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US 2003/0225091 A1Published application
Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein
AssigneeBristol-Myers Squibb Company
InventorsDavid R. Magnin, Richard B. Sulsky, Jeffrey A. Robl, Thomas J. Caulfield, Rex A. Parker
Life of this patent
Estimating the term…
Abstract
Compounds that are dual aP2/k-FABP inhibitors are provided having the formula 1 wherein A, B, X, Y, R1, R2 and R3 are as described herein. A method is also provided for treating diabetes and related diseases, especially Type II diabetes, employing dual aP2/k-FABP inhibitors alone or in combination with at least one other antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin.
Claims21
A compound of the following formula I
- 214
- or pharmaceutically acceptable salts thereof, or prodrug esters thereof, or stereoisomers thereof, or solvates thereof
- wherein
- A is
- a bond;
- a C1-C3 alkylene group optionally independently substituted on available atoms with one to six halo, hydroxy, alkoxy, hydroxyalkyl, SR4, alkyl, alkenyl, cyano, CONHR4, COOR4, oxo, NHOR4, ═NOR4, or N(R8)COR4;
- or
- a C2-C3 alkenylene group optionally independently substituted on available atoms with one to four halo, hydroxy, alkoxy, hydroxyalkyl, SR4, alkyl, alkenyl, cyano, CONHR4, COOR4, oxo, NHOR4, ═NOR4, or N(R8)COR4;
- B is carboxyl or tetrazole;
- X and Y are independently
- —O(CR5R6)q—,
- —(CR5R6)qO—,
- —(CR5R6)qN(R7)CO—,
- —N(R7)CO(CR5R6)q—,
- —N(R7)CO(CR5R6)qO—,
- —N(R7)CO(CR5R6)qC(O)O—,
- —N(R7)CO—CR5═CR6—,
- —(CR5R6)qN(R7)SO2—,
- —N(R7)SO2(CR5R6)q—,
- —O—CO(CR5R6)q—,
- —O(CR5R6)qCO—,
- —(CR5R6)qO—CO—, or
- —(CR5R6)qS(O)t—;
- R1 is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z1a, Z2a and one or more Z3a;
- R2 is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z1b, Z2b and one or more Z3b;
- R3 is H, OH, alkyl, hydroxyalkyl, aryl, nitro, halo, amino, alkylamino, alkoxy, cyano, thioalkyl, carboxyl, COOR4, NR7COR4, or NR7COOR4;
- R4 is
- (1) H;
- or
- (2) alkyl, haloalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl or heteroaryl any of which may be optionally substituted with Z1c, Z2c and one or more Z3c;
- R5 and R6 are independently
- (1) H, OH, halo, cyano or oxo;
- or
- (2) alkoxy, alkyl, alkenyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylthio, aryloxy or heteroaryloxy any of which may be optionally subsituted with Z1d, Z2d and one more Z3d;
- R7 is
- (1) H, OH, or cyano;
- or
- (2) alkoxy, alkyl, alkenyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylthio, aryloxy or heteroaryloxy any of which may be optionally subsituted with Z1e, Z2e and one more Z3e;
- R8 is
- (1) H, OH;
- or
- (2) alkyl, aryl, heteroaryl, alkoxy, aryloxy, or alkenyl any of which may be optionally subtituted with Z1f, Z2f and one or more Z3f;
- t is 0, 1 or 2;
- q is 0 to 5.
- Z1a-1f, Z2a-2f, and Z3a-3f are optional substituents independently selected from
- (1) V, where V is
- (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
- (ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
- or
- (iii) a group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13) of the definition of Z1a,
- (2) —OH or —OV,
- (3) —SH or —SV,
- (4) —C(O)pH, —C(O)pV, or —O—C(O)V, where p is 1 or 2,
- (5) —SO3H, —S(O)pV, or S(O)pN(V1)V,
- (6) halo,
- (7) cyano,
- (8) nitro,
- (9) —U1—NV2V3,
- (10) —U1—N(V1)—U2—NV2V3,
- (11) —U1—N(V4)—U2—V,
- (12) —U1—N(V4)—U2—H,
- (13) oxo;
- U1 and U2 are each independently
- (1) a single bond,
- (2) —U3—S(O)p—U4—,
- (3) —U3—C(O)—U4—,
- (4) —U3—C(S)—U4—,
- (5) —U3—O—U4—,
- (6) —U3—S—U4—,
- (7) —U3—O—C(O)—U4—,
- (8) —U3—C(O)—O—U4—,
- (9) —U3C(═NV1a)—U4—, or
- (10) —U3—C(O)—C(O)—U4—;
- V1, V1a, V2, V3 and V4
- (1) are each independently hydrogen or a group provided in the definition of Z1a;
- or
- (2) V2 and V3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z1a;
- or
- (3) V2 or V3, together with V1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z1a;
- or
- (4) V2 and V3 together with the nitrogen atom to which they are attached may combine to form a group —N═CV5V6 where V5 and V6 are each independently H or a group provided in the definition of V;
- and
- U3 and U4 are each independently
- (1) a single bond,
- (2) alkylene,
- (3) alkenylene, or
- (4) alkynylene;
- provided that said compound is other than a compound of
- 215
- wherein
- R15 is H, hydroxy or alkoxy.
88 more elements
A method for treating diabetes, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, elevated fatty acids or glycerol, Syndrome X, atherosclerosis or inflammation which comprises administering an effective amount of at least one compound of formula I
- 216
- Or pharmaceutically acceptable salts thereof, or prodrug esters thereof, or stereoisomers thereof, or solvates thereof
- wherein
- A is
- a bond;
- a C1-C3 alkylene group optionally independently substituted on available atoms with one to six halo, hydroxy, alkoxy, hydroxyalkyl, SR4, alkyl, alkenyl, cyano, CONHR4, COOR4, oxo, NHOR4, ═NOR4, or N(R8)COR4;
- or
- a C2-C3 alkenylene group optionally independently substituted on available atoms with one to four halo, hydroxy, alkoxy, hydroxyalkyl, SR4, alkyl, alkenyl, cyano, CONHR4, COOR4, oxo, NHOR4, ═NOR4, or N(R8)COR4;
- B is carboxyl or tetrazole;
- X and Y are independently
- —O(CR5R6)q—,
- —(CR5R6)qO—,
- —(CR5R6)qN(R7)CO—,
- —N(R7)CO(CR5R6)q—,
- —N(R7)CO(CR5R6)qO—,
- —N(R7)CO(CR5R6)qC(O)O—,
- —N(R7)CO—CR5═CR6—,
- —(CR5R6)qN(R7)SO2—,
- —N(R7)SO2(CR5R6)q—,
- —O—CO(CR5R6)q—,
- —O(CR5R6)qCO—,
- —(CR5R6)qO—CO—, or
- —(CR5R6)qS(O)t—;
- R1 is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z1a, Z2a and one or more Z3a;
- R2 is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z1b, Z2b and one or more Z3b;
- R3 is H, OH, alkyl, hydroxyalkyl, aryl, nitro, halo, amino, alkylamino, alkoxy, cyano, thioalkyl, carboxyl, COOR4, NR7COR4, or NR7COOR4;
- R4 is
- (1) H;
- or
- (2) alkyl, haloalkyl, aminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl or heteroaryl any of which may be optionally substituted with Z1c, Z2c and one or more Z3c;
- R5 and R6 are independently
- (1) H, OH, halo, cyano or oxo;
- or
- (2) alkoxy, alkyl, alkenyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylthio, aryloxy or heteroaryloxy any of which may be optionally subsituted with Z1d, Z2d and one more Z3d;
- R7 is
- (1) H, OH, or cyano;
- or
- (2) alkoxy, alkyl, alkenyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylthio, aryloxy or heteroaryloxy any of which may be optionally subsituted with Z1e, Z2e and one more Z3e;
- R8 is
- (1) H, OH;
- or
- (2) alkyl, aryl, heteroaryl, alkoxy, aryloxy, or alkenyl any of which may be optionally subtituted with Z1f, Z2f and one or more Z3f;
- t is 0, 1 or 2;
- q is 0 to 5.
- Z1a-1f, Z2a-2f, and Z3a-3f are optional substituents independently selected from
- (1) V, where V is
- (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
- (ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
- or
- (iii) a group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13) of the definition of Z1a,
- (2) —OH or —OV,
- (3) —SH or —SV,
- (4) —C(O)pH, —C(O)pV, or —O—C(O)V, where p is 1 or 2,
- (5) —SO3H, —S(O)pV, or S(O)pN(V1)V,
- (6) halo,
- (7) cyano,
- (8) nitro,
- (9) —U1—NV2V3,
- (10) —U1—N(V1)—U2—NV2V3,
- (11) —U1—N(V4)—U2—V,
- (12) —U1—N(V4)—U2—H,
- (13) oxo;
- U1 and U2 are each independently
- (1) a single bond,
- (2) —U3—S(O)p—U4—,
- (3) —U3—C(O)—U4—,
- (4) —U3—C(S)—U4—,
- (5) —U3—O—U4—,
- (6) —U3—S—U4—,
- (7) —U3—O—C(O)—U4—,
- (8) —U3—C(O)—O—U4—,
- (9) —U3C(═NV1a)—U4—, or
- (10) —U3—C(O)—C(O)—U4—;
- V1, V1a, V2, V3 and V4
- (1) are each independently hydrogen or a group provided in the definition of Z1a;
- or
- (2) V2 and V3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z1a;
- or
- (3) V2 or V3, together with V1, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z1a;
- or
- (4) V2 and V3 together with the nitrogen atom to which they are attached may combine to form a group —N═CV5V6 where V5 and V6 are each independently H or a group provided in the definition of V;
- and
- U3 and U4 are each independently
- (1) a single bond,
- (2) alkylene,
- (3) alkenylene, or
- (4) alkynylene.
84 more elements
A method for treating diabetes, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, elevated fatty acids or glycerol, Syndrome X, atherosclerosis or inflammation which comprises administering an effective amount of at least one dual aP2/k-FABP inhibitor.
Dependencies are inferred from the claim text.