Use of substituted pyranone acid derivatives for the treatment of metabolic syndrome
View Patent ↗The invention relates to the use of substituted pyranone acid derivatives and of their physiologically acceptable salts for producing medicaments for treating the metabolic syndrome.
1. A method for reducing plasma free fatty acids, reducing plasma glycerol, reducing plasma triglycerides, or treating diabetic dyslipidemia in a patient in need thereof, said method comprising administering to said patient a compound of the formula I:
wherein:
R1 is selected from H, OH, COOH, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, O—(C 1 -C 8 )-alkyl, and O—(C 2 -C 8 )-alkenyl, and wherein the (C 1 -C 8 )-alkyl and (C 2 -C 8 )-alkenyl radicals may be substituted by one or more groups selected from F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, ═O, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON[(C 1 -C 6 )-alkyl] 2 , cycloalkyl, (C 1 -C 10 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 6 )alkyl, and O—CO—(C 1 -C 6 )-alkyl, provided that the (C 1 -C 8 )-alkyl radicals are not substituted by O—(C 1 -C 6 )alkyl or O—CO—(C 1 -C 6 )-alkyl;
PO 3 H 2 , P(O)(Oalkyl) 2 , (C 1 -C 6 )-alkylene-P(O)(Oalkyl) 2 , O—P(O)(OH) 2 , O—P(O)(Oalkyl)2, SO 3 H, SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )-alkyl, SO 2 N[(C 1 -C 6 )-alkyl] 2 , S—(C 1 -C 6 )-alkyl, S—(CH 2 ) n -aryl, S—(CH 2 ) n -heterocyclyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -aryl, SO—(CH 2 ) n -heterocyclyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -aryl, SO 2 —(CH 2 ) n -heterocyclyl, SO 2 —NH(CH 2 ) n -aryl, SO 2 —NH(CH 2 ) n -heterocyclyl, SO 2 —N((C 1 -C 6 )-alkyl)(CH 2 ) n -aryl, SO 2 —N((C 1 -C 6 )-alkyl)(CH 2 ) n -heterocyclyl, SO 2 —N((CH 2 ) n -aryl) 2 , SO 2 —N((CH 2 ) n -(heterocyclyl) 2 where n=0-6 and the aryl radical or heterocyclic radical may be substituted up to two times by groups selected from F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, and NH 2 ;
C(NH)(NH 2 ), NH 2 , NH—(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , NH(C 1 -C 7 )-acyl, NH—CO—(C 1 -C 6 )-alkyl, NH—COO—(C 1 -C 6 )-alkyl, NH—CO-aryl, NH—CO-heterocyclyl, NH—COO-aryl, NH—COO-heterocyclyl, NH—CO—NH—(C 1 -C 6 )-alkyl), NH—CO—NH-aryl, NH—CO—NH-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—(C 1 -C 6 )-alkyl, N[(C 1 -C 6 )-alkyl]-COO—(C 1 -C 6 )-alkyl, N[(C 1 -C 6 )-alkyl]-CO-aryl, N[(C 1 -C 6 )-alkyl]-CO-heterocyclyl, N[(C 1 -C 6 )-alkyl]-COO-aryl, N[(C 1 -C 6 )-alkyl]-COO-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—NH—(C 1 -C 6 )-alkyl), N[(C 1 -C 6 )-alkyl]-CO—NH-aryl, N[(C 1 -C 6 )-alkyl]-CO—NH-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—N((C 1 -C 6 )-alkyl) 2 , N[(C 1 -C 6 )-alkyl]-CO—N((C 1 -C 6 )-alkyl)-aryl, N[(C 1 -C 6 )-alkyl]-CO—N((C 1 -C 6 )-alkyl)-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—N(aryl) 2 , N[(C 1 -C 6 )-alkyl]-CO—N(heterocyclyl) 2 , N(aryl)-CO—(C 1 -C 6 )-alkyl, N(heterocyclyl)-CO—(C 1 -C 6 )-alkyl, N(aryl)-COO—(C 1 -C 6 )-alkyl, N(heterocyclyl)-COO—(C 1 -C 6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO—NH—(C 1 -C 6 )-alkyl, N(heterocyclyl)-CO—NH—(C 1 -C 6 )-alkyl, N(aryl)-CO—NH-aryl, N(heterocyclyl)-CO—NH-aryl, N(aryl)-CO—N((C 1 -C 6 )-alkyl) 2 , N(heterocyclyl)-CO—N((C 1 -C 6 )-alkyl) 2 , N(aryl)-CO—N[(C 1 -C 6 )-alkyl]-aryl, N(heterocyclyl)-CO—N[(C 1 -C 6 )-alkyl]-aryl, N(aryl)-CO—N(aryl) 2 , N(heterocyclyl)-CO—N(aryl) 2 , O—(CH 2 ) n -aryl, O—(CH 2 ) n -heterocyclyl, where n=0-6 and where the aryl or heterocyclyl radical may be substituted by one to three groups selected from F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SF 5 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, and CONH 2 ; and
R2 is selected from H, OH, COOH, (C 3 -C 8 )-cycloalkyl, (C 2 -C 8 )-alkenyl, O—(C 1 -C 8 )-alkyl, and O—(C 2 -C 8 )-alkenyl, and wherein the alkyl, cycloalkyl, and alkenyl radicals may be substituted by one or more groups selected from F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, ═O, COOH, COO(C 1 -C 6 )-alkyl, CONH 2 , CONH(C 1 -C 6 )-alkyl, CON[(C 1 -C 6 )-alkyl] 2 , cycloalkyl, (C 1 -C 10 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 6 )alkyl, O—CO—(C 1 -C 6 )-alkyl, O—CO—(C 1 -C 6 )-aryl, and O—CO—(C 1 -C 6 )-heterocyclyl, provided that the alkyl radicals are not substituted by O—(C 1 -C 6 )alkyl or O—CO—(C 1 -C 6 )-alkyl;
PO 3 H 2 , P(O)(Oalkyl) 2 , (C 1 -C 6 )-alkylene-P(O)(Oalkyl) 2 , O—P(O)(OH) 2 , O—P(O)(Oalkyl)2, SO 3 H, SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )-alkyl, SO 2 N[(C 1 -C 6 )-alkyl] 2 , S—(C 1 -C 6 )-alkyl, S—(CH 2 ) n -aryl, S—(CH 2 ) n -heterocyclyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -aryl, SO—(CH 2 ) n -heterocyclyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -aryl, SO 2 —(CH 2 ) n -heterocyclyl, SO 2 —NH(CH 2 ) n -aryl, SO 2 —NH(CH 2 ) n -heterocyclyl, SO 2 —N((C 1 -C 6 )-alkyl)(CH 2 ) n -aryl, SO 2 —N((C 1 -C 6 )-alkyl)(CH 2 ) n -heterocyclyl, SO 2 —N((CH 2 ) n -aryl) 2 , SO 2 —N((CH 2 ) n -(heterocyclyl) 2 where n=0-6 and the aryl radical or heterocyclic radical may be substituted up to two times by groups selected from F, Cl, Br, OH, CF 3 , SF 5 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, and NH 2 ;
C(NH)(NH 2 ), NH 2 , NH—(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , NH(C 1 -C 7 )-acyl, NH—CO—(C 1 -C 6 )-alkyl, NH—COO—(C 1 -C 6 )-alkyl, NH—CO-aryl, NH—CO-heterocyclyl, NH—COO-aryl, NH—COO-heterocyclyl, NH—CO—NH—(C 1 -C 6 )-alkyl), NH—CO—NH-aryl, NH—CO—NH-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—(C 1 -C 6 )-alkyl, N[(C 1 -C 6 )-alkyl]-COO—(C 1 -C 6 )-alkyl, N[(C 1 -C 6 )-alkyl]-CO-aryl, N[(C 1 -C 6 )-alkyl]-CO-heterocyclyl, N[(C 1 -C 6 )-alkyl]-COO-aryl, N[(C 1 -C 6 )-alkyl]-COO-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—NH—(C 1 -C 6 )-alkyl), N[(C 1 -C 6 )-alkyl]-CO—NH-aryl, N[(C 1 -C 6 )-alkyl]-CO—NH-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—N((C 1 -C 6 )-alkyl) 2 , N[(C 1 -C 6 )-alkyl]-CO—N((C 1 -C 6 )-alkyl)-aryl, N[(C 1 -C 6 )-alkyl]-CO—N((C 1 -C 6 )-alkyl)-heterocyclyl, N[(C 1 -C 6 )-alkyl]-CO—N(aryl) 2 , N[(C 1 -C 6 )-alkyl]-CO—N(heterocyclyl) 2 , N(aryl)-CO—(C 1 -C 6 )-alkyl, N(heterocyclyl)-CO—(C 1 -C 6 )-alkyl, N(aryl)-COO—(C 1 -C 6 )-alkyl, N(heterocyclyl)-COO—(C 1 -C 6 )-alkyl, N(aryl)-CO-aryl, N(heterocyclyl)-CO-aryl, N(aryl)-COO-aryl, N(heterocyclyl)-COO-aryl, N(aryl)-CO—NH—(C 1 -C 6 )-alkyl, N(heterocyclyl)-CO—NH—(C 1 -C 6 )-alkyl, N(aryl)-CO—NH-aryl, N(heterocyclyl)-CO—NH-aryl, N(aryl)-CO—N((C 1 -C 6 )-alkyl) 2 , N(heterocyclyl)-CO—N((C 1 -C 6 )-alkyl) 2 , N(aryl)-CO—N[(C 1 -C 6 )-alkyl]-aryl, N(heterocyclyl)-CO—N[(C 1 -C 6 )-alkyl]-aryl, N(aryl)-CO—N(aryl) 2 , N(heterocyclyl)-CO—N(aryl) 2 , aryl, O—(CH 2 ) n -aryl, O—(CH 2 ) n -heterocyclyl, where n=0-6, where the aryl or heterocyclyl radical may be substituted by one to three groups selected from by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SF 5 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, and CONH 2 ;
or R1 and R2 together form a 3- to 8-membered aryl, cycloalkyl or heterocyclyl ring, where the aryl, cycloalkyl or heterocyclyl ring may be substituted by groups selected from F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SF 5 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, and CONH 2
provided that, if R1 is OH, then R2 is not H, and if R2 is OH, then R1 is not H;
and provided that if R1 is O—(C 1 -C 8 )-alkyl, then R2 is not H, and if R2 is O—(C 1 -C 8 )-alkyl, then R1 is not H.
2. The method according to claim 1 , wherein:
R1 is selected from H, OH, COOH, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, O—(C 1 -C 8 )-alkyl, and O—(C 2 -C 8 )-alkenyl, and wherein the (C 1 -C 8 )-alkyl and (C 2 -C 8 )-alkenyl radicals may be substituted by one or more ═O groups;
and
R2 is selected from H, (C 1 -C 8 )-alkyl, and (C 2 -C 8 )-alkenyl.
3. The method according to claim 1 , wherein:
R1 is selected from H, OH, (C 1 -C 8 )-alkyl, (C 2 -C 4 )-alkenyl, O—(C 1 -C 8 )-alkyl, and O—(C 2 -C 4 )-alkenyl, and wherein the alkyl and alkenyl radicals may be substituted by one or more ═O groups;
and
R2 is selected from H, (C 1 -C 8 )-alkyl, and (C 2 -C 4 )-alkenyl.
4. The method according to claim 1 , wherein:
R1 is selected from H, OH, COOH, (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, O—(C 1 -C 8 )-alkyl, and O—(C 2 -C 8 )-alkenyl, wherein the (C 1 -C 8 )-alkyl and (C 2 -C 8 )-alkenyl radicals may be substituted by one or more groups selected from F and ═O;
and
R2 is selected from H, (C 1 -C 8 )-alkyl, and (C 2 -C 8 )-alkenyl.
5. The method according to claim 1 , wherein:
R1 is selected from H, OH, (C 1 -C 8 )-alkyl, (C 2 -C 4 )-alkenyl, O—(C 1 -C 8 )-alkyl, and O—(C 2 -C 8 )-alkenyl, wherein the (C 1 -C 8 )-alkyl and (C 2 -C 8 )-alkenyl radicals may be substituted by one or more groups selected from F and ═O;
and
R2 is selected from H, (C 1 -C 8 )-alkyl, and (C 2 -C 4 )-alkenyl.