Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use

Abstract

The invention describes novel substituted aryl compounds that are cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective 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, such as, steroids, nonsterodal anti-inflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H 2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton-pump-inhibitors, isoprostane inhibitors, and mixtures thereof. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity or other toxicities; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

1 . A composition comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and, at least one compound selected from isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino: 
 wherein the compound of Formula (I) is:                          wherein: 
 X 1  is:  
                     
 Y 1  is: 
 (a) —(CR 1 R 2 ) a -;  
 (b) —(CR 1 R 2 ) b -A 1 -;  
 (c) -A 1 —(CR 1 R 2 ) b -;  
 (d) —CR 1 R 2 -A 1 —CR 1 R 2 -; or  
 (e) —CR 1 ═;  
 
   Z 1  is: 
 (a) mono-, di- or tri-substituted phenyl or 2-naphthyl, wherein the substituents are each independently: 
 (1) hydrogen;  
 (2) halo;  
 (3) lower alkyl;  
 (4) haloalkyl;  
 (5) alkylthio;  
 (6) —NR 4 R 5 ;  
 (7) —C(O)-lower alkyl;  
 (8) —(CH 2 ) a -C(O)O—R 6 ;  
 (9) —OR 11 ; or  
 (10) —(CR e R f ) q —U—V  
 
 (b) mono-, di- or tri-substituted cycloalkyl or heterocyclic ring, wherein the substituents are each independently: 
 (1) hydrogen;  
 (2) halo;  
 (3) lower alkyl;  
 (4) haloalkyl;  
 (5) alkylthio;  
 (6) —NR 4 R 5 ;  
 (7) —C(O)-lower alkyl;  
 (8) —(CH 2 ) q —C(O)O—R 6 ;  
 (9) —OR 11 ;  
 (10) —(CR e R f ) q —U—V;  
 (11) oxo; or  
 (12) thial;  
 
 (c) alkyl;  
   and the bond between Y 1  and Z 1  may be a single bond or a double bond such that the valencies are satisfied; 
 A 1  is: 
 (a) oxygen;  
 (b) thio;  
 (c) sulfinyl;  
 (d) sulfonyl; or  
 (c) —N(R 12 )-;  
 
   -J═K—L═ is: 
 (a) —CR 7 ═CR 8 —N═;  
 (b) —N═CR 7 —CR 8 ═;  
 (c) —CR 8 ═CR 7 —N═;  
 (d) —N═CR 8 —CR 7 ═;  
 (e) —CR 7′ ═CR 7 —CR 8 ═; or  
 (f) —CR 7 ═CR 8 —CR 7′ ;  
   R 1  and R 2  are each independently: 
 (a) hydrogen;  
 (b) lower alkyl;  
 (c) substituted lower alkyl;  
 (d) lower alkoxy;  
 (e) lower haloalkyl; or  
 (f) halo; or  
   R 1  and R 2  taken together are; 
 (a) oxo; or  
 (b) thial  
   R 3  is: 
 (a) —S(O) 2 —CH 3 ;  
 (b) —S(O) 2 —NH 2 ;  
 (c) —S(O) 2 —N(H)—C(O)—CF 3 ;  
 (d) —S(O)(NH)—NH 2 ;  
 (e) —S(O)(NH)—CH 3 ;  
 (f) —S(O)(NH)—N(H)—C(O)—CF 3 ;  
 (g) —S(O) 2 -haloalkyl; or  
 (h) —CH 2 —U—V;  
   R 4  is: 
 (a) hydrogen;  
 (b) substituted lower alkyl  
 (c) cycloalkyl  
 (d) cycloalkylalkyl;  
 (e) lower alkenyl;  
 (f) lower alkoxy;  
 (g) alkylcarbonyl;  
 (h) carboxylic ester;  
 (i) carboxamido;  
 (j) arylcarbonyl;  
 (k) alkylsulfonyl;  
 (l) arylsufonyl;  
 (m) alkylarylsulfonyl; or  
 (n) arylalkylsulfonyl;  
   R 5  is: 
 (a) hydrogen; or  
 (b) lower alkyl; or  
   R 4  and R 5  taken together with the nitrogen to which they are attached form a heterocyclic ring;    R 6  is: 
 (a) lower alkyl; or  
 (b) arylalkyl;  
   R 7′  is: 
 (a) hydrogen;  
 (b) halo; or  
 (c) -D  
   R 7  and R 8  must be taken together with the carbons to which they are attached to form an aromatic or nonaromatic 5-7 membered carbocyclic or heterocyclic ring system having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur;    R 9  is: 
 (a) lower alkyl;  
 (b) haloalkyl;  
 (c) phenyl; or  
 (d) benzyl;  
   R 10  is: 
 (a) hydrogen;  
 (b) lower alkyl;  
 (c) aryl;  
 (d) cycloalkyl;  
 (e) cycloalkylalkyl;  
 (f) lower alkenyl; or  
 (g) lower alkoxy;  
   R 11  is: 
 (a) lower alkyl;  
 (b) lower haloalkyl;  
 (c) alkoxyalkyl;  
 (d) alkylcarbonyl;  
 (e) arylalkylcarbonyl;  
 (f) carboxamido; or  
 (g) arylcarbonyl;  
   R 12  is: 
 (a) lower alky;  
 (b) hydrogen; or  
 (c) —C(O)H;  
   R 13  is: 
 (a) hydrogen;  
 (b) halogen;  
 (c) lower alkyl;  
 (d) lower alkoxy; or  
 (e) lower haloalkyl;  
   a is an integer equal to 1 or 3;    b is an integer equal to 2 or 3;    o is an integer from 0-2;    D is —W k —E l  (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 c, d, g, i, j, k and 1 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) alkylaryl;  
 (j) cycloalkylalkyl;  
 (k) heterocyclicalkyl;  
 (l) alkoxy;  
 (m) haloalkoxy;  
 (n) amino;  
 (o) alkylamino;  
 (p) dialkylamino;  
 (q) arylamino;  
 (r) diarylamino;  
 (s) alkylarylamino;  
 (t) alkoxyhaloalkyl;  
 (u) sulfonic acid;  
 (v) alkylsulfonic acid;  
 (w) arylsulfonic acid;  
 (x) arylalkoxy;  
 (y) alkylthio;  
 (z) arylthio;  
 (aa) cyano;  
 (bb) aminoalkyl;  
 (cc) aminoaryl;  
 (dd) aryl;  
 (ee) arylalkyl;  
 (ff) alkylaryl;  
 (gg) carboxamido;  
 (hh) alkylcarboxamido;  
 (ii) arylcarboxamido;  
 (j) 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) sulfonamido;  
 (vv) alkylsulfonamido;  
 (ww) arylsulfonamido;  
 (xx) sulfonic ester;  
 (yy) urea;  
 (zz) nitro; or  
 (aaa) —(C(R e )(R f )) k —U—V; or  
   R e  and R f  taken together with the carbon to which they are attached are: 
 (a) oxo;  
 (b) thial;  
 (c) aryl;  
 (d) heterocyclic ring;  
 (e) cycloalkyl group; or  
 (f) bridged cycloalkyl group;  
   U is: 
 (a) oxygen;  
 (b) sulfur; or  
 (c) —N(R a )R i -;  
   V is: 
 (a) —NO; or  
 (b) —NO 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 1 -;  
   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) aryl carboxylic acid;  
 (f) alkylcarboxylic ester;  
 (g) arylcarboxylic ester;  
 (h) alkylcarboxamido;  
 (i) arylcarboxamido;  
 (j) alkylaryl;  
 (k) alkylsulfinyl;  
 (l) alkylsulfonyl;  
 (m) arylsulfinyl;  
 (n) arylsulfonyl;  
 (o) sulfonamido;  
 (p) carboxamido;  
 (q) carboxylic ester;  
 (r) aminoalkyl;  
 (s) aminoaryl;  
 (t) —CH 2 —C(U—V)(R e )(R f ); or  
 (u) —(N 2 O 2 —).M + , wherein M +  is an organic or inorganic cation.  
   
     
     
         2 . The composition of  claim 1 , wherein at least one substituent in the compound of Formula (I) contains a “—U—V” moiety, wherein U and V are as defined herein.  
     
     
         3 . The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier.  
     
     
         4 . The composition of  claim 1 , further comprising 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 thrombin inhibitor, a thromboxane inhibitor, 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 . A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 3  or  4 .  
     
     
         7 . A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 3  or  4 .  
     
     
         8 . The method of  claim 7 , wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendonitis, bursitis, a skin-related condition, neoplasia, inflammation in disease, ophthalmic disorder, pulmonary inflammation, central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation, microbial infection, cardiovascular disorder, urinary disorder, urological disorder, endothelial dysfunction, a disorder treated by the preservation of organs and tissues, a disorder treated by inhibition of activation, adhesion and infiltration of neutrophils at the site of inflammation, or a disorder treated by inhibition of platelet aggregation.  
     
     
         9 . A method for treating a gastrointestinal disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 3  or  4 .  
     
     
         10 . The method of  claim 9 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, a hypersecretory state associated with systemic mastocytosis or basophilic leukemia or hyperhistaminemia.  
     
     
         11 . A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 3  or  4 .  
     
     
         12 . The method of  claim 1 , wherein the wound is an ulcer.  
     
     
         13 . A method for treating or reversing renal toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 3  or  4 .  
     
     
         14 . A method for improving the cardiovascular profile of a COX-2 selective inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 3  or  4 .  
     
     
         15 . The method of  claim 14 , further comprising administering to the patient a therapeutically effective amount of at least one of a 3-hydroxy-3-methylglutaryl coenzyme A, an antiplatelet agent, a thrombin inhibitor or a thromboxane inhibitor.  
     
     
         16 . The composition of  claim 1 , wherein the least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and, the at least one compound selected from isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino are administered separately or are administered together.  
     
     
         17 . The composition of  claim 1 , wherein the least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and, the at least one compound selected from isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino are administered orally, bucally, topically, by injection, by inhalation, or by transdermal application.  
     
     
         18 . A kit comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof, and, at least one compound selected from isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino.  
     
     
         19 . The kit of  claim 18 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and, the at least one compound selected from isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino are separate components in the kit or are in the form of a composition in the kit.  
     
     
         20 . The kit of  claim 17 , further comprising and at least one therapeutic agent.  
     
     
         21 . The composition of  claim 1 , wherein the compound of Formula (I) is selected from 1-(6-(cyclohexylidenemethyl) (2-H-benzo(3,4-d)1,3-dioxolen-5-yl))-4-(methylsulfonyl)benzene, 1-(6-(cyclohexylmethyl)(2-H-benzo(3,4-d)1,3-dioxolen-5-yl))-4-(methylsulfonyl)benzene, 1-(6-(cyclohexylhydroxymethyl) (2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, cyclohexyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 1-(6-(hydroxyphenylmethyl) (2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 4-(methylsulfonyl)-1-(6-benzyl(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))benzene, 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) phenyl ketone, (2-fluorophenyl)(6-(4-methylthiophenyl)(2H-benzo(d) 1,3-dioxolan-5-yl))methan-1-ol, 1-(6-((2-fluorophenyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 2-fluorophenyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 1-(6-((3-fluorophenyl)hydroxymethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 1-(6-((3-fluorophenyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 3-fluorophenyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 1-(6-(hydroxy-3-pyridylmethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 4-(methylsulfonyl)-1-(6-(3-pyridylmethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))benzene, 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) 3-pyridyl ketone, ethyl (2E)-2-methyl-3-(6-(4-(methylsulfonyl)phenyl)(2H-benzo(d) 1,3-dioxolan-5-yl))prop-2-enoate, 1-(6-((1E)-3-hydroxy-2-methylprop-1-enyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 4-(methylsulfonyl)-1-(6-((3-((nitrooxy)methyl)piperidyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))benzene, 1-(6-((3-(hydroxymethyl)piperidyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl) benzene, 4-(methylsulfonyl)-1-(6-((3-((nitrooxy)methyl)piperidyl)methyl) (2H-benzo(3,4-d)1,3-dioxolan-5-yl))benzene, 1-((6-(4-methylsulfonyl)phenyl)-2H-benzo(d)1,3-dioxolan-5-yl)methyl)piperidin-2-one, 4-(6-(cyclopentylidenemethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-(cyclopenthylmethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-(cycloheptylidenemethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl) benzene, 4-(6-(cycloheptylmethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-(hydroxy(3-methylphenyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 3-methylphenyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl)ketone, 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) 3 -((nitrooxy) methyl)phenylketone, 3-methoxyphenyl-6-(4-(methylsulfonyl) phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 4-(6-(3-methoxyphenyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-((2-fluoro-5-methylphenyl) hydroxymethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 2-fluoro-5-methylphenyl6-(4-(methylsulfonyl)phenyl)(2H-benzo(d) 1,3-dioxolan-5-yl)ketone, 4-(1-(3′,5′-difluorophenyl)-1-hydroxymethyl)-1,2-methylenedioxy-5-(4-methylsulfonylphenyl) benzene, 5-(1-(3′,5′-difluorophenyl)methyl)-1,2-methylenedioxy-4-(4-methylsulfonylphenyl)benzene, 4-(1-(3′,5′-difluorophenyl)-1-oxomethyl)-1,2-methylenedioxy-5-(4-methylsulfonylphenyl)benzene, ethyl 7-((3,5-difluorophenyl) methyl)-6-(4-(methylsulfonyl) phenyl)-2H, 3H-benzo(e)1,4-dioxin-2-carboxylate, ethyl 6-((3,5-difluorophenyl)methyl)-7-(4-(methylsulfonyl)phenyl)-2H, 3H-benzo(e)1,4-dioxin-2-carboxylate, (7-((3,5-difluorophenyl) methyl)-6-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)l, 4-dioxin-2-yl))-N-(2-hydroxyethyl)carboxamido, (6-((3,5-difluorophenyl)methyl)-7-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e) 1,4-dioxin-2-yl))-N-(2-hydroxyethyl)carboxamido, (7-((3,5-difluorophenyl) methyl)-6-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)1,4-dioxin-2-yl))-N-(2-(nitrooxy) ethyl)carboxamido, 1-(7-((3,5-difluorophenyl)methyl)-2-(hydroxymethyl)(2H, 3H-benzo(3,4-e) 1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl) methyl)-3-(hydroxymethyl)(2H, 3H-benzo(e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)-2-((nitrooxy)methyl)(2H, 3H-benzo(3,4-e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)-3-((nitrooxy)methyl)(2H, 3H-benzo(e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)(2H, 3H-benzo(3,4-e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 7-((3,5-difluorophenyl)methyl)-6-(4-(methylsulfonyl)phenyl)-2H, 3H-benzo(e)1,4-dioxin-2-carboxamide, 3,5-difluorophenyl 7-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)1,4-dioxin-6-yl) ketone, ((4-(6-((3,5-difluorophenyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))phenyl)methyl)nitrooxy, or a pharmaceutically acceptable salt thereof.