US2004209845A1PendingUtilityA1
Novel compounds for modulating cell proliferation
Est. expiryApr 13, 2020(expired)· nominal 20-yr term from priority
A61P 35/00A61P 7/00A61P 35/04A61P 35/02A61P 19/00C07C 45/292C07C 255/41C07C 255/42C07F 7/1804C07C 327/44Y02P20/582
50
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Claims
Abstract
Novel styrylacrylonitrile compounds which are useful in treating a variety of cell proliferative disorders such as cancer are disclosed. The compounds are of the Formula I:
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of Formula I, and salts, solvates or hydrates thereof:
wherein
R 1 and R 2 are each independently selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkyl, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S—C 1-6 alkyl, O—Si(C 1-6 alkyl)(C 1-6 alkyl)(C 1-6 alkyl), NO 2 , CF 3 , OCF 3 and halo;
R 3 is selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S—C 1-6 alkyl, O—Si(C 1-6 alkyl)(C 1-6 alkyl)(C 1-6 alkyl), NO 2 , halo and CH 2 —S—(CH 2 ) n Ar;
R 4 is selected from the group consisting of C(X)R 5 , SO3Ar, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), P(O)(OH) 2 , P(O)(OC 1-6 alkyl) 2 , and C(NH 2 )═C(CN) 2 ;
X is selected from O,S, NH and N—C 1-6 alkyl;
R 5 is selected from the group consisting of NH 2 , OH, NH(CH 2 ) p Ar, NH(CH 2 ) p OH, (CH 2 ) p OC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, NHNH 2 , NHC(O)NH 2 , NHC(O)C 1-6 alkoxy, N-morpholino and N-pyrrolidino; and
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S—C 1-6 alkyl, NO 2 , CF 3 , OCF 3 and halo;
n is 0 to 4; and
p is 1-4.
2 . The compound according to claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of H, OH, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , NH—C 1-4 alkyl, SH, S—C 1-4 alkyl, O—Si(C 1-4 alkyl)(C 1-4 alkyl)(C 1-4 alkyl), NO 2 , CF 3 , OCF 3 and halo.
3 . The compound according to claim 2 , wherein R 1 and R 2 are each independently selected from the group consisting H, OH, OCH 3 , O—Si(CH 3 ) 2 ( t Bu), S—Me, SH and NO 2 .
4 . The compound according to claim 3 , wherein R 1 and R 2 are both OH or R 1 and R 2 are both OCH 3 .
5 . The compound according to claim 4 , wherein R 1 is OCH 3 and R 2 is OH.
6 . The compound according to claim 1 , wherein R 3 is selected from the group consisting of H, OH, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , NH—C 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), SH, S—C 1-4 alkyl, NO 2 and halo.
7 . The compound according to claim 6 , wherein R 3 is selected from the group consisting of H, OH, OCH 3 , SH, SMe, NO 2 and halo.
8 . The compound according to claim 7 , wherein R 3 is selected from the group consisting of H, OH and OCH 3 .
9 . The compound according to claim 1 , wherein R 4 is selected from the group consisting of C(X)R 5 and C(NH 2 )═C(CN) 2 .
10 . The compound according to claim 9 , wherein R 4 is C(X)R 5 .
11 . The compound according to claim 10 , wherein X is selected from the group consisting of O and S.
12 . The compound according to claim 10 , wherein R 5 is selected from the group consisting of NH 2 , OH, NH(CH 2 ) p Ar, NH(CH 2 ) p OH and C 1-4 alkoxy.
13 . The compound according to claim 12 , wherein p is 1-3.
14 . The compound according to claim 13 , wherein R 5 is selected from the group consisting of NH 2 , OH, NH(CH 2 ) p Ar, NH(CH 2 ) p OH and OCH 3 .
15 . The compound according to claim 14 , wherein p is 1-2.
16 . The compound according to claim 1 , wherein Ar is an unsubstituted phenyl group or a phenyl group substituted with 1-4 substituents optionally selected from the group consisting of OH, C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S—C 1-6 alkyl, NO 2 , CF 3 , OCF 3 and halo.
17 . The compound according to claim 14 , wherein Ar is an unsubstituted phenyl group or a phenyl group substituted with 1-4 substituents optionally selected from the group consisting of OH, C 1-6 alkyl, C 1-6 alkoxy, NH 2 , NH—C 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH, S—C 1-6 alkyl, NO 2 , CF 3 , OCF 3 and halo.
18 . The compound according to any of claims 16 or 17 , wherein Ar is an unsubstituted phenyl group or phenyl group substituted with 1-2 substituents optionally selected from the group consisting of OH, C 1-4 alkyl, C 1-4 alkoxy, NH 2 , NH—C 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), SH, S—C 1-4 alkyl, NO 2 , CF 3 , OCF 3 and halo.
19 . The compound according to claim 18 , wherein Ar is an unsubstituted phenyl group or phenyl group substituted with 1-2 substituents optionally selected from the group consisting of OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , SH, SCH 3 , CF 3 , OCF 3 and halo.
20 . The compound according to claim 19 , wherein Ar is selected from the group consisting of phenyl and 3,4-dihydroxyphenyl.
21 . The compound according to claim 1 , selected from the group consisting of:
(E,E)-2-(benzylamido)-3-styrylacrylonitrile (CR1); (E,E)-2-(benzylamido)-3-(3,4-dimethoxystyryl)acrylonitrile (CR2); (E,E)-2-(benzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR3); (E,E)-2-(benzylamido)-3-(3,4-dihydroxystyryl )acrylonitrile (CR4); (E,E)-2-(phenylethylamido)-3-(3,4-dimethoxystyryl)acrylonitrile (CR5); (E,E)-2-(phenylethylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR8); (E,E)-2-(phenylpropylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR9); (E,E)-2-(3,4-dihydroxybenzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR11); (E,E)-2-thioacetamido-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR12); (E,E)-2-acetamido-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR13); (E,E)-2-carboxy-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR14); (E,E)-2-carbomethoxy-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR15); (E,E)-2-acetamido-3-[3,4-bis(t-butyldimethylsilyloxystyryl)]acrylonitrile(CR16); (E,E)-2-acetamido-3-(3,4-dihydroxystyryl )acrylonitrile (CR17); (E,E)-2-(benzylamido)-3-(3,4-bis(t-butyldimethylsilyloxystyryl))acrylonitrile (CR18); (E,E)-2-(3,4-dihydroxybenzylamido)-3-styrylacrylonitrile (CR19); (E,E)-2-(3,4-dihydroxybenzylamido)-3-[3,4-bis(t-butyldimethylsilyloxystyryl)]acrylonitrile (CR20); (E,E)-2-(3,4-dihydroxybenzylamido)-3-(3,4-dihydroxystyryl )acrylonitrile (CR21); (E,E)-2-(β-ethanolamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR24); (E,E)-2-(benzylamido)-3-(4-nitrostyryl)acrylonitrile (CR27); (E,E)-2-(3,4-dihydroxybenzylamido)-3-(4-nitrostyryl)acrylonitrile(CR28); and (E,E)-2-(1-amino-2,2-dicyanoethenyl)-3-(4-nitrostyryl)acrylonitrile (CR29).
22 . The compound according to claim 21 , selected from the group consisting of:
(E,E)-2-(benzylamido)-3-styrylacrylonitrile (CR1); (E,E)-2-(benzylamido)-3-(3,4-dimethoxystyryl)acrylonitrile (CR2); (E,E)-2-(benzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR3); (E,E)-2-(benzylamido)-3-(3,4-dihydroxystyryl)acrylonitrile (CR4); (E,E)-2-(phenylethylamido)-3-(3,4-dimethoxystyryl)acrylonitrile (CR5); (E,E)-2-(phenylpropylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR9); (E,E)-2-(3,4-dihydroxybenzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR11); (E,E)-2-thioacetamido-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR12); (E,E)-2-acetamido-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR13); (E,E)-2-carboxy-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR14); (E,E)-2-carbomethoxy-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR15); (E,E)-2-acetamido-3-(3,4-dihydroxystyryl)acrylonitrile (CR17); (E,E)-2-(3,4 dihydroxybenzylamido)-3-styrylacrylonitrile (CR19); (E,E)-2-(3,4 dihydroxybenzylamido)-3-(3,4-dihydroxystyryl)acrylonitrile (CR21); and (E,E)-2-(β-ethanolamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR24).
23 . The compound according to claim 22 , selected from the group consisting of:
(E,E)-2-(benzylamido)-3-(3,4-dihydroxystyryl)acrylonitrile (CR4); (E,E)-2-(3,4-dihydroxybenzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR11); (E,E)-2-acetamido-3-(3,4-dihydroxystyryl )acrylonitrile (CR17); (E,E)-2-(3,4 dihydroxybenzylamido)-3-styrylacrylonitrile (CR19); (E,E)-2-(3,4 dihydroxybenzylamido)-3-(3,4-dihydroxystyryl)acrylonitrile (CR21); and (E,E)-2-(β-ethanolamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR24).
24 . The compound (E,E)-2-(benzylamido)-3-(3,4-dihydroxystyryl) acrylonitrile (CR4).
25 . The compound (E,E)-2-(3,4-dihydroxybenzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR11).
26 . The compound (E,E)-2-(3,4-dihydroxybenzylamido)-3-(3,5-dimethoxy-4-hydroxystyryl)acrylonitrile (CR11).
27 . A composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable diluent or carrier.
28 . A method of modulating cell proliferation comprising administering an effective amount of a compound of claim 23 to modulate cell proliferation to a cell or animal in need thereof.
29 . A method of inhibiting cell proliferation comprising administering an effective amount of a compound of claim 23 to inhibit cell proliferation to a cell or animal in need thereof.
30 . The method of claim 29 , wherein the cell proliferation that is inhibited is cancer cell proliferation.
31 . A method of treating cancer comprising administering to an animal in need thereof an effective amount of a compound of claim 23 .
32 . The method of claim 30 or 31 wherein said cancer is a hematopoietic cell cancer.
33 . The method of claim 30 or 31 wherein said cancer is a leukemia, a lymphoma, a myeloma or a carcinoma.
34 . The method of claim 33 wherein said leukemia is acute lymphoblastic leukemia, aggressive Philadelphia+leukemia, acute myelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia or juvenile myelomonocyte leukemia.
35 . The method of claim 34 wherein said leukemia is acute lymphoblastic leukemia.
36 . A method of modulating cell proliferation comprising administering an effective amount of a compound capable of modulating cell proliferation according to claim 1 or a composition of claim 27 to a cell or animal in need thereof.
37 . A method of inhibiting cell proliferation comprising administering an effective amount of a compound capable of inhibiting cell proliferation according to claim 1 or a composition according to claim 27 to a cell or animal in need thereof.
38 . A method of inhibiting cancer cell proliferation comprising administering an effective amount of a compound capable of inhibiting cancer cell proliferation according to any one of claim 1 or a composition according to claim 27 to a cell or animal in need thereof.
39 . A method of treating cancer comprising administering an effective amount of a compound capable of inhibiting cancer cell proliferation according to claim 1 or a composition according to claim 27 to a cell or animal in need thereof.
40 . A method according to claim 38 or 39 wherein said cancer is a hematopoietic cell cancer.
41 . A method according to claim 38 or 39 wherein said cancer is a leukemia, a lymphoma, a myeloma or a carcinoma.
41 . A method according to claim 41 wherein said leukemia is acute lymphoblastic leukemia, aggressive Philadelphia+leukemia, acute myelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia or juvenile myelomonocyte leukemia,
43 . A method according to claim 42 wherein said leukemia is acute lymphoblastic leukemia.Cited by (0)
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