Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

Abstract

The present invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or optionally, at least one therapeutic agent. The present invention also provides novel compositions comprising at least one parent COX-2 inhibitor and at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The present invention also provides kits and methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2.

1 . A compound of Formula (V) or a pharmaceutically acceptable salt thereof: wherein the compound of formula (V) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 5  is:
 (a) oxygen; or 
 (b) sulfur; 
 
 R 31  is:
 (a) alkoxy; 
 (b) haloalkoxy preferably —OCH 2 F, —OCHF 2 , or —OCHF 2 ; 
 (c) alkylthio; 
 (d) haloalkyl, preferably CF 3 ; 
 (e) halo; or 
 (f) lower alkyl; 
 
 R 32 , R 33 , R 34 , R 35 , R 36  and R 37  are each independently:
 (a) hydrogen; 
 (b) halo, preferably F or Cl; 
 (c) lower alkyl; 
 (d) cycloalkyl; 
 (e) haloalkyl, preferably CF 3 , CF 2 H or CFH 2 ; 
 (f) —OD 1 ; 
 (g) —OR 43 ; 
 (h) —SD 1 ; 
 (i) —SR 43 ; 
 (j) —S(O)R 43 ; 
 (k) —S(O) 2 R 43 ; 
 (l) unsubstituted, mono- or di-substituted benzyl, wherein the substituents are each independently:
 (1) haloalkyl, preferably CF 3 ; 
 (2) CN; 
 (3) halo; 
 (4) lower alkyl; 
 (5) —OR 43 ; 
 (6) —SR 43 ; 
 (7) —S(O)R 43 ; or 
 (8) —S(O) 2 R 41 ; 
 
 (m) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently:
 (1) haloalkyl, preferably CF 3 ; 
 (2) CN; 
 (3) halo; 
 (4) lower alkyl; 
 (5) —OR 43 ; 
 (6) —SR 43 ; 
 (7) —S(O)R 43 ; or 
 (8) —S(O) 2 R 41 ; or 
 
 
 R 32  together with R 33  form an oxo group; or 
 R 34  together with R 35  form an oxo group; or 
 R 36  together with R 37  form an oxo group; or 
 R 32  and R 33  are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and, optionally, contain one heteroatom which is preferably oxygen; or 
 R 33  and R 34  are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or 
 R 33  and R 36  are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or 
 R 34  and R 35  are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and optionally, contain one heteroatom which is preferably oxygen; or 
 R 34  and R 36  are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or 
 R 36  and R 37  are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and, optionally, contain one heteroatom which is preferably oxygen; 
 R 38  and R 39  are hydrogen or R 38  and R 39  when taken together are oxo; 
 R 40 , R 41  and R 42  are each independently:
 (c) hydrogen; 
 (d) halo; 
 (c) lower alkyl; 
 (d) alkoxy; 
 (e) alkylthio; 
 (f) —S(O)-lower alkyl; 
 (g) haloalkyl, preferably CF 3 ; 
 (h) CN; 
 (i) —N 3 ; 
 (j) —NO 2 ; 
 (k) —SCF 3 ; or 
 (l) —OCF 3 ; 
 
 R 43  is:
 (a) lower alkyl; or 
 (b) benzyl, optionally mono- or di-substituted, wherein the substituents are each independently:
 (1) haloalkyl, preferably CF 3 ; 
 (2) CN; 
 (3) halo; or 
 (4) lower alkyl; 
 
 
 alternatively, X 5  and U taken together with the carbon atom to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; 
 n at each occurrence is an integer from 0 to 1; 
 D 1  is:
 (a) hydrogen or 
 (b) D; 
 
 D is:
 (a) V; or 
 (b) K; 
 
 U is:
 (a) oxygen; 
 (b) sulfur; or 
 (c) —N(R a )R i —; 
 
 V is:
 (a) —NO; 
 (b) —NO 2 ; or 
 (c) hydrogen 
 
 K is —W aa -E b -(C(R e )(R f )) p -E c -(C(R e )(R f )) x —W d —(C(R e )(R f )) y —W i -E j -W g —(C(R e )(R f )) z —U—V; 
 
       wherein aa, b, c, d, g, i and j are each independently an integer from 0 to 3;
 p, x, y and z are each independently an integer from 0 to 10; 
 W at each occurrence is independently:
 (a) —C(O)—; 
 (b) —C(S)—; 
 (c) -T-; 
 (d) —(C(R e )(R f )) h —; 
 (e) alkyl; 
 (f) aryl; 
 (g) heterocyclic ring; 
 (h) arylheterocyclic ring, or 
 (i) —(CH 2 CH 2 O) q —; 
 
 E at each occurrence is independently:
 (a) -T-; 
 (b) alkyl; 
 (c) aryl; 
 (d) —(C(R e )(R f )) h —; 
 (e) heterocyclic ring; 
 (f) arylheterocyclic ring; or 
 (g) -(CH 2 CH 2 O) q —; 
 
 h is an integer form 1 to 10; 
 q is an integer from 1 to 5; 
 R e  and R f  are each independently:
 (a) hydrogen; 
 (b) alkyl; 
 (c) cycloalkoxy; 
 (d) halogen; 
 (e) hydroxy; 
 (f) hydroxyalkyl; 
 (g) alkoxyalkyl; 
 (h) arylheterocyclic ring; 
 (i) cycloalkylalkyl; 
 (j) heterocyclicalkyl; 
 (k) alkoxy; 
 (l) haloalkoxy; 
 (m) amino; 
 (n) alkylamino; 
 (o) dialkylamino; 
 (p) arylamino; 
 (q) diarylamino; 
 (r) alkylarylamino; 
 (s) alkoxyhaloalkyl; 
 (t) haloalkoxy; 
 (u) sulfonic acid; 
 (v) alkylsulfonic acid; 
 (w) arylsulfonic acid; 
 (x) arylalkoxy; 
 (y) alkylthio; 
 (z) arylthio; 
 (aa) cyano; 
 (bb) aminoalkyl; 
 (cc) aminoaryl; 
 (dd) alkoxy; 
 (ee) aryl; 
 (ff) arylalkyl; 
 (gg) carboxamido; 
 (hh) alkylcarboxamido; 
 (ii) arylcarboxamido; 
 (jj) amidyl; 
 (kk) carboxyl; 
 (ll) carbamoyl; 
 (mm) alkylcarboxylic acid; 
 (nn) arylcarboxylic acid; 
 (oo) alkylcarbonyl; 
 (pp) arylcarbonyl; 
 (qq) ester; 
 (rr) carboxylic ester; 
 (ss) alkylcarboxylic ester; 
 (tt) arylcarboxylic ester; 
 (uu) haloalkoxy; 
 (vv) sulfonamido; 
 (ww) alkylsulfonamido; 
 (xx) arylsulfonamido; 
 (yy) alkylsulfonyl, 
 (zz) alkylsulfonyloxy, 
 (aaa) arylsulfonyl, 
 (bbb) arylsulphonyloxy 
 (ccc) sulfonic ester; 
 (ddd) carbamoyl; 
 (eee) urea; 
 (fff) nitro; or 
 (ggg) —U—V; or 
 
 R e  and R f  taken together are:
 (a) oxo; 
 (b) thial; or 
 
 R e  and R f  taken together with the carbon to which they are attached are:
 (a) heterocyclic ring; 
 (b) cycloalkyl group; or 
 (c) bridged cycloalkyl group; 
 
 k is an integer from 1 to 2; 
 T at each occurrence is independently:
 (a) a covalent bond, 
 (b) carbonyl, 
 (c) an oxygen, 
 (d) —S(O) o —; or 
 (e) —N(R a )R i —; 
 
 o is an integer from 0 to 2; 
 Q is:
 (a) —C(O)—U-D 1 ; 
 (b) —CO 2 -lower alkyl; 
 (c) tetrazolyl-5-yl; 
 (d) —C(R 7 )(R 8 )(S-D 1 ); 
 (e) —C(R 7 )(R 8 )(O-D 1 ); or 
 (f) —C(R 7 )(R 8 )(O-lower alkyl); 
 
 R a  is:
 (a) a lone pair of electron; 
 (b) hydrogen; or 
 (c) lower alkyl; 
 
 R i  is:
 (a) hydrogen; 
 (b) alkyl; 
 (c) aryl; 
 (d) alkylcarboxylic acid; 
 (e) arylcarboxylic acid; 
 (f) alkylcarboxylic ester; 
 (g) arylcarboxylic ester; 
 (h) alkylcarboxamido; 
 (i) arylcarboxamido; 
 (j) alkylsulfinyl; 
 (k) alkylsulfonyl; 
 (l) alkylsulfonyloxy, 
 (m) arylsulfinyl; 
 (n) arylsulfonyl; 
 (o) arylsulphonyloxy; 
 (p) sulfonamido; 
 (q) carboxamido; 
 (r) carboxylic ester; 
 (s) aminoalkyl; 
 (t) aminoaryl; 
 (u) —CH 2 —C(U—V)(R e )(R f ); 
 (v) a bond to an adjacent atom creating a double bond to that atom; or 
 (w) —(N 2 O 2 —) − M + , wherein M +  is an organic or inorganic cation; and 
 
 with the proviso that the compounds of Formula V must contain at least one nitrite, nitrate, thionitrite or thionitrate group. 
 
     
     
         2 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         3 . A method for (i) treating or reducing inflammation, pain or fever; (ii) treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor; (iii) facilitating wound healing; (iv) treating or reversing renal toxicity; (v) treating a disorder resulting from elevated levels of COX-2; or (vi) inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 . 
     
     
         4 . The composition of  claim 2 , further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent. 
     
     
         5 . The composition of  claim 4 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B 4  receptor antagonist, a leukotriene A 4  hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H 2  receptor antagonist, an antineoplastic agent, an antiplatelet agent, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a  Helicobacter pylori  inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof. 
     
     
         6 . The composition of  claim 5 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen or naproxen. 
     
     
         7 . The composition of  claim 4 , further comprising a pharmaceutically acceptable carrier. 
     
     
         8 . A method for (i) treating or reducing inflammation, pain or fever; (ii) treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor; (iii) facilitating wound healing; (iv) treating or reversing renal toxicity; (v) treating a disorder resulting from elevated levels of COX-2; or (vi) inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 7 . 
     
     
         9 . A kit comprising at least one compound of  claim 1 . 
     
     
         10 . The kit of  claim 9 , further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent. 
     
     
         11 . The kit of  claim 10 , wherein the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; the at least one therapeutic agent; or the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent; are in the form of separate components in the kit 
     
     
         12 . A compound selected from the group consisting of (2-(1-((4-chlorophenyl)methyl)-5-methoxy-2-methylindol-3-yl)ethyl)nitrooxy, 2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)-N-(2-methyl-2-(nitrosothio)propyl)acetamide, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A composition comprising at least one compound of  claim 12  and a pharmaceutically acceptable carrier. 
     
     
         14 . The composition of  claim 13 , further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent. 
     
     
         15 . A kit comprising at least one compound of  claim 12 .