US2005171028A1PendingUtilityA1
Thioketals and thioethers for inhibiting the expression of VCAM-1
Individually held — no corporate assignee on recordPriority: Mar 21, 2000Filed: Feb 8, 2005Published: Aug 4, 2005
Est. expiryMar 21, 2020(expired)· nominal 20-yr term from priority
C07C 323/67C07C 323/20C07C 323/25C07C 323/60C07C 323/21C07H 15/203A61K 31/222A61K 31/225C07C 323/66C07C 323/56
48
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Claims
Abstract
Thioketals and thioethers are provided that inhibit the expression of VCAM-1, and which can be used in the treatment of VCAM-1 mediated diseases including inflammatory disorders, cardiovascular diseases, occular diseases, autoimmune diseases, neurological disorders, and cancer. The compounds also can be used to treat hyperlipidemia and/or hypercholesterolemia.
Claims
exact text as granted — not AI-modified1 ) A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
a) R a , R b , R c , and R d are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and
b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C 1-10 alkyl or substituted C 1-10 alkyl terminated by sulfonic acid, (iv) C 1-10 alkyl or substituted C 1-10 alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C 1-10 alkyl-O—C(O)—C 1-10 alkyl, (vi) straight chained polyhydroxylated C 3-10 alkyl; (vii) —(CR 2 ) 1-6 —COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii) —(CR 2 ) 1-6 —X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
2 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl.
3 ) The compound of claim 1 wherein Z is a substituted or unsubstituted monosaccharide, disaccharide, oligosaccharide, or polysaccharide.
4 ) The compound of claim 1 wherein Z is substituted or unsubstituted furanose or pyranose.
5 ) The compound of claim 1 wherein Z is threose, ribulose, ketose, gentiobiose, aldose, aldotetrose, aldopentose, aldohexose, ketohexose, ketotetrose, ketopentose, erythrose, threose, ribose, deoxyribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, glactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose, cellulose, aldose, amylose, palatinose, trehalose, turanose, cellobiose, amylopectin, glucosamine, mannosamine, fucose, phamnose, glucuronate, gluconate, gluconolactone, muramic acid, abequose, rhamnose, gluconic acid, glucuronic acid, or galactosamine.
6 ) The compound of claim 1 wherein Z is —CH 2 —(CHOH) 3 CH 2 OH.
7 ) The compound of claim 1 wherein Z is —CH 2 —(CHOH) 4 CH 2 OH.
8 ) The compound of claim 1 wherein Z is —(CR 2 ) 1-6 -sulfonic acid, and R is independently hydrogen, halo, amino, or hydroxy.
9 ) The compound of claim 1 wherein Z is substituted or unsubstituted alditol.
10 ) The compound of claim 1 wherein Z is —(CR 2 ) 1-6 -phosphonic acid, and R is independently hydrogen, halo, amino, or hydroxy.
11 ) The compound of claim 1 wherein Z is —(CR 2 ) 1-4 -phosphonic acid, and R is independently hydrogen, halo, or hydroxy.
12 ) The compound of claim 1 wherein Z is —(CHR) 1-6 —O—C(O)—(CHR) 1-6 —CH 2 R, and R is independently hydrogen, halo, amino, or hydroxy.
13 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl, and Z is —(CR 2 ) 1-6 —X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.
14 ) The compound of claim 1 wherein Z is —CH 2 —(CHR′) 1-8 —CH 2 R′, R′ is independently hydrogen or hydroxy, and at least two of R′ are hydroxy.
15 ) The compound of claim 1 wherein Z is —CH 2 —(CHR′) 1-6 —CH 2 R′, R′ is independently hydrogen or hydroxy, and at least three of R′ are hydroxy.
16 ) The compound of claim 1 wherein Z is —(CH 2 ) 0-6 —CF 2 —COOH.
17 ) The compound of claim 1 wherein Z is —(CH 2 ) 1-6 —CH(NR 1 R 2 )—COOH, and R 1 and R 2 are independently hydrogen or lower alkyl.
18 ) The compound of claim 1 wherein Z is —(CR 2 ) 1-6 —X, R is independently hydrogen, halo, amino, or hydroxy; and X is substituted or unsubstituted pyrolidine, imidazole, pyridine, or pyrimidine.
19 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl, and Z is 2-amino-3-carboxypropyl; 3-amino-4-carboxybutyl; 1,1-difluoro-1-carboxymethyl; phosphonomethyl; 1,1-difluoro-1-phosphono-methyl; 2-(2-carboxy-N-pyrrolidine)ethyl; (2H-imidazol-5-yl)methyl; 2-pyridylmethyl; 3-pyridylmethyl; or 5-pyrimidinylmethyl.
20 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl, and Z is arabitol.
21 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl, and Z is ribofuranose.
22 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl, and Z is 2-hydroxy-3-propyl-D-gluconate.
23 ) The compound of claim 1 wherein R a , R b , R c , and R d are t-butyl, and Z is 2-hydroxypropan-3-sulfonic acid.
24 ) A compound of formula (II) or its pharmaceutically acceptable salt:
wherein:
a) X is O, S, SO, SO 2 , CH 2 , or NH;
b) spacer is —(CH 2 ) n —, —(CH 2 ) n —CO—, —(CH 2 ) n —NH—, —(CH 2 ) n —O—, —(CH 2 ) n —S—, —(OCH 2 )—, —(SCH 2 )—, —(CH 2 S—), -(aryl-O)—, —(O-aryl)-, -(alkyl-O)—, —(O-alkyl)-; —O—C(O)—(CH 2 ) n , —(CH 2 ) n —C(O)—O—, S—C(S)—(CH 2 ) n , —(CH 2 ) n —C(S)—S—, —C(O)—, —C(S)—;
c) n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
d) R 1 and R 2 are independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, or aralkyl;
e) R 3 and R 4 are independently any group that does not otherwise adversely affect the desired properties of the molecule, including H, halogen, or R 1 ; and
f) Y is aryl or heteroaryl monosubstituted by —C(O)NR 5 R 6 , wherein R 5 and R 6 are independently hydrogen or alkyl.
25 ) The compound of claim 24 wherein:
a) —X-spacer- is —S—CH 2 —; b) R 1 and R 2 are t-butyl; c) R 3 and R 4 are hydrogen; and d) Y is aryl or heteroaryl monosubstituted by —C(O)NR 5 R 6 , wherein R 5 and R 6 are independently hydrogen or alkyl.
26 ) The compound of claim 24 which is 2,6-Di-tert-butyl-[4′-(N,N-diethylaminocarbonyl)benzyl]thiophenol.
27 ) The compound of claim 24 which is 2,6-Di-tert-butyl-[4′-(N,N-dimethylaminocarbonyl)benzyl]thiophenol.
28 ) A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
29 ) The pharmaceutical composition of claim 28 wherein Z is substituted or unsubstituted furanose or pyranose.
30 ) The pharmaceutical composition of claim 28 wherein Z is substituted or unsubstituted alditol.
31 ) The pharmaceutical composition of claim 28 wherein R a , R b , R c , and R d are t-butyl, and Z is 2-amino-3-carboxypropyl; 3-amino-4-carboxybutyl; 1,1-difluoro-1-carboxymethyl; phosphonomethyl; 1,1-difluoro-1-phosphono-methyl; 2-(2-carboxy-N-pyrrolidine)ethyl; (2H-imidazol-5-yl)methyl; 2-pyridylmethyl; 3-pyridylmethyl; and 5-pyrimidinylmethyl.
32 ) The pharmaceutical composition of claim 28 wherein R a , R b , R c , and R d are t-butyl, and Z is arabitol.
33 ) The pharmaceutical composition of claim 28 wherein R a , R b , R c , and R d are t-butyl, and Z is ribofuranose.
34 ) The pharmaceutical composition of claim 28 wherein R a , R b , R c , and R d are t-butyl, and Z is 2-hydroxy-3-propyl-D-gluconate.
35 ) The pharmaceutical composition of claim 28 wherein R a , R b , R c , and R d are t-butyl, and Z is 2-hydroxypropan-3-sulfonic acid.
36 ) A method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of claim 1 .
37 ) The method of claim 36 wherein Z is substituted or unsubstituted furanose or pyranose.
38 ) The method of claim 36 wherein Z is substituted or unsubstituted alditol.
39 ) A method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of claim 24 .
40 ) The method of claim 36 wherein the VCAM-1 mediated disease is an inflammatory disorder.
41 ) The method of claim 37 wherein the VCAM-1 mediated disease is an inflammatory disorder.
42 ) The method of claim 38 wherein the VCAM-1 mediated disease is an inflammatory disorder.
43 ) The method of claim 39 wherein the VCAM-1 mediated disease is an inflammatory disorder.
44 ) The method of claim 36 wherein the VCAM-1 mediated disease is an inflammatory disorder selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, and multiple sclerosis.
45 ) The method of claim 37 wherein the VCAM-1 mediated disease is an inflammatory disorder selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, and multiple sclerosis.
46 ) The method of claim 38 wherein the VCAM-1 mediated disease is an inflammatory disorder selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, and multiple sclerosis.
47 ) The method of claim 38 wherein the VCAM-1 mediated disease is an inflammatory disorder selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, and multiple sclerosis.
48 ) The method of claim 36 wherein the VCAM-1 mediated disease is a cardiovascular disease.
49 ) The method of claim 37 wherein the VCAM-1 mediated disease is a cardiovascular disease.
50 ) The method of claim 38 wherein the VCAM-1 mediated disease is a cardiovascular disease.
51 ) The method of claim 39 wherein the VCAM-1 mediated disease is an inflammatory disorder selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, and multiple sclerosis.
52 ) The method of claim 36 wherein the VCAM-1 mediated disease is an occular disease, an autoimmune disease, a neurological disorder, or cancer.
53 ) The method of claim 37 wherein the VCAM-1 mediated disease is an occular disease, an autoimmune disease, a neurological disorder, or cancer.
54 ) The method of claim 38 wherein the VCAM-1 mediated disease is an occular disease, an autoimmune disease, a neurological disorder, or cancer.
55 ) The method of claim 39 wherein the VCAM-1 mediated disease is an inflammatory disorder selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, and multiple sclerosis.
56 ) The method of claim 36 wherein the VCAM-1 mediated disease is a cardiovascular disease selected from atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy, and diabetic retinopathy.
57 ) The method of claim 37 wherein the VCAM-1 mediated disease is a cardiovascular disease selected from atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy, and diabetic retinopathy.
58 ) The method of claim 38 wherein the VCAM-1 mediated disease is a cardiovascular disease selected from atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy, and diabetic retinopathy.
59 ) The method of claim 39 wherein the VCAM-1 mediated disease is a cardiovascular disease selected from atherosclerosis, post-angioplasty restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy, and diabetic retinopathy.
60 ) A method for treating hypercholesterolemia or hyperlipidemia comprising administering to a patient an effective treatment amount of a compound of claim 1 .
61 ) The method of claim 60 wherein Z is furanose or pyranose.
62 ) The method of claim 60 wherein Z is substituted or unsubstituted alditol.
63 ) A method for treating hypercholesterolemia or hyperlipidemia comprising administering to a patient an effective treatment amount of a compound of claim 24 .
64 ) The method of claim 56 further comprising administering a platelet aggregation inhibitor, and antithrombotic agent, a calcium channel blocker, an angiotensin converting enzyme (ACE) inhibitor, or a β-blocker.
65 ) The method of claim 57 further comprising administering a platelet aggregation inhibitor, and antithrombotic agent, a calcium channel blocker, an angiotensin converting enzyme (ACE) inhibitor, or a β-blocker.
66 ) The method of claim 58 further comprising administering a platelet aggregation inhibitor, and antithrombotic agent, a calcium channel blocker, an angiotensin converting enzyme (ACE) inhibitor, or a β-blocker.
67 ) The method of claim 59 further comprising administering a platelet aggregation inhibitor, and antithrombotic agent, a calcium channel blocker, an angiotensin converting enzyme (ACE) inhibitor, or a βblocker.
68 ) The method of claim 40 further comprising administering a nonsteroidal antiinflammatory, a COX-2 inhibitor, a corticosteriod, or a TNF-α modulating agent.
69 ) The method of claim 41 further comprising administering a nonsteroidal antiinflammatory, a COX-2 inhibitor, a corticosteriod, or a TNF-α modulating agent.
70 ) The method of claim 42 further comprising administering a nonsteroidal antiinflammatory, a COX-2 inhibitor, a corticosteriod, or a TNF-α modulating agent.
71 ) The method of claim 43 further comprising administering a nonsteroidal antiinflammatory, a COX-2 inhibitor, a corticosteriod, or a TNF-α modulating agent.Join the waitlist — get patent alerts
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