US 7,888,343 B2Granted

Substituted, bicyclic 8-pyrrolidinoxanthines, and methods for their use as inhibitors of dipeptidyl peptidase

AssigneeSanofi-A Ventis Deutschland GmbH

InventorsKarl Schoenafinger, Gerhard Jaehne, Elisabeth Defossa, Lothar Schwink, Holger Wagner, Christian Buning, Georg Tschank, Ulrich Werner

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Abstract

The present invention involves substituted bicyclic 8-pyrrolidinoxanthines and their derivatives of formula I: wherein the various R groups are defined herein. The present invention also comprises pharmaceutical compositions comprising them as well as processes for the preparation of these compounds and methods for the treatment of metabolic disorders such as type-2 diabetes, insulin resistance, hyperglycemia, arteriosclerosis diseases and the like through the administration of said compositions.

Claims8

Dependent claims

A compound of the formula I,

wherein:
R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C6-C10)-aryl, and heterocycle, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocycle groups may be substituted one or more times by F, Cl, Br, I, CN, NO2, SH, OH, (C1-C6)-alkyl, —CF3, —OCF3, —SCF3, (C2-C6)-alkenyl, (C2-C6)-alkynyl, OR7, OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C1-C6)-alkylene-OR7, (C1-C6)-alkylene-NR7R8, (C1-C6)-alkylene-NR7SO2R7, (C1-C6)-alkylene-SR7, alkylene-S(O)R7, alkylene-S(O)2R7, alkylene-S(O)2NR7R8, (C1-C6)-alkylene-COR7, (C1-C6)-alkylene-COOR7, (C1-C6)-alkylene-CONR7R8, SR7, SOR7, SO2R7, SO2NR7R8, NR7SO2R7, (C1-C6)-alkylene-(C3-C10)-cycloalkyl, (C1-C6)-alkylene-(C6-C10)-aryl, (C1-C6)-alkylene-heterocycle, (C3-C10)-cycloalkyl, (C6-C10)-aryl and heterocycle;
R7 and R8 are independently selected from the group consisting of H, (C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C6-C10-aryl, heterocycle, (C1-C6)-alkylene-CONR9R10, (C1-C6)-alkylene-COOR9, (C1-C6)-alkylene-COR9, (C1-C6)-alkylene-OR9, (C1-C6)-alkylene-NR9R10, (C1-C6)-alkylene-SR9, (C1-C6)-alkylene-S(O)R9, (C1-C6)-alkylene-S(O)2R9, (C1-C4)-alkylene-(C6-C10)-aryl and (C1-C4)-alkylene-heterocycle;
R9 and R10 are independently selected from the group consisting of H, (C1-C6)-alkyl, (C1-C6)-alkylene-(C6-C10)-aryl, and (C1-C6)-alkylene-heterocycle;
R12 is selected from the group consisting of F, Cl, Br, I, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, NH(C3-C7)-cycloalkyl, N((C1-C6)-alkyl)2 and O—(C1-C6)-alkyl, where the alkyl groups may be substituted one or more times by F, Cl, Br, I;
n is 0 and
wherein the portion of formula I represented by structure A
is selected from the group consisting of structures A1 to A6
where optionally the carbon atoms in structures A1 to A6 may be substituted one to four times by a moiety selected from the group consisting of F, Cl, Br, I, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, NH(C3-C7)-cycloalkyl, N((C1-C6)-alkyl)2 and O—(C1-C6)-alkyl, and wherein optionally the alkyl groups may be substituted one or more times by F, Cl, Br, I;
R11 is selected from the group consisting of hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C4)-alkylene-aryl and (C1-C4)-alkylene-heterocycle;
and
or a physiologically tolerated salt thereof.

9 more elements

A pharmaceutical composition comprising a compound of formula I

wherein:
R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C2-C10-alkenyl, (C2-C10)-alkynyl, (C6-C10)-aryl, and heterocycle wherein the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocycle groups may be substituted one or more times by F, Cl, Br, I, CN, NO2, SH, OH, (C1-C6)-alkyl, —CF3, —OCF3, —SCF3, (C2-C6)-alkenyl, (C2-C6)-alkynyl, OR7, OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C1-C6)-alkylene-OR7, (C1-C6)-alkylene-NR7R8, (C1-C6)-alkylene-NR7SO2R7, (C1-C6)-alkylene-SR7, alkylene-S(O)R7, alkylene-S(O)2R7, alkylene-S(O)2NR7R8, (C1-C6)-alkylene-COR7, (C1-C6)-alkylene-COOR7, (C1-C6)-alkylene-CONR7R8, SR7, SOR7, SO2R7, SO2NR7R8, NR7SO2R7, (C1-C6)-alkylene-(C3-C10)-cycloalkyl, (C1-C6)-alkylene-(C6-C10)-aryl, (C1-C6)-alkylene-heterocycle, (C3-C10)-cycloalkyl, (C6-C10)-aryl and heterocycle;
R7 and R8 are independently selected from the group consisting of H, (C1-C6)-alkyl, —CF3, (C3-C10)-cycloalkyl, (C6-C10)-aryl, (C6-C10)-heterocycle, (C1-C6)-alkylene-CONR9R10, CONR9R10, (C1-C6)-alkylene-COOR9, COOR9, COR9, (C1-C6)-alkylene-COR9, (C1-C6)-alkylene-OR9, (C1-C6)-alkylene-NR9R10, (C1-C6)-alkylene-SR9, (C1-C6)-alkylene-S(O)R9, (C1-C6)-alkylene-S(O)2R9, S(O)R9, S(O)2R9, (C1-C4)-alkylene-(C6-C10)-aryl and (C1-C4)-alkylene-heterocycle;
R9 and R10 are independently selected from the group consisting of H, (C1-C6)-alkyl, (C1-C6)-alkylene, (C6-C10)-aryl, (C6-C10)-aryl, (C6-C10)-heterocycle, and (C1-C6)-alkylene-heterocycle;
R4 and R5 form together a 3-5-membered alkylene chain in which one CH2 group is replaced by NR11 and wherein R6 is equal to H or R12, or
R5 and R6 form together a 3 to 5-member alkylene chain in which one CH2 group is replaced by NR11, where R4 is equal to H or R12;
where the 3 to 5-member alkylene chain may be substituted in each case one or more times by F, Cl, Br, I, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, NH(C3-C7)-cycloalkyl, N((C1-C6)-alkyl)2 or O—(C1-C6)-alkyl, where the alkyl groups may be substituted one or more times by F, Cl, Br, I;
R11 is selected from the group consisting of hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C4)-alkylene-aryl and (C1-C4)-alkylene-heterocycle;
R12 is selected from the group consisting of F, Cl, Br, I, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, NH2, NH(C1-C6)-alkyl, NH(C3-C7)-cycloalkyl, N((C1-C6)-alkyl)2 and O—(C1-C6)-alkyl, where the alkyl groups may be substituted one or more times by F, Cl, Br, I;
n is 0 and
wherein the portion of formula I represented by structure A comprises:
is selected from the group consisting of structures A1 to A6
or a physiologically tolerated salt thereof in combination with one or more pharmaceutically acceptable carriers, fillers, excipients, solvents, adjuvants and mixtures thereof.

10 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/624,511Filed 18 Jan 2007 · continuation
Priority: DE 10 2004 038 2686 Aug 2004
Published: US 2007/0197563 A123 Aug 2007
Granted: 15 Feb 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/08
Drugs for disorders of the metabolism: for glucose homeostasis
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics