USRE38761EExpiredUtility
Styryl compounds which inhibit EGF receptor protein tyrosine kinase
Est. expiryDec 24, 2007(expired)· nominal 20-yr term from priority
A61K 31/19A61K 31/165C07D 317/62C07C 255/00A61K 31/36A61K 31/275
51
PatentIndex Score
13
Cited by
16
References
32
Claims
Abstract
A method of inhibiting cell proliferation in a patient suffering from such disorder comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, which is a substituted styrene compound which can also be a naphthalene, an indane or a benzoxazine; including nitrile and molononitrile compounds, and pharmaceutical compositions comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceutically-effective amount of such compound.
Claims
exact text as granted — not AI-modified1. A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis and restenosis comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
(A) a substituted styrene compound having the formula
wherein:
one of R 1 and R 2 is alkyl, —H, —CN, —OH, —CONRR or —CSNRR;
the other of R 1 and R 2 is alkyl, —H, —CN, —OH, —CONRR, —CSNRR, —CONHR 9 , —CONHCH 2 CN, —CH═C(CN) 2 , —C(NH 2 )═C(CN) 2 or —NHCHO
wherein R 1 and R 2 are not both alkyl, —H, —CN or —OH;
R is alkyl or —H;
R 3 is alkyl, —H, —CN, —OH, —CONRR, —CSNRR, —CH 2 CN or —CH═C(CN)COHN 2 ;
R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN, halo, —NO 2 or —NHCOCH 3 ;
R 3 and R 7 together may be —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —or, starting from R 3 , —CONH—;
R 9 is, —CONH 2 ,
R 10 is alkyl, halo or —NO 2 ;
R 11 is alkyl, —CN, halo, —NO 2 or —NHCOCH 3 ;
R 12 is alkyl, —H, halo,;
n is 0 to about 6; and
m is 2 to about 10,
provided that when one of R 1 and R 2 is —CH═C(CN) 2 , at least one of R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is not —H;
(B) an α-substituted benzylidene malononitrile compound having the formula
wherein:
R 3 is alkyl, —CN, —OH, —CONRR, —CSNRR, —CH 2 CN or —CH═C(CN)CONH 2 ;
R is alkyl or —H; and
R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN, halo, —NO 2 or —NHCOCH 3 ;
(C) an α-unsubstituted benzylidene malononitrile compound having the formula
wherein:
at least one of R 4 , R 5 , R 6 , R 7 and R 8 is C 2 to about C 6 alkyl or —CN;
the remainder of R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN, halo, —NO 2 or —NHCOCH 3 ; and
R is alkyl or —H; and
(D) a bicyclic benzylidene malononitrile compound having the formula
wherein:
R 3 and R 7 together are —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —or, starting from R 3 , —CONH—; and
R 4 , R 5 R 6 and R 8 are each independently alkyl, —H, —CN, halo, —NO 2 or —NHCOCH 3 .
2. A method according to claim 1 wherein said compound has the formula
R 1 is —CN, —CONRR or —CSNRR;
R 2 is —H, —CN, —CONRR, —CSNRR or —CONHR 9 ;
wherein R 1 and R 2 are not both —CN;
R is alkyl or —H;
R 3 is —H;
R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, or halo;
R 3 and R 7 together may be —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —or, starting from R 3 , —CONH—;
R 9 is —CONH 2 ,
R 10 is alkyl, halo or —NO 2 ;
R 11 is alkyl or halo;
R 12 is alkyl or —H;
n is 0 to about 4; and
m is 2 to about 6.
3. A method according to claim 1 wherein said compound has the formula
wherein:
at least one of R 4 , R 5 , R 6 , R 7 and R 8 is C 2 to C 6 alkyl; and
the remainder of R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H or halo.
4. A method according to claim 1 wherein said compound has the formula
wherein:
R 3 and R 7 together are —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —or, starting from R 3 , —CONH—; and
R 4 , R 5 , R 6 and R 8 are each independently alkyl, —H or halo.
5. A method according to claim 2 wherein R 1 is —CN.
6. A method according to claim 2 wherein said compound has the formula
7. A method according to claim 1 wherein said compound has the formula
8. A method according to claim 2 wherein said compound has the formula
9. A method according to claim 5 wherein
R 2 is —H, CN, —CONRR, —CSNRR or —CONHR 9 ;
wherein R 1 and R 2 are not both —CN;
R is alkyl or —H;
R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, —H or halo;
R 9 is —CONH 2 ,
R 10 is lower alkyl;
R 11 is lower alkyl or halo; and
m is 2 to about 10.
10. A method according to claim 6 wherein
R 1 is —CN, —CONRR or —CSNRR;
R is alkyl or —H;
R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, —H or halo; and
R 10 is lower alkyl.
11. A method according to claim 7 wherein
R 1 is —CN, —CONRR or —CSNRR;
R 2 is —H, —CN, —CONRR, —CSNRR, —CONHR 9 ;
R is alkyl or —H;
R 4 , R 5 , R 6 and R 8 are each independently lower alkyl, —H or halo; and
R 10 is lower alkyl.
12. A method according to claim 8 wherein
R 1 is —CN, —CONRR or —CSNRR;
R is alkyl or —H;
R 4 , R 5 , R 6 and R 8 are each independently lower alkyl, —H or halo;
R 11 is lower alkyl or halo; and
m is 2 to about 6.
13. A method according to claim 1 wherein said compound is α-cyano-β-(3,5-di-tert butylphenyl)propenethioamide.
14. A method according to claim 1 wherein said cell proliferation condition comprises psoriasis.
15. A method according to claim 1 wherein said cell proliferation condition comprises atherosclerosis.
16. A method according to claim 14 wherein said compound is α-cyano-β-(3,5-di-tert-butylphenyl)propenethioamide.
17. A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis and restenosis comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
(A) a substituted styrene compound having the formula
wherein:
R 1 and R 2 are each independently —CN or —CONH 2 or one of R 1 and R 2 may be —CSNH 2 or , when R 1 is CN, R 2 can also be the group —C(NH 2 )═C(CN) 2 , with the proviso that R 1 and R 2 are not both CN;
R 3 is —H, —CN 3 or —OH;
R 4 , R 5 , R 6 and R 7 are each independently alkyl of 1-5 carbons, —H, halo, or —NO 2 ; and
R 8 is H;
(B) an α-substituted benzylidene malononitrile compound having the formula
wherein:
R 3 is —CH 3 or —OH;
R 4 , R 5 , R 6 and R 7 are each independently alkyl of 1-5 carbons, —H, halo, or —NO 2 ; and
R 8 is —H; or
(C) an α-unsubstituted benzylidene malononitrile compound having the formula
wherein:
at least one of R 4 , R 5 , R 6 and R 7 is alkyl or 2-5 carbons;
the remainder of R 4 , R 5 , R 6 and R 7 are each independently alkyl of 1-5 carbons, H, halo or —NO 2 ; and
R 8 is —H;
or a pharmaceutically acceptable salt thereof.
18. A method according to claim 17 wherein said disorder comprises psoriasis.
19. A method according to claim 17 wherein said disorder comprises psoriasis and said compound comprises α-cyano-β-(3,5-di-tert-butylphenyl)propenethioamide.
20. A method according to claim 1 wherein said compound has the formula
wherein:
R is alkyl or —H;
R 1 is —H, —CN, —OH or —CONRR;
R 3 is alkyl, —H, —CN or —OH;
R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN or halo.
21. A method according to claim 17 wherein said compound has the formula
wherein:
R 1 is —CN or —CONH 2 ;
R 3 is —H, —CH 3 or —OH;
R 4 , R 5 , R 6 and R 7 are each independently alkyl of 2≧4 carbons, —H, halo or —NO 2 ; and
R 8 is —H.
22. A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis, restenosis, and leukemia comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, comprising a substituted styrene compound having the formula
wherein:
one of R
1
and R
2
is alkyl, —H, —CN, —OH, —COOR, —CONRR or —CSNRR;
the other of R 1 and R 2 is alkyl, —H, —CN, —OH, —COOR, —CONRR, —CSNRR, —CHO, —CONHR 9 , —CONHCH 2 CN, —CH═C ( CN ) 2 , —C ( NH 2 )═ C ( CN ) 2 , —NHCHO,
wherein R
1
and R
2
are not both alkyl, —H, —CN or —OH;
R is alkyl or —H;
R 3 is alkyl, —H, —CN, —OH, —COOR, —CONRR, —CSNRR, —CH 2 CN or —CH═C ( CN ) CONH 2 ;
R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN, halo, —OR, —CHO, —COOH, —NRR, —NO 2 , —NHCOCH 3 , —SR, —CH═CHCOOH, —NHCO ( CH 2 ) 2 COOH or morpholino;
R
3
and R
7
together may be —CH
2
CH
2
—, —CH
2
CH
2
CH
2
—or, starting R
3
, —CONH—;
R 9 is —NH 2 , —CONH 2 ,
R 10 is alkyl, halo, —OR, —COOR, or —NO 2 ;
R 11 is alkyl, —CN, halo, —OR, CHO, COOH, NRR, —NO 2 , —NHCOCH 3 , —SR, —CH═CHCOOH, —NHCO ( CH 2 ) 2 COOH or morpholino;
R
12
is alkyl, —H, halo, —OR, or —COOR;
n is 0 or about 6 ; and
m is 2 to about 10 ;
provided that when each of R
4
and R
7
is OH, when each of R
3
, R
5
, R
6
, and R
8
is —H and when one of R
1
and R
2
is —CN, then other of R
1
and R
2
is not —CONH
2
; and also
provided that when one of R 1 and R 2 is —CH═C ( CN ) 2 , at least one of R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is not —H; and
provided that when said R
1
or R
2
is COOR or CONRR, the other of said R
1
or R
2
is not alkyl or cyano.
23. A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis, restenosis, and leukemia comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, comprising a substituted benzylidene malononitrile compound having the formula
wherein:
R 3 is alkyl, —CN, —OH, —COOR, —CONRR, —CSNRR, —CH 2 CN or —CH═C ( CN ) COHN 2 ;
R is alkyl or —H; and
R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN, halo, —OR, —CHO, —COOH, —NRR, —NO 2 , —NHCOCH 3 , —SR, —CH═CHCOOH, —NHCO ( CH 2 ) 2 COOH or morpholino.
24. A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis, restenosis, and leukemia comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, comprising unsubstituted benzylidene malononitrile compound having the formula
wherein:
at least one of R 4 , R 5 , R 6 , R 7 and R 8 is C 2 to about C 6 alkyl, —CN, —CHO, —COOH, —NHR, —SR, —CH═CHCOOH, —NHCO ( CH 2 ) 2 COOH or morpholino;
the remainder of R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, —H, —CN, halo, —OR, —CHO, —COOH, —NRR, —NO 2 , —NHCOCH 3 , —SR, —CH═CHCOOH, —NHCO ( CH 2 ) 2 COOH or morpholino; and
R is alkyl or —H.
25. A method for inhibiting, in a patient, cell proliferation associated with a disorder selected from the group consisting of psoriasis, atherosclerosis, restenosis, and leukemia comprising administering to said patient an effective amount of a composition comprising, in admixture with a pharmaceutically acceptable carrier, a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a bicyclic benzylidene malononitrile compound having the formula
wherein:
R
3
and R
7
together are —CH
2
CH
2
—, —CH
2
CH
2
CH
2
—or, starting from R
3
, —CONH—; and
R 4 , R 5 , R 6 and R 8 are each independently alkyl, —H, —CN, halo, —OR, —CHO, —COOH, —NRR, —NO 2 , —NHCOCH 3 , —SR, —CH═CHCOOH, —NHCO ( CH 2 ) 2 COOH or morpholino; and
R is alkyl or —H.
26. A method according to claim 22 wherein said compound has the formula
wherein
R
1
is —CN, —COOR, —CONRR or —CSNRR;
R
2
is —H, —CN, —COOR, —CONRR, —CSNRR, —CONHR
9
or
wherein R
1
and R
2
are not both —CN;
R is alkyl or —H;
R
3
is —H;
R
4
, R
5
, R
6
, R
7
and R
8
are each independently alkyl, —H, halo or —OR;
R
3
and R
7
together may be —CH
2
CH
2
—, —CH
2
CH
2
CH
2
—or, starting from R
3
, —CONH—; and
R 9 is —NH 2 , —CONH 2 ,
R 10 is alkyl, halo, —OH, —COOR, or —NO 2 ;
R
11
is alkyl, halo or —OR;
R
12
is alkyl or —H;
n is 0 to about 4 ; and
m is 2 to about 10 .
27. A method according to claim 22 wherein said compound has the formula
wherein:
at least one of R
4
, R
5
, R
6
, R
7
and R
8
is C
2
to C
6
alkyl; and
the remainder of R
4
, R
5
, R
6
, R
7
and R
8
are each independently alkyl, —H, halo or —OR; and
R is alkyl or —H.
28. A method according to claim 22 wherein said compound has the formula
wherein:
R
3
and R
7
together are —CH
2
CH
2
—, —CH
2
CH
2
C—H
2
—or, starting from R
3
, —CONH—; and
R
4
, R
5
, R
6
, and R
8
are each independently alkyl, —H, halo or —OR; and
R is alkyl or —H.
29. A method according to claim 5 , wherein
R 2 is —H, CN, —COOR, —CONRR, —CSNRR, —CONHR 9 or wherein R 1 and R 2 are not both —CN; R is alkyl or —H; R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, —H, —OH, lower alkoxy or halo; R 9 is NH 2 , CONH 3 ,
R 10 is lower alkyl or —COOR; R 11 is lower alkyl, —OH, lower alkoxy or halo; and m is 2 to about 10 .
30. A method according to claim 6 wherein
R 1 is —CN, —COOR, —CONRR or CSNRR; R is alkyl or —H; R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, —H, —OH, lower alkoxy or halo; and R 10 is lower alkyl or —COOR.
31. A method according to claim 7 wherein
R 1 is —CN, —COOR, —CONRR or CSNRR; R 2 is —H, —CN, —COOR, —CONRR, —CSNRR, —CONHR 9 ; R is alkyl or —H; R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, —H, —OH, lower alkoxy or halo; and R 10 is lower alkyl or —COOR.
32. A method according to claim 8 wherein
R 1 is —CN, —COOR, —CONRR or CSNRR; R is alkyl or —H; R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, —H, —OH, lower alkoxy or halo; and R 11 is lower alkyl, —OH, lower alkoxy or halo; and m is 2 to about 6 .Cited by (0)
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