Patent IL-105715-A (IL)
Title: 7b SUBSTITUTED-4-AZA-5a- ANDROSTAN-3-ONES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
IPC: A61P15/00
Filed: 1993-05-17
Abstract: Compounds having 5a-reductase inhibiting activity of the formula Ae ab ONZ HaR wherein R is selected from hydrogen, methyl or ethyl; the dashed lines-a, b, e indicate double bonds which can be present, providing that if b double bond is present, then the 5a hydrogen, Ha, is not present; Z can be: (1) oxo, (2) hydrogen and a b-substituent selected from C1-C4 alkyl, C2-C4 alkenyl, -CH2COOH, hydroxy, carboxy, COOC1-C4 alkyl esters; OCONR1R2, where R1 and R2 are independently H, C1-C4 alkyl, phenyl, benzyl, and where R1 and R2 together with the nitrogen can form a 5-6 membered saturated heterocyclic ring, optionally with one other heteroatom; OC1-C4 alkyl, OC3-C6 cycloalkyl, -OCOCH3, halo, halo C1-C2 alkyl, or trifluoromethyl, C3-C6 cycloalkyl; (3) =CH-R1 where R1 is H, C1-C4 allyl; (4) Spiro R1 where R1 is H, C1-C4 alkyl; and A is: O IA) -C-Q, where Q is: (1) NR2R3, where R3 is independently hydrogen, methyl or ethyl; and R2 is a hydrocarbon radical, selected from substituted or unsubstituted straight or branched chain alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/ or 1 or more halogen substituents, with the proviso that Z is not beta-methyl where R2 is C1-C8 alkyl; (2) a hydrocarbon radical being: (a) a monovalent aliphatic radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which can be substituted by one or more of C1-C2 alkyl or halo, excluding C1-C4 alkyl when Z is betamethyl; (b) an aralkyl radical selected from benzyl or phenethyl; (c) a polycyclic aromatic radical which can be substituted with one or more of: -OH, organosilyl protected -OH, -OC1-C4 alkyl, C1-C4 alkyl, halo or nitro; (d) a monocyclic aromatic radical which can be substituted with one or more of: (i) -OH, -OC1-C4 alkyl, C1-C4 alkyl, -(CH2)mOH, -(CH2)n COOH, including organosilyl protected hydroxy, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above oxygen- containing radicals is present; (ii) -SH, -SC1-C4 alkyl, -SOC1-C4 alkyl, -SO2C1-C4 alkyl, -SO2N(C1-C4-alkyl)2, -SO2NH(C1-C4 alkyl), -(CH2)mSH, -S- (CH2)n-O-COCH3, where m is 1-4, n is 1-3, providing C1-C4 alkyl is only present when one of the above sulfur containing radicals is present; (iii) N(R3)n, which can be protected, where R3 is independently H or C1-C4 alkyl, where the monoaryl ring can also be further substituted with C1-C4 alkyl; and (iv) heterocyclic radical selected from 2-, 3-, or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl; and (IIA), where: A is -XR4, or -(CHR1)n-XR4; n is 1-10; X is -O- or -S(O)p-, wherein p is zero, 1 or 2; and R1 can be the same or different when n is greater than 1 and is -H, aryl, or -C1-3 alkyl unsubstituted or substituted with C6-C10 aryl; R is -H, methyl or ethyl; R4 is (1) hydrogen or -C1-20 alkyl, unsubstituted or substituted with one or more of: (a) -OH, (b) halo, (c) -C1-8 alkoxy, (d) -C1-6 alkenyl, (e) -CONR5R5, wherein R5 is independently (i) -H, (ii) -C1-8 alkyl unsubstituted or substituted with one or more of R7, aryl or heterocyclic, defined below, the aryl being unsubstituted or substituted with one or more of R7 or R9, (iii) aryl unsubstituted or substituted with one or more of R7 or R9, or (iv) heterocyclic, defined below, unsubstituted or substituted with one or more of R7 or R9, (f) -COOR6, wherein R6 is (i) -H, (ii) -C1-8 alkyl unsubstituted or substituted with one or more of R7 or aryl, the aryl being unsubstituted or substituted with one or more of R7 or R9, or (iii) aryl, unsubstituted or substituted with one or more of R7 or R9, (g) -S(O)p-R5, wherein p is defined above, (h) -N(R5)2, (i) aryl, unsubstituted or substituted with one or more of aryl, R7 or R9, (j) heterocycle, unsubstituted or substituted with one or more of R7 or R9, (k) -C3-10 cycloalkyl, such as cyclohexyl, norbornyl, or adamantyl, unsubstituted or substituted with one or more of R7 or R9, or (1) -CONR8-CO-NHR8, wherein R8 is -H, -C1-8 alkyl, benzyl or cyclohexyl; or (2) aryl, unsubstituted or substituted with one or more of aryl, R7 or R9, or (3) heterocycle or -C3-10 cycloalkyl, either of which is unsubstituted or substituted with one or more of R7 or R9; R7 is (1) -OH, (2) -C1-3 alkoxy, (3) -CN, (4) -COOR6 (5) -C1-8 alkyl-COOR6 (6) -NO2, or (7) -halo; and (8) amino, mono C1-C4 alkylamino, di C1-C4 alkylamino; R9 is (1) -C1-8 alkyl, unsubstituted or substituted with one or more of aryl or R7, (2) -CO-A, -C1-8 alkyl-CO-A, -NHCO-A, or -S(O)p-A, wherein p is defined above and A is (a) -H, (b) -C1-8 alkyl, unsubstituted or substituted with one or more of (i) -R7, or (ii) aryl, unsubstituted or substituted with one or more of R7, or (c) aryl, unsubstituted or substituted with one or more of R7, (3) -NHCO-heterocycle, (4) -N(R10)2 or -CON(R10)n wherein R10 is independently -H, heterocycle, or -A, (5) -NHCO-(CH2)q-CO-Q, wherein q is 1-4, and Q is -N(R10)2 or -OR10; (IIIA), where: A is (CHR1)n-X-C-R4; R1 can be the same or different when n is greater than 1 and is -H, aryl, or -C1-3 alkyl unsubstituted or substituted with aryl; R is -H, methyl or ethyl; n is zero through 10; X is -O- or -S-; and R4 is (1) hydrogen or -C1-20 alkyl, unsubstituted or substituted with one or more of: (a) -OH, (b) halo, (c) -C1-8 alkoxy, (d) -C1-6 alkenyl, (e) -CONR5R5, wherein R5 is independently (i) -H, (ii) -C1-8 alkyl unsubstituted or substituted with one or more of R7, aryl or heterocycle, the aryl being unsubstituted or substituted with one or more of R7 or R9, (iii) aryl unsubstituted or substituted with one or more of R7 or R9, or (iv) heterocycle, unsubstituted or substituted with one or more of R7 or R9, (f) -COOR6, wherein R6 is (i) -H, (ii) -C1-8 alkyl unsubstituted or substituted with one or more of R7 or aryl, the aryl being unsubstituted or substituted with one or more of R7 or R9, or (iii) aryl, unsubstituted or substituted with one or more of R7 or R9, (g) -S(O)p-R5, wherein p is zero, 1 or 2; (h) -N(R5)2, (i) aryl, unsubstituted or substituted with one or more of aryl, R7 or R9, (j) heterocycle, unsubstituted or substituted with one or more of R7 or R9, (k) -C3-10 cycloalkyl, such as cyclohexyl, norbornyl, or adamantyl, unsubstituted or substituted with one or more of R7 or R9, or (l) -CONR8-CO-NHR8, wherein R8 is -H, -C1-8 alkyl, benzyl or cyclohexyl, (2) aryl, unsubstituted or substituted with one or more of aryl, R7 or R9, (3) heterocycle or -C3-10 cycloalkyl, either of which is unsubstituted or substituted with one or more of R7 or R9, (4) -NR5R5, or (5) -OR5; R7 is (1) -OH, (2) -C1-3 alkoxy, (3) -CN, (4) -COOR6, (5) -C1-8 alkyl-COOR6, (6) -NO2, or (7) halo; and (8) amino, mono C1-C4 alkylamino, di C1-C4 alkylamino; R9 is (1) -C1-8 alkyl, unsubstituted or substituted with one or more of aryl or R7, (2) -CO-A, -C1-8 alkyl-CO-A, -NHCO-A, or -S(O)p-A, wherein p is defined above and A is (a) -H, (b) -C1-8 alkyl, unsubstituted or substituted with one or more of (i) -R7, or (ii) aryl, unsubstituted or substituted with one or more of R7, or (c) aryl, unsubstituted or substituted with one or more of R7, (3) -NHCO-heterocycle, (4) -N(R10)2 or -CON(R10)2 wherein R10 is independently, heterocycle or -A, (5) -NHCO-(CH2)q-CO-Q, wherein q is 1-4, and Q is -N(R10)2 or -OR10; with the provisos that when Z is beta- methyl, the following are excluded: when n is 1-12, R1 is -H at each occurrence, X is -O-, and R4 is -C1-6 alkyl, R4 is not substituted with an unsubstituted phenyl ring; when n is 1-12, R1 is -H at each occurrence, and X is -O-, R4 is not unsubstituted C5-10 cycloalkyl, unsubstituted phenyl, amino, -C1-8 alkyl substituted amino, or -C1-8 alkoxy; and when n is zero, R4 is not -CH3; and (IVA), where A is: (a) R2 R4N-W-R3 (b) R2W-R3 N except when Z is beta methyl R2 equals H, the 5aH is present, W equals C(O), and R3 cannot be C1-12 alkyl, (c) R5R2 R4(CH)x N-W-R3; wherein R2 is: H, methyl or ethyl; R3 is: H, mono C1-C4 alkylaminoaryl, di C1-C4 alkylaminoaryl, C1-20 alkyl, C6-C14 aryl, heteroaryl, as defined below, C6-C14 aryl C1-20 alkyl, heteroaryl C1-20 alkyl, C1-20 alkylthio C1-20 alkyl, C1-20 alkylsulfonyl C1-20 alkyl, carboxyl C1-20, C1-20 alkylcarbonyl C1-20 alkyl, C3-20 cycloalkyl, C3-20 cycloalkyl C1-20 alkyl, C6-C14 aryl C1-20 alkyloxycarbonyl C1-20 alkyl, heteroaryl C1-20 alkyloxycarbonyl C1-20 alkyl, halo C1-20 alkyl, hydroxyl C1-20 alkyl, thiosulfato C1-20 alkyl, C6-C14 aryl C1-20 alkyloxy C1-20 alkyl, C1-20 alkyloxy C1-20 alkyl, arylcarbonylaryl C1-20 alkyl, diaryl C1-20 alkyl, triaryl C1-20 alkyl, C2-20 alkenyl, C2-20 alkenyl C1-20 alkyl, heteroaryl C2-20 alkenyl, aryl C2-20 alkenyl, C2-20 alkynyl C1-20 alkyl, aryl C2-20 alkynyl C1-20 alkyl, or heteroaryl C2-20 alkynyl C1-20 alkyl; R4 is: H, C1-20 alkyl, C6-14 aryl or heteroaryl; R5 can be the same or different when X is greater than 1 and is: H, or C1-20 alkyl; W is: O -C-, or O -S-, O x is an integer from 1-25; (VA), where: A is: R2YR6 (a) R4NC XR3 YR6 (b) R2CXR3 N except when Z is beta methyl, R2 equals H, Y equals O, X equals N and the 5aH is present, R6 and R3 can not be independently selected from H, C1-8 alkyl, C3-6 cycloalkyl, phenyl and R6 and R3 cannot be taken together with the adjacent N to form a 5-6 membered ring comprising up to one other heteroatom selected from O or N, or (c) R5R2YR6 R4(CH)x-N-C-X-R3; wherein R2 is: H, or C1-20 alkyl; R3 is: H, amino, mono C1-C4 alkylamino, di C1-C4 alkylamino, mono C1-C4 alkylaminoaryl, di C1-C4 alkylaminoaryl, C1-20 alkyl, C6-C14 aryl, heteroaryl, C6-C14 aryl C0-20 alkyl, C3-20 cycloalkyl, C3-20 cycloalkyl C1-20 alkyl, heteroaryl C1-20 alkyl, C2-20 alkenyl C1-20 alkyl, halo C1-20 alkyl, C1-20 alkyloxycarbonyl, C1-20 alkyl, C1-20 alkyloxy C1-20 alkyl, carboxy C1-20 alkyl, C6-14 arylcarbonylaryl C1-20 alkyl, C1-20 alkylcarbonyl C1-20 alkyl, C6-14 aryl C1-20 alkyloxycarbonyl C1-20 alkyl, hydroxyl C1-20 alkyl, halohydroxyl C1-20 alkyl, aryl C1-20 alkyloxy C1-20 alkyl, heteroaryl C1-