US2002028933A1PendingUtilityA1
Thioamide derivatives
Priority: Feb 18, 1999Filed: Mar 20, 2001Published: Mar 7, 2002
Est. expiryFeb 18, 2019(expired)· nominal 20-yr term from priority
A61P 43/00A61P 29/00A61P 1/00A61P 11/06C07D 213/82C07D 213/56C07C 327/46C07D 233/38C07C 327/48C07C 2601/04C07C 2601/08C07D 239/28C07D 401/06
51
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Claims
Abstract
It has been discovered that compounds of the formula: and the pharmaceutically acceptable salts and esters thereof wherein X and Y are as defined below, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, (MS), asthma, and inflammatory bowel disease (I BD).
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
wherein X is defined as X-1, X-2, or X-3 and Y is defined as Y-1, Y-2, or Y-3 as follows:
X is a group of the formula
wherein:
R 15 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy; R 16 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio;
X is a group of formula X-2
wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,O, and S, or
Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
R 15 and R 16 are as above;
R 30 is hydrogen or lower alkyl; and p is an integer from 0 to 1;
X is a group of formula X-3
wherein:
R 18 is aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl
R 19 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
R 20 is substituted or unsubstituted lower alkanoyl or aroyl;
Y is a group of formula Y-1
wherein:
R 22 and R 23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R 22 and R 23 is other than hydrogen, and R 24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen;
Y-2 is a group of the formula:
Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R 30 and R 31 are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R 30 and R 31 is adjacent to the point of attachment; p is an integer of from 0 to 1;
Y is a group of formula Y-3
wherein:
R 25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R 26 —(CH 2 ) e -, R 26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R 26 is a group of formula —NR 28 R 29 , wherein
R 28 is H or lower alkyl,
R 29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or R 28 and R 29 taken together form a 4, 5 or 6-membered saturated carbacyclic ring optionally containing one heteroatom selected from O, S, and N; with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen,
Q is —(CH 2 ) f O—, —(CH 2 ) f S—, —(CH 2 ) f N(R 27 )—, or —(CH 2 ) f -,
R 27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl,
e is an integer from 0 to 4, and
f is an integer from 0 to 3; and the dotted bond is optionally hydrogenated;
when Y is a group of formula Y-1, then X is a group of formula X-2 or X-3;
and when X is a group of formula X-1, then Y is a group of formula Y-2 or Y-3;
and pharmaceutically acceptable salts and esters thereof.
2 . A compound of claim 1 wherein X is a group of the formula
and Y, R 15 and R 16 are as in claim 1 .
3 . A compound of claim 2 wherein R 15 is lower alkyl, nitro, halogen, perfluoromethyl, or cyano and R 16 is hydrogen, lower alkyl, nitro, halogen, perfluoromethyl, or cyano.
4 . A compound of claim 3 wherein R 15 and R 16 are independently chloro or fluoro.
5 . A compound of claim 3 wherein X-1 is selected from the group of
6 . A compound of claim 1 wherein X is a group of the formula X-2
and p, Y, R 15 , R 16 , and R 30 are as in claim 1 .
7 . A compound of claim 6 wherein Het is a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen.
8 . A compound of claim 6 wherein Het is a bicyclic heteroaromatic ring containing from 1 to 3 nitrogens.
9 . A compound of claim 6 wherein R 15 is nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl.
10 . A compound of claim 9 wherein R 15 is unsubstituted phenyl.
11 . A compound of claim 6 wherein R 16 is hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R 30 is hydrogen or lower alkyl.
12 . A compound of claim 6 wherein Het is a 6 membered monocyclic heteroaromatic ring containing 1 or 2 nitrogens or a 10 membered bicyclic heteroaromatic ring containing one nitrogen, R 15 is lower alkyl, or perfluoroalkyl and R 16 is hydrogen, lower alkyl, or perfluoroalkyl, and R 30 is absent.
13 . A compound of claim 6 wherein X-2 is selected from the group of
14 . A compound of claim 1 wherein X is a group of formula X-3
and Y, R 18 , R 19 , and R 20 are as in claim 1 .
15 . A compound of claim 14 wherein R 18 is phenyl.
16 . A compound of claim 14 wherein R 19 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl.
17 . A compound of claim 14 wherein R 20 is substituted or unsubsituted lower alkanoyl.
18 . A compound of claim 14 wherein R 18 is phenyl, R 19 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl and R 20 is lower alkanoyl.
19 . A compound of claim 14 wherein R 18 is phenyl which is unsubstituted or substituted by halogen or lower alkoxy; R 19 is phenyl lower alkyl which is unsubstituted or substituted by lower alkoxy, pyridyl lower alkyl, or lower alkyl; and R 20 is substituted or unsubstituted lower alkanoyl.
20 . A compound of claim 19 wherein X-3 is selected from the group of
21 . A compound of claim 1 wherein Y is a group of formula
and X, R 22 , R 23 , and R 24 are as in claim 1 .
22 . A compound of claim 21 wherein R 22 and R 23 are lower alkyl, trifluoromethyl, or halogen and R 24 is hydrogen, lower alkyl, lower alkoxy, or halogen.
23 . A compound of claim 22 wherein Y-1 is selected from the group of
24 . A compound of claim 1 wherein Yis a group of the formula Y-2
and p, X, Het, R 30 and R 31 , are as in claim 1 .
25 . A compound of claim 24 wherein Het is a 6 membered heteroaromatic ring.
26 . A compound of claim 25 wherein the heteroatom is N.
27 . A compound of claim 26 wherein Y-2 is selected from the group of
28 . A compound of claim 1 wherein Y is a group of formula Y-3
and Y, R 25 and Q are as in claim 1 , and the dotted bond can be optionally hydrogenated.
29 . A compound of claim 28 wherein Y-3 is selected from the group of
30 . A compound of claim 1 wherein X is a group of the formula X-1
and Y is a group of the formula Y-2
31 . A compound of claim 1 wherein X is a group of the formula X-1
and Y is a group of the formula Y-3
wherein R 15 , R 16 , R 25 and Q are as above; and the dotted bond can be optionally hydrogenated.
32 . A compound of claim 1 wherein X is a group of the formula X-2
and Y is a group of the formula Y-1
33 . A compound of claim 1 wherein X is a group of the formula X-2
and Y is a group of the formula Y-2.
34 . A compound of claim 1 wherein X is a group of the formula X-2
and Y is a group of the formula Y-3
wherein R 15 , R 16 , R 25 , R 30 , Q and p are as above and the dotted bond can be optionally hydrogenated.
35 . A compound of claim 1 wherein X is a group of the formula X-3
and Y is a group of the formula Y-1
36 . A compound of claim 1 wherein X is a group of the formula X-3
and Y is a group of the formula Y-2
37 . A compound of claim 1 wherein X is a group of the formula X-3
and Y is a group of the formula Y-3
wherein R 18 , R 19 , R 20 , R 25 , and Q are as above and the dotted bond can be optionally hydrogenated.
38 . A compound of claim 1 wherein X is a group of the formula X-1
wherein R 16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R 15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl, and Y is a group of the formula Y-3
wherein Q is as above and the dotted bond can be optionally hydrogenated; R 25 is R 26 —(CH 2 )e-; e is 2-4 and R 26 is azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio or R 25 is NHR 29 where R 29 is lower alkanoyl or lower alkylamino carbonyl.
39 . A compound of claim 38 wherein X is a group of the formula X-1
wherein R 16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R 15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl; and Y is a group of the formula Y-3
which is a four to six membered cycloalkyl ring, R 25 is R 26 —(CH 2 )e-; e is 2-4 and R 26 is azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio; and the dotted bond is hydrogenated.
40 . A compound of claim 39 wherein R 16 is hydrogen or halogen and R 15 is halogen; and Y-3 is a four or five membered ring and R 26 is lower alkoxy, lower alkyl sulfonyl, lower alkyl sulfinyl, or lower alkylthio.
41 . A compound of claim 40 wherein R 16 is in the ortho position and R 15 and R 16 are both chlorine, and R 26 is lower alkyl sulfonyl or lower alkylthio.
42 . A compound of claim 41 which is 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
43 . A compound of claim 38 wherein X is a group of the formula X-1
where R 16 is hydrogen or halogen and R 15 is halogen and Y is a group of the formula Y-3
where Y-3 is a four or five membered ring, R 25 is as in claim 35 and R 26 is lower alkoxy, lower alkyl sulfonyl, lower alkyl sulfinyl, or lower alkylthio, and the dotted bond is optionally hydrogenated.
44 . A compound of claim 43 wherein R 16 is in the ortho position and R 15 and R 16 are both chlorine, and when Y is Y-1 then R 22 is methyl and R 23 is chlorine or ethyl and Y-3 is a four or five membered ring and R 26 is lower alkyl sulfonyl or lower alkylthio.
45 . A compound of claim 1 wherein Y is as in formula 1 and X is X-1
where R 15 is ortho and is halogen, lower alkyl, or perfluoroalkyl and R 16 is hydrogen, halogen, lower alkyl, or perfluoroalkyl.
46 . A compound of claim 45 wherein R 15 is chlorine and R 16 is hydrogen or chlorine.
47 . A compound of claim 1 wherein Y is as in formula 1 and X is X-2
where Het is pyridine or pyrimidine and R 15 is lower alkyl or perfluoroalkyl R 16 , and R 20 are hydrogen, lower alkyl, or perfluoroalkyl.
48 . A compound of claim 1 wherein Y is as in formula 1 and X is X-3
where R 19 is pyridinyl lower alkyl or phenyl lower alkyl, R 20 is lower alkanoyl, and R18 is phenyl.
49 . A compound of claim 1 wherein X is as in formula 1 and Y is Y-1
where R 22 is hydrogen or lower alkyl, R 23 is halogen, lower alkyl, or perfluoroalkyl, and R24 is hydrogen.
50 . A compound of claim 49 wherein R 22 is hydrogen or methyl and R 23 is halogen, ethyl, or trifluoromethyl.
51 . A compound of claim 1 wherein X is as in formula 1 and Y is Y-3
which is a four to six membered cycloalkyl ring, R 25 is R 26 —(CH 2 )e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR 29 where R 29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated.
52 . A compound of claim 51 wherein R 26 is methoxy, methyl sulfonyl, or methylthio.
53 . A compound of claim 47 wherein Y is Y-1
where R 22 is hydrogen or lower alkyl, R 23 is halogen, lower alkyl, or perfluoroalkyl, and R 24 is hydrogen.
54 . A compound of claim 48 wherein Y is Y-1
where R 22 is hydrogen or lower alkyl, R 23 is halogen, lower alkyl, or perfluoroalkyl, and R 24 is hydrogen.
55 . A compound of claim 54 which is 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-oxo-imidazolidin-1-yl]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]-L-phenylalanine.
56 . A compound of claim 45 wherein Y is Y-3
which is a four to six membered cycloalkyl ring, R 25 is R 26 —(CH 2 )e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR 29 where R 29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated.
57 . A compound of claim 56 wherein R 15 is chlorine and R 16 is hydrogen or chlorine.
58 . A compound of claim 57 which is 4-[[2,6-dichlorophenyl)carbonyl]amino-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
59 . A compound of claim 57 which is [[1-[2-[[(methylamino)carbonyl] amino]ethyl]cyclopentyl]thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]L-phenylalanine.
60 . A compound of claim 57 which is 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine.
61 . A compound of claim 57 which is 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
62 . A compound of claim 57 which is 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-(3-methylthio)propyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
63 . A compound of claim 57 which is 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[1-(3-methylsulfonyl)propyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
64 . A compound of claim 56 wherein R 26 is methoxy, methyl sulfonyl, or methyl thio.
65 . A compound of claim 57 wherein R 26 is methoxy, methyl sulfonyl, or methyl thio.
66 . A compound of claim 47 wherein Y is Y-3
which is a four to six membered cycloalkyl ring, R 25 is R 26 —(CH 2 )e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR 29 where R 29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated.
67 . A compound of claim 66 wherein R 26 is methoxy, methyl sulfonyl, or methyl thio.
68 . A compound of claim 67 which is 4-[(2,6-dimethyl-3-pyridinylcarbonyl)amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
69 . A compound of claim 67 which is 4-[[[4-(trifluoromethyl)-5-pyrimidinyl]carbonyl]amino]-N-[[1-(4-methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
70 . A compound of claim 67 which is 4-[[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]amino]-N-[[1-[(4-methylsulfonyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine.
71 . A compound of claim 48 wherein Y is Y-3
which is a four to six membered cycloalkyl ring, R 25 is R 26 —(CH 2 )e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, or NHR 29 where R 29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is optionally hydrogenated.
72 . A compound of claim 71 wherein R 26 is methoxy, methyl sulfonyl, or methyl thio.
73 . A compound of claim 72 which is 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-oxo-imidazolidin-1-yl]-N-[[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.
74 . A compound of claim 72 which is 4-[(2R,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-oxo-imidazolidin-1-yl]-N-[[(4-methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine.Join the waitlist — get patent alerts
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