US2008255126A1PendingUtilityA1
Inhibitors of post-proline cleaving proteases
Est. expiryOct 23, 2021(expired)· nominal 20-yr term from priority
A61P 31/18A61P 3/10A61P 37/02A61P 43/00A61P 35/04A61P 15/00C07D 207/10C07D 251/50C07D 417/14C07D 317/66C07D 295/185C07D 251/52C07D 211/38C07D 417/12C07D 211/62C07D 211/14C07D 277/04C07D 333/20C07D 401/12C07D 207/335C07D 409/12C07D 307/06C07D 407/12C07D 401/14C07D 307/81C07D 207/16C07D 215/12C07D 213/82C07D 213/38C07D 213/74
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Claims
Abstract
Novel compounds that are inhibitors of one or most post-proline cleaving proteases, e.g. dipeptidyl peptidase IV, according to general formula (1). R 1 is H or CN, X 1 is O, S, CH 2 , CHF, CF 2 , CH(CH 3 ), C(CH 3 ) 2 or CH(CN), and b is 1 or 2. G 1 is H or a group according to the formula —CH 2 —X 2 —(CH 2 ) a -G 3 and G 2 is H or a group according to the formula —CH 2 —(CH 2 9 a -G 3 , provided that one of G 1 and G 2 is H and the other is not H. X 2 is O, S, or CH 2 , and a is 0, 1 or 2, provided that when a is 1 then X 2 is CH 2 . G 3 is a group according to one of general formulae 2-4, where the variables have meaning given in the description. The compounds are useful in the treatment of i.a. type 2 diabetes and impaired glucose tolerance.
Claims
exact text as granted — not AI-modified1 . A compound according to general formula 1, or a pharmaceutically acceptable salt thereof,
wherein:
either G 1 is —CH 2 —X 2 —(CH 2 ) a -G 3 and G 2 is H, or
G 2 is —CH 2 —(CH 2 ) a -G 3 and G 1 is H;
G 3 is selected from a group according to general formula 2, a group according to general formula 3, and a group according to general formula 4;
a is 0, 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
X 2 is selected from CH 2 , O and S, provided that if a is 1 then X 2 is CH 2 ;
X 3 , X 4 and X 5 are selected from N and CH, provided that at least two of X 3 , X 4 and X 5 are N;
X 6 is selected from O and NH;
X 7 is selected from CH 2 , O, S and NH;
R 1 is selected from H and CN;
R 2 is selected from H and alkyl;
R 3 is selected from H, Cl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, Br, Cl, F, CF 3 , alkyl, acyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , NH-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN;
R 9 is selected from H and alkyl;
R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from H, Br, Cl, F, CF 3 , alkyl, acyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , NH-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN;
R 15 and R 16 are independently selected from H, alkyl, alkenyl, polyfluoroalkyl, aralkyl, aryl and —CH 2 -L-R 7 , or R 15 and R 16 together form a group according to general formula 5, general formula 6 or general formula 7;
R 17 is selected from H, alkyl and aryl;
R 18 is selected from H, alkyl, aryl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
R 19 is selected from H, alkyl, aryl, F, Cl, Br, CF 3 , OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
L is selected from a covalent bond, CH═CH, C≡C and —C 6 H 4 —;
d and e are selected from 0, 1, 2 and 3 such that d+e is 3, 4 or 5; and
f is selected from 1, 2 and 3;
provided that when R 15 and R 16 are both H and b is 1 then X 1 is not S or CH 2 .
2 . A compound according to general formula 8, or a pharmaceutically acceptable salt thereof,
wherein:
a is 0, 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
X 2 is selected from CH 2 , O and S, provided that if a is 1 then X 2 is CH 2 ;
X 3 , X 4 and X 5 are selected from N and CH, provided that at least two of X 3 , X 4 and X 5 are N;
X 6 is selected from O and NH;
R 1 is selected from H and CN;
R 2 is selected from H and alkyl;
R 3 is selected from H, Cl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, Br, Cl, F, CF 3 , alkyl, acyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , NH-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN.
3 . A compound according to claim 2 wherein R 1 is H.
4 . A compound according to claim 2 wherein R 1 is CN.
5 . A compound according to any of claims 2 to 4 wherein X 1 is CH 2 .
6 . A compound according to any of claims 2 to 4 wherein X 1 is S.
7 . A compound according to any of claims 2 to 6 wherein b is 1.
8 . A compound according to any of claims 2 to 6 wherein b is 2.
9 . A compound according to any of claims 2 to 8 wherein a is 1.
10 . A compound according to any of claims 2 to 8 wherein a is 2 and X 2 is CH 2 .
11 . A compound according to any of claims 2 to 10 wherein X 3 , X 4 and X 5 are all N.
12 . A compound according to general formula 9, or a pharmaceutically acceptable salt thereof,
wherein:
a is 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
X 3 , X 4 and X 5 are selected from N and CH, provided that at least two of X 3 , X 4 and X 5 are N;
X 6 is selected from O and NH;
R 1 is selected from H and CN;
R 2 is selected from H and alkyl;
R 3 is selected from H, Cl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, Br, Cl, F, CF 3 , alkyl, acyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , NH-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN.
13 . A compound according to claim 12 wherein R 1 is H.
14 . A compound according to claim 12 wherein R 1 is CN.
15 . A compound according to any of claims 12 to 14 wherein X 1 is CH 2 .
16 . A compound according to any of claims 12 to 14 wherein X 1 is S.
17 . A compound according to any of claims 12 to 16 wherein b is 1.
18 . A compound according to any of claims 12 to 16 wherein b is 2.
19 . A compound according to any of claims 12 to 18 wherein a is 1.
20 . A compound according to any of claims 12 to 19 wherein X 3 , X 4 and X 5 are all N.
21 . A compound according to general formula 10, or a pharmaceutically acceptable salt thereof,
wherein:
a is 0, 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
X 2 is selected from CH 2 , O and S, provided that if a is 1 then X 2 is CH 2 ;
X 7 is selected from O, S, CH 2 and NH;
R 1 is selected from H and CN;
R 9 is selected from H and alkyl;
R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from H, Br, Cl, F, CF 3 , alkyl, acyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , NH-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN is selected from H, Cl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 .
22 . A compound according to claim 21 wherein R 1 is H.
23 . A compound according to claim 21 wherein R 1 is CN.
24 . A compound according to any of claims 21 to 23 wherein X 1 is CH 2 .
25 . A compound according to any of claims 21 to 23 wherein X 1 is S.
26 . A compound according to any of claims 21 to 25 wherein b is 1.
27 . A compound according to any of claims 21 to 25 wherein b is 2.
28 . A compound according to any of claims 21 to 27 wherein a is 1.
29 . A compound according to any of claims 21 to 27 wherein a is 2 and X 2 is CH 2 .
30 . A compound according to general formula 11, or a pharmaceutically acceptable salt thereof,
wherein:
a is 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
X 7 is selected from O, S, CH 2 and NH;
R 1 is selected from H and CN;
R 9 is selected from H and alkyl;
R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from H, Br, Cl, F, CF 3 , alkyl, acyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , NH-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN is selected from H, Cl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 .
31 . A compound according to claim 30 wherein R 1 is H.
32 . A compound according to claim 30 wherein R 1 is CN.
33 . A compound according to any of claims 30 to 32 wherein X 1 is CH 2 .
34 . A compound according to any of claims 30 to 32 wherein X 1 is S.
35 . A compound according to any of claims 30 to 34 wherein b is 1.
36 . A compound according to any of claims 30 to 34 wherein b is 2.
37 . A compound according to any of claims 30 to 36 wherein a is 1.
38 . A compound according to general formula 12, or a pharmaceutically acceptable salt thereof,
wherein:
a is 0, 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
X 2 is selected from CH 2 , O and S, provided that if a is 1 then X 2 is CH 2 ;
R 1 is selected from H and CN;
R 15 and R 16 are each independently selected from H, alkyl, alkenyl, polyfluoroalkyl, aralkyl, aryl and CH 2 -L-R 17 ;
or R 15 and R 16 together are a group according to general formula 5, a group according to general formula 6 or a group according to general formula 7;
R 17 is selected from H, alkyl and aryl;
R 18 is selected from H, alkyl, aryl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
R 19 is selected from H, alkyl, aryl, F, Cl, Br, CF 3 , OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
L is selected from a covalent bond, CH═CH, C≡C and —C 6 H 4 —;
d and e are selected from 0, 1, 2 and 3 such that d+e is 3, 4 or 5; and
f is selected from 1, 2 and 3;
provided that when R 15 and R 16 are both H and b is 1 then X 1 is not S or CH 2 .
39 . A compound according to claim 38 wherein R 1 is H.
40 . A compound according to claim 38 wherein R 1 is CN.
41 . A compound according to any of claims 38 to 40 wherein X 1 is CH 2 .
42 . A compound according to any of claims 38 to 40 wherein X 1 is S.
43 . A compound according to any of claims 38 to 42 wherein b is 1.
44 . A compound according to any of claims 38 to 42 wherein b is 2.
45 . A compound according to any of claims 38 to 44 wherein a is 1.
46 . A compound according to any of claims 38 to 44 wherein a is 2 and X 2 is CH 2 .
47 . A compound according to general formula 13, or a pharmaceutically acceptable salt thereof,
wherein:
a is 1 or 2;
b is 1 or 2;
X 1 is selected from CH 2 , S, CF 2 , CHF, CH(CH 3 ), C(CH 3 ) 2 , CH(CN) and O;
R 1 is selected from H and CN;
R 15 and R 16 are each independently selected from H, alkyl, alkenyl, polyfluoroalkyl, aralkyl, aryl and CH 2 -L-R 17 ;
or R 15 and R 16 together are a group according to general formula 5, a group according to general formula 6 or a group according to general formula 7;
R 17 is selected from H, alkyl and aryl;
R 18 is selected from H, alkyl, aryl, OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
R 19 is selected from H, alkyl, aryl, F, Cl, Br, CF 3 , OH, O-alkyl, NH 2 , NH-alkyl and N(alkyl) 2 ;
L is selected from a covalent bond, CH═CH, C≡C and —C 6 H 4 —;
d and e are selected from 0, 1, 2 and 3 such that d+e is 3, 4 or 5; and
f is selected from 1, 2 and 3.
48 . A compound according to claim 47 wherein R 1 is H.
49 . A compound according to claim 47 wherein R 1 is CN.
50 . A compound according to any of claims 47 to 49 wherein X 1 is CH 2 .
51 . A compound according to any of claims 47 to 49 wherein X 1 is S.
52 . A compound according to any of claims 47 to 51 wherein b is 1.
53 . A compound according to any of claims 47 to 51 wherein b is 2.
54 . A compound according to any of claims 47 to 53 wherein a is 1.
55 . A pharmaceutical composition comprising a compound according to any of claims 1 to 54 .
56 . A use for a compound according to any of claims 1 to 54 , which is as a component in the preparation of a pharmaceutical composition.
57 . A method of treatment of disease in a human or animal subject, comprising a step of administering to the subject a therapeutically active amount of a compound according to any of claims 1 to 54 .
58 . A method of treatment according to claim 57 where the disease is caused by dysregulation of a post-proline cleaving proteases or their endogenous substrates.
59 . A method of treatment according to claim 57 where the disease is ameliorated by inhibition of a post-proline cleaving proteases.
60 . A method of treatment according to claim 57 where the disease is caused by dysregulation of a post-proline cleaving proteases or its endogenous substrates which is an intracellular protease.
61 . A composition according to claim 1 or 38 with the proviso that when X 1 ═S; b=1; R 1 ═H; G 2 =H; G 1 is —CH 2 —X 2 —(CH 2 ) a -G 3 ; a=1, X 2 ═CH 2 ; G 3 =NR 15 R 16 ; and one of R 15 , R 16 ═H, the other of R 15 , R 16 is not pyridyl, substituted pyridyl, pyrazinyl or substituted pyrazinyl.
62 . A composition according to claim 1 , 38 , 47 or 60 with the proviso that when b=1, R 1 is H and X 1 is S; G 1 =H; G 2 is —CH 2 —(CH 2 ) a -G 3 ; a=1; G 3 is NR 15 R 16 and one of R 15 and R 16 is H the other of R 15 , R 16 is not pyridyl, substituted pyridyl, pyrazinyl or substituted pyrazinyl.
63 . A composition according to claim 1 , 38 , 47 , 60 or 61 with the proviso that when b=1, R 1 is CN and X 1 is CH 2 ; G 1 =H; G 2 is —CH 2 —(CH 2 ) a -G 3 ; a=1; G 3 is NR 15 R 16 and one of R 15 and R 16 is H, the other of R 15 , R 16 is not pyridyl, substituted pyridyl, pyrazinyl or substituted pyrazinyl.
64 . A composition according to claim 1 , 38 , 47 , 60 , 61 or 62 with the proviso that when G 2 =H; G 1 =-CH2-X 2 —(CH 2 ) a -G 3 ; X 2 is CH 2 ; a=1; G3=NR 15 R 16 and R 15 ═R 16 ═H; b is not 2 when X 1 is O or CH 2 , and b is not 1 when X 1 is CH 2 .
65 . A method of treatment according to claim 57 where the disease is caused by dysregulation of a non-membrane associated post-proline cleaving proteases such as QPP, DPP-8 and DPP-9 enzymes or their endogenous substrates.
66 . A method of treatment according to claim 57 where the disease is ameliorated by inhibition of a non-membrane associated post-proline cleaving proteases such as QPP, DPP-8 and DPP-9 enzymes.
67 . A method according to claim 64 where the compound is a selective inhibitor of non-membrane associated post-proline cleaving proteases.Cited by (0)
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