Methods and Compositions for Selectin Inhibition

Abstract

The present invention relates to the field of anti-inflammatory substances, and more particularly to novel compounds that act as antagonists of the mammalian adhesion proteins known as selecting. In some embodiments, methods for treating selectin mediated disorders are provided which include administration of compound of Formula I: wherein the constituent variables are defined herein.

1 . A method of inhibiting selectin-mediated intracellular adhesion associated with a disease, disorder, condition or undesired process in a mammal, said method comprising administering to said mammal an effective amount of a compound of Formula II: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       Y is O, (CR 3 R 4 ) p  or NR 5 ; 
       p is 1 to 3; 
       X is OH, OR 3 , OC 1-6  alkyl, OC(═O)aryl, OC(═O)C 1-6  alkyl, OC(═O)OC 1-6  alkyl or NR 3 R 3′ ; 
       each R 1 , R 2 , R 3 , R 3′  and R 4  is independently hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, OC 1-6  perhaloalkyl, halogen, thioalkyl, CN, OH, SH, (CH 2 ) n OSO 3 H, (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 R 6 , OSO 3 R 6 , SO 2 R 6 , SO 3 R 6 , PO 3 R 6 R 7 , (CH 2 ) n SO 2 NR 8 R 9 , (CH 2 ) n C(═O)NR 8 R 9 , NR  8 R 9 , C(═O)R 12 , aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, OC(═O)aryl, OC(═O)heterocyclo, Oaryl, Oheterocyclo, arylalkyl, C(═O)arylalkyl, OC(═O)arylalkyl, Oarylalkyl, alkenyl, alkynyl, or NHCOR 8 , wherein any of said alkyl, Oalkyl, aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, O—C(═O)aryl, O—C(═O)heterocyclo, O-aryl, O-heterocyclo, arylalkyl, C(═O)arylalkyl, O—C(═O)arylalkyl, O-arylalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl and CN; 
       each R 6  and R 7  is independently selected from the group consisting of hydrogen and C 1-6  alkyl that is optionally substituted with up to three substituents selected from OH, CF 3 , SH and halogen; 
       each R 5 , R 8  and R 9  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6 haloalkyl, thioalkyl, OH, (CH 2 ) l OSO 3 H, (CH 2 ) l SO 3 R 10 , (CH 2 ) n CO 2 R 10 , SO 3 R 10 , PO 3 R 10 R 11 , (CH 2 ) n SO 2 (CH 2 ) n NR 10 R 11 , (CH 2 ) n CONR 10 R 11 , COR 10 , aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, O—C(═O)aryl, O—C(═O)heterocyclo, Oaryl, Oheterocyclo, arylalkyl, C(═O)arylalkyl, OC(═O)arylalkyl, Oarylalkyl, alkenyl, or alkynyl, wherein any of said alkyl, aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, OC(═O)aryl, OC(═O)heterocyclo, Oaryl, Oheterocyclo, arylalkyl, C(═O)arylalkyl, OC(═O)arylalkyl, Oarylalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl and CN; 
       each n is an independently selected integer from 0 to 6; 
       each l is an independently selected integer from 1 to 6; 
       each R 10  and R 11  is independently selected from the group consisting of hydrogen and C 1-6  alkyl that is optionally substituted with up to three substituents selected from OH, CF 3 , SH and halogen; 
       each R 12  is independently hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, OC 1-6  alkyl, OC 1-6  perhaloalkyl, thioalkyl, OH, (CH 2 ) 1 OSO 3 H, (CH 2 ) 1 SO 3 H, (CH 2 ) l CO 2 R 6 , (CH 2 ) l SO 2 NR 8 R 9 , (CH 2 ) n C(═O)NR 8 R 9 , NR 8 R 9 , alkenyl, alkynyl, or NHCOR 8 , wherein any of said alkyl, Oalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl and CN; and 
     
     Z is aryl, arylalkyl, heteroaryl or heterocyclo, wherein each of said aryl, arylalkyl, heteroaryl and heterocyclo is optionally substituted. 
   
   
       2 . The method of  claim 1  wherein said disease, disorder, condition or undesired process is selected from the group consisting of inflammation, infection, metastasis, an undesired immunological process, and an undesired thrombotic process. 
   
   
       3 . The method of  claim 1  wherein said disease, disorder, condition or undesired process is selected from the group consisting of atherosclerosis, restenosis, myocardial infarction, Reynauld's syndrome, inflammatory bowel disease, osteoarthritis, acute respiratory distress syndrome, asthma, emphysema, delayed type hypersensitivity reaction, thermal injury, experimental allergic encephalomyelitis, multiple organ injury syndrome secondary to trauma, neutrophilic dermatosis (Sweet's disease), glomerulonephritis, ulcerative colitis, Crohn's disease, necrotizing enterocolitis, cytokine-induced toxicity, gingivitis, periodontitis, hemolytic uremic syndrome, psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease, immunological-mediated side effects of treatment associated with hemodialysis or leukapheresis, granulocyte transfusion associated syndrome, deep vein thrombosis, unstable angina, transient ischemic attacks, peripheral vascular disease, metastasis associated with cancer and congestive heart failure. 
   
   
       4 . The method of  claim 1  wherein said disease, disorder, condition or undesired process is an undesired infection process mediated by a bacteria, a virus, or a parasite. 
   
   
       5 . The method of  claim 4  wherein said undesired infection process is gingivitis, periodontitis, hemolytic uremic syndrome, or granulocyte transfusion. 
   
   
       6 . The method of  claim 1  wherein said disease, disorder, condition or undesired process is metastasis associated with cancer. 
   
   
       7 . The method of  claim 1  wherein said disease, disorder, condition or undesired process is a disease or disorder associated with an undesired immunological process selected from psoriasis, systemic lupus erythematosus, autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, Grave's disease and immunological-mediated side effects of treatment associated with hemodialysis or leukapheresis. 
   
   
       8 . The method of  claim 1  wherein said disease, disorder, condition or undesired process is a condition associated with an undesired thrombotic process selected from deep vein thrombosis, unstable angina, transient ischemic attacks, peripheral vascular disease, and congestive heart failure. 
   
   
       9 . A method of ameliorating an undesired immunological process in a transplanted organ comprising administering to said organ an immunosupressive agent in conjunction with a compound of  claim 1 . 
   
   
       10 . The method of  claim 1  wherein Y is CR 3 R 4 . 
   
   
       11 . The method of  claim 1  wherein Y is CH 2  and X is OH. 
   
   
       12 . The method of  claim 1  wherein Z is selected from:
 (a) a five-membered heterocyclic ring containing one to three ring heteroatoms selected from N, S or O; wherein said five-membered heterocyclic ring is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-10  alkyl, OC 1-10  alkyl, NO 2 , NH 2 , CN, CF 3 , and CO 2 H;   (b) a six-membered heterocyclic ring containing one to three ring heteroatoms selected from N, S or O; wherein said six-membered heterocyclic ring is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-10  alkyl, OC 1-10  alkyl, CHO, CO 2 H, C(═O)R 20 , SO 2 R 20 , NO 2 , NH 2 , CN, CF 3  and OH; wherein each R 20  is independently selected from the group consisting of C 1-10  alkyl, OC 1-10  alkyl and NR 6 R 7 ;   (c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N or O; wherein said bicyclic ring moiety is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl, CHO, NO 2 , NH 2 , CN, CF 3 , CO 2 H, C(═O)R 20 , SO 2 R 20 , and OH; and   (d) a benzyl, naphthyl, or phenyl ring, each of which is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-6  alkyl, phenyl, benzyl, Ophenyl, Obenzyl, SO 2 NH 2 , SO 2 NH(C 1-6  alkyl), SO 2 N(C 1-6  alkyl) 2 , CH 2 COOH, CO 2 H, CO 2 Me, CO 2 Et, CO 2 iPr, C(═O)NH 2 , C(═O)NH(C 1 alkyl), C(═O)N(C 1 alkyl).su-b.2, OH, SC 1-6  alkyl, OC 1-6  alkyl, NO 2 , NH 2 , CF 3 , and CN.   
   
   
       13 . The method of  claim 1  wherein Y is CH 2 , X is OH, and Z is selected from:
 (a) a five-membered heterocyclic ring containing one to three ring heteroatoms selected from N, S or O; wherein said five-membered heterocyclic ring is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-10  alkyl, OC 1-10  alkyl, NO 2 , NH 2 , CN, CF 3 , and CO 2 H;   (b) a six-membered heterocyclic ring containing one to three ring heteroatoms selected from N, S or O; wherein said six-membered heterocyclic ring is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-10  alkyl, OC 1-10  alkyl, CHO, CO 2 H, C(═O)R 20 , SO 2 R 20 , NO 2 , NH 2 , CN, CF 3  and OH; wherein each R 20  is independently selected from the group consisting of C 1-10  alkyl, OC 1-10  alkyl and NR 6 R 7 ;   (c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N or O; wherein said bicyclic ring moiety is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl, CHO, NO 2 , NH 2 , CN, CF 3 , CO 2 H, C(═O)R 20 , SO 2 R 20 , and OH; and   (d) a benzyl, naphthyl, or phenyl ring, each of which is optionally substituted by from 1 to 3 substituents selected from halogen, C 1-6  alkyl, phenyl, benzyl, Ophenyl, Obenzyl, SO 2 NH 2 , SO 2 NH(C 1-6  alkyl), SO 2 N(C 1-6  alkyl) 2 , CH 2 COOH, CO 2 H, CO 2 Me, CO 2 Et, CO 2 iPr, C(═O)NH 2 , C(═O)NH(C 1-6  alkyl), C(═O)N(C 1-6  alkyl) 2 , OH, SC 1-6  alkyl, OC 1-6  alkyl, NO 2 , NH 2 , CF 3 , and CN.   
   
   
       14 . The method of  claim 1  wherein said compound has the Formula III: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salts thereof, 
       wherein: 
       R 21  and R 22  are independently, H, halogen, OH, CN, SH, C 1-6  alkyl, OC 1-6  alkyl, C 1-6  perhaloalkyl, C 1-6  thioalkyl, aryl or heteroaryl; 
       wherein said aryl and said heteroaryl can each optionally be substituted with up to three substituents selected from halogen, OH, CN, SH, NH 2 , C 1-6  alkyl, OC 1-6  alkyl, C 1-6  perhaloalkyl and C 1  thioalkyl; and 
       wherein said C 1-6  alkyl, OC 1-6  alkyl and C 1-6  thioalkyl can each optionally be substituted with up to three substituents selected from halogen, OH, CN, SH, NH 2 , OC 1-6  alkyl, C 1-6  perhaloalkyl and C 1-6  thioalkyl; and 
       R 23  is aryl or heteroaryl, wherein said aryl and said heteroaryl can each optionally be substituted with up to three substituents selected from halogen, OH, CN, SH, NH 2 , C 1-6  alkyl, OC 1-6  alkyl, C 1-6  perhaloalkyl and C 1-6  thioalkyl. 
     
   
   
       15 . The method of  claim 14  wherein:
 R 2  and R 2  are independently selected from the group consisting of H, C 1-6  alkyl, halogen, aryl, heteroaryl, and OC 1-6  alkyl wherein said heteroaryl is 3-furanyl or 3-thiophenyl and said aryl is unsubstituted phenyl; and said C 1-6  alkyl and said OC 1-6  alkyl can each optionally be substituted with up to three substituents selected from halogen, OH, CN, SH, NH 2 , OC 1-6  alkyl, C 1-6  perhaloalkyl and C 1  thioalkyl; and   R 23  is a phenyl group substituted at the 4′-position with halogen, C 1  alkyl, SC 1-6  alkyl, or OC, alkyl.   
   
   
       16 . The method of  claim 14  wherein R 1  and R 2  are located on the 7 and 8 positions of the quinoline ring and are independently selected from the group consisting of H, methyl, and unsubstituted phenyl; and
 R 23  is phenyl substituted at the 4′-position with Cl or OCF 3 .   
   
   
       17 . The method of  claim 14  wherein:
 R 1  is located at the 7 position of the quinoline ring and R 2  is located at the 8 position of the quinoline ring; and either:   R 1  is CH 3 , R 2  is CH 3  and R 23  is 4-chlorophenyl; or   R 1  is H, R 2  is unsubstituted phenyl and R 23  is 4-chlorophenyl.   
   
   
       18 . The method of  claim 1  wherein said compound is selected from the group consisting of: 
     a) 2-(4-Chloro-benzyl)-3-hydroxy-8-trifluoromethyl-quinoli-ne-4-carboxylic acid; 
     b) 2-(4-Chloro-benzyl)-3-hydroxy-8-trifluoromethoxy-quinoline-4-carboxylic acid; 
     c) 2-(4-Chlorobenzyl)-3-hydroxy-8-isopropylqu-inoline-4-carboxylic acid; 
     d) 2-(4-Chlorobenzyl)-3-hydroxy-8-methylquinoli-ne-4-carboxylic acid; 
     e) 2-(4-Chlorobenzyl)-8-ethyl-3-hydroxyquinoline-4-c-arboxylic acid; 
     f) 2-(4-Chlorobenzyl)-3-hydroxy-8-(thien-3-yl)quinoline-4-c-arboxylic acid; 
     g) 8-Bromo-2-(4-chlorobenzyl)-3-hydroxyquinoline-4-carboxy-lic acid; 
     h) 8-(sec-Butyl)-2-(4-chlorobenzyl)-3-hydroxyquinoline-4-carboxy-lic acid; 
     i) 2-(4-Chlorobenzyl) 3 -hydroxy-6-phenylquinoline-4-carboxyl-ic acid; 
     j) 2-(4-Chlorobenzyl)-8-(fur-3-yl)-3-hydroxyquinoline-4-carboxyli-c acid; 
     k) 2-(4-Chlorobenzyl)-8-fluoro-3-hydroxyquinoline-4-carboxylic acid; 
     l) 2-(4-Chlorobenzyl)-8-fluoro-3-hydroxyquinoline-4-carboxylic acid; 
     m) 2-(4-Chloro-benzyl)-3-hydroxy-8-(2,2,2-trifluoro-1-hydroxy-1-tri-fluoromethyl-ethyl)-quinoline-4-carboxylic acid; and 
     n) 2-(4-Chloro-benzyl)-3-hydroxy-quinoline-4-carboxylic acid. 
   
   
       19 . A method of ameliorating an undesired immunological process in a transplanted organ comprising administering to said organ an immunosupressive agent in conjunction with a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       20 . A process for preparing a compound of formula I 
     
       
         
         
             
             
         
       
       wherein: L is CO 2 H, an ester thereof, or a pharmaceutically acceptable acid mimetic; 
       Y is O, (CR 3 R 4 ) p  or NR 5 ; 
       p is 1 to 3; 
       X is hydrogen, OH, OR 3 , OC 1-6  alkyl, OC(═O)aryl, OC(═O)C 1-6  alkyl OC(═O)OC 1-6  alkyl or NR 3 R 3 ′; 
       each R 1 , R 2 , R 3 , R 3  and R 4  is independently hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, OC 1-6  alkyl, OC 1-6  perhaloalkyl, halogen, thioalkyl, CN, OH, SH, (CH 2 ) n OSO 3 H, (CH 2 ) n SO 3 H, (CH 2 ) n CO 2 R 6 , OSO 3 R 6 , SO 2 R 6 , SO 3 R 6 , PO 3 R 6 R 7 , (CH 2 ) n SO 2 NR 8 R 9 , (CH 2 ) n C(═O)NR 8 R 9 , NR  8 R 9 , C(═O)R 12 , aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, OC(═O)aryl, OC(═O)heterocyclo, Oaryl, Oheterocyclo, arylalkyl, C(═O)arylalkyl, OC(═O)arylalkyl, Oarylalkyl, alkenyl, alkynyl, or NHCOR 8 , wherein any of said alkyl, Oalkyl, aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, O—C(═O)aryl, O—C(═O)heterocyclo, O-aryl, O-heterocyclo, arylalkyl, C(═O)arylalkyl, O—C(═O)arylalkyl, O-arylalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl and CN; 
       each R 6  and R 7  is independently selected from the group consisting of hydrogen and C 1-6  alkyl that is optionally substituted with up to three substituents selected from OH, CF 3 , SH and halogen; 
       each R 5 , R 8  and R 9  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6 haloalkyl, thioalkyl, OH, (CH 2 ) l OSO 3 H, (CH 2 ) l SO 3 R 10 , (CH 2 ) n CO 2 R 10 , SO 3 R 10 , PO 3 R 10 R 11 , (CH 2 ) n SO 2 (CH 2 ) n NR 10 R 11 , (CH 2 ) n CONR 10 R 11 , COR 10 , aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, O—C(═O)aryl, O—C(═O)heterocyclo, Oaryl, Oheterocyclo, arylalkyl, C(═O)arylalkyl, OC(═O)arylalkyl, Oarylalkyl, alkenyl, or alkynyl, wherein any of said alkyl, aryl, heterocyclo, C(═O)aryl, C(═O)heterocyclo, OC(═O)aryl, OC(═O)heterocyclo, Oaryl, Oheterocyclo, arylalkyl, C(═O)arylalkyl, OC(═O)arylalkyl, Oarylalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl and CN; 
       each n is an independently selected integer from 0 to 6; 
       each l is an independently selected integer from 1 to 6; 
       each R 10  and R 11  is independently selected from the group consisting of hydrogen and C 1-6  alkyl that is optionally substituted with up to three substituents selected from OH, CF 3 , SH and halogen; 
       each R 12  is independently hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, OC 1-6  alkyl, OC 1-6  perhaloalkyl, thioalkyl, OH, (CH 2 ) 1 OSO 3 H, (CH 2 ) 1 SO 3 H, (CH 2 ) l CO 2 R 6 , (CH 2 ) l SO 2 NR 8 R 9 , (CH 2 ) n C(═O)NR 8 R 9 , NR 8 R 9 , alkenyl, alkynyl, or NHCOR 8 , wherein any of said alkyl, Oalkyl, alkenyl or alkynyl can optionally be substituted with up to three substituents selected from halogen, C 1-6  alkyl, OC 1-6  alkyl and CN; and 
       Z is aryl, arylalkyl, heteroaryl or heterocyclo, wherein each of said aryl, arylalkyl, heteroaryl and heterocyclo is optionally substituted; and 
       which comprises one of the following:
 a) reacting a compound of formula 
 
     
     
       
         
         
             
             
         
       
       with a compound of formula: 
     
     
       
         
         
             
             
         
       
       wherein Ac is acetyl and Y and Z are as defined in  claim 1  to give a corresponding compound of formula I wherein L is CO 2 H in the 4 position and X is OH in the 3 position; or 
       b) converting a compound of formula I to a pharmaceutically acceptable salt thereof or vice versa. 
     
   
   
       21 . A method comprising: identifying a human, mammal or animal as having a biomarker for a disease or disorder involving selectin-mediated intracellular adhesion; and administering to said human, mammal or animal a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       22 . The method of  claim 21  wherein the biomarker is one or more of CD 40, CD 40 Ligand, MAC-1, TGF beta, ICAM, VCAM, IL-1, IL-6, IL-8, Eotaxin, RANTES, MCP-1, PIGF, CRP, SAA, and platelet monocyte aggregates.