Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein

• US 6,984,645 B2
• Filed: 11/15/2002
• Issued: 01/10/2006
• Est. Priority Date: 11/16/2001
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sulsky, Richard B., Robl, Jeffrey A., Magnin, David R., Parker, Rex A., Caulfield, Thomas J.
• Primary Examiner(s): Zucker, Paul A.
• Application Number:
  US10/295,819
• Publication Number:
  US 20030225091A1
• Time in Patent Office: 1,152 Days
• Field of Search: 514/277, 514/358, 514/400, 514/563, 514/568, 546/342, 546/347, 548/341.5, 562/476
• US Class Current: 514/277
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 205/35 having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 205/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 233/47 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/81 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/87 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/12 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 251/48 with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 255/54 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/18 with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 323/56 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 45/41 : by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
• CPC Class Codes: C07C 45/59 : in five-membered rings from ozonides C07C45/40
• CPC Class Codes: C07C 45/71 : being hydroxy groups
• CPC Class Codes: C07C 47/565 : all hydroxy groups bound to the ring
• CPC Class Codes: C07C 47/575 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 51/487 : by treatment giving rise to chemical modification by chemisorption C07C51/47
• CPC Class Codes: C07C 59/68 : the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 65/24 : polycyclic
• CPC Class Codes: C40B 40/00 : Libraries per se, e.g. arrays, mixtures

Abstract

Compounds that are dual aP2/k-FABP inhibitors are provided having the formula
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.

Claims

1. A compound of the following formula I

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;

with the proviso that A is a bond only when Z^1a, Z^2a and Z^3a are independently halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl; and

Z^1b, Z^2b and Z^3b are independently halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl;

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 Z^1a, Z^2a and one or more Z^3a;

R² is aryl, heteroaryl, alkyl, cycloalkyl, aralkyl, heteroarylalkyl, cylcoalkenyl or heterocyclo any of which may be optionally substituted with Z^1b, Z^2b and one or more Z^3b;

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 Z^1c, Z^2c and one or more Z^3c;

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 substituted with Z^1d, Z^2d and one more Z^3d;

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 substituted with Z^1e, Z^2e and one more Z^3e;

R⁸ is

(1) H, OH;

or

(2) alkyl, aryl, heteroaryl, alkoxy, aryloxy, or alkenyl any of which may be optionally substituted with Z^1f, Z^2f and one or more Z^3f;

t is 0, 1 or 2;

q is 0 to 5,

Z^1a-1f, Z^2a-2f, and Z^3a-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 Z^1a,

(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) —

U³—

C(═

NV^1a)—

U⁴—

, or

(10) —

U³—

C(O)—

C(O)—

U⁴—

;

V¹,V^1a,V²,V³ and V⁴

(1) are each independently hydrogen or a group provided in the definition of Z^1a;

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 Z^1a;

or

(3) V² or V³, together with V¹, may be alkylene or alkenylene completing a 3- to 8-memberd 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 Z^1a;

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 formula X

wherein

R¹⁵ is H, hydroxy or alkoxy.

2. A compound of claim 1 wherein

A is a bond, an optionally substituted C₁-C₂ alkylene group, or an optionally substituted C₂ alkenylene group;

X and Y are independently —

O(CR⁵R⁶)_q—

, —

(CR⁵R⁶)_qO—

, —

N(R⁷)CO(CR⁵R⁶)_qO—

, —

N(R⁷)CO(CR⁵R⁶)_q—

—

N(R⁷)CO(CR⁵R⁶)_qC(O)O—

, —

N(R⁷)CO—

CR⁵═

CR⁶—

, —

N(R⁷)SO₂(CR⁵R⁶)_q—

, or —

O(CR⁵R⁶)_qCO—

where

q is 0, 1 or 2;

R¹ is aryl, heteroaryl, cycloalkyl or alkyl, any of which may be optionally substituted with Z^1a, Z^2a and one more Z^3a;

R² is aryl, heeteroaryl, cycloalkyl or alkyl, any of which be optionally substituted with Z^1b, Z^2b and one more Z^3b;

R³ is H, OH, halo, alkyl, haloalkyl or hydroxyalkyl;

R⁵ and R⁶ are independently

(1)H or OH;

or

(2) alkyl, aryl, aralkyl or heteroarylalkyl any of which may be optionally substituted with Z^1d, Z^2d and one or more Z^3d; and

R⁷ is

(1) H or OH;

or

(2) alkyl, aryl, aralkyl or heteroarylalkyl any of which may be optionally substituted with Z^1e, Z^2e and one or more Z^3e.

3. A compound of claim 1 wherein B is carboxyl or an ester thereof.

4. A compound of claim 2 wherein

A is a bond, or a C₁-C₂ alkylene group optionally substituted with one OH, SH, NH², or NHOR⁴, or optionally substituted with at least one COOR⁴, halogen N(R⁸)COR⁴, hydroxyalkyl or oxo;

X and Y are independently —

O(CR⁵R⁶)_q—

, —

(CR⁵R⁶)_qO—

, —

N R⁷)CO(CR⁵R⁶)_q—

or —

N(R⁷)SO₂(CR⁵R⁶)_q—

;

where

q is 0 or 1;

R¹ is aryl, heteroaryl or C₃-C₆ cycloalkyl any of which may be optionally substituted with one or more Z^1a, Z^2a and one or more Z^3a;

R² is aryl, heteroaryl or C₃-C₆ cycloalkyl any of which may be optionally substituted with Z^1b, Z^2b and one or more Z^3b;

R³ is H, OH, halo;

alkyl, or haloalkyl;

R⁵ and R⁶ are independently

(1) H;

or

(2) alkyl, aralkyl, or heteroarylalkyl any of which may be optionally substituted with Z^1d, Z^2d and one or more Z^3d; and

R⁷ is

(1) H;

or

(2) alkyl, aralkyl, or heteroarylalkyl any of which may be optionally substituted with Z^1d, Z^2d and one or more Z^3d.

5. A compound of claim 4 wherein

R¹ is aryl or heteroaryl either of which may be optionally substituted with Z^1a, Z^2a and one or more Z^3a;

and

R² is aryl or heteroaryl either of which may be optionally substituted with Z^1b, Z^2b and one or more Z^3ab.

6. A compound of claim 5 wherein

Z^1a, Z^2a and Z^3a are independently halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl;

and

Z^1b, Z^2b and Z^3b are independently halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, aryloxy, aralkoxy, aryl, arylcarbonyl, carboxyl, cyano, nitro, oxo, arylsulfonylalkyl or alkylsulfonyl.

7. A compound of claim 6 wherein B is carboxyl or an ester thereof.

8. A compound of claim 6 wherein R⁵, R⁶ and R⁷ are independently H, alkyl, aralkyl, or heteroarylalkyl.

9. A compound of claim 8 wherein

R⁵ and R⁶ are hydrogen;

and

R⁷ is hydrogen, alkyl, or aralkyl.

10. A compound of claim 5 wherein

R¹ is phenyl, napthyl, benzodioxolyl, benzodioxinyl, anthracenyl, pyridinyl, benzimidazolyl, quinoxalinyl, furanyl, thienyl, benzothiophenyl, or isothiozolyl any of which may be optionally substituted with Z^1a, Z^2a and one or more Z^3a;

and

R² is phenyl, napthyl, benzodioxolyl, benzodioxinyl, anthracenyl, pyridinyl, benzimidazolyl, quinoxalinyl, furanyl, thienyl, benzothiophenyl, or isothiozolyl any of which may be optionally substituted with Z^1b, Z^2b and one or more Z^3b.

11. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmacuetically acceptable vehicle or carrier therefor.

12. The pharmaceutical composition of claim 11 further comprising at least one additional therapeutic agent selected from antidiabetic agents, antihyperglycemic agents, hypolipidemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiinfective agents, anti-athersclerotic agents and anti-inflammatory agents.

13. The pharmaceutical composition of claim 12 wherein the other therapeutic agent is at least one antidiabetic agent selected from biguanides, sulfonyl ureas, glucosidase inhibitors, PPAR modulators, insulin sensitizers, glucagon-like peptide-1 (GLP-1), insulin or biguanide/glyburide combination.

14. The pharmaceutical composition of claim 13 wherein the antidiabetic agent is metformin, glyburide, glimepiride, glipyride, glipizide, chiorpropamide, gliclazide, acarbose, miglitol, troglitazone, rosiglitizone, piaglitazone, insulin, and/or metformin/glyburide combinations.