	US 7,514,458 B2
	Anti-cytokine heterocyclic compounds
Derek Cogan, Sandy Hook, Conn. (US); Ming-Hong Hao, Ridgefield, Conn. (US); Victor Marc Kamhi, Framingham, Mass. (US); Craig Andrew Miller, Ridgefield, Conn. (US); Matthew Russell Netherton, Danbury, Conn. (US); and Alan David Swinamer, Bethel, Conn. (US)
Assigned to Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn. (US)
Filed on Jan. 30, 2007, as Appl. No. 11/668,704.
Application 11/668704 is a division of application No. 11/074354, filed on Mar. 07, 2005, granted, now 7,214,802.
Claims priority of provisional application 60/551445, filed on Mar. 09, 2004.
Prior Publication US 2007/0142371 A1, Jun. 21, 2007
Int. Cl. A61K 31/4192 (2006.01); A61K 31/429 (2006.01); A61K 31/4025 (2006.01); A61K 31/402 (2006.01)

U.S. Cl. 514—359 [514/397; 514/368; 514/387; 514/365; 514/341; 514/326; 514/252.14]

10 Claims

1. A method of treating a disease or condition chosen from osteoarthritis, atherosclerosis, contact dermatitis, bone resorption diseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, systemic lupus erythematosus, insulin-dependent diabetes mellitus, rheumatoid arthritis, toxic shock syndrome, diabetes, inflammatory bowel diseases, acute and chronic pain, stroke, myocardial infarction alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, necrotizing entrerocolitis, traumatic arthritis, sepsis and chronic obstructive pulmonary disease, said method comprising administering to a patient a pharmaceutically effective amount of a compound of the formula (I)

wherein:

Ar¹is chosen from (i) (ii) and (iii) below:

(i) a carbocycle substituted by R¹, R²and R^x,

wherein one of E or F is nitrogen and the other is carbon R¹is covalently attached to either E or F, and when nitrogen is N—R¹the double bond between E and F is not present;

wherein c is a benzo ring fused to ring d which is a 5-7 membered heterocyclic ring optionally substituted by an oxo (═O) group and one to two R groups each independently being H or C1-3 alkyl;

R¹is chosen from hydrogen NO₂, —N(R^c)₂, J-C(O)—N(R^c)—, J-S(O)_m—N(R^c)—, C1-6 alkylS(O)_m—,

or R¹is chosen from C1-6 alkyl, C3-7 cylcoalkyl, C1-5 alkoxyl or C3-7 cycloalkoxyl, C1-5 alkylthiol or C3-7 cycloalkylthiol, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, C2-5 alkenyl, C2-5 alkynyl, heterocycle, heterocycleC1-6 alkyl, heteroaryl, heteroarylC1-6 alkyl and nitrile; each of the aforementioned where possible are optionally partially or fully halogenated or are optionally further substituted with alkylsulfonylamino, aminocarboxyl, alkoxyl, amino, alkylamino, dialkylamino, hydroxyl, oxo, nitro or nitrile;

R²is chosen from:

hydrogen, halogens nitrile, C1-5 alkylS(O)_m—, arylS(O)_m, J-O—C(O)—O—, N(R^c)₂—C(O)—(CH₂)_n—, C1-6 acetyl aroyl C1-6alkoxycarbonyl, C1-6 alkyl C3-7cycloalkyl C1-6 alkoxy, C3-5cycloalkoxy, C1-5 alkylC1-5 alkoxy, hydroxy, hydroxy C1-5 alkyl, and amino optionally mono- or di-substituted by C1-5 alkyl, aryl or aryl C1-5 alkyl; each of the aforementioned where possible are optionally partially or fully halogenated or are optionally further substituted with C1-3 alkyl, alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino, hydroxyl, oxo, nitro or nitrile;

each R^xis chosen from C1-6 alkyl or C3-7 cycloalkyl each being optionally substituted by C1-3 alkyl and optionally partially or fully halogenated, C1-4 acyl aroyl C1-4 alkoxy, C1-5alkylS(O)_m—, each may optionally be partially or fully halogenated, halogens C1-6 alkoxycarbonyl, carbocyclesulfonyl;

each R^cis independently hydrogen or C1-5 alkyl;

D, A and B in

of the formula (I) are each independently chosen from N or CH wherein the hydrogen atom is optionally replaced by R⁶;

Het is a heterocyclic or heteroaryl rind wherein Het is optionally substituted by one to three R⁵;

m is 0, 1 or 2

J is chosen from C1-10 alkyl and C3-7cycloalkyl each optionally substituted by R^b;

R³, R⁴, R⁶, R⁷and R⁸are each independently chosen from hydrogen, halogens C1-5 alkyl C1-5 alkoxy, C1-5 alkylC1-5 alkoxy, hydroxy, hydroxy C1-5 alkyl or amino optionally mono- or di-substituted by C1-5 alkyl, aryl or aryl C1-5 alkyl;

R⁵is:

R^a, —O—R^a, —S(O)_m—R^a, —N(R^a)₂, —C(O)—R^a, —NH(CR⁷R⁸)_n—R^a, N(R^a)₂—(CH₂)_1-2—(CR⁷R⁸)_n—R^a, —O(CR⁷R⁸)_n—R^a, —C(O)—O(CR⁷R⁸)_n—R^a, —C(O)(CR⁷R⁸)_n—R^a—C(O)C(O)R^a, —C(O)C(O)OR^a, —C(O)NHR^aor —C(O)NH(CR⁷R⁸)_n—, each optionally substituted by C1-3 alkyl, halogen or hydroxy,

wherein n is 1-5;

or R⁵is aryl, heteroaryl or heterocyclyl each optionally substituted by R^a;

R^aand R^bare each independently chosen from hydrogen, C1-6 alkyl hydroxyC1-5 alkyl C2-5 alkenyl, C2-5 alkynyl, carbocycle, carbocycleC0-2 alkyl, aryl, heterocycle, heteroaryl, C1-5 alkoxy, C1-5 alkylthio, amino, C1-5 alkylamino, C1-5 dialkylamino, arylamino, aryl C1-5 alkylamino, diarylamino, C1-5 acyl, C1-5 alkoxycarbonyl, C1-5 acyloxy, C1-5 acylamino, each of the aforementioned are optionally partially or fully halogenated, or R^aand R^bare chosen from C1-5 alkylsulphonylamino, hydroxy, oxo, halogens —CF₃, —CH₂—CF₃, nitro and nitrile, wherein each carbocycle, heterocycle or heteroaryl for R^aand R^bis optionally substituted by amino, C1-3 alkyl, halogen or hydroxy;

and

X is O or S

or the pharmaceutically acceptable salts thereof.