US 6,586,447 B1Granted

3,3-disubstituted-oxindole derivatives useful as anticancer agents

AssigneePfizer Inc.

InventorsJoseph Peter Lyssikatos, Bingwei Vera Yang

Life of this patent

Estimating the term…

Abstract

The present invention relates to compounds of formula 1 and to pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein n is 0 or 1 and R1, R2, R3, R4, and R5 are as defined herein. The above compounds of formula 1 are useful in the treatment of hyperproliferative disorders, such as cancer, in mammals. The invention also relates to pharmaceutical compositions containing the compounds of formula 1, to methods of inhibiting abnormal cell growth, including cancer, in a mammal by administering the compounds of formula 1 to a mammal requiring such treatment, and to methods of preparing compounds of formula 1.

Claims21

Dependent claims

A compound of the formula 1

or a pharmaceutically acceptable salt, prodrug, or solvate thereof wherein:
n is 0 or 1;
R1 is C1-C3 alkylpyridyl or C1-C3 alkylimidazolyl;
R2 is selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)p(C6-C10 aryl), and —(CH2)p(4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 through 3, and wherein any of said R1 and R2 groups are optionally substituted with 1 to 3 R6 groups;
R3 is —(CH2)m(1- or 2-adamantyl), —C1-C10 alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, —(CH2)m(C6-C10 aryl),
X1, X2, and X3 are each independently C1-C7 alkylene optionally containing 1 or 2 carbon-carbon double bonds, X4 is a bond or C1-C7 alkylene optionally containing 1 or 2 carbon-carbon double or triple bonds, and, in formula (1b), the X4 moiety is attached to the X1 moiety at any available carbon in the X1 moiety,
and each of the foregoing R3 groups are substituted with an R5 group and optionally with 1 to 4 R6 groups;
or R3 is —(CH2)tSO2R9, —(CH2)tC(O)R9, or —(CH2)m(4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups;
m, in the aforementioned R3 groups, is independently an integer from 0 through 6 and t is independently an integer from 1 through 5;
R4 is C6-C10 aryl or 4-10 membered heterocyclyl, each of said R4 groups being optionally substituted by 1 to 3 R6 groups;
each R5 is independently selected from halo, C1-C6 alkyl optionally substituted by 1 to 3 halo, nitro, cyano, —OR9, —C(O)R9, —SR9, —SO2R9, —SO3H, —S(O)R9, —NR7R8, —CH═NOR7, —C(O)OR9, —OC(O)R9, —SO2NR9R8, —C(O)NR9R8, —NR8C(O)R9, —OC(O)NR9R8, —C(O)ONR7R9, —NR8C(O)NR9R8, —NR8C(O)O(C1-C4 alkyl), —C(NR8)NR9R8, —C(NCN)NR9R8, —C(NCN)S(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(NCN)S(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(NCN)NR7R8, —NR8SO2(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(O)C(O)R8, —NR8C(O)C(O)NR9R8, —P(O)(OR7)2, and —CH2)q(4-10 membered heterocyclyl), q is an integer from 0 through 3, and the alkyl and heterocyclyl moieties of the foregoing R5 groups are optionally substituted by 1 to 3 R10 groups;
each R6 is independently selected from R5, C2-C10 alkenyl, C2-C10 alkynyl and —(CH2)t(C6-C10 aryl) optionally substituted with 1 to 3 R10 groups, t being an integer from 0 through 3;
each R7 is independently hydrogen or C1-C4 alkyl optionally substituted by 1 to 3 halo;
each R8 is independently R7 or —OR7;
each R9 is independently selected from hydrogen, C1-C6 alkyl, —(CH2)q(C6-C10 aryl) and —(CH2)q(4-10 membered heterocyclyl), said R9 groups, except H, are optionally substituted with 1 to 3 R10 groups, and each q is independently an integer from 0 through 3;
and
each R10 is independently selected from halo, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —C(O)O(C1-C6 alkyl), and C6-C10 aryl.

14 more elements

A compound selected from the group consisting of:

4-[6-(4-Cyano-phenyl)-3,3-bis-(1H-imidazol-4-ylmethyl)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide;
4-[3,3-Bis-(3H-imidazol-4-ylmethyl)-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[1-Adamantan-1-ylmethyl-3-(1H-imidazol-4-ylmethyl)-3-(3H-imidazol-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[3-(1H-Imidazol-4-ylmethyl)-3-(3H-imidazol-4-ylmethyl)-2-oxo-1-quinolin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[6-(4-Formyl-phenyl)-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide;
4-[6-(4-Cyano-phenyl)-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide;
4-(1-Naphthalen-1-ylmethyl-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-benzonitrile;
4-(2-Oxo-3,3-bis-pyridin-4-ylmethyl-1-quinolin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-benzonitrile;
4-[1-Adamantan-1-ylmethyl-3,3-bis-(3-methyl-3H-imidazol-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-(7-Methyl-1-naphthalen-2-ylmethyl-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-benzonitrile;
4-(7-Methyl-1-naphthalen-1-ylmethyl-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-benzonitrile;
4-[6-(4-Cyano-phenyl)-7-methyl-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide;
4-[7-Methyl-1-naphthalen-1-ylmethyl-2-oxo-3-(1H-pyrazol-4-ylmethyl)-3-pyridin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[3,3-Bis-(1H-imidazol-4-ylmethyl)-7-methyl-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-[7-Methyl-3,3-bis-(5-methyl-1H-imidazol-4-ylmethyl)-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzonitrile;
4-(2-Naphthalen-1-ylmethyl-1,3-dioxo-4,4-bis-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzonitrile;
and
4-{1,3-Dioxo-4,4-bis-pyridin-4-ylmethyl-2-[1-(thiophene-2-sulfonyl)-pyrrolidin-3-yl]-1,2,3,4-tetrahydro-isoquinolin-7-yl}-benzonitrile;
and the pharmaceutically acceptable salts, prodrugs, and solvates of the foregoing compounds.

16 more elements

A method of preparing a compound of formula 1:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof wherein:
n is 0 or 1;
R1 and R2 are C1-C3 alkylpyridyl or C1-C3 alkylimidazolyl;
R3 is —(CH2)m(1- or 2-adamantyl), —C1-C10 alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, —(CH2)m(C6-C10 aryl),
X1, X2, and X3 are each independently C1-C7 alkylene optionally containing 1 or 2 carbon-carbon double bonds, X4 is a bond or C1-C7 alkylene optionally containing 1 or 2 carbon-carbon double or triple bonds, and, in formula (1b), the X4 moiety is attached to the X1 moiety at any available carbon in the X1 moiety,
and each of the foregoing R3 groups are substituted with an R5 group and optionally with 1 to 4 R6 groups;
or R3 is —(CH2)tSO2R9, —(CH2)tC(O)R9, or —(CH2)m(4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups;
m, in the aforementioned R3 groups, is independently an integer from 0 through 6 and t is independently an integer from 1 through 5;
R4 is C6-C10 aryl or 4-10 membered heterocyclyl, each of said R4 groups being optionally substituted by 1 to 3 R6 groups;
each R5 is independently selected from halo, C1-C6 alkyl optionally substituted by 1 to 3 halo, nitro, cyano, —OR9, —C(O)R9, —SR9, —SO2R9, —SO3H, —S(O)R9, —NR7R8, —CH═NOR7, —C(O)OR9, —OC(O)R9, —SO2NR9R8, —C(O)NR9R8, —NR8C(O)R9, —OC(O)NR9R8, —C(O)ONR7R9, —NR8C(O)NR9R8, —NR8C(O)O(C1-C4 alkyl), —C(NR8)NR9R8, —C(NCN)NR9R8, —C(NCN)S(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(NCN)S(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(NCN)NR7R8, —NR8SO2(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(O)C(O)R8, —NR8C(O)C(O)NR9R8, —P(O)(OR7)2, and —CH2)q(4-10 membered heterocyclyl), q is an integer from 0 through 3, and the alkyl and heterocyclyl moieties of the foregoing R5 groups are optionally substituted by 1 to 3 R10 groups;
each R6 is independently selected from R5, C2-C10 alkenyl, C2-C10 alkynyl and —(CH2)t(C6-C10 aryl) optionally substituted with 1 to 3 R10 groups, t being an integer from 0 through 3;
each R7 is independently hydrogen or C1-C4 alkyl optionally substituted by 1 to 3 halo;
each R8 is independently R7 or —OR7;
each R9 is independently selected from hydrogen, C1-C6 alkyl, —(CH2)q(C6-C10 aryl) and —(CH2)q(4-10 membered heterocyclyl), said R9 groups, except H, are optionally substituted with 1 to 3 R10 groups, and each q is independently an integer from 0 through 3;
and
each R10 is independently selected from halo, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —C(O)O(C1-C6 alkyl), and C6-C10 aryl;
which comprises treating a compound of formula 2:
wherein the substituents are as described above;
with a compound of formula RW, wherein W is a leaving group and R is C1-C3 alkylpyridyl or C1-C3 alkylimidazolyl.

16 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/539,930Filed 31 Mar 2000 · us provisional application
Priority: 1 Apr 1999
Granted: 1 Jul 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 35/00
Antineoplastic agents
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
C07D 409/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms: containing three…

Family

Application60/127,340Us provisional application · filed 1 Apr 1999
US 6,586,447 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula 1

or a pharmaceutically acceptable salt, prodrug, or solvate thereof wherein:
n is 0 or 1;
R1 is C1-C3 alkylpyridyl or C1-C3 alkylimidazolyl;
R2 is selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)p(C6-C10 aryl), and —(CH2)p(4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 through 3, and wherein any of said R1 and R2 groups are optionally substituted with 1 to 3 R6 groups;
R3 is —(CH2)m(1- or 2-adamantyl), —C1-C10 alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, —(CH2)m(C6-C10 aryl),
X1, X2, and X3 are each independently C1-C7 alkylene optionally containing 1 or 2 carbon-carbon double bonds, X4 is a bond or C1-C7 alkylene optionally containing 1 or 2 carbon-carbon double or triple bonds, and, in formula (1b), the X4 moiety is attached to the X1 moiety at any available carbon in the X1 moiety,
and each of the foregoing R3 groups are substituted with an R5 group and optionally with 1 to 4 R6 groups;
or R3 is —(CH2)tSO2R9, —(CH2)tC(O)R9, or —(CH2)m(4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups;
m, in the aforementioned R3 groups, is independently an integer from 0 through 6 and t is independently an integer from 1 through 5;
R4 is C6-C10 aryl or 4-10 membered heterocyclyl, each of said R4 groups being optionally substituted by 1 to 3 R6 groups;
each R5 is independently selected from halo, C1-C6 alkyl optionally substituted by 1 to 3 halo, nitro, cyano, —OR9, —C(O)R9, —SR9, —SO2R9, —SO3H, —S(O)R9, —NR7R8, —CH═NOR7, —C(O)OR9, —OC(O)R9, —SO2NR9R8, —C(O)NR9R8, —NR8C(O)R9, —OC(O)NR9R8, —C(O)ONR7R9, —NR8C(O)NR9R8, —NR8C(O)O(C1-C4 alkyl), —C(NR8)NR9R8, —C(NCN)NR9R8, —C(NCN)S(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(NCN)S(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(NCN)NR7R8, —NR8SO2(C1-C4 alkyl or C1-C4 haloalkyl), —NR8C(O)C(O)R8, —NR8C(O)C(O)NR9R8, —P(O)(OR7)2, and —CH2)q(4-10 membered heterocyclyl), q is an integer from 0 through 3, and the alkyl and heterocyclyl moieties of the foregoing R5 groups are optionally substituted by 1 to 3 R10 groups;
each R6 is independently selected from R5, C2-C10 alkenyl, C2-C10 alkynyl and —(CH2)t(C6-C10 aryl) optionally substituted with 1 to 3 R10 groups, t being an integer from 0 through 3;
each R7 is independently hydrogen or C1-C4 alkyl optionally substituted by 1 to 3 halo;
each R8 is independently R7 or —OR7;
each R9 is independently selected from hydrogen, C1-C6 alkyl, —(CH2)q(C6-C10 aryl) and —(CH2)q(4-10 membered heterocyclyl), said R9 groups, except H, are optionally substituted with 1 to 3 R10 groups, and each q is independently an integer from 0 through 3;
and
each R10 is independently selected from halo, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, —C(O)O(C1-C6 alkyl), and C6-C10 aryl.

14 more elements

Facts

Application

09/539,930Filed 31 Mar 2000 · us provisional application

Priority

1 Apr 1999

Granted

1 Jul 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 35/00
Antineoplastic agents
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
C07D 409/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms: containing three…