US 2010/0144688 A1 · 23-Substituted Derivatives of Lupane-type Pentacyclic Triterpenoids

Abstract

The present invention comprises small molecule inhibitors of cell proliferative conditions, in particular cancer and conditions associated with cancer. For example, associated malignancies include ovarian cancer, cervical cancer, breast cancer, colorectal cancer, and glioblastomas, among others. Accordingly, the compounds of the present invention are useful for treating, preventing, and/or inhibiting these diseases. Thus, the present invention also comprises pharmaceutical formulations comprising the compounds and methods of using the compounds and formulations to inhibit cancer and treat, prevent, or inhibit the foregoing diseases.

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
each is independently a single or double bond;
when bond a is a double bond, R1 is ═O, ═S, ═N—OH, ═N—OR5, or ═N—OCOR5;
or when bond a is a single bond, R1 is H, halogen, NH2, OH, SH, NHOH, NHR5, NH(CH2)nX, NR5R6, OR5, OCOR5, OCO(CH2)nX, OC(O)OR5, OCO(HC═CH)nR5, OC(O)NHR5, OC(O)NR5R6, OSO2H, OSO3H, OSO2(R5), OSO2(CH2)nX, OSi(R5)m(R6)3-m, SR5, SCOR5, SCO(CH2)nX, SC(O)NH2, SC(O)NHR5, SC(O)NR5R6, NHCOR5, NHC(O)OR5, N(R6)C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)NR5R6, N(R6)C(O)NH2, N(R6)C(O)NHR5, N(R6)C(O)NR5R6;
R2 and R3 are independently selected from CH2NH2, CH2OH, CH2SH, CH2SePh, CH2X, CH2NHOH, CN, CHO, CO2H, CH2NHOR5, CH═N—OH, CH═N—OR5, CH═N—OCOR5, CH2NHR5, CH2NH(CH2)nX, CH2NR5R6, CH2OR5, CH2OCOR5, CH2OC(O)OR5, CH2OCO(CH2)nX, CH2OCO(HC═CH)nR5, CH2OC(O)NH2, CH2OC(O)NHR5, CH2OC(O)NR5R6, CH2OSO2(R5), CH2OSO2(CH2)nX, CH2OSi(R5)m(R6)3-m, CH2SR5, CH2SCOR5, CH2SCO(CH2)nX, CH2SC(O)NH2, CH2SC(O)NHR5, CH2SC(O)NR5R6, CH2NHCOR5, CH2NHC(O)OR5, CH2NHC(O)NH2, CH2NHC(O)NHR5, CH2NHC(O)NR5R6, CH2N(R6)COR5, CH2N(R6)C(O)OR5, CH2N(R6)C(O)NH2, CH2N(R6)C(O)NHR5, CH2N(R6)C(O)NR5R6, CH(OR5)2, CH(OH)OR5, CO2R5, C(O)NH2, C(O)NHR5, C(O)NR5R6, C(O)NHOH, or C(O)NHOR5;
R4 is selected from CH3, CH2NH2, CH2OH, CH2SH, CH2SePh, CH2X, CH2NHOH, CN, CHO, CO2H, CH2NHOR5, CH═N—OH, CH═N—OR5, CH═N—OCOR5, CH2NHR5, CH2NH(CH2)nX, CH2NR5R6, CH2OR5, CH2OCOR5, CH2OC(O)OR5, CH2OCO(CH2)nX, CH2OCO(HC═CH)nR5, CH2OC(O)NH2, CH2OC(O)NHR5, CH2OC(O)NR5R6, CH2OSO2(R5), CH2OSO2(CH2)nX, CH2OSi(R5)m(R6)3-m, CH2SR5, CH2SCOR5, CH2SCO(CH2)nX, CH2SC(O)NH2, CH2SC(O)NHR5, CH2SC(O)NR5R6, CH2NHCOR5, CH2NHC(O)OR5, CH2NHC(O)NH2, CH2NHC(O)NHR5, CH2NHC(O)NR5R6, CH2N(R6)COR5, CH2N(R6)C(O)OR5, CH2N(R6)C(O)NH2, CH2N(R6)C(O)NHR5, CH2N(R6)C(O)NR5R6, CH(OR5)2, CH(OH)OR5, CO2R5, C(O)NH2, C(O)NHR5, C(O)NR5R6, C(O)NHOH, or C(O)NHOR5;
R5 and R6 are independently a straight or branched C1-8 alkyl, aryl-C1-8 alkyl, heterocycle-C1-8 alkyl, cyclo(C3-9)alkyl, aryl, or heterocycle, wherein
the aryl comprises phenyl or a polycyclic aryl group such as naphthyl;
the heterocyle comprises
a five or six membered aromatic heterocycle such as pyridyl, diazinyl, pyrimidinyl, 5-methoxy pyrimidinyl, (1,2,4)triazine-3,5-dione-6-yl, 6-mercaptopyrimidine-4-yl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, or thienyl;
a 3 to 9 membered non-aromatic heterocycle comprising piperazinyl, 4-methyl piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, thiazolidinyl, thiazolinyl, isothiazolidinyl, isothiazolinyl, pyranyl, or morpholinyl;
or
a polycyclic heterocycle such as indolyl, benzthienyl, benzofuranyl, isoindolyl, isobenzothienyl, or isobenzofuranyl;
wherein each alkyl, cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups (e.g., 1, 2, or 3 group) which are each independently C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino, di(C1-8 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, OC(O)OR7, OC(O)N(R7)2, C(O)OR7, C(O)N(R7)2, S(O)2R7, S(O)2N(R7)2, N(R7)C(O)N(R7)2, N(R7)C(O)OR7, CN, N3, NHOH, ═NOH, NH2, NO2, OH, SH, F, Cl, Br, or I, wherein each R7 is independently H or C1-8 alkyl;
or
R5 and R6 taken together with the carbon atoms to which they are attached form a cyclo(C3-9)alkyl, aryl, or heterocycle, wherein
the aryl comprises a phenyl or a polycyclic aryl group;
the heterocyle comprises
a five or six membered aromatic heterocycle, such as pyridyl, diazinyl, pyrimidinyl, 5-methoxy pyrimidinyl, (1,2,4)triazine-3,5-dione-6-yl, 6-mercaptopyrimidine-4-yl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, or thienyl;
a 3 to 9 membered non-aromatic heterocycle comprising piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, thiazolidinyl, thiazolinyl, isothiazolidinyl, isothiazolinyl, 4-methyl piperazinyl, pyranyl, or morpholinyl;
or
a polycyclic heterocycle such as indolyl, benzthienyl, benzofuranyl, isoindolyl, isobenzothienyl, or isobenzofuranyl;
wherein the cycloalkyl, aryl, and heterocycle are each optionally substituted with one or more groups (e.g., 1, 2, or 3 groups) which are each independently C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino, di(C1-8 alkyl)amino, C1-8 alkylamino-C1-8 alkyl, di(C1-6 alkyl)amino-C1-8 alkyl, OC(O)OR7, OC(O)N(R7)2, C(O)OR7, C(O)N(R7)2, S(O)2R7, S(O)2N(R7)2, N(R7)C(O)N(R7)2, N(R7)C(O)OR7, CN, N3, NHOH, ═NOH, NH2, NO2, OH, SH, F, Cl, Br, or I wherein each R7 is independently H or C1-8 alkyl;
each X is independently Y or aryl, heterocycle, or cyclo(C3-9)alkyl, wherein the aryl, heterocycle, or cyclo(C3-9)alkyl are each optionally substituted with one or more Y groups (e.g., 1, 2, or 3 Y groups), wherein each Y is independently F, Cl, Br, I, CN, N3, NHOH, ═NOH, NH2, OH, SH, NHR5, NR5R6, OR5, SR5, CO2H, CO2R5, SO(OH)2, or SO(OR5)2;
each m is independently 0, 1, 2, or 3;
each n is independently 1, 2, 3, 4, or 5;
with the proviso that:
when bond a is a single bond, bond b is a double bond, R1 is α-OH, R2 is CH2OH, and R3 is CO2H, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is α-OH, R2 and R3 are CO2H or CO2Me, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is α-OCOCH3, R2 and R3 are CO2H, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is β-OH, R2 and R3 are CO2Me, then R4 is not CH3;
when bond a is a double bond, bond b is a double bond, R1 is ═O, R2 and R3 are CO2Me, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is α-OH, R2 and R3 are CH2OH, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is β-OH, R2 and R3 are CH2OH, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is β-OH, R3 is CO2H, and R4 is CH3, then R2 is not CHO;
when bond a is a single bond, bond b is a double bond, R1 is β-OH, R2 is CH2OH, and R4 is CH3, then R3 is not CHO, CO2H, CH2CH═CH2, CH2C≡CH, CH2C≡CCH3;
CH2CH2OH, (CH2)4OH, or (CH2)6OH;
when bond a is a double bond, bond b is a double bond, R1 is ═O, R3 is CO2H, and R4 is CH3, then R2 is not CH2OH, or CO2H;
when bond a is a single bond, bond b is a double bond, R1 is β-OCOCH3, R2 is CH2OCOCH3, and R4 is CH3, then R3 is not CO2H, CH2CH2OH, (CH2)4OH, or (CH2)6OH;
when bond a is a single bond, bond b is a double bond, R1 is β-OCOCH2CH3, R2 is CH2OCOCH2CH3, and R4 is CH3, then R3 is not CO2H;
when bond a is a single bond, bond b is a double bond, R1 is α-OSO2Ph, R2 and R3 are CH2OSO2Ph, then R4 is not CH3;
when bond a is a single bond, bond b is a double bond, R1 is β-OCO-4′-Cl-Ph, R3 is CO2H, and R4 is CH3, then R2 is not CH2OCO-4′-Cl-Ph;
and
when bond a is a single bond, bond b is a double bond, R1 is β-OCO-benzyl, R3 is CO2H, and R4 is CH3, then R2 is not CH2OCO-benzyl.

41 more elements

23-Substituted Derivatives of Lupane-type Pentacyclic Triterpenoids

Life of this patent

23-Substituted Derivatives of Lupane-type Pentacyclic Triterpenoids

Life of this patent

Abstract

Claims16