-
C14) ou aryl(C6-C14)oxy éventuellement substitué, un hétérocycle ou hétéroaryloxy de 5 à 8 chainons éventuellement substitué et contenant un ou plusieurs hétéroatomes choisis parmi O. N ou S. un radical -NR9R'9, R9 et R'9, identiques ou différents, peuvent être un atome d'hydrogène, un radical alkyle (C1-C5) éventuellement substitué, un radical aryle (C6-C14) éventuellement substitué, un radical -COR7, R9 et R9' peuvent constituer un cycle de 3 à 10 chainons contenant éventuellement un ou plusieurs hétéroatomes O. N ou S; lorsque X représente -NR6, R1 et R6 peuvent former ensemble un cycle de 3 à chainons contenant éventuellement un ou plusieurs hétéroatomes O. N ou S; C14) or optionally substituted aryl (C6-C14) oxy, a 5 to 8 membered heterocycle or heteroaryloxy optionally substituted and containing one or more heteroatoms chosen from O. N or S. a radical -NR9R'9, R9 and R'9 , identical or different, can be a hydrogen atom, an optionally substituted (C1-C5) alkyl radical, an optionally substituted (C6-C14) aryl radical, a -COR7 radical, R9 and R9 'can constitute a ring of 3 10-membered optionally containing one or more heteroatoms O. N or S; when X represents -NR6, R1 and R6 can together form a 3-membered ring optionally containing one or more O. N or S heteroatoms;
3 28297663 2829766
à l'exclusion des composés présentant la formule (I) dans laquelle: - (i) X est NR6, o R6 représente un radical phényl substitué en position para par un radical méthyle et en position méta par un atome d'halogène; - (ii) X est NR6, o R6 représente un radical benzyle ou p-phénéthyle, - (iii) X est O et R1, R2, R3 et R4 représentent un atome d'hydrogène, - (iv) X est CR5R'5 et R1, R2, R3, R4, R5 et R'5 représentent un atome d'hydrogène, ainsi que leurs formes tautomères, énantiomères, diastéréoisomères et épimères with the exclusion of the compounds exhibiting formula (I) in which: - (i) X is NR6, o R6 represents a phenyl radical substituted in the para position with a methyl radical and in the meta position with a halogen atom; - (ii) X is NR6, o R6 represents a benzyl or p-phenethyl radical, - (iii) X is O and R1, R2, R3 and R4 represent a hydrogen atom, - (iv) X is CR5R'5 and R1, R2, R3, R4, R5 and R'5 represent a hydrogen atom, as well as their tautomeric, enantiomeric, diastereomeric and epimeric forms
et les sels pharmaceutiquement acceptables. and pharmaceutically acceptable salts.
Lorsque les radicaux aryle, aryloxy ou hétérocycle sont substitués, ils peuvent étre substitués par au moins un groupe choisi parmi un radical hydroxyle, un atome d'halogène, un radical alkoxy (C1-C5), alkyle (C1-C5-) éventuellement substitué, un radical cyano, un radical perfluoroalkyle (C1-C5), un radical perfluoroalkoxy (C1-C5), acyle (C1-C5), un groupement nitro, un radical -NR9R'9, un radical aryle (C6-C14), R9 et R'9 étant tels que définis ci dessus. Les radicaux aryl(C6-C14)alkyle(C1-C10), alkylaryle ou hétérocycle substitué par un radical aryle peuvent être interrompus par un groupement When the aryl, aryloxy or heterocycle radicals are substituted, they can be substituted by at least one group chosen from a hydroxyl radical, a halogen atom, an alkoxy (C1-C5), alkyl (C1-C5-) radical optionally substituted. , a cyano radical, a perfluoroalkyl radical (C1-C5), a perfluoroalkoxy (C1-C5), acyl (C1-C5) radical, a nitro group, a radical -NR9R'9, an aryl radical (C6-C14), R9 and R'9 being as defined above. The aryl (C6-C14) alkyl (C1-C10), alkylaryl or heterocycle radicals substituted with an aryl radical can be interrupted by a group
sulfonamide ou sulfone.sulfonamide or sulfone.
Lorsque les radicaux alkyle et alkène sont substitués, ils peuvent étre substitués par un ou plusieurs groupes suivants: groupe alkyle (C1-C5), un atome d'halogène, un radical -NR9R'9, R9 et R'9 étant tels que définis ci-dessus, hydroxyle, alkoxy (C1-C5), cyano, un radical de formule -CO-R7, R7. étant tel que défini ci-dessus, ary-le (C6-14) éventuellement substitué, aryloxy éventuellement substitué, hétérocycle de 5 à 8 chainons comportant un ou plusieurs hétéroatomes O. N ou S. cycloalkyle de 5 à 8 chainons contenant When the alkyl and alkene radicals are substituted, they can be substituted by one or more of the following groups: alkyl group (C1-C5), a halogen atom, a radical -NR9R'9, R9 and R'9 being as defined above, hydroxyl, alkoxy (C1-C5), cyano, a radical of formula -CO-R7, R7. being as defined above, optionally substituted (C6-14) aryl, optionally substituted aryloxy, 5 to 8 membered heterocycle comprising one or more O. N or S heteroatoms 5 to 8 membered cycloalkyl containing
éventuellement un ou plusieurs hétéroatomes O. N ou S. un radical sulfonyle. optionally one or more heteroatoms O. N or S. a sulfonyl radical.
Les radicaux cycloalkyle substitués sont de préférence substitués par au The substituted cycloalkyl radicals are preferably substituted with
moins un radical alkyle (C1-C5).less one alkyl radical (C1-C5).
Dans ce qui précède, parmi les radicaux aryle, on pourra citer comme structure homocarbonée le radical phényle, u-naphtyle, p-napUtyle, anthracénique ou fluorényle. Parmi les radicaux aryle, on préfère le radical In the foregoing, among the aryl radicals, mention may be made as the homocarbon structure of the phenyl, u-naphthyl, p-naphthyl, anthracene or fluorenyl radical. Among the aryl radicals, the radical
phényle ou naphtyle.phenyl or naphthyl.
Dans la présente invention, les hétérocycles sont éventuellement a romatiq u es (h été roaryl e) Parmi les radicaux hétérocycle, on pourra citer le cycle thiényle, benzothiazole, benzimidezole, diazine-1,2, imidezolyle, pyrazolyle, pyrazinyle, benzothiényle, morpholinyle, furyle, 2H-furyle, pyrrolyle, pyridyle, piperidinyle, pyrrolidinyle, quinoléinyle ou carbazolyle. On préfère, parmi les radicaux hétérocycle, le radical quinoléinyle, furyle, benzothiényle, morpholinyle ou In the present invention, the heterocycles are optionally aromatic (heterocycle) Among the heterocycle radicals, mention may be made of the thienyl, benzothiazole, benzimidezole, 1,2-diazine, imidezolyl, pyrazolyl, pyrazinyl, benzothienyl, morpholinyl ring , furyl, 2H-furyl, pyrrolyl, pyridyl, piperidinyl, pyrrolidinyl, quinolinyl or carbazolyl. Preference is given, among the heterocycle radicals, to the quinolinyl, furyl, benzothienyl, morpholinyl or
1 0 thiényle.10 thienyl.
Parmi les groupes alkyle ayant notamment de 1 à 20 atomes de carbone, linéaire ou ramifié, on peut notamment citer un radical méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertiobutyle, pentyl, hexyle, octyle, nonyle, décyle, dodécyle, pentadécyle, héxadécyle, 2-ethylhexyl, 2-méthylbutyle, 2 Among the alkyl groups having in particular from 1 to 20 carbon atoms, linear or branched, there may be mentioned in particular a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl radical, pentadecyl, hexadecyl, 2-ethylhexyl, 2-methylbutyl, 2
methylpentyle, 1-methylhexyle ou 3-methylhoptyle. methylpentyl, 1-methylhexyle or 3-methylhoptyle.
Parmi les groupes alkène, on peut notamment citer éthényl, propényl, 2 Among the alkene groups, mention may in particular be made of ethenyl, propenyl, 2
propényl, 2-méthyl-propényl, 2-méthyl-propène-2-yl. propenyl, 2-methyl-propenyl, 2-methyl-propen-2-yl.
Parmi les groupes alcoxy ayant de 1 à 6 atomes de carbone, on peut notamment citer un radical méthoxy, éthoxy, propoxy, isopropoxy, butoxy ou isobutoxy. Les radicaux (hétéro)aryloxy sont des radicaux (hétérocycliques) Among the alkoxy groups having 1 to 6 carbon atoms, mention may in particular be made of a methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy radical. (Hetero) aryloxy radicals are (heterocyclic) radicals
aromatiques liés avec le reste du composé par un atome d'oxygène. aromatics linked with the rest of the compound by an oxygen atom.
Parmi les radicaux cycloalkyle, on peut notamment citer le cyclopropyle, cycloLutyle, cyclopentyle ou le cyclohexyle, au moins un des carbones du cycle pouvant être remplacé par un hétérontome O. N ou S. Lorsqu'ils sont substitués, les cycloalkyle peuvent être substitués par un Among the cycloalkyl radicals, mention may in particular be made of cyclopropyl, cycloLutyl, cyclopentyl or cyclohexyl, at least one of the carbons of the ring possibly being replaced by an O. N or S heterontome. When they are substituted, the cycloalkyls can be substituted by a
radical alkyle (C1-C5), alkoxy (C1-C5) ou une fonction cétone. alkyl radical (C1-C5), alkoxy (C1-C5) or a ketone function.
Les radicaux cycloalkoxy sont des radicaux cycloalkyle liés avec le reste du Cycloalkoxy radicals are cycloalkyl radicals linked with the rest of the
composé par atome d'oxygène.compound per oxygen atom.
Parmi les groupes halogène, on peut notamment citer le fluor, le chlore, le Among the halogen groups, mention may in particular be made of fluorine, chlorine,
brome ou l'iode.bromine or iodine.
28297662829766
Parmi les cycles de 3 à 10 chainons contenant éventuellement un ou plusieurs hétéroatomes O. N ou S. on peut notamment citer le cycle Among the 3 to 10-membered rings optionally containing one or more O. N or S heteroatoms, mention may in particular be made of the ring
be nzi mid azol e.be nzi mid azol e.
Les composés exclus de la présente invention sont décrits dans le brevet The compounds excluded from the present invention are described in the patent
US 2 875 205 à titre d'agents antiparasitaires, dans une publication Acta Pol. US 2,875,205 as antiparasitic agents, in an Acta Pol publication.
Pharma. 28 (1971) 267-270 et dans la demande de brevet JP 62-209051 déposée par Sumitomo Kagaku Kogyo K.K L'invention se rapporte également aux formes tautomères, aux énantiomères, d iastéréoisomères et épimères d es composés de formu le Pharma. 28 (1971) 267-270 and in the patent application JP 62-209051 filed by Sumitomo Kagaku Kogyo K.K The invention also relates to the tautomeric forms, to the enantiomers, of iastereomers and epimers of the compounds of the formula.
générale (i).general (i).
Les composés de formule générale (I) possèdent des atomes d'azote, des fonctions carboxyliques et peuvent être monosalifiés ou disalifiés par des acides The compounds of general formula (I) have nitrogen atoms, carboxylic functions and can be monosalified or disalified by acids
minéraux ou organiques.mineral or organic.
Les composés de formule générale (I) comprennent aussi les solvates et les sels pharmaceutiquement acceptables. Les composés de l'invention de formule (I) définis tel que précédemment possédant une fonction suffisamment acide ou une fonction suffisamment basique ou les deux, peuvent inclure les sels correspondants d'acide organique ou minéral ou de base organique ou minérale The compounds of general formula (I) also include solvates and pharmaceutically acceptable salts. The compounds of the invention of formula (I) defined as previously possessing a sufficiently acidic function or a sufficiently basic function or both, can include the corresponding salts of organic or inorganic acid or of an organic or inorganic base.
pharmaceutiquement acceptables.pharmaceutically acceptable.
Il peut par exemple s'agir de sels tels que les chlorhydrate, acétate, benzoate, citrate, fumarate, embonate, chlorophénoxyacétate, glycolate, palmoate, aspartate, méthanesulfonate, maléate, parachlorophénoxyisobutyrate, formate, lactate, succin ate, sulfate, tartrate, cyclohexa necarboxyl ate, hexanoste, octanoate, décanoate, hexadécanoate, octodécanoate, benzènesulfonate, triméthoxybenzoste, paratoluènesulfonate, adamantanecarboxylate, glycoxylate, g lutamate, pyrrolidonocarboxylate, n apUtalènesulfonate, gl u cose-1 phosphate, nitrate, sulfite, dithionate, phosphate, dobesilate, thioctate, hippurate, 3 benzamidopropanoste, glucuronate, L-pyrrolidone-5-carboxylate, cholate, a It may for example be salts such as hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palmoate, aspartate, methanesulfonate, maleate, parachlorophenoxyisobutyrate, formate, lactate, succin ate, sulfate, tartrate, cyclohe necarboxyl ate, hexanoste, octanoate, decanoate, hexadecanoate, octodecanoate, benzenesulphonate, trimethoxybenzoste, paratoluenesulphonate, adamantanecarboxylate, glycoxylate, g lutamate, pyrrolidonocarboxylate, napUthalenesulphonate, phosphate, dithion-u-cose-1 hippurate, 3 benzamidopropanoste, glucuronate, L-pyrrolidone-5-carboxylate, cholate, a
glucose-1-phosphate, alginate, 4-amino-benzoste ou chondrotine sulfate. glucose-1-phosphate, alginate, 4-amino-benzost or chondrotin sulfate.
6 28297666 2829766
Les sels des composés de formule générale (I) sont avantageusement des The salts of the compounds of general formula (I) are advantageously
sels de métal alcalin, et de préférence de sodium, ou de métal alcalinoterreux. alkali metal, and preferably sodium, or alkaline earth metal salts.
Des exemples de sels des composés de formule générale (I) incluent des sels pharmacologiquement acceptables, tels que les sels de sodium, sels de potassium, sels de magnésium, sels de calcium, sels d'amine et autres sels du même type (aluminium, fer, bismuth, etc.). Les sels d'amine qui ne sont pas pharmacologiquement acceptables peuvent servir de moyen d'identification, de Examples of salts of compounds of general formula (I) include pharmacologically acceptable salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and the like (aluminum, iron, bismuth, etc.). Amine salts which are not pharmacologically acceptable may serve as a means of identification,
purification ou de dédoublement.purification or doubling.
Les composés de formule générale (I) peuvent être notamment préparés selon deux voies de synthèse: 1- Couplage d'un cycle aminé sur un chlorure d'oxalyle dans un solvant polaire à une température de -20 à 50 C, plus particulièrement 0-20 C, suivi d'une saponification dans un solvant polaire à une température de à 50 C, plus particulièrement 0-20 C, 2Couplage de la pipérezine sur un chlorure d'oxalyle dans un solvant polaire à une température de -20 à 50 C, plus particulièrement 0-20 C, suivi d'un couplage avec un chlorure d'acide dans un solvant polaire à une température de -20 à 50 C, plus particulièrement 0-20 C, et enfin une saponification dans un solvant polaire à une température de -20 à The compounds of general formula (I) can in particular be prepared according to two synthetic routes: 1- Coupling of an amino ring on an oxalyl chloride in a polar solvent at a temperature of -20 to 50 C, more particularly 0- 20 C, followed by saponification in a polar solvent at a temperature of to 50 C, more particularly 0-20 C, 2 Coupling of pipereine on an oxalyl chloride in a polar solvent at a temperature of -20 to 50 C , more particularly 0-20 C, followed by coupling with an acid chloride in a polar solvent at a temperature of -20 to 50 C, more particularly 0-20 C, and finally a saponification in a polar solvent at a temperature from -20 to
50 C, plus particulièrement 0-20 C. 50 C, more particularly 0-20 C.
Ainsi, la présente invention concerne également un procédé de préparation de composés de formule (I) tel que définis ci-dessus comprenant les étapes suivantes: (i) couplage d'un cycle aminé sur un chlorure d'oxalyle dans un solvant polaire à une température de -20 à 50 C, plus particulièrement 0-20 C, (ii) suivi d'une saponification dans un solvant polaire à une température de -20 à Thus, the present invention also relates to a process for the preparation of compounds of formula (I) as defined above comprising the following steps: (i) coupling of an amino ring on an oxalyl chloride in a polar solvent to a temperature of -20 to 50 C, more particularly 0-20 C, (ii) followed by saponification in a polar solvent at a temperature of -20 to
C, plus particulièrement 0-20 C. C, more particularly 0-20 C.
Elle concerne un autre procédé de préparation de composés de formule (I) tel que définis ci-dessus comprenant les étapes suivantes: (i) couplage de la pipérezine sur un chlorure d'oxalyle dans un solvant polaire à une température de -20 à 50 C, plus particulièrement 0-20 C, (ii) suivi d'un couplage avec un chlorure d'acide dans un solvant polaire à une température de -20 à 50 C, plus particulièrement 0-20 C, et (iii) enfin une saponification dans un solvant polaire à It relates to another process for the preparation of compounds of formula (I) as defined above comprising the following steps: (i) coupling of the pipereine to an oxalyl chloride in a polar solvent at a temperature of -20 to 50 C, more particularly 0-20 C, (ii) followed by coupling with an acid chloride in a polar solvent at a temperature of -20 to 50 C, more particularly 0-20 C, and (iii) finally a saponification in a polar solvent at
une température de -20 à 50 C, plus particulièrement 0-20 C. a temperature of -20 to 50 C, more particularly 0-20 C.
7 28297667 2829766
Le mode d'introduction d'un chlorure d'oxalyle sur un composé aminé est notamment décrit par Kubo, Akinori et al dans J.Org.Chem.; EN; 53; 18; 1988; 4295-4310. L'étape de saponification a été notamment décrite par Naumov, Yu.A. et al. dans J.Org.Chem.USSR (Engl.Transl.); EN; 12; 1976; 2428-2432; Zh.Org.Khim.; RU; 12; 1976; 2507-2511. Un groupe particulier de composés de formule (I) est celui dans laquelle X représente -NR6 o R6 représente un radical de formule: o R8 The method of introducing an oxalyl chloride into an amino compound is in particular described by Kubo, Akinori et al in J.Org.Chem .; IN; 53; 18; 1988; 4295-4310. The saponification step has been described in particular by Naumov, Yu.A. et al. in J.Org.Chem.USSR (Engl.Transl.); IN; 12; 1976; 2428-2432; Zh.Org.Khim .; RU; 12; 1976; 2507-2511. A particular group of compounds of formula (I) is that in which X represents -NR6 o R6 represents a radical of formula: o R8
R8, m et n étant tels que définis ci-dessus. R8, m and n being as defined above.
Un autre groupe particulier de composés de formule (I) est celui dans laquelle X représente -NR6 o R6 représente un radical sulfonyle Another particular group of compounds of formula (I) is that in which X represents -NR6 o R6 represents a sulfonyl radical
éventuellement substitué tel que défini ci-dessus. optionally substituted as defined above.
L'insulinorésistance se caractérise par une réduction de l'action de l'insuline (cf. Presse Médicale, 1997, 26(n 14), 671-677) et est impliquce dans un nombre important d'états pathologiques, tel que le diabète et plus particulièrement le diabète non-insulino-dépendant (diabète de type 11 ou NIDDM), la dyslipidémie, I'obésité, I'hypertension artérieile, ainsi que certaines complications microvasculaires et macrovasculaires comme l'athérosclérose, les rétinopathies Insulin resistance is characterized by a reduction in the action of insulin (cf. Presse Médicale, 1997, 26 (n 14), 671-677) and is involved in a large number of pathological conditions, such as diabetes. and more particularly non-insulin-dependent diabetes (type 11 diabetes or NIDDM), dyslipidemia, obesity, arterial hypertension, as well as certain microvascular and macrovascular complications such as atherosclerosis, retinopathies
et les neuropathies.and neuropathies.
A ce sujet, on se rapportera par exemple à Diabètes, vol 37, 1988, 1595 On this subject, we refer for example to Diabetes, vol 37, 1988, 1595
1607; Journal of Diabetes and its complications, 1998, 12, 110-119 ou Horm. 1607; Journal of Diabetes and its complications, 1998, 12, 110-119 or Horm.
Res., 1992, 38, 28-32.Res., 1992, 38, 28-32.
Les composés de l'invention présentent une forte activité hypoglycémiante. The compounds of the invention exhibit a strong hypoglycaemic activity.
Les composés de formule (I) sont donc utiles dans le traitement des pathologies associées à une hyperglycémie. Dans ce cas, les composés de formule (I) sont ceux précédemment décrits, en y incluant ceux antérieurement The compounds of formula (I) are therefore useful in the treatment of pathologies associated with hyperglycemia. In this case, the compounds of formula (I) are those previously described, including those previously
exclus par (i), (ii), (iii) et (iv). excluded by (i), (ii), (iii) and (iv).
La présente invention a donc également pour objet des compositions pharmaceutiques comprenant, à titre de principe actif, au moins un composé A subject of the present invention is therefore also pharmaceutical compositions comprising, as active principle, at least one compound.
3 28297663 2829766
seion i'invention, en y incluant ceux précédemment excius par (i), (ii), (iii) et (iv), according to the invention, including those previously excused by (i), (ii), (iii) and (iv),
dans un support pharmacologiquement acceptable. in a pharmacologically acceptable carrier.
Plus particulièrement, ces compositions sont destinées à traiter des pathologies associées à une hyperglycémie, telle que notamment le diabète, la dyslipidémie, I'obésité, I'hypertension artérielle, les neuropathies, les More particularly, these compositions are intended for treating pathologies associated with hyperglycemia, such as in particular diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies,
néphropathies ou l'athérosciérose. nephropathies or atheroscierosis.
Plus spécifiquement, ces compositions sont destinées à traiter le diabète. More specifically, these compositions are intended for treating diabetes.
La présente invention a aussi pour objet l'utilisation d'au moins un composé selon l'invention, en y incluant ceux précédemment exclus par (i), (ii), (iii) et (iv) pour la préparation d'une composition pharmaceutique destinée à traiter des A subject of the present invention is also the use of at least one compound according to the invention, including therein those previously excluded by (i), (ii), (iii) and (iv) for the preparation of a composition pharmaceutical intended to treat
pathologies associées à une hyperglycémie et plus spécifiquement le diabète. pathologies associated with hyperglycemia and more specifically diabetes.
Les compositions pharmaceutiques selon l'invention peuvent être présentées sous des formes destinées à l'administration par voie parentérale, The pharmaceutical compositions according to the invention can be presented in forms intended for parenteral administration,
orale, rectale, permuqueuse ou percutanée. oral, rectal, permucosal or percutaneous.
Elles seront donc présentées sous forme de solutés ou de suspensions injectables ou flacons multi-doses, sous forme de comprimés nus ou enrobés, de dragées, de capsules, de gélules, de pilules, de cachets, de poudres, de suppositoires ou de capsules rectales, de solutions ou de suspensions, pour They will therefore be presented in the form of solutes or injectable suspensions or multi-dose vials, in the form of naked or coated tablets, dragees, capsules, hard capsules, pills, cachets, powders, suppositories or rectal capsules. , solutions or suspensions, for
l'usage percutané dans un solvant polaire, pour l'usage permuqueux. percutaneous use in a polar solvent, for permucosal use.
Les excipients qui conviennent pour de telles administrations sont les dérivés de la cellulose ou de la cellulose microcristalline, les carbonates alcalino terreux, le phosphate de magnésium ou de potassium, les amidons, les amidons The excipients which are suitable for such administrations are cellulose or microcrystalline cellulose derivatives, alkaline earth carbonates, magnesium or potassium phosphate, starches, starches.
modifiés, le lactose, le glucose pour les formes solides. modified, lactose, glucose for solid forms.
Pour l'usage rectal, le bourre de cacao ou les stéarates de For rectal use, cocoa powder or cocoa stearates
polyéthylèneglycol sont les excipients préférés. polyethylene glycol are the preferred excipients.
Pour l'usage parentérai, I'eau, les solutés aqueux, le sérum physiologique, For parenteral use, water, aqueous solutions, physiological serum,
les solutés isotoniques sont les véhicules les plus commodément utilisés. isotonic solutes are the most conveniently used vehicles.
Sur la base de ses connaissances, I'homme du métier détermine aisément les adjuvants qui sont appropriés à la formulation désirée de la composition selon l'invention de manière à préparer un support pharmacologiquement On the basis of his knowledge, a person skilled in the art easily determines the adjuvants which are suitable for the desired formulation of the composition according to the invention so as to prepare a support pharmacologically.
acceptable.acceptable.
La posologie peut varier dans les limites importantes en fonction de l'indication thérapeutique et de la voie d'administration, ainsi que de l'âge et du The dosage may vary within wide limits depending on the therapeutic indication and the route of administration, as well as on age and
9 28297669 2829766
poids du sujet. Ainsi, en moyenne, pour un patient pesant environ 75kg, la dose journalière peut varier de 0,5 mg à 1000 mg/kg, de préférence de 0,5 mg à 500 mg/kg, de manière plus préférentielle de 0,05 mg à 100 mg/kg, et subject weight. Thus, on average, for a patient weighing about 75kg, the daily dose may vary from 0.5 mg to 1000 mg / kg, preferably from 0.5 mg to 500 mg / kg, more preferably from 0.05 mg. at 100 mg / kg, and
avantageusement de 0,01 mg à 20 mg/kg de poids corporel. preferably from 0.01 mg to 20 mg / kg of body weight.
Les exemples suivants illustrent l'invention, sans toutefois la limiter. The following examples illustrate the invention without, however, limiting it.
A- Exemple de préparation de composé de formule (I) Voie 1 - Préparation de l'acide l4-(3-methoxy-phenyl)-piperazin-1-yl]-oxo acétique A 10 g (0, 052 mol) de 1-(3-methoxyphenyl)-piperezine dans 125 ml de THF à 0 C, on ajoute 8,62 g de carbonate de potassium (1,2 éq.) et 7,07 g de chlorure d'éthoxalyle dans 30 ml de toluène. Le mélange est agité pendant 3 h à température ambiante. Après hydrolyse (100 ml, H20), le produit est extrait 3 fois avec du dichlorométhane. Les phases organiques rassemblées sont séchées sur du sulfate de magnésium puis concentrées sous vide pour obtenir A- Example of preparation of compound of formula (I) Route 1 - Preparation of 14- (3-methoxy-phenyl) -piperazin-1-yl] -oxoacetic acid A 10 g (0.052 mol) of 1 - (3-methoxyphenyl) -piperezine in 125 ml of THF at 0 C, 8.62 g of potassium carbonate (1.2 eq.) And 7.07 g of ethoxalyl chloride in 30 ml of toluene are added. The mixture is stirred for 3 h at room temperature. After hydrolysis (100 ml, H20), the product is extracted 3 times with dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated under vacuum to obtain
6,7 g d'une huile orange (0,023 mol. 44%). 6.7 g of an orange oil (0.023 mol. 44%).
A 6,6 g (0,023 mol) de l'ester éthylique de l'acide [4-(3-methoxy-phenyl) piperezin-1-yl]-oxo-acétique dans 28 ml de méthanol, on ajoute 1,89 g (1 éq.) de NaOH et on agiteà température ambiante pendant 10 h. Le produit est filtré, séché pour obtenir 6,1 g (0.021 mol. 93%) de l'acide [4-(3methoxy-phenyl) piperezin-1-yl]-oxo-acétique sous forme de poudre blanche, un produit de To 6.6 g (0.023 mol) of [4- (3-methoxy-phenyl) piperezin-1-yl] -oxo-acetic acid ethyl ester in 28 ml of methanol is added 1.89 g (1 eq.) Of NaOH and stirred at room temperature for 10 h. The product is filtered and dried to obtain 6.1 g (0.021 mol. 93%) of [4- (3methoxy-phenyl) piperezin-1-yl] -oxo-acetic acid in the form of a white powder, a product of
formule (I).formula (I).
Voie 2 - Préparation de l'ester éthylique de l'acide 2-oxo-[4-(toluene-4 sulfonyl)-piperazin-1 -yl]-acétique A 86,14 g (1 mol) de piperazine dans 800 ml d'acide acétique, on ajoute 75 ml d'une solution de chlorure d'éthoxalyle dans l'acide acétique (0,667 mol). Le mélange est agité pendant 10 h à température ambiante. Après filtration du précipité, le filtrat est concentré sous vide, puis le produit purifié sur colonne chromatographique (silice, éluant dichlorométhane/MeOH 10%) pour obtenir 94 g de l'ester éthylique de l'acide 2-oxo-2-piperezin-1-yl acétique. 90, 0 g (0,483 mol. 61 %) de sel de chlorhydrate sont obtenus après ajout d'une solution 7N HCI Route 2 - Preparation of 2-oxo- [4- (toluene-4 sulfonyl) -piperazin-1 -yl] -acetic acid ethyl ester A 86.14 g (1 mol) of piperazine in 800 ml of Acetic acid, 75 ml of a solution of ethoxalyl chloride in acetic acid (0.667 mol) are added. The mixture is stirred for 10 h at room temperature. After filtration of the precipitate, the filtrate is concentrated under vacuum, then the product purified on a chromatographic column (silica, eluent dichloromethane / MeOH 10%) to obtain 94 g of the ethyl ester of 2-oxo-2-piperezin- acid. 1-yl acetic. 90.0 g (0.483 mol. 61%) of hydrochloride salt are obtained after addition of a 7N HCl solution
dans l'éthanol.in ethanol.
A 50 mg (0,224 mmol) de l'ester éthylique-de l'acide 2-oxo-2-piperezin-1yl acétique dans 5 ml de dichlorométhane, on ajoute 30 1ll de triéthylamine (2 éq) et 1.1 éq. de toluène sulfonyl. Le mélange réactionnel est agité pendant 10 h. Le mélange est filtré sur silice (acétate d'éthyle), le solvant évaporé pour obtenir 675 To 50 mg (0.224 mmol) of 2-oxo-2-piperezin-1yl acetic acid ethyl ester in 5 ml of dichloromethane, 30 µl of triethylamine (2 eq) and 1.1 eq are added. of toluene sulfonyl. The reaction mixture is stirred for 10 h. The mixture is filtered on silica (ethyl acetate), the solvent evaporated to obtain 675
mg (0,198 mmol, 88,5 %) de l'ester éthyliqe de l'acide 2-oxo-4-(toluene-4- mg (0.198 mmol, 88.5%) 2-oxo-4- (toluene-4-) ethyl ester
sulfonyl)-piperazin-1 -yl]-acétique. sulfonyl) -piperazin-1 -yl] -acetic.
On a rassemblé dans le tableau A les formules et caractéristiques des composés The formulas and characteristics of the compounds are collated in Table A.
de formule (I).of formula (I).
Tableau ATable A
Composé Structure Pf en RMN 'H C 200 MHz ppm (Kofler) Compound Structure Pf in NMR 'H C 200 MHz ppm (Kofler)
1,CH3 >250 C D201, CH3> 250 C D20
Ol. 2.9 (m, 4H) 3.35 (dt, 4H) 5.55 (sn 3H) N/ O 66542((md 12H 'N::ONa 7.1 (t,1 H 2 /\ >250 C DMSO-d6 3.18 (s,4H) N O 36.5990 ((St 14HH) :'NlONa 7. 32 (t 2H) O Ol. 2.9 (m, 4H) 3.35 (dt, 4H) 5.55 (sn 3H) N / O 66542 ((md 12H 'N :: ONa 7.1 (t, 1 H 2 / \> 250 C DMSO-d6 3.18 (s, 4H ) NO 36.5990 ((St 14HH): 'NlONa 7.32 (t 2H) O
1 1 28297661 1 2829766
O >250 CDMSO-c16 11 O 3.24 (t 4H) /\N 3.43 (t 4H) J ONa 7.06 (cl 2H) F F 1 l t 4F >250 C DMSO-d6 11 O 3.37 (t 4H) /\N 3.69 (t 4H) Clf<N J ONa 717 (cicl 1H) 1 7.62(cl 1H) C O >250 C DMSO-d6 1 O 1.95 (s 3H) /\N 2.00 (s 3H) H3CNwJ ONa 2 83 (t 4H) 6.49 (dd H) H3C \' 6.60 (s 1H) 6.80 (d H) 6 CI1 DMSO-c16 F N/ O 734704(mt 24H) F N d4:oNa 7.74 (cl 2H) >250 C DMSO-d6 - O. L 1.73 (m 2H) / ONa 2.37 (t 4H) I 2.58 (m 4H) N: 3.40 (t 4H) J 7.30 (m 5H) O> 250 CDMSO-c16 11 O 3.24 (t 4H) / \ N 3.43 (t 4H) J ONa 7.06 (cl 2H) FF 1 lt 4F> 250 C DMSO-d6 11 O 3.37 (t 4H) / \ N 3.69 ( t 4H) Clf <NJ ONa 717 (cicl 1H) 1 7.62 (cl 1H) CO> 250 C DMSO-d6 1 O 1.95 (s 3H) / \ N 2.00 (s 3H) H3CNwJ ONa 2 83 (t 4H) 6.49 ( dd H) H3C \ '6.60 (s 1H) 6.80 (d H) 6 CI1 DMSO-c16 FN / O 734704 (mt 24H) FN d4: oNa 7.74 (cl 2H)> 250 C DMSO-d6 - O. L 1.73 ( m 2H) / ONa 2.37 (t 4H) I 2.58 (m 4H) N: 3.40 (t 4H) J 7.30 (m 5H)
12 282976612 2829766
>DMSO-d6 AL 250 C2.24 (s,4H) 1 3.39 (s,4H) letJ 4.46 (s,1 H) \ 7.16(t,4H) I 7.46 (t,4H) F/ Id IN J 9 O > DMSO-d6 O 11 O 250 C 2.10 (q, 4H) oX;N ONa 3.21 (s, 2H) 6.60 (d, 1 H) 6.66 (d 2H) , O >250 C DMSO-d6 O 14: 2.97 (t, 4H) H3C NJ ONa 5 88 (s,1 H) 5.99 (d, 2H) > DMSO-d6 AL 250 C2.24 (s, 4H) 1 3.39 (s, 4H) letJ 4.46 (s, 1 H) \ 7.16 (t, 4H) I 7.46 (t, 4H) F / Id IN J 9 O > DMSO-d6 O 11 O 250 C 2.10 (q, 4H) oX; N ONa 3.21 (s, 2H) 6.60 (d, 1 H) 6.66 (d 2H), O> 250 C DMSO-d6 O 14: 2.97 ( t, 4H) H3C NJ ONa 5 88 (s, 1H) 5.99 (d, 2H)
H. C'.H. C '.
11 O >250 C DMSO-d6 0 1: 3.25 (d, 4H) ONa 3.68 (d, 4H) N 6.48 (d, 1 H) 6. 63 (d, 2H) J 7.22 (t,1 H) N. _ _ 12 >250 CDMSO-d6 2.60 (s,4H) O5oNa 333641 ((ds' 4H) 6.54 (m, 1 H) I I 6.79 (d, 1 H) N 7.55 (m, 3H) 1 7. 69 (d, 2H) 13 >250 C DMSO-d6 3.24 (s,4H) CIN O 638598 (d 14H) l N 7.03 (m, 2H) "' ONa 7.31 (t,1H) O 14 O >250 C DMSO-d6 2 89 s,4H EN ONa 6.74 (d, 2H) - 1 1. 6.93 (d, 2H) 11 O> 250 C DMSO-d6 0 1: 3.25 (d, 4H) ONa 3.68 (d, 4H) N 6.48 (d, 1 H) 6. 63 (d, 2H) J 7.22 (t, 1 H) N. _ _ 12> 250 CDMSO-d6 2.60 (s, 4H) O5oNa 333641 ((ds' 4H) 6.54 (m, 1 H) II 6.79 (d, 1 H) N 7.55 (m, 3H) 1 7. 69 (d , 2H) 13> 250 C DMSO-d6 3.24 (s, 4H) CIN O 638598 (d 14H) l N 7.03 (m, 2H) "'ONa 7.31 (t, 1H) O 14 O> 250 C DMSO-d6 2 89 s, 4H EN ONa 6.74 (d, 2H) - 1 1. 6.93 (d, 2H)
H3C'-,>H3C '-,>
>250 C DMSO-d6 N ONa 2 08 (s 4H) 3 22 (s 4H) NJ O 7.14 (m, 1 OH 16 ONa 214 C D20 O. ( 1.96 (s,3H) O 2.20 (s,4H) N 3.13 (m, 4H) > 250 C DMSO-d6 N ONa 2 08 (s 4H) 3 22 (s 4H) NJ O 7.14 (m, 1 OH 16 ONa 214 C D20 O. (1.96 (s, 3H) O 2.20 (s, 4H) N 3.13 (m, 4H)
17 206-D2017 206-D20
J] O 208 C2.37 (s, 6H) \N \ 3.26 (t, 2H) Ho/\/NwJ ONa 3 35 (t 2H) J] O 208 C2.37 (s, 6H) \ N \ 3.26 (t, 2H) Ho / \ / NwJ ONa 3 35 (t 2H)
18 O 198 CD2018 O 198 CD20
11 O 1.26 (t, 3H) I 2.55 (m, 6H) H3C:'NJ ONa 3.59 (m, 4H) 11 O 1.26 (t, 3H) I 2.55 (m, 6H) H3C: 'NJ ONa 3.59 (m, 4H)
19 206-D2019 206-D20
H C 11 O 208 C1.22 (m, 6H) N 2.58 (t,1 H) 0 ONa 3 i4 (m 3H) 4.21 (d, lH) CH3 N'N >250 C3.31 (t, 2H) ONa 3.40 (t, 2H) O 3.54 (s,2H) HC 11 O 208 C1.22 (m, 6H) N 2.58 (t, 1H) 0 ONa 3 i4 (m 3H) 4.21 (d, lH) CH3 N'N> 250 C3.31 (t, 2H) ONa 3.40 (t, 2H) O 3.54 (s, 2H)
21 >250 CD2021> 250 CD20
ll 1 3.48 (s, 4H) Cl/<N N/ O 6 84 (d 1H) N: 7.59 (t,1H) : ONa 22 O 250 C DMSO-d6 Cl ONa 3.54 (s 8H) \ o'f NJ 0 7 10 (d 2H) 23 > 250 C DMSO-d6 / 1.94 (s+m 5H) H3C \1 1 0 3.07 (m, 2H) / 3.57 (d, 1 H) 11 1 3.80 (d, 1 H) J 7.38 (m, 5H) ll 1 3.48 (s, 4H) Cl / <NN / O 6 84 (d 1H) N: 7.59 (t, 1H): ONa 22 O 250 C DMSO-d6 Cl ONa 3.54 (s 8H) \ o'f NJ 0 7 10 (d 2H) 23> 250 C DMSO-d6 / 1.94 (s + m 5H) H3C \ 1 1 0 3.07 (m, 2H) / 3.57 (d, 1 H) 11 1 3.80 (d, 1 H) J 7.38 (m, 5H)
28297662829766
24 >250 CDMSO-d6 J1 ONa 3.54 (m, 4H) /\N 3.73 (s, 4H) ,NJ O 7 13 (d 1H) O 7.96 (s,1 H) >250 CDMSO-d6 J: ONa. 1.43 (s, 9H) H3C 1'' 3.30 (s, 8H) 24> 250 CDMSO-d6 J1 ONa 3.54 (m, 4H) / \ N 3.73 (s, 4H), NJ O 7 13 (d 1H) O 7.96 (s, 1H)> 250 CDMSO-d6 J: ONa. 1.43 (s, 9H) H3C 1 '' 3.30 (s, 8H)
3 CH3(3 CH3 (
26 >250 C DMSO-d6 J: ONa 1.87 (m, 2H) N 2.05 (m, 2H) N J O 3.42 (m, 8H) O f \/ 3.81 (m, 2H) O 4.72 (t,- 1 H) 27 O'\ 235 C DMSO-d6 1 1 2.29 (m, 12H) \/\N/ O 33 45 (tt,44HH) NONa. 28 / N >250 C DMSO-d6 I \> O 4.06 (q, 2H) N N 4.26 (m, 2H) / \ 4.91 (d, 2H) -,ONa 7.33 (d, 2H) O 7.68 (m, 2H) 26> 250 C DMSO-d6 J: ONa 1.87 (m, 2H) N 2.05 (m, 2H) NJO 3.42 (m, 8H) O f \ / 3.81 (m, 2H) O 4.72 (t, - 1 H) 27 O '\ 235 C DMSO-d6 1 1 2.29 (m, 12H) \ / \ N / O 33 45 (tt, 44HH) NOa. 28 / N> 250 C DMSO-d6 I \> O 4.06 (q, 2H) N N 4.26 (m, 2H) / \ 4.91 (d, 2H) -, ONa 7.33 (d, 2H) O 7.68 (m, 2H)
29 >250 C- P2029> 250 C- P20
O NONa. 2 895 (s'42H) ONa'NJ O 3 327 (ss' 22H) O NO a. 2 895 (s'42H) ONa'NJ O 3 327 (ss' 22H)
>250 C D20> 250 C D20
1 29 (m, 5H) "NJ o 224724((mS, 4H l J 3.51 (s, 2H) \/ 3.60 (s, 2H) 1 29 (m, 5H) "NJ o 224724 ((mS, 4H l J 3.51 (s, 2H) \ / 3.60 (s, 2H)
31 O >260 CD2031 O> 260 CD20
ONa 3.71 t, 2H) SJ . 3.81 it, 2H)ONa 3.71 t, 2H) SJ. 3.81 it, 2H)
32 >260 CD2032> 260 CD20
Jo, 3 70 (s 8H) H if N J OJo, 3 70 (s 8H) H if N J O
33 240 C D2033 240 C D20
N ONa 1.45 (s 6H) 3 20 (dt 4H) ON ONa 1.45 (s 6H) 3 20 (dt 4H) O
34 248 C D2034 248 C D20
go 9 63 t,4 H Igo 9 63 t, 4 H I
215 C D20215 C D20
3 /\N 0 89 (t 6H) 1 2.66 (t,1H) 0 0. 3.27 (d, 1 H) 1 3.41 (m, 2H) CH3 3. 89 (d, 1 H) 3 / \ N 0 89 (t 6H) 1 2.66 (t, 1H) 0 0. 3.27 (d, 1 H) 1 3.41 (m, 2H) CH3 3. 89 (d, 1 H)
36 O >250 C D2036 O> 250 C D20
N'ONa 2 67 (m, 2H) \J 3.59 (d, 1 H) 11 1. 4.19 (dj 1H) . 7.25 (m, 5H) N'ONa 267 (m, 2H) \ J 3.59 (d, 1H) 11 1.19 (dj 1H). 7.25 (m, 5H)
37 250 C D2037 250 C D20
N/ O 323444((m, 64H)N / O 323444 ((m, 64H)
_ O 7 24 (: I 1_ O 7 24 (: I 1
1 7 28297661 7 2829766
38 O 236 CD2038 O 236 CD20
ONa 2 08 (s, 3H) \ 350 (m, 8H) H3Cf N. J o ONa 2 08 (s, 3H) \ 350 (m, 8H) H3Cf N. J o
39 / D2039 / D20
N 3.77(m,8H) N'1 >260 C 6.88( t,1 H) O 8,46 (d, 2H) N 3.77 (m, 8H) N'1> 260 C 6.88 (t, 1H) O 8.46 (d, 2H)
O D20O D20
J ONa >260 C 2.35(s,4H) N \ N 3.23 (m, 1 4H) og:WNJ J ONa> 260 C 2.35 (s, 4H) N \ N 3.23 (m, 1 4H) og: WNJ
41 D2041 D20
1 1 ONa 21 S- 0.93(t,6H) / 220 C 1.56(s,2H) 1 O 2.4(m,6H) N,/ 3.50(d,4H) 42 1 ON >250 C 1.36(dd,D32HO) O N \r: a 3.1 7(m,4H) NJ ô 4.30(m,3H) HO O 1 1 ONa 21 S- 0.93 (t, 6H) / 220 C 1.56 (s, 2H) 1 O 2.4 (m, 6H) N, / 3.50 (d, 4H) 42 1 ON> 250 C 1.36 (dd, D32HO) ON \ r: a 3.1 7 (m, 4H) NJ ô 4.30 (m, 3H) HO O
On donnera ci-après des résultats des études pharmacologiques. The results of pharmacological studies will be given below.
ETUDE DE L'ACTIVITE ANTIDIABETIQUE CHEZ LE RAT NOSTZ STUDY OF ANTIDIABETIC ACTIVITY IN RAT NOSTZ
On a déterminé l'activité antidiabétique des composés de formule (I) par voie oral sur un modèle expérirnental de diabète non insulinodépendant, induit The antidiabetic activity of the compounds of formula (I) was determined orally on an experimental model of non-insulin-dependent diabetes, induced
chez le rat par la Streptozotocine.in rats by Streptozotocin.
1 8 28297661 8 2829766
Le modèle de diabète, non insulinodépendant, est obtenu chez le rat par un The non-insulin-dependent diabetes model is obtained in rats by a
indection néonatale de streptozotocine. neonatal streptozotocin indection.
Les rats diabétiques utilisés sont âgés de 8 semaines. La stabulation des animaux est réalisée, du jour de leur naissance au jour de l'expérimentation, dans une animalerie à température réqulée de 21 à 22 C et soumise à un cycle fixe de lumière (de 7 à 19 h) et d'obscurité (de 19 à 7 h). Leur alimentation a consisté en un régime d'entretien, eau et nourriture ont été fournies "ab libitum", à l'exception du jeûne de 2 heures précédent les tests o la nourriture est retirée The diabetic rats used are 8 weeks old. Stabling of animals is carried out, from the day of their birth to the day of the experiment, in an animal facility with a requisite temperature of 21 to 22 C and subjected to a fixed cycle of light (from 7 to 19 h) and darkness ( from 7 p.m. to 7 a.m.). Their diet consisted of a maintenance diet, water and food were provided "ab libitum", with the exception of the 2 hour fast preceding the tests where food was withdrawn.
(état postabsorptif).(postabsorptive state).
Les rats sont traités par voie orale pendant un (J1) ou quatre (J4) jours avec le produit à tester. Deux heures après la dernière administration du produit et 30 min utes après an esthésie des ani maux au Pentobarbital sod ique (Nembutal(), un prélèvement sanguin de 300 L est effectué à l'extrémité de la queue. The rats are treated orally for one (D1) or four (D4) days with the product to be tested. Two hours after the last administration of the product and 30 minutes after anesthesia of the animals with sodium pentobarbital (Nembutal (), a blood sample of 300 L is taken from the end of the tail.
A titre d'exemple sont rassemblés dans le tableau B des résultats obtenus. By way of example, the results obtained are collated in Table B.
Ces résultats montrent l'efficacité des composés de formule (I) pour faire diminuer la glycémie chez les animaux diabétiques. Ces résultats sont exprimés en pourcentage d'évolution de la glycémie à J1 et J4 (nombre de jours de These results show the effectiveness of the compounds of formula (I) for reducing blood sugar in diabetic animals. These results are expressed as a percentage change in glycemia on D1 and D4 (number of days of
traitement) par rapport à JO (avant le traitement). treatment) compared to OJ (before treatment).
Tableau BTable B
composés 20 m glkglJ 200 m glkglJ.compounds 20 m glkglJ 200 m glkglJ.
J1 J4 J1 J4J1 J4 J1 J4
-12 2-12 2
16 -15 -12 -8 -316 -15 -12 -8 -3
17 -8 -8 -13 -1617 -8 -8 -13 -16
19 -13 -5 -5 -1219 -13 -5 -5 -12
-15 -12 -14 -13-15 -12 -14 -13
21 9 1 -17 -1121 9 1 -17 -11
22 1 -12 -13 -1222 1 -12 -13 -12
24 -12 -8 -11 -524 -12 -8 -11 -5
31 -5 -13 -10 -731 -5 -13 -10 -7
33 9 -11 -8 -333 9 -11 -8 -3
34 -13 -18 -18 -1534 -13 -18 -18 -15
-13 -26 -17 -22-13 -26 -17 -22
36 -20 - 15 -23 -1836 -20 - 15 -23 -18
49 282976649 2829766
38 -18 -24 -16 -1838 -18 -24 -16 -18
39 -10 -12 -8 -639 -10 -12 -8 -6
-10 0 -4 0-10 0 -4 0
41 8 5 0 441 8 5 0 4
42 -1 -2 -4 -742 -1 -2 -4 -7
D'autres composés ont été synthétisés, puis analysés; il sont présentés Other compounds were synthesized, then analyzed; they are presented
dans le tableau (C) suivant.in the following table (C).
Composé structure Masse Masse Pureté Temps théorique M trouvoe (%) rétention (g) (g) (mix) Compound structure Mass Mass Purity Theoretical time M found (%) retention (g) (g) (mix)
43 O O 324 24 301.1 96 2 343 O O 324 24 301.1 96 2 3
Fat 44 rage,] a (:i: 25: OMe - N. Na 286.27 263.1 99 2.60 Fat 44 rage,] a (: i: 25: OMe - N. Na 286.27 263.1 99 2.60
28297662829766
46 N Na 286.27 263.1 99 2.61 47 Na 307.28 97.4 2.21 N 46 N Na 286.27 263.1 99 2.61 47 Na 307.28 97.4 2.21 N
48 N 325.13 100 1.0748 N 325.13 100 1.07
Cltç:Nw: On 49Onto 316.29 9927.1306- 1.16 H3C,O391,N'J ONa at, = 72.23- 0. 96 51 o 270.27 96.78 Cltç: Nw: On 49Onto 316.29 9927.1306- 1.16 H3C, O391, N'J ONa at, = 72.23- 0. 96 51 o 270.27 96.78
H3CN: ON 96.79H3CN: ON 96.79
52 -at-_ 707 _ 100 2.0152 -at-_ 707 _ 100 2.01
53 CH3 INS 284.29 100 2.2653 CH3 INS 284.29 100 2.26
:-0a: -0a
2 1 28297662 1 2829766
54'- 1: 274.23 92.5 0.53354'- 1: 274.23 92.5 0.533
' I";$l',. 274.23 95.6-99 0.525'I "; $ l' ,. 274.23 95.6-99 0.525
56 N O 281.25 74 0.52556 N O 281.25 74 0.525
N 57 tall') J 254 2s 962-99 0.525 8 ON 0 Na _ _ _. - 59 t'l:;, Hi. 301. 24 0.45 N 57 tall ') J 254 2s 962-99 0.525 8 ON 0 Na _ _ _. - 59 t'l:;, Hi. 301. 24 0.45
,:' 279.32 256.1 __,: '279.32 256.1 __
61 am -: 266.23 243 99.186 0.73 6.,41:JJj''.. 63 two" 35013 3,1 90 49 61 am -: 266.23 243 99.186 0.73 6., 41: JJj '' .. 63 two "35013 3.1 90 49
22 282976622 2829766
64 292.66 1 269.1 97.6964 292.66 1 269.1 97.69
BINS OBINS O
NOH 404.44 381.3 94.73 2.93NOH 404.44 381.3 94.73 2.93
66 art 220.20 197.2 97.32 2.9566 art 220.20 197.2 97.32 2.95
H2C-NJ OH2C-NJ O
67 1Ol 327.32 304 99 4.26 NJ: Nit o67 1Ol 327.32 304 99 4.26 NJ: Nit o
68 373.70 35068 373.70 350
F -. -F -. -
69 - Net 380.31 335 98.39 4.9369 - Net 380.31 335 98.39 4.93
INS O 281.25 96.8 0.38INS O 281.25 96.8 0.38
<'N. i0, Na<'N. i0, Na
71 IN - O 481.51 458.10 64.4 1.171 IN - O 481.51 458.10 64.4 1.1
O\\ H <ON j<,NG CH3O \\ H <ON j <, NG CH3
72 F NO 292.22 100 1.1472 F NO 292.22 100 1.14
"A Na"A Na
73 1 291.28 __73 1 291.28 __
N NaN Na
74 298.28 263.1 92.6 2.3974 298.28 263.1 92.6 2.39
)O INS Na) O INS Na
320.23 297 79 0.91320.23 297 79 0.91
(: J:' Nd]O,Na F O(: J: 'Nd] O, Na F O
76 0 280.26 257 72 1.376 0 280.26 257 72 1.3
*H3Cf o J:N O O* H3Cf o J: N O O
77 306.34 283 >99 1.1377 306.34 283> 99 1.13
H,CN:H, CN:
78 353.14 328.9 75.5 1.1378 353.14 328.9 75.5 1.13
:' No Gina: 'No Gina
79 290.28 267 79 1.179 290.28 267 79 1.1
IN Net O 313.29 290 97 1.09 CH3 NO'Na O 81 H3co: Chin 376.43 353 70 1.44 IN Net O 313.29 290 97 1.09 CH3 NO'Na O 81 H3co: Chin 376.43 353 70 1.44
"<c 3 ')<Do."<c 3 ') <Do.
82 1 Chi al 481.51 458 64 1.1 O CH3 82 1 Chi al 481.51 458 64 1.1 O CH3
83O)_CH3 377.35 354 821.1483O) _CH3 377.35 354 821.14
N/\N-S4HN / \ N-S4H
NatO O 84o CI 354.75 331 53 1.2 NaNatO O 84o CI 354.75 331 53 1.2 Na
24 282976624 2829766
o: 394.43 371 71 i.14 È 86 o If 350.33 327 63 1.2 87 I'd_. 3 542 63 1.18 88 Nr>N aft 334 33 311 97 5.02 59 c}:,/:;,C36 3'/ As 6.25 o: 394.43 371 71 i.14 È 86 o If 350.33 327 63 1.2 87 I'd_. 3 542 63 1.18 88 Nr> N aft 334 33 311 97 5.02 59 c}:, /:;, C36 3 '/ As 6.25
9 O _J ô 334.33 311 > 99 4.759 O _J ô 334.33 311> 99 4.75
91 o-cH3 380.35 357,99 4.76 N-S 92,_J or 338.29 315 8 4.8 93 r - EN - it 356.28 333 95 5.17 94 b 338.29 315 98 4.98 , : l 401 > 99 5.79 91 o-cH3 380.35 357.99 4.76 N-S 92, _J or 338.29 315 8 4.8 93 r - EN - it 356.28 333 95 5.17 94 b 338.29 315 98 4.98,: l 401> 99 5.79
96 ô 9 - - 373 > 99 5.8396 ô 9 - - 373> 99 5.83
97 r_NN-O 362.24 339 98 4.6797 r_NN-O 362.24 339 98 4.67
98 4_, ''' SOCK]98 4_, '' 'SOCK]
99 r'N CH3 382.41 369 96 7.4g 1 0 0 i N: - N - 5 CH3 413.43 390 90 7.37 101 art - N-3,: 370.35 347 >99 6.64 102 r - N - S 320.3 297 97 4.62 s; t se b >9à 99 r'N CH3 382.41 369 96 7.4g 1 0 0 i N: - N - 5 CH3 413.43 390 90 7.37 101 art - N-3 ,: 370.35 347> 99 6.64 102 r - N - S 320.3 297 97 4.62 s; t se b> 9à
104 _<H3 3 446.5 423 95 8.03104 _ <H3 3446.5 423 95 8.03
IN Nit 3 r - N- 3 362.38 339 95 5.89 106 s:H3 376.41 353 98 5.73 107, , \'' 312 2 289 83 5l 108, it,? j 7 346.34 323 96 5 56 109 r_ - co380. 35 357 >99 4.48 Fy-F404.3 381 94 7.17 È_ IN Nit 3 r - N- 3 362.38 339 95 5.89 106 s: H3 376.41 353 98 5.73 107,, \ '' 312 2 289 83 5l 108, it ,? j 7 346.34 323 96 5 56 109 r_ - co380. 35 357> 99 4.48 Fy-F404.3 381 94 7.17 È_
111 ô3Z 93 303 ô 7 5.97111 ô3Z 93 303 ô 7 5.97
112 o NF->N_:371.35 346 77 4.34 Na O 113 of 466.49 443 81 7.59 N-S 114 o (-$ S404 3 381 >99 5.88 112 o NF-> N_: 371.35 346 77 4.34 Na O 113 of 466.49 443 81 7.59 N-S 114 o (- $ S404 3 381> 99 5.88
_: O O_: O O
>, o 392.41 369 > 99 5.77 116 o r' " 352.32 329 > 99 5.38 0 H3C >, o 392.41 369> 99 5.77 116 o r '"352.32 329> 99 5.38 0 H3C
117 F≥=\ 356.28 333 96 4.66117 F≥ = \ 356.28 333 96 4.66
KNIN -St,.KNIN -St ,.
118 r: 'sat 376.41 353 >99 5.29118 r: 'sat 376.41 353> 99 5.29
119 " 350.33 327 97 4.71119 "350.33 327 97 4.71
o d 5. d 339 94 7.08o d 5.d 339 94 7.08
27 282976627 2829766
121 u 338.29 315 >99 4.8 122o ret> A< 334.3 311,99 4.95 Na' O 123off 466. 49 442 9 >99 6.3 \t 124 t 390.31 367 > 99 5.38 Na _ o - N " 345. 31 322 98 4.48 Na O N 126 ON O'Na 314.28 121 u 338.29 315> 99 4.8 122o ret> A <334.3 311.99 4.95 Na 'O 123off 466. 49 442 9> 99 6.3 \ t 124 t 390.31 367> 99 5.38 Na _ o - N "345. 31 322 98 4.48 Na ON 126 ON O'Na 314.28
127 INS O 284.25 261 40 1.05127 INS O 284.25 261 40 1.05
Id:.'N:O'Na 128 o 363.15Id:. 'N: O'Na 128 o 363.15
129 - N-: O 360.35 337 38 0.89129 - N-: O 360.35 337 38 0.89
J <NoNaJ <NoNa
H CN O 278.29 255 >99 1.36H CN O 278.29 255> 99 1.36
'No,Na'No, Na
131 IN - O 340.36 317 37 1.28131 IN - O 340.36 317 37 1.28
CH3 0CH3 0
132 O ONO,Na 302.2 nt 72.69 1.38 133 NaO) J:N) O 316.22 nt 100 1.60 to,Na 132 O ONO, Na 302.2 nt 72.69 1.38 133 NaO) J: N) O 316.22 nt 100 1.60 to, Na
28 282976628 2829766
c 332.72 nt 52.74- 1.16-1.75 cl N O'N 318.69- 295 70 1.36 136 Cl No, Na 69 nt 98 35 2127 c 332.72 nt 52.74- 1.16-1.75 cl N O'N 318.69- 295 70 1.36 136 Cl No, Na 69 nt 98 35 2127
137 310.29 287 39 1.93137 310.29 287 39 1.93
138 H conch c.l 592.8 nt 88.33 1.36138 H conch c.l 592.8 nt 88.33 1.36
139 H CAIN::N O 279.27 256 65 1.36L C No,Na 3 - nit L__ 2.69139 H CAIN :: N O 279.27 256 65 1.36L C No, Na 3 - nit L__ 2.69
141 353.14 329 87 1.37141 353.14 329 87 1.37
142 IN o,Na 288.17 n t 64.64 1.37 143 Na IN - O 302.3 nt 55.34 1.36 142 IN o, Na 288.17 n t 64.64 1.37 143 Na IN - O 302.3 nt 55.34 1.36
O <'N:/Jo'Na.O <'N: / Jo'Na.
144 0 30/ 7 279 30 1.37144 0 30/7 279 30 1.37
LIMO Pa OZ Z4 279 70 1 34LIMO Pa OZ Z4 279 70 1 34
146 O 312.3 289 52 1 36146 O 312.3 289 52 1 36
147oNo'Na 264.26 241 64 1.36147oNo'Na 264.26 241 64 1.36
148INS O 334.31 311 63 0.87148INS O 334.31 311 63 0.87
t BIND JONa 149 NO,Na 314.28 nt 61.17 1.41 298.28 n t 45.7 1.18 t BIND JONa 149 NO, Na 314.28 nt 61.17 1.41 298.28 n t 45.7 1.18
151 264.26 241 84 1.35151 264.26 241 84 1.35
152 298.28 nt 42.34 2.23 CH3NO'Na 153 H3C:No'Na 29C 28 nt 45 99 2 23 152 298.28 nt 42.34 2.23 CH3NO'Na 153 H3C: No'Na 29C 28 nt 45 99 2 23
154 OH 187.20 186.0154 OH 187.20 186.0
awl CiN O 269.69 267.9 99 3.17awl CiN O 269.69 267.9 99 3.17
:'N:OH -: 'N: OH -
Tab/eau (C): Plowlett Packard LC/MSD (Simple Quad)- Orthogonal Spray Source APCI et API-EC, Chaine HP Séries 1100 avec barette de diodes, Nt: non trouvée Tab / water (C): Plowlett Packard LC / MSD (Simple Quad) - Orthogonal Spray Source APCI and API-EC, Chaine HP Series 1100 with diode array, Nt: not found
28297662829766
Claims (7)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0111950A FR2829766A1 (en) | 2001-09-14 | 2001-09-14 | Composition useful in the treatment of pathologies associated with e.g. hyperglycemia, diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, and nephropathies, comprises oxamate derivatives |
| AU2002337009A AU2002337009A1 (en) | 2001-09-14 | 2002-08-23 | Oxamate derivatives containing a variously substituted nitrogen heterocycle |
| PCT/EP2002/009435 WO2003024946A2 (en) | 2001-09-14 | 2002-08-23 | Oxamate derivatives containing a variously substituted nitrogen heterocycle |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0111950A FR2829766A1 (en) | 2001-09-14 | 2001-09-14 | Composition useful in the treatment of pathologies associated with e.g. hyperglycemia, diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, and nephropathies, comprises oxamate derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| FR2829766A1 true FR2829766A1 (en) | 2003-03-21 |
Family
ID=8867317
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR0111950A Withdrawn FR2829766A1 (en) | 2001-09-14 | 2001-09-14 | Composition useful in the treatment of pathologies associated with e.g. hyperglycemia, diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, and nephropathies, comprises oxamate derivatives |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2002337009A1 (en) |
| FR (1) | FR2829766A1 (en) |
| WO (1) | WO2003024946A2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013060860A1 (en) * | 2011-10-27 | 2013-05-02 | National University Of Ireland, Maynooth | N-acyl-n'-phenylpiperazine derivatives as srbp modulators for use in the treatment of diabetes and obesity |
| US9006244B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9073931B2 (en) | 2012-03-16 | 2015-07-07 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US10399951B2 (en) | 2013-03-13 | 2019-09-03 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10793554B2 (en) | 2018-10-29 | 2020-10-06 | Forma Therapeutics, Inc. | Solid forms of 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone |
| US10875848B2 (en) | 2018-10-10 | 2020-12-29 | Forma Therapeutics, Inc. | Inhibiting fatty acid synthase (FASN) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260225B (en) * | 2011-06-02 | 2013-08-21 | 蒋杰 | Phenylpiperazine derivatives for inhibiting tumor metastasis and tumor angiogenesis |
| JP6363616B2 (en) | 2012-12-19 | 2018-07-25 | ノバルティス アーゲー | Autotaxin inhibitor |
| US9409895B2 (en) * | 2012-12-19 | 2016-08-09 | Novartis Ag | Autotaxin inhibitors |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1515291A (en) * | 1975-05-05 | 1978-06-21 | Shell Int Research | Organic compositions containing an antioxidant |
| EP0106462A2 (en) * | 1982-09-04 | 1984-04-25 | Pfizer Limited | Dihydropyridines |
| EP0469889A1 (en) * | 1990-08-02 | 1992-02-05 | Zeneca Limited | (p-Carbonylaminophenyl)-sulphonyl-nitromethane derivatives |
| EP0718287A2 (en) * | 1994-12-23 | 1996-06-26 | Dr. Karl Thomae GmbH | Piperazine derivatives, medicaments containing them, their use, and processes for their preparation |
| WO1996020173A1 (en) * | 1994-12-23 | 1996-07-04 | Dr. Karl Thomae Gmbh | Piperazine derivatives, medicaments containing the same, their use and process for preparing the same |
| WO1999046237A1 (en) * | 1998-03-12 | 1999-09-16 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases |
| WO2000059880A1 (en) * | 1999-04-02 | 2000-10-12 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds |
| WO2001007440A1 (en) * | 1999-07-21 | 2001-02-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | Imidazoimidazoles and triazoles as anti-inflammatory agents |
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
-
2001
- 2001-09-14 FR FR0111950A patent/FR2829766A1/en not_active Withdrawn
-
2002
- 2002-08-23 WO PCT/EP2002/009435 patent/WO2003024946A2/en not_active Application Discontinuation
- 2002-08-23 AU AU2002337009A patent/AU2002337009A1/en not_active Abandoned
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1515291A (en) * | 1975-05-05 | 1978-06-21 | Shell Int Research | Organic compositions containing an antioxidant |
| EP0106462A2 (en) * | 1982-09-04 | 1984-04-25 | Pfizer Limited | Dihydropyridines |
| EP0469889A1 (en) * | 1990-08-02 | 1992-02-05 | Zeneca Limited | (p-Carbonylaminophenyl)-sulphonyl-nitromethane derivatives |
| EP0718287A2 (en) * | 1994-12-23 | 1996-06-26 | Dr. Karl Thomae GmbH | Piperazine derivatives, medicaments containing them, their use, and processes for their preparation |
| WO1996020173A1 (en) * | 1994-12-23 | 1996-07-04 | Dr. Karl Thomae Gmbh | Piperazine derivatives, medicaments containing the same, their use and process for preparing the same |
| WO1999046237A1 (en) * | 1998-03-12 | 1999-09-16 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases |
| WO2000059880A1 (en) * | 1999-04-02 | 2000-10-12 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds |
| WO2001007440A1 (en) * | 1999-07-21 | 2001-02-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | Imidazoimidazoles and triazoles as anti-inflammatory agents |
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
Non-Patent Citations (7)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 69, no. 17, 21 October 1968, Columbus, Ohio, US; abstract no. 67324, KATAOKA, HIROSHI ET AL: "Synthesis of oligomer of trans-2,5-dimethylpiperazine oxamide having terminal amino groups" * |
| DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002201589, retrieved from STN Database accession no. 69:67324 * |
| G. RODALSKY: "Untersuchungen aus dem organischen Laboratorium der technischen Hochschule zu Dresden", J. PRAKT. CHEM., vol. 53, 1896, pages 19 - 24, XP008003576 * |
| H. MORREN ET AL.: "Contribution à l'étude des dérivés filaricides de la N.methylpipérazine", BULLETIN DES SOCIETES CHIMIQUES BELGES., vol. 59, 1950, PERGAMON PRESS LTD. OXFORD., GB, pages 228 - 237, XP002201587 * |
| MAYER, P. ET AL: "Metabolism of O,O-dipropyl S-[2-(2'-methyl-1'-piperidinyl)-2-oxo- ethyl] phosphorodithioate (C 19 490) in paddy rice", AGRIC. BIOL. CHEM. (1981), 45(2), 355-60, XP002201588 * |
| RYLSKI, LESZEK ET AL: "Synthesis of basic amides derived from.alpha.,.alpha.-bis(4- methoxyphenyl)glycolicacid", ACTA POL. PHARM. (1971), 28(3), 267-72, XP008003589 * |
| YUKI GOSEI KAGAKU KYOKAI SHI (1968), 26(5), 424-7 * |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013060860A1 (en) * | 2011-10-27 | 2013-05-02 | National University Of Ireland, Maynooth | N-acyl-n'-phenylpiperazine derivatives as srbp modulators for use in the treatment of diabetes and obesity |
| US9006244B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9006245B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9073931B2 (en) | 2012-03-16 | 2015-07-07 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9388190B2 (en) | 2012-03-16 | 2016-07-12 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9416135B2 (en) | 2012-03-16 | 2016-08-16 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9707232B2 (en) | 2012-03-16 | 2017-07-18 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
| US9814715B2 (en) | 2012-03-16 | 2017-11-14 | Vitae Pharamceuticals, Inc. | Liver X receptor modulators |
| US10399951B2 (en) | 2013-03-13 | 2019-09-03 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10450286B2 (en) | 2013-03-13 | 2019-10-22 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10457655B2 (en) | 2013-03-13 | 2019-10-29 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10472342B2 (en) | 2013-03-13 | 2019-11-12 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10800750B2 (en) | 2013-03-13 | 2020-10-13 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10995078B2 (en) | 2013-03-13 | 2021-05-04 | Forma Therapeutics, Inc. | Compounds and compositions for inhibition of FASN |
| US10875848B2 (en) | 2018-10-10 | 2020-12-29 | Forma Therapeutics, Inc. | Inhibiting fatty acid synthase (FASN) |
| US11299484B2 (en) | 2018-10-10 | 2022-04-12 | Forma Therapeutics, Inc. | Inhibiting fatty acid synthase (FASN) |
| US10793554B2 (en) | 2018-10-29 | 2020-10-06 | Forma Therapeutics, Inc. | Solid forms of 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone |
| US11267805B2 (en) | 2018-10-29 | 2022-03-08 | Forma Therapeutics, Inc. | Solid forms of (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl) piperazine-1-yl)(1-hydroxycyclopropyl)methanone |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002337009A1 (en) | 2003-04-01 |
| WO2003024946A3 (en) | 2003-12-04 |
| WO2003024946A2 (en) | 2003-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0099789B1 (en) | 3-aminoquinuclidin derivatives, process for their preparation and their use as therapeutical agents | |
| EP0530087B1 (en) | Naphthylethylurea and naphthylethylthiourea compounds, process for their preparation and pharmaceutical compositions containing them | |
| EP0506539B1 (en) | Heterocyclic alkylamides, process for their preparation and pharmaceutical compositions containing them | |
| EP0370901B1 (en) | Central nervous system active chromane derivatives, process for their preparation and pharmaceutical compositions containing them | |
| CH653999A5 (en) | AMINOMETHYL-5 OXAZOLIDINIC DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITION. | |
| CH639653A5 (en) | AMINOTHIAZOLES AND PHARMACEUTICAL COMPOSITION CONTAINING THEM. | |
| CA1132543A (en) | Process for preparing novel derivatives of 3-(aminoethyl)phenol and their salts | |
| EP0005689B1 (en) | Lactam-n-acetic acids, their amides, process for their preparation and therapeutic compositions containing them | |
| FR2829766A1 (en) | Composition useful in the treatment of pathologies associated with e.g. hyperglycemia, diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, and nephropathies, comprises oxamate derivatives | |
| EP1786759A1 (en) | Novel derivatives of 3,5-seco-4-norcholestane and use thereof | |
| FR2625678A1 (en) | Anorexigenic agents based on N-(3-quinuclidinyl)benzamides or -thiobenzamides | |
| CH639078A5 (en) | AMIDES DERIVED FROM 5-PYRIMIDINIC CARBOXYLIC ACIDS, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM. | |
| EP0673933A1 (en) | Aminoalkyl benzoxazolinones and benzothiazolinones process for their preparation and compositions containing them | |
| EP0613898A1 (en) | Aryl or arylalkyl-carbonyl heterocyclic derivatives, processes for their preparation and compositions containing them | |
| CH661661A5 (en) | ANTINEOPLASTIC AGENT. | |
| EP0571243A1 (en) | Thiochromane derivatives, process for their preparation and pharmaceutical compositions containing them | |
| EP0280603A1 (en) | Absolute S confirmation enantiomers of amide derivatives of 3-aminoquinuclidine, process for their preparation and their therapeutical use | |
| FR2822463A1 (en) | New N-bicyclo-substituted methyl-guanidine derivatives, useful for treating insulin-resistance syndrome and associated conditions | |
| EP0173585B1 (en) | Medicines based on piperidine derivatives, piperidine derivatives and process for their preparation | |
| EP0143016A1 (en) | Derivatives of 4-(3-alkynyloxy-2-hydroxy-propyl)-piperazin-1-yl-N-phenyl acetamide, their preparation and their therapeutical use | |
| EP0101379B1 (en) | Benzamides, their salts, process for their preparation and pharmaceutical compositions containing them | |
| FR2846654A1 (en) | New dihydro-4(1H)-pyridinone derivatives are useful in the treatment of cognitive disorders, neurodegenerative diseases and pain | |
| EP0347305B1 (en) | [(Aryl-4-piperazinyl-1)-2-ethoxy]-3 p cymene, the ortho-, meta-, para-monosubstituted or disubstituted phenyl ring derivatives, process for their preparation and medicaments containing the same as the active principle | |
| FR2507180A1 (en) | NOVEL PHENYLALKYLAMINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES | |
| EP0157762B1 (en) | New substituted piperidinoguanidines, preparation process and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| ST | Notification of lapse |