Combination therapies utilizing benzamide inhibitors of the P2X7 receptor
First Claim
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.
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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.
98 Citations
10 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;
orj) 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. - View Dependent Claims (2, 3, 4, 6)
-
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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.
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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.
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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.
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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.
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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.
Specification