Modulators of chemokine receptor activity

• US 6,821,964 B2
• Filed: 03/06/2002
• Issued: 11/23/2004
• Est. Priority Date: 03/07/2001
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Didiuk, Mary T., Lau, Wan F., Garigipati, Ravi, Duffy, Erin M., Colon-Cruz, Roberto, McDonald, Wayne S.
• Primary Examiner(s): POWERS, FIONA
• Application Number:
  US10/093,273
• Publication Number:
  US 20030008893A1
• Time in Patent Office: 993 Days
• Field of Search: 548/453, 548/126, 548/181, 548/248, 548/266.8, 544/281, 546/176, 546/276.7, 514/210.16, 514/412
• US Class Current: 514/210.16
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Chemokine receptor antagonists, in particular, bicyclic diamine compounds of Formula (I) that act as antagonists of chemokine CCR2 and CCR3 receptors including pharmaceutical compositions and uses thereof to treat or prevent diseases associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation are described herein.

Claims

1. A compound of the formula (I)

wherein

A is a substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₂-C₆)alkenyl, substituted or unsubstituted partially saturated or fully saturated (C₃-C₆)cycloalkyl, substituted or unsubstituted partially saturated or fully saturated 5 to 6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

a is 0, 1, 2 or 3;

w, x, y and z are each independently 0, 1 or 2 with the proviso that (i) w is not 0 when x is 0;

(ii) y is not 0 when z is 0;

(iii) x is not 0 when w is 1, y is 0 and z is 1;

(iv) x is not 0 when w is 1, z is 0 and y is 1;

(v) x is not 0 when y is 0; and

(vi) w is not 0 when z is 0;

p is 0 or 1;

L is a linking group selected from the group consisting of —

(CH₂)_q—

X—

, where X is NH, O, or oxo and q is an integer from 1 to 4, —

S(O)_r—

(CH₂)_t—

NH—

, where r is 0, 1 or 2 and t is an integer from 1 to 4, —

(aryl)-NH—

, -(heteroaryl)-NH—

, and an amino acid residue whree the amino nitrogen of said amino acid residue is attached to B and the carbonyl of said amino acid residue is attached to the ring nitrogen; and

B is a substituted or unsubstituted (C₁-C₆)alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted (C₁-C₆)alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted (C₁-C₆)alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted (C₁-C₆)alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted (C₁-C₆)alkylthiocarbonyl, substituted or unsubstituted arylthiocarbonyl, substituted or unsubstituted (C₁-C₆)alkylcarbamoyl, substituted or unsubstituted arylcarbamoyl, substituted or unsubstituted (C₁-C₆)alkyl-C(═

NH)—

, substituted or unsubstituted aryl-C(═

NH)—

, or a protecting group;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compoundor the prodrug.

2. The compound of claim 1 wherein L is an amino acid residue of the formula

where the α -amino nitrogen of said amino acid residue is attached to B, R¹ and R² are each independently ydrogen, substituted or unsubstituted (C₁-C₆)alkyl, substituted or unsubstituted (C₂-C₆)alkenyl, substituted or unsubstituted partially saturated or fully saturated (C₃-C₆)cycloalkyl, substituted or unsutstituted partially saturated or fully saturated 5 to 6 membered heterocyclic ring, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

or R₁ or R² is taken together with R³ to form a 5 to 6 membered ring;

or R¹ and R² are taken together to form a 3 to 6 membered ring; and

R³ is hydrogen, taken together with a substituent of B forms a substituted or unsubstituted five or six membered partially saturated or fully saturated heterocyclic ring, or taken together with R¹ or R² forms a 5 to 6 membered ring;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.

6. A pharmaceutical composition comprising a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug and a pharmaceutically acceptable excipient, diluent or carrier.

7. The pharmaceutical composition of claim 6 wherein said compound, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug is present in a therapeutically effective amount for the treatment of a disease associated with monocyte accumulation, lymphocyte accumulation or both.

8. The pharmaceutical composition of claim 6 wherein said compound, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug is present in a therapeutically effective amount for the treatment of a disease associated with leucocyte accumulation.

9. A method for treating a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation wherein said disease is atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, wound healing, Crohn'"'"'s disease, chronic inflammatory disease, encephalomyelitis or transplant rejection, said method comprising the step of administering a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug to an animal in need thereof.

10. The method of claim 9 wherein said disease is atherosclerosis.

11. The method of claim 9 or 10 wherein said compound is a compound of Formula 1B

where

w, x, y and z are each independently 0, 1 or 2 with the proviso that (i) w is not 0 when x is 0;

(ii) y is not 0 when z is 0;

(iii) x is not 0 when w is 1, y is 0 and z is 1;

(iv) x is not 0 when w is 1, z is 0 and y is 1;

(v) x is not 0 when y is 0; and

(vi) w is not 0 when z is 0;

p is 0 or 1;

L is a linking group selected from the group consisting of —

(CH₂)_g—

X—

, where X is NH, O, or oxo and g is an integer from 1 to 4, —

S(O)_r—

(CH₂)_t—

NH—

, where r is 0, 1 or 2 and t is an integer from 1 to 4, -(aryl)-NH—

, -(heteroaryl)-NH—

, and an amino acid residue whree the amino nitrogen of said amino acid residue is attached to B and the carbonyl of said amino acid residue is attached to the ring nitrogen; and

B is a substituted or unsubstituted (C₁-C₆)alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted (C₁-C₆)alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted (C₁-C₆)alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted (C₁-C₆)alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted (C₁-C₆)alkylthiocarbonyl, substituted or unsubstituted arylthiocarbonyl, substituted or unsubstituted (C₁-C₆)alkylcarbamoyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted (C₁-C₆)alkyl-C(═

NH)—

, substituted or unsubstituted aryl-C(═

NH)—

, or a protecting group;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.

12. The method of claim 11 wherein said compound is selected from the group consisting of

N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide;

2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide;

2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide;

2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.

13. The method of claim 9 wherein said disease is a chronic inflammatory disease.

14. The method of claim 13 wherein said chronic inflammatory disease is selected from the group consisting If allergic rhinitis, eczema and atopic dermatitis.

15. The method of claim 13 or 14 wherein said compound is a compound of Formula 1C

where x, y, w, z, L, p, and B are as defined in claim 1;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.

16. The method of claim 1 wherein said compound is selected from the group consisting of

3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.

17. A pharmaceutical kit comprising a) a suitable dosage form comprising a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug;

and b) instructions describing a method of using the dosage form to treat a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation.

18. A pharmaceutical combination comprising a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug and at least one other pharmaceutical agent selected from the group consisting of a nutraceutical, a cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor, a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor.

19. A pharmaceutical kit comprising:

a) a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate, or hydrate of said compound or said prodrug, and a pharmaceutically acceptable carrier, excipient or diluent in a first unit dosage form;

b) a pharmaceutical agent selected from the group consisting of a nutraceutical, a cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor, a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor, and a pharmaceutically acceptable carrier, excipient or diluent in a second unit dosage form; and

c) a container.

20. A method for treating a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation wherein said disease is atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, wound healing, Crohn'"'"'s disease, encephalomyelitis or transplant rejection, said method comprising administering to a mammal in need of such treatment

a) a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate, or hydrate of said compound or said prodrug;

and

b) a therapeutically effective amount of at least one pharmaceutical agent selected from the group consisting of a a nutraceutical, a cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor, a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor.

21. The method of claim 20 wherein said compound, prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered simultaneously.

22. The method of claim 20 wherein said compound, prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered sequentially.

23. The method of claim 20 wherein said compound, prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered as a single pharmaceutical composition comprising said compound of claim 1, prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug, said pharmaceutical agent, and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof.

24. The method of claim 20 wherein said compound, prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered as two separate pharmaceutical compositions comprising (i) a first composition comprising said compound of claim 1, a thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof;

and (ii) a second composition comprising said pharmaceutical agent and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof.

25. The method of claim 24 wherein said first composition and said second composition are administered simultaneously.

26. The method of claim 24 wherein said first composition and said second composition are administered sequentially.

3. A compound of the formula (IA):

wherein

R^1a for each occurrence is independently hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl(C₁-C₆)alkoxy, or two adjacent R^1a groups taken together form a substituted unsubstituted carboxylic, heterocyclic, aromatic or heteroaromatic 5 to 6 membered fused ring;

m is 0, 1, 2, 3, 4, or 5;

R¹ and R² are independently hydrogen, (C₁-C₆)alkyl, or aryl(C₁-C₆)alkyl, or R¹ and R² are taken together to form a three- or six-membered ring, R¹ or R² are taken together with R³ to form a five to six membered ring;

R³ is hydrogen, taken together with R^1b forms a substituted or unsubstituted five or six membered partially saturated or fully saturated heterocyclic ring, or taken together with R¹ or R² form a five to six membered ring;

R^1b for each occurrence is independently hydrogen, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, amino, amido, nitro, aryloxy, (C₁-C₆)alkylthio, taken together with R³ forms a substituted or unsubstituted five or six membered partially saturated or fully saturated heterocyclic ring, or two adjacent R_1b substituents taken together form a heteroaromatic 5 to 6 membered fused ring; and

n is 0, 1, 2, 3, 4, or 5;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound or the prodrug.

4. The compound of claim 3 wherein R^1a is methyl or chloro;

m is 2;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

R^1b is methyl, trifluoromethyl, amino, iodo, bromo, chloro or nitro; and

n is 1 or 2;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound or the prodrug.

5. A compound selected from the group consisting of

N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-triflouromethyl-benzamide;

2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide;

2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide;

2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl)benzylamide;

3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-2-oxo-ethyl}-4-fluoro-benzamide;

3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and

3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide;

a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of said compound or said prodrug.