Compounds and Methods for the Inhibition of the Expression of VCAM-1

Abstract

This invention is in the area of methods and compositions for the inhibition of the expression of VCAM-1 and, in particular, for the treatment of diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 X is O, S, SO, SO 2 , CH 2 , or NH; 
 Spacer is a group selected from the group consisting of —(CH 2 ) n —, —(CH 2 ) n —CO—, —(CH 2 ) n —N—, —(CH 2 ) n —O—, —(C 2 ) n —S—, —(CH 2 O)—, —(OCH 2 )—, —(SCH 2 )—, —(CH 2 S—), -(aryl-O)—, —(O-aryl)-, -(alkyl-O)—, —(O-alkyl)-; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 
 Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfinylalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH 2 , NHR, NR 2 , SO 2 —OH, OC(O)R, C(O)OH, C(O)OR, C(O)NH 2 , C(O)NHR, C(O)NR 2 , SO 2 NH 2 , SO 2 NHR, SO 2 NR 2 ; 
 R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; 
 R 1  and R 2  are independently straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents on the R 1  or R 2  groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, and acyloxy; 
 R 3  and R 4  are independently any group that does not otherwise adversely affect the desired properties of the molecule, or RI; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein X is S, SO, or SO 2 ; Spacer is —(CH 2 ) n — or —(CH 2 ) n —CO—; n is 0-10; Y is aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH 2 , NHR, NR 2 , alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; R 1  and R 2  are independently straight chained, branched or cyclic C 1-5  alkyl; R 1  and R 4  are independently H, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (I) wherein
 X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-carboxymethylphenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-nitrophenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—(CH 2 ) 2 —; Y=4-nitrophenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=2-carboxyethyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=3,5-di-t-butyl-4-carboxypropanoyloxy;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-carboxyphenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=1-acetyloxy-1-methylethyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=3-nitrophenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=2,4-dinitrophenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-trifluoromethylphenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=2-carboxyfuranyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-(N,N-dimethyl)sulfonamidophenyl;   X═SO; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-nitrophenyl;   X═SO 2 ; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-nitrophenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-acetyloxyphenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-methylphenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-fluorophenyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=ethylsulfonic acid;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=2-dimethylaminomethyl;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—(CH 2 ) 3 —; Y-dimethylamino;   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—(CH 2 ) 5 —; Y=acetyloxy; and   X═S; R 1 =t-butyl; R 2 =t-butyl; R 3 ═H; R 4 ═H; Spacer=—CH 2 —; Y=4-(2-hydroxy)ethylphenyl.   
     
     
         4 . A pharmaceutical composition for the treatment of a disease mediated by the expression of VCAM-1, comprising an effective amount of a compound of any one of  claims 1 ,  2  or  3  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         5 . A method for the treatment of a disorder mediated by the expression of VCAM-1, comprising administering to a patient an effective amount of a compound of formula (I) as claimed in any one of  claims 1 ,  2  or  3 , or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 
     
     
         6 . The method of  claim 5 , wherein the disorder is a cardiovascular disorder. 
     
     
         7 . The method of  claim 6 , wherein the cardiovascular disorder is selected from the group consisting of atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, or small artery disease. 
     
     
         8 . The method of  claim 5 , wherein the disorder is an inflammatory disease. 
     
     
         9 . The method of  claim 8 , wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis. 
     
     
         10 . A compound of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 R a , R b , R c , and R d  are independently any group that does not otherwise adversely affect the desired properties of the molecule selected from the group consisting of hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R a , R b , R c  and R d  groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylarnino, acyl, and acyloxy; 
 Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, —(CH 2 )—R e , —C(O)—R g , and —C(O)—(CH 2 ) n —R h , wherein (a) when each of R a , R b , R c , and R d  are t-butyl, Z cannot be hydrogen and (b) when each of R a , R b , R c , and R d  are t-butyl, Z cannot be the residue of succinic acid; 
 R e  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R k , hydroxy, C(O)NH 2 , C(O)NHR, C(O)NR 2 ; 
 R g  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; 
 R h  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R k , hydroxy, O-phosphate, C(O)NH 2 , C(O)NH 2 , C(O)NR 2  and pharmaceutically acceptable salts thereof; 
 Or, in an alternative embodiment, R e , R g , and R h  can independently be a substituent which improves the water solubility of the compound, selected from the group consisting of C(O)-spacer-SO 3 H, wherein spacer is as defined above, C(O)-spacer-SO 3 M, wherein M is a metal used to form a pharmaceutically acceptable salt, C(O)-spacer-P O   3 H 2 , C(O)-spacer-PO 3 M 2 , C(O)-spacer-PO 3 HM, C(O)-spacer-PO 4 H, C(O)-spacer-PO 4 M, SO 3 M, —PO 3 H 2 , —PO 3 M 2 , —PO 3 HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C 1-3  alkyl) p ] n , wherein n is as defined above and p is 1, 2, or 3, —[O(C 1-3  alkyl) p ] n , carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl or a pharmaceutically acceptable salt thereof. 
 
     
     
         11 . The compound of  claim 10 , wherein R a , R b , R c , and R d  are independently hydrogen or straight chained, branched, or cyclic C 1-10  alkyl; Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, —(CH 2 )—R e , —C(O)—R g , and —C(O)—(CH 2 ) n —R h , and a pharmaceutically acceptable salt thereof, provided that (a) when each of R a , R b , R c , and R d  are t-butyl, Z cannot be hydrogen and (b) when each of R a , R b , R c , and R d  are t-butyl, Z cannot be the residue of succinic acid. 
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (II) wherein
 R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=4-nitrophenyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO—(CH 2 ) 2 —COOH;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-(5-nitrofuran-2-yl);   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-carboxypropyl;   R a =1-methylethyl, R b =t-butyl, R c =methyl, and R d =methyl; Z=4-aminobutyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=4-aminobutyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-hydroxypropanoyl;   R a =t-butyl, R b =t-butyl, R c -butyl, and R d =t-butyl; Z-t-butylcarbonyloxymethyl;   R a =t-butyl, R b =t-butyl, R c ═H, and R d ═H; Z=4-aminobutyl;   R a =t-butyl, R b =t-butyl, R c ═H, and R d ═H; Z=3-carboxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=carboxymethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-(CONH 2 )ethanoyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-aminomethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-(2-carboxyethyl);   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-(2-methoxycarbonylethyl);   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-aminomethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-3-carboxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-carboxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-2-carboxyethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z-CO-ammonium methyl(chloride)   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-hydroxy-2-oxiranyl-ethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-hydroxymethyloxirany-2-ylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-(2-hydroxy-2-oxiranyl)ethoxyoxiran-2-ylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=oxiranylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-hydroxy-3-carboxymethylaminopropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z-2,3,4-trihydroxybutyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-hydroxy-3-ethoxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2,3-dihydroxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=ethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-ethoxycarbonylethenyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=4-N,N-dimethylaminophenethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-2-carboxyethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-2-carboxyethyl (L-arginine ester);   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-methoxycarbonylpropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-carboxyethenyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=galactopyranosylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-(N—N-diethylamino)propyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-ethoxycarbonylethenyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=carboxymethylaminocarbonylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=1,3-dicarboxypropylaminocarbonylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-hydroxy-3-(1,3-diethoxycarbonyl)propylaminopropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2,3-dihydroxy-4-carboxymethylaminobutyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-hydroxy-3-(5-amino-5-carboxy)propylaminopropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=4-ethylcarbonyloxybutyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=4-hydroxybutyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=glucopyranosylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-3-tetrazolylpropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=3-hydroxypropenyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CH 2 CONH—(CH 2 )CH(NH 2 )COOH;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl;   Z=CH 2 CONHCH(COOet)CH 2 CH 2 (COOet);   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=glucopyranosylmethyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2,3,4,5,6-pentahydroxyhexane;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =-butyl; Z=CO-3-(2-hydroxyphenyloxyphosphoxy)propyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CO-2,2-dimethyl-3-hydroxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-hydroxy-3-acetoxypropyl;   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=2-acetoxy-3-hydroxypropyl; and   R a =t-butyl, R b =t-butyl, R c =t-butyl, and R d =t-butyl; Z=CH 2 CH(OH)CH 2 NH(2,3,4,5,6-pentahydroxyhexane.   
     
     
         13 . A pharmaceutical composition for the treatment of a disorder mediated by the expression of VCAM-1 comprising an effective amount of a compound of any one of  claims 10 ,  11  or  12 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for the treatment of a disorder mediated by the expression of VCAM-1 comprising administering to a patient an effective amount of a compound of any one of  claims 10 ,  11  or  12 , or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 
     
     
         15 . The method of  claim 14 , wherein the disorder is a cardiovascular disorder. 
     
     
         16 . The method of  claim 15 , wherein the cardiovascular disorder is selected from the group consisting of atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, and small artery disease. 
     
     
         17 . The method of  claim 14 , wherein the disorder is an inflammatory disease. 
     
     
         18 . The method of  claim 17 , wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis and psoriasis. 
     
     
         19 . The method of  claim 6 , comprising administering the compound in combination with another cardiovascular drug selected from the group consisting of lipid lowering agents, platelet aggregation inhibitors, antithrombotic agents, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and β-blockers. 
     
     
         20 . The method of  claim 15 , comprising administering the compound in combination with another cardiovascular drug selected from the group consisting of lipid lowering agents, platelet aggregation inhibitors, antithrombotic agents, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and β-blockers. 
     
     
         21 . The method of  claim 8 , comprising administering the compound in combination with another antiinflammatory drug. 
     
     
         22 . The method of  claim 16 , comprising administering the compound in combination with another antiinflammatory drug.