US 2004/0006087 A1Published application

Method of treating cancer using FPT inhibitors and antineoplastic agents

AssigneeSchering Corporation

InventorsDavid L. Cutler, Charles Baum, Sara L. Zaknoen

Life of this patent

Estimating the term…

Abstract

Disclosed is a method of treating cancer in a patient in need of such treatment comprising administering a therapeutically effective amount of an FPT inhibitor and therapeutically effective amounts of one or more antineoplastic agents. Methods of treating non small cell lung cancer, squamous cell cancer of the head and neck, CML, AML, non-Hodgkin's lymphoma and multiple myeloma are disclosed.

Claims91

Dependent claims

A method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

(a) an FPT inhibitor of formula 1.0;
and
(b) at least two different antineoplastic agents selected from the group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothilones;
(10) topoisomerase inhibitors;
(11) vinca alkaloids;
(12) antibodies that are inhibitors of αVβ3 integrins;
(13) small molecule inhibitors of αVβ3 integrins;
(14) folate antagonists;
(15) ribonucleotide reductase inhibitors;
(16) anthracyclines;
(17) biologics;
(18) Thalidomide (or related Imid);
and
(19) Gleevec;
wherein said FPT inhibitor is a compound of the formula:
892
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or N+O−, and the remaining a, b, c, and d groups represent carbon, wherein each carbon has an R1 or R2 group bound to said carbon;
or
each of a, b, c, and d is carbon, wherein each carbon has an R1 or R2 group bound to said carbon;
the dotted lines (—) represent optional bonds;
X represents N or CH when the optional bond is absent, and represents C when the optional bond is present;
when the optional bond is present between carbon atom 5 and carbon atom 6 then there is only one A substituent bound to carbon atom 5 and there is only one B substituent bound to carbon atom 6 and A or B is other than H;
when the optional bond is not present between carbon atom 5 and carbon atom 6, then there are two A substituents bound to carbon atom 5 and two B substituents bound to carbon atom 6, wherein each A and B substituent is independently selected from the group consisting of:
(1) —H;
(2) —R9;
(3) —R9—C(O)—R9;
(4) —R9—CO2—R9a;
(5) —(CH2)pR26;
(6) —C(O)N(R9)2, wherein each R9 is the same or different;
(7) —C(O)NHR9;
(8) —C(O)NH—CH2—C(O)—NH2;
(9) —C(O)NHR26;
(10) —(CH2)pC(R9)—O—R9a;
(11) —(CH2)p(R9)2, wherein each R9 is the same or different;
(12) —(CH2)pC(O)R9;
(13) —(CH2)pC(O)R27a;
(14) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;
(15) —(CH2)pC(O)NH(R9);
(16) —(CH2)pC(O)N(R26)2, wherein each R26 is the same or different;
(17) —(CH2)pN(R9)—R9a;
(18) —(CH2)pN(R26)2, wherein R26 is the same or different;
(19) —(CH2)pNHC(O)R50;
(20) —(CH2)pNHC(O)2R50;
(21) —(CH2)pN(C(O)R27a)2 wherein each R27a is the same or different;
(22) —(CH2)pNR51C(O)R27, or R51 and R27 taken together with the atoms to which they are bound form a heterocycloalkyl ring consisting of, 5 or 6 members, provided that when R51 and R27 form a ring, R51 is not H;
(23) —(CH2)pNR51C(O)NR27, or R51 and R27 taken together with the atoms to which they are bound form a heterocycloalkyl ring consisting or 5 or 6 members, provided that when R51 and R27 form a ring, R51 is not H;
(24) —(CH2)pNR51C(O)N(R27a)2, wherein each R27a is the same or different;
(25) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;
(26) —(CH2)pNHCO2R50;
(27) —(CH2)pNC(O)NHR51;
(28) —(CH2)pCO2R51;
(29) —NHR9;
(30)
893
wherein
R30 and R31 are the same or different;
(31)
894
wherein
R30, R31, R32 and R33 are the same or different;
(32) -alkenyl-CO2R9a;
(33) -alkenyl-C(O)R9a;
(34) -alkenyl-CO2R51;
(35) -alkenyl-C(O)—R27a;
(36) (CH2)p-alkenyl-CO2—R51;
(37) —(CH2)pC═NOR51 and
(38) —(CH2)p-Phthalimid;
p is 0, 1, 2, 3 or 4;
each R1 and R2 is independently selected from H, Halogen, —CF3, —OR10, COR10, —SR10, —S(O)t15 wherein t is 0, 1 or 2, —N(R10)2, —NO2, —OC(O)R10, CO2R10, —OCO2R15, —CN, —NR10COOR15, —SR15C(O)OR15 —SR15N(R13)2 provided that R15 in —SR15N(R13)2 is not —CH2, and wherein each R13 is independently selected from H or —C(O)OR15, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halogen, —OR10 or —CO2R10;
R3 and R4 are the same or different and each independently represent H, or any of the substituents of R1 and R2;
R5, R6, R7 and R7a each independently represent H, —CF3, —COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR10, —SR10, —S(O)tR15, —NR10COOR15, —N(R10)2, —NO2, —C(O)R10, —OCOR10, —OCO2R15, —CO2R10, OPO3R10, or R5 is combined with R6 to represent ═O or ═S;
R8 is selected from the group consisting of:
895
R9 is selected from the group consisting of:
(1) heteroaryl;
(2) substituted heteroaryl;
(3) arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocycloalkyl;
(6) substituted heterocycloalkyl;
(7) heterocycloalkylalkyl;
(8) substituted heterocycloalkylalkyl;
(9) heteroarylalkyl;
(10) substituted heteroarylalkyl;
(11) heteroarylalkenyl;
(12) substituted heteroarylalkenyl;
(13) heteroarylalkynyl;
(14) substituted heteroarylalkynyl;
(15) arylalkyl;
(16) substituted arylalkyl;
(17) alkenyl, and
(18) substituted alkenyl;
wherein said substituted R9 groups are substituted with one or more substituents selected from the group consisting of:
(1) —OH;
(2) —CO2R14;
(3) —CH2OR14,
(4) halogen;
(5) alkyl;
(6) amino;
(7) trityl;
(8) heterocycloalkyl;
(9) cycloalkyl;
(10) arylalkyl;
(11) heteroaryl;
(12) heteroarylalkyl and
(13)
896
wherein
R14 is independently selected from the group consisting of:
H;
alkyl;
aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R9a is selected from the group consisting of:
alky and arylalkyl;
R10 is selected from the group consisting of:
H;
alkyl;
aryl and arylalkyl;
R11 is selected from the group consisting of:
(1) alkyl;
(2) substituted alkyl;
(3) aryl;
(4) substituted aryl;
(5) cycloalkyl;
(6) substituted cycloalkyl;
(7) heteroaryl;
(8) substituted heteroaryl;
(9) heterocycloalkyl;
and
(10) substituted heterocycloalkyl;
wherein said substituted R11 groups have 1, 2 or 3 substituents selected from the group consisting of:
(1) —OH;
(2) halogen and
(3) alkyl;
R11a is selected from the group consisting of:
(1) H;
(2) OH;
(3) alkyl;
(4) substituted alkyl;
(5) aryl;
(6) substituted aryl;
(7) cycloalkyl;
(8) substituted cycloalkyl;
(9) heteroaryl;
(10) substituted heteroaryl;
(11) heterocycloalkyl;
and
(12) substituted heterocycloalkyl;
wherein said substituted R11a groups have one or more substituents selected from the group consisting of:
(1) —OH;
(2) —CN;
(3) —CF3;
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) heterocycloalkyl,
(8) arylalkyl;
(9) heteroarylalkyl;
(10) alkenyl and
(11) heteroalkenyl;
R12 is selected from the group consisting of:
H, and alkyl;
R15 is selected from the group consisting of:
alkyl and aryl;
R21, R22 and R46 are independently selected from the group consisting of:
(1) —H;
(2) alkyl;
(3) aryl;
(4) substituted aryl,
optionally substituted with one or more substituents selected from the group consisting of:
alkyl, halogen, CF3 and OH;
(5) cycloalkyl;
(6) substituted cycloalkyl;
optionally substituted with one or more substituents selected from the group consisting of:
alkyl, halogen, CF3 and OH;
(7) heteroaryl of the formula,
897
(8) heterocycloalkyl of the formula:
898
wherein
R44 is selected from the group consisting of:
(1) —H;
(2) alkyl;
(3) alkylcarbonyl;
(4) alkyloxy carbonyl;
(5) haloalkyl and
(6) —C(O)NH(R51);
when R21, R22 or R46 is the heterocycloalkyl of the formula above, Ring V is selected from the group consisting of:
899
R26 is selected from the group consisting of:
(1) —H;
(2) alkyl;
(3) alkoxyl;
(4) —CH2—CN;
(5) R9;
(6) —CH2CO2H;
(7) —C(O)alkyl and
(8) CH2CO2alkyl;
R27 is selected from the group consisting of:
(1) —H;
(2) —OH;
(3) alkyl and
(4) alkoxy;
R27a is selected from the group consisting of:
(1) alkyl and
(2) alkoxy;
R30 through R33 are independently selected from the group consisting of:
(1) —H;
(2) —OH;
(3) ═O;
(4) alkyl;
(5) aryl and
(6) arylalkyl;
R50 is selected from the group consisting of:
(1) alkyl;
(2) heteroaryl;
(3) substituted heteroaryl and
(4) amino;
wherein said substituents on said substituted R50 groups are independently selected from the group consisting of:
alkyl;
halogen;
and —OH;
R50a is selected from the group consisting of:
(1) heteroaryl;
(2) substituted heteroaryl and
(3) amino;
R51 is selected from the group consisting of:
—H, and alkyl.

235 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/308,813Filed 3 Dec 2002
Priority: 3 Dec 2001
Published: 8 Jan 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61K 31/473
Quinolines; Isoquinolines: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
A61K 31/4745
Ortho- or peri-condensed with heterocyclic ring systems: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines

Family

Application60/336,961Us provisional application · filed 3 Dec 2001
US 2004/0006087 A1This patent

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

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Abstract

A method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

(a) an FPT inhibitor of formula 1.0;
and
(b) at least two different antineoplastic agents selected from the group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothilones;
(10) topoisomerase inhibitors;
(11) vinca alkaloids;
(12) antibodies that are inhibitors of αVβ3 integrins;
(13) small molecule inhibitors of αVβ3 integrins;
(14) folate antagonists;
(15) ribonucleotide reductase inhibitors;
(16) anthracyclines;
(17) biologics;
(18) Thalidomide (or related Imid);
and
(19) Gleevec;
wherein said FPT inhibitor is a compound of the formula:
892
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or N+O−, and the remaining a, b, c, and d groups represent carbon, wherein each carbon has an R1 or R2 group bound to said carbon;
or
each of a, b, c, and d is carbon, wherein each carbon has an R1 or R2 group bound to said carbon;
the dotted lines (—) represent optional bonds;
X represents N or CH when the optional bond is absent, and represents C when the optional bond is present;
when the optional bond is present between carbon atom 5 and carbon atom 6 then there is only one A substituent bound to carbon atom 5 and there is only one B substituent bound to carbon atom 6 and A or B is other than H;
when the optional bond is not present between carbon atom 5 and carbon atom 6, then there are two A substituents bound to carbon atom 5 and two B substituents bound to carbon atom 6, wherein each A and B substituent is independently selected from the group consisting of:
(1) —H;
(2) —R9;
(3) —R9—C(O)—R9;
(4) —R9—CO2—R9a;
(5) —(CH2)pR26;
(6) —C(O)N(R9)2, wherein each R9 is the same or different;
(7) —C(O)NHR9;
(8) —C(O)NH—CH2—C(O)—NH2;
(9) —C(O)NHR26;
(10) —(CH2)pC(R9)—O—R9a;
(11) —(CH2)p(R9)2, wherein each R9 is the same or different;
(12) —(CH2)pC(O)R9;
(13) —(CH2)pC(O)R27a;
(14) —(CH2)pC(O)N(R9)2, wherein each R9 is the same or different;
(15) —(CH2)pC(O)NH(R9);
(16) —(CH2)pC(O)N(R26)2, wherein each R26 is the same or different;
(17) —(CH2)pN(R9)—R9a;
(18) —(CH2)pN(R26)2, wherein R26 is the same or different;
(19) —(CH2)pNHC(O)R50;
(20) —(CH2)pNHC(O)2R50;
(21) —(CH2)pN(C(O)R27a)2 wherein each R27a is the same or different;
(22) —(CH2)pNR51C(O)R27, or R51 and R27 taken together with the atoms to which they are bound form a heterocycloalkyl ring consisting of, 5 or 6 members, provided that when R51 and R27 form a ring, R51 is not H;
(23) —(CH2)pNR51C(O)NR27, or R51 and R27 taken together with the atoms to which they are bound form a heterocycloalkyl ring consisting or 5 or 6 members, provided that when R51 and R27 form a ring, R51 is not H;
(24) —(CH2)pNR51C(O)N(R27a)2, wherein each R27a is the same or different;
(25) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;
(26) —(CH2)pNHCO2R50;
(27) —(CH2)pNC(O)NHR51;
(28) —(CH2)pCO2R51;
(29) —NHR9;
(30)
893
wherein
R30 and R31 are the same or different;
(31)
894
wherein
R30, R31, R32 and R33 are the same or different;
(32) -alkenyl-CO2R9a;
(33) -alkenyl-C(O)R9a;
(34) -alkenyl-CO2R51;
(35) -alkenyl-C(O)—R27a;
(36) (CH2)p-alkenyl-CO2—R51;
(37) —(CH2)pC═NOR51 and
(38) —(CH2)p-Phthalimid;
p is 0, 1, 2, 3 or 4;
each R1 and R2 is independently selected from H, Halogen, —CF3, —OR10, COR10, —SR10, —S(O)t15 wherein t is 0, 1 or 2, —N(R10)2, —NO2, —OC(O)R10, CO2R10, —OCO2R15, —CN, —NR10COOR15, —SR15C(O)OR15 —SR15N(R13)2 provided that R15 in —SR15N(R13)2 is not —CH2, and wherein each R13 is independently selected from H or —C(O)OR15, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halogen, —OR10 or —CO2R10;
R3 and R4 are the same or different and each independently represent H, or any of the substituents of R1 and R2;
R5, R6, R7 and R7a each independently represent H, —CF3, —COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR10, —SR10, —S(O)tR15, —NR10COOR15, —N(R10)2, —NO2, —C(O)R10, —OCOR10, —OCO2R15, —CO2R10, OPO3R10, or R5 is combined with R6 to represent ═O or ═S;
R8 is selected from the group consisting of:
895
R9 is selected from the group consisting of:
(1) heteroaryl;
(2) substituted heteroaryl;
(3) arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocycloalkyl;
(6) substituted heterocycloalkyl;
(7) heterocycloalkylalkyl;
(8) substituted heterocycloalkylalkyl;
(9) heteroarylalkyl;
(10) substituted heteroarylalkyl;
(11) heteroarylalkenyl;
(12) substituted heteroarylalkenyl;
(13) heteroarylalkynyl;
(14) substituted heteroarylalkynyl;
(15) arylalkyl;
(16) substituted arylalkyl;
(17) alkenyl, and
(18) substituted alkenyl;
wherein said substituted R9 groups are substituted with one or more substituents selected from the group consisting of:
(1) —OH;
(2) —CO2R14;
(3) —CH2OR14,
(4) halogen;
(5) alkyl;
(6) amino;
(7) trityl;
(8) heterocycloalkyl;
(9) cycloalkyl;
(10) arylalkyl;
(11) heteroaryl;
(12) heteroarylalkyl and
(13)
896
wherein
R14 is independently selected from the group consisting of:
H;
alkyl;
aryl, arylalkyl, heteroaryl and heteroarylalkyl;
R9a is selected from the group consisting of:
alky and arylalkyl;
R10 is selected from the group consisting of:
H;
alkyl;
aryl and arylalkyl;
R11 is selected from the group consisting of:
(1) alkyl;
(2) substituted alkyl;
(3) aryl;
(4) substituted aryl;
(5) cycloalkyl;
(6) substituted cycloalkyl;
(7) heteroaryl;
(8) substituted heteroaryl;
(9) heterocycloalkyl;
and
(10) substituted heterocycloalkyl;
wherein said substituted R11 groups have 1, 2 or 3 substituents selected from the group consisting of:
(1) —OH;
(2) halogen and
(3) alkyl;
R11a is selected from the group consisting of:
(1) H;
(2) OH;
(3) alkyl;
(4) substituted alkyl;
(5) aryl;
(6) substituted aryl;
(7) cycloalkyl;
(8) substituted cycloalkyl;
(9) heteroaryl;
(10) substituted heteroaryl;
(11) heterocycloalkyl;
and
(12) substituted heterocycloalkyl;
wherein said substituted R11a groups have one or more substituents selected from the group consisting of:
(1) —OH;
(2) —CN;
(3) —CF3;
(4) halogen;
(5) alkyl;
(6) cycloalkyl;
(7) heterocycloalkyl,
(8) arylalkyl;
(9) heteroarylalkyl;
(10) alkenyl and
(11) heteroalkenyl;
R12 is selected from the group consisting of:
H, and alkyl;
R15 is selected from the group consisting of:
alkyl and aryl;
R21, R22 and R46 are independently selected from the group consisting of:
(1) —H;
(2) alkyl;
(3) aryl;
(4) substituted aryl,
optionally substituted with one or more substituents selected from the group consisting of:
alkyl, halogen, CF3 and OH;
(5) cycloalkyl;
(6) substituted cycloalkyl;
optionally substituted with one or more substituents selected from the group consisting of:
alkyl, halogen, CF3 and OH;
(7) heteroaryl of the formula,
897
(8) heterocycloalkyl of the formula:
898
wherein
R44 is selected from the group consisting of:
(1) —H;
(2) alkyl;
(3) alkylcarbonyl;
(4) alkyloxy carbonyl;
(5) haloalkyl and
(6) —C(O)NH(R51);
when R21, R22 or R46 is the heterocycloalkyl of the formula above, Ring V is selected from the group consisting of:
899
R26 is selected from the group consisting of:
(1) —H;
(2) alkyl;
(3) alkoxyl;
(4) —CH2—CN;
(5) R9;
(6) —CH2CO2H;
(7) —C(O)alkyl and
(8) CH2CO2alkyl;
R27 is selected from the group consisting of:
(1) —H;
(2) —OH;
(3) alkyl and
(4) alkoxy;
R27a is selected from the group consisting of:
(1) alkyl and
(2) alkoxy;
R30 through R33 are independently selected from the group consisting of:
(1) —H;
(2) —OH;
(3) ═O;
(4) alkyl;
(5) aryl and
(6) arylalkyl;
R50 is selected from the group consisting of:
(1) alkyl;
(2) heteroaryl;
(3) substituted heteroaryl and
(4) amino;
wherein said substituents on said substituted R50 groups are independently selected from the group consisting of:
alkyl;
halogen;
and —OH;
R50a is selected from the group consisting of:
(1) heteroaryl;
(2) substituted heteroaryl and
(3) amino;
R51 is selected from the group consisting of:
—H, and alkyl.

235 more elements

Facts

Application

10/308,813Filed 3 Dec 2002

Priority

3 Dec 2001

Published

8 Jan 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61K 31/473
Quinolines; Isoquinolines: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
A61K 31/4745
Ortho- or peri-condensed with heterocyclic ring systems: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines