US 2003/0229099 A1 · Novel farnesyl protein transferase inhibitors as antitumor agents

Abstract

Disclosed are novel tricyclic compounds represented by the formula (1.0): 1 or a pharmaceutically acceptable salt or solvate thereof. The compounds are useful for inhibiting farnesyl protein transferase. Also disclosed are pharmaceutical compositions comprising compounds of formula 1.0. Also disclosed are methods of treating cancer using the compounds of formula 1.0.

A compound of the formula:

2238
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 line (---) represents optional bonds;
X represents N or CH when the optional bond to C11 is absent, and represents C when the optional bond to C11 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 C-5 and there is only one B substituent bound to C-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 C-5, wherein each A substituent is independently selected, and two B substituents bound to C-6, wherein each B substituent is independently selected, and wherein at least one of the two A substituents or one of the two B substituents are H, and wherein at least one of the two A substituents or one of the two B substituents is other than H;
A and B are 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)R27,;
(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)R5;
(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;
(23) —(CH2)pNR51C(O)R27 wherein R51 is not H, and R51 and R27 taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloalkyl ring consisting;
(24) —(CH2)pNR51C(O)NR27;
(25) —(CH2)pNR51C(O)NR27 wherein R51 is not H, and R51 and R27 taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloalkyl ring;
(26) —(CH2)pNR51C(O)N(R27a)2, wherein each R27a is the same or different;
(27) —(CH2)pNHSO2N(R51)2, wherein each R51 is the same or different;
(28) —(CH2)pNHCO2R50;
(29) —(CH2)pNC(O)NHR51;
(30) —(CH2)pCO2R51;
(31) —NHR9;
(32)
2239
wherein R30 and R31 are the same or different, and each p is independently selected;
(33)
2240
wherein R30, R31, R32 and R33 are the same or different;
(34)-alkenyl-CO2R9a;
(35)-alkenyl-C(O)R9a;
(36)-alkenyl-CO2R51;
(37)-alkenyl-C(O)—R27a;
(38) (CH2)p-alkenyl-CO2—R51;
(37) —(CH2)pC═NOR51;
and
(39) —(CH2)p-phthalimid;
p is 0, 1, 2, 3 or 4;
each R1 and R2 is independently selected from the group consisting of:
(1) H;
(2) Halo;
(3) —CF3,
(4) —OR10;
(5) —COR10;
(6) —SR10;
(7) —S(O)tR15 wherein t is 0, 1 or 2;
(8) —N(R10)2;
(9) —NO2;
(10) —OC(O)R10;
(11) —CO2R10;
(12) —OCO2R15;
(13) —CN;
(14) —NR10COOR15;
(15) —SR15C(O)OR15;
(16) —SR15N(R13)2 provided that R15 in —SR15N(R3)2 is not —CH2 and wherein each R is independently selected from the group consisting of:
H and —C(O)OR15;
(17) benzotriazol-1-yloxy;
(18) tetrazol-5-ylthio;
(19) substituted tetrazol-5-ylthio;
(20) alkynyl;
(21) alkenyl;
and
(22) 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, and 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 —S(O)tR15, —NR10COOR15, —C(O)R10;
or —CO2R10, or R5 is combined with R6 to represent ═O or ═S;
R8 is selected from the group consisting of:
2241
R9 is selected from the group consisting of:
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocycloalkyl;
(6) substituted heterocycloalkyl;
(7) heterocycloalkylalkyl;
(8) substituted heterocycloalkylalkyl;
(9) unsubstituted heteroarylalkyl;
(10) substituted heteroarylalkyl;
(11) unsubstituted heteroarylalkenyl;
(12) substituted heteroarylalkenyl;
(13) unsubstituted heteroarylalkynyl and
(14) substituted heteroarylalkynyl;
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
2242
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) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) heterocycloalkyl;
and
(10) substituted heterocycloalkyl;
wherein said substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl R11 groups are substituted with one or more substituents selected from the group consisting of:
(1) —OH;
(2) fluoro;
and
(3) alkyl;
and
wherein said substituted aryl and substituted heteroaryl R11 groups are substituted with one or more substituents independently 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) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyl;
(8) substituted cycloalkyl;
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) heterocycloalkyl;
and
(12) substituted heterocycloalkyl;
wherein said substituted alkyl, substituted cycloalkyl, and substituted heterocycloalkyl R11a groups are substituted with one or more substituents independently selected from the group consisting of:
(1) —OH;
(2) —CN;
(3) —CF3;
(4) fluoro;
(5) alkyl;
(6) cycloalkyl;
(7) heterocycloalkyl;
(8) arylalkyl;
(9) heteroarylalkyl;
(10) alkenyl and
(11) heteroalkenyl;
and
wherein said substituted aryl and substituted heteroaryl R11a groups have one or more substituents independently 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, alkyl, piperidine Ring V, cycloalkyl, and -alkyl-(piperidine Ring V);
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) unsubstituted aryl;
(4) substituted aryl substituted with one or more substituents independently selected from the group consisting of:
alkyl, halogen, CF3 and OH;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl substituted with one or more substituents independently selected from the group consisting of:
alkyl, halogen, CF3 and OH;
(7) heteroaryl of the formula,
2243
(8) heterocycloalkyl of the formula:
2244
wherein R44 is selected from the group consisting of:
(a) —H,
(b) alkyl;
(c) alkylcarbonyl;
(d) alkyloxy carbonyl;
(e) haloalkyl;
and
(f) —C(O)NH(R51);
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, R31, R32 and R33 are independently selected from the group consisting of:
(1) —H;
(2) —OH;
(3) ═O;
(4) alkyl;
(5) aryl (e.g. phenyl);
(6) arylalkyl (e.g. benzyl);
(7) —OR9a;
(8) —NH2;
(9) —NHR9a;
and
(10) —N(R9a)2 wherein each R9a is independently selected;
R50 is selected from the group consisting of:
(1) alkyl;
(2) unsubstituted heteroaryl;
(3) substituted heteroary;
and
(4) amino;
wherein said substituents on said substituted R50 groups are independently selected from the group consisting of:
alkyl, halogen, and —OH;
R51 is selected from the group consisting of:
H, and alkyl;
provided that a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyl moiety is not substituted with a heteroatom or a halo atom;
and
provided that a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with more than one heteroatom;
and
provided that a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with a heteroatom and a halo atom;
and
provided that a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom;
and
provided that a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom;
and
provided that the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms.

265 more elements

Novel farnesyl protein transferase inhibitors as antitumor agents

Life of this patent

Novel farnesyl protein transferase inhibitors as antitumor agents

Life of this patent

Abstract

Claims88