Combination therapies utilizing benzamide inhibitors of the P2X7 receptor

• US 20060018904A1
• Filed: 06/28/2005
• Published: 01/26/2006
• Est. Priority Date: 06/29/2004
• Status: Abandoned Application

• Current Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Inventors: Jungbluth, Gail L., Chung, James B., Gabel, Christopher A.
• Application Number:
  US11/168,602
• Publication Number:
  US 20060018904A1
• Time in Patent Office: Days
• US Class Current: 424/145.100
• 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 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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

Abstract

This invention provides methods of treatment of IL-1 mediated diseases comprising administering a pharmaceutically effective amount of a pharmaceutical agent selected from the group of sulfasalazine, a statin, a glucocorticoid agent, an inhibitor of p38 kinase, an anti-IL-6-receptor antibody, anakinra, an IL-1 monoclonal antibody, an inhibitor of JAK3 protein tyrosine kinase, a M-CSF monoclonal antibody or a humanized anti-CD20 monoclonal antibody and a benzamide inhibitor of the P2X₇ receptor of the formula:
wherein R¹-R³ are as defined herein. The methods of the invention are useful in the treatment of IL-1 mediated disorders, including, without limitation, inflammatory diseases such as osteoarthritis and rheumatoid arthritis; allergies, asthma, COPD, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

Claims

1. A method of treatment of an IL-1 mediated disease in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a pharmaceutical agent selected from:

a) sulfasalazine;

b) a statin;

c) a glucocorticoid agent;

d) an inhibitor of p38 kinase;

e) an anti-IL-6-receptor antibody;

f) anakinra;

g) an anti-IL-1 monoclonal antibody;

h) an inhibitor of JAK3 protein tyrosine kinase;

i) a M-CSF monoclonal antibody;

or

j) an anti-CD20 monoclonal antibody;

and a pharmaceutically effective amount of a compound of formula (I);

wherein R¹ is (C₁-C₆)alkyl, optionally substituted by (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₁₀)heterocyclyl, or (C₁-C₁₀)heteroaryl, wherein each of said (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₁₀)heterocyclyl, or (C₁-C₁₀)heteroaryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, —

CN, (C₁-C₆)alkyl, HO(C₁-C₆)alkyl-, (C₁-C₆)alkyl-NH(C═

O)—

, NH₂(C═

O)—

, (C₁-C₆)alkoxy, or (C₃-C₁₀)cycloalkyl, wherein said (C₃-C₁₀)cycloalkyl is optionally substituted by one or more moieties selected from halogen, or (C₁-C₆)alkyl-;

R² is hydrogen, halogen, —

CN, and (C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl is optionally substituted by one to three moieties independently selected from halo, hydroxy, amino, —

CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —

CF₃, CF₃O—

, (C₁-C₆)alkyl-NH—

, [(C₁-C₆)alkyl]₂—

N—

, (C₁-C₆)alkyl-S—

, (C₁-C₆)alkyl-(S═

O)—

, (C₁-C₆)alkyl-(SO₂)—

, (C₁-C₆)alkyl-O—

(C═

O)—

, formyl, (C₁-C₆)alkyl-(C═

O)—

, or (C₃-C₆)cycloalkyl; and

R³ is a suitably substituted nitrogen linked (C₁-C₁₀)heterocyclyl of the formula;

or the pharmaceutically acceptable salts or solvates or prodrugs thereof.

2. The method of claim 1 wherein the compound of formula (I) has the structure:

wherein R⁷ is as defined in claim 1 and R¹ is C₁-C₃ alkyl substituted by a C₃-C₈ or phenyl ring, the C₃-C₈ and phenyl rings being optionally substituted by from 1 to 4 substituents selected from the group of OH, halo, C₁-C₃ alkyl, C₁-C₃ alkoxy, or C₁-C₃ alkyl substituted by OH.

3. The method of claim 1 wherein the IL-1 mediated disease is selected from rheumatoid arthritis, osteoarthritis, Crohn'"'"'s disease, chronic obstructive pulmonary disease, inflammatory bowel disease, Alzheimer'"'"'s disease, psoriasis, psoriatic arthritis or atherosclerosis.

4. The method of claim 1 wherein the compound of formula (I) is selected from the group consisting of:

2-Chloro-N-(1-hydroxy-cyclohexylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;

2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cyclohexylmethyl)-benzamide;

2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;

2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide;

2-Chloro-5-(4-cyanomethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-benzamide;

2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxymethyl-cycloheptylmethyl)-benzamide;

2-Chloro-5-[4-(2-cyano-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide;

N-(1-Hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-methyl-benzamide;

2-Chloro-5-[4-(2,3-dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cyclohexylmethyl)-benzamide;

2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-methyl-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;

2-Chloro-N-(1-hydroxy-cyclooctylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;

2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-2-phenyl-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;

2-Chloro-5-[3,5-dioxo-4-(3,3,3-trifluoro-2-hydroxy-propyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-benzamide;

2-Chloro-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(2-hydroxy-2-phenyl-ethyl)-benzamide;

5-(4-Carbamoylmethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide;

2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-methoxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide;

5-[4-(2,3-Dihydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide;

5-[4-(3-Amino-2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2-chloro-N-(1-hydroxy-cycloheptylmethyl)-benzamide; and

2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.

6. The method of claim 4 wherein compound of formula (I) is 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.

5. A method of treatment in a mammal of an IL-1 mediated disease selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, Crohn'"'"'s disease, chronic obstructive pulmonary disease, inflammatory bowel disease, Alzheimer'"'"'s disease, psoriasis, psoriatic arthritis or atherosclerosis, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of sulfasalazine, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically effective amount of a compound of formula (I):

wherein R¹ is (C₁-C₆)alkyl, optionally substituted by (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₁₀)heterocyclyl, or (C₁-C₁₀)heteroaryl, wherein each of said (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₁-C₁₀)heterocyclyl, or (C₁-C₁₀)heteroaryl are optionally substituted by one to three suitable moieties independently selected from the group consisting of hydroxy, halogen, —

CN, (C₁-C₆)alkyl, HO(C₁-C₆)alkyl, (C₁-C₆)alkyl-NH(C═

O)—

, NH₂(C═

O)—

, (C₁-C₆)alkoxy, or (C₃-C₁₀)cycloalkyl, wherein said (C₃-C₁₀)cycloalkyl is optionally substituted by one or more moieties selected from halogen, or (C₁-C₆)alkyl-;

R² is hydrogen, halogen, —

CN, and (C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl is optionally substituted by one to three suitable moieties, independently selected from the group consisting of halo, hydroxy, amino, —

CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —

CF₃, CF₃O—

, (C₁-C₆)alkyl-NH—

, [(C₁-C₆)alkyl]₂—

N—

, (C₁-C₆)alkyl-S—

, (C₁-C₆)alkyl-(S═

O)—

, (C₁-C₆)alkyl-(SO₂)—

, (C₁-C₆)alkyl-O—

(C═

O)—

, formyl, (C₁-C₆)alkyl-(C═

O)—

, and (C₃-C₆)cycloalkyl; and

R³ is a suitably substituted nitrogen linked (C₁-C₁₀)heterocyclyl of the formula;

or the pharmaceutically acceptable salts or solvates or prodrugs thereof.

7. A method of treatment of rheumatoid arthritis in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of sulfasalazine, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically effective amount of 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.

8. A pharmaceutical composition comprising a pharmaceutically effective amount of sulfasalazine, or a pharmaceutically acceptable salt form thereof, a pharmaceutically effective amount of 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide and one or more pharmaceutically acceptable carriers or excipients.

9. A kit comprising a pharmaceutical formulation containing a pharmaceutically effective amount of sulfasalazine, or a pharmaceutically acceptable salt form thereof, and a pharmaceutical formulation containing a pharmaceutically effective amount of 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.

10. A method of treatment of rheumatoid arthritis in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of atorvastatin, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically effective amount of 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.