Patent EA-004886-B1 (EA)
Title: Glucocorticoid receptor modulators
Inventor: DOW ROBERT LEE
IPC: C07C35/42
Filed: 2000-03-27
Abstract: 1. A compound of formula I an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is phenyl, unsubstituted or substituted with one of the following substituents: -OH, -NR12R13, -NR12-C(O)-(C1-C4)alkyl, -CN, -(C0-C2)alkyl-het, -O-(C1-C3)alkyl-C(O)-NR12R13, NR12-(C0-C2)alkyl-C(O)-NR12R13, -(C0-C2)alkyl-NR12-SO2-R13, -NR12-SO2-het, -O-C(O)-(C1-C4)alkyl or -O-SO2-(C1-C4)alkyl; R2 is -OH; R3 is a) -(C1-C6)alkyl, unsubstituted or substituted with one of the following substituents: -CF3, -CN, -(C3-C6)cycloalkyl, phenyl or -N3, b) -C [triple bond] C-, substituted with one of the following substituents: -(C1-C5)alkyl, Cl, -CF3, (C3-C6)cycloalkyl, phenyl or benzyl, c) -CH2OH, d) -CH2O-(C1-C5)alkyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, e) CH2O-(C2-C5)alkenyl, f) CH2O-(C2-C5)alkynyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, g) -CH2ORy, h) -CN or i) -CF3; wherein Ry is a) -(C1-C3)alkyl-CF3, b) -(C3-C6)cycloalkyl, c) phenyl or d) benzyl; R10 is -C(O)-NH-Z-het; het is a 5-, 6 or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and substituted with 0 to 3 Rx; Rx is for each occurrence is independently a) -halo, b) -OH, c) -(C1-C8)alkyl, d) -(C2-C6)alkenyl, e) -O(C2-C6)alkynyl, f) -O(C1-C6)alkyl, g) -O(C2-C6)alkenyl, h) -(C2-C6)alkynyl, i) -(C0-C6)alkyl-NR12R13, j) -C(O)-NR12R13, k) -Z-SO2R12, l) -(C0-C2)alkyl-SOR12, m) -(C0-C2)alkyl-SR12, n) -NR12SO2R13, o) -NR12-C(O)-R13, p) -NR12-OR13, q) -SO2-NR12R13, r) -CN, s) -CF3, t) -C(O)(C1-C6)alkyl, u) =O or v) -(C0-C6)alkyl SO2-phenyl; Z is (C1-C6)alkyl; R12 and R13 are independently a) -H or b) -(C1-C6)alkyl. 2. A compound according to claim 1 of formula II: an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is phenyl, unsubstituted or substituted with one of the following substituents: -OH, -NR12R13, -NR12-C(O)-(C1-C4)alkyl, -CN, -(C0-C2)alkyl-het, -O-(C1-C3)alkyl-C(O)-NR12R13, NR12-(C0-C2)alkyl-C(O)-NR12R13, -(C0-C2)alkyl-NR12-SO2-R13, -NR12-SO2-het, -O-C(O)-(C1-C4)alkyl or, -O-SO2-(C1-C4)alkyl; R2 is -OH; R3 is a) -(C1-C6)alkyl, unsubstituted or substituted with one of the following substituents: -CF3, -CN, -(C3-C6)cycloalkyl, phenyl or -N3, b) -C [triple bond] C-, substituted with one of the following substituents: -(C1-C5)alkyl, Cl, -CF3, (C3-C6)cycloalkyl, phenyl or benzyl, c) -CH2OH, d) -CH2O-(C1-C5)alkyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, e) CH2O-(C2-C5)alkenyl, f) CH2O-(C2-C5)alkynyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, g) -CH2ORy, h) -CN or i) -CF3; wherein Ry is a) -(C1-C3)alkyl-CF3, b) -(C3-C6)cycloalkyl, c) phenyl or d) benzyl; R10 is -C(O)-NH-Z-het; het is selected from the group comprising a) pyridinyl, unsubstituted or substituted with methyl, b) pyrimidinyl, c) pyrazinyl, d) morphonyl, e) oxadiazolyl, f) pyrrolidinyl, g) piperidinyl and h) triazolyl; Z is (C1-C6)alkyl; R12 and R13 are independently a) -H or b) -(C1-C6)alkyl. 3. A compound according to claim 2 of formula II: an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is phenyl, unsubstituted or substituted with one of the following substituents: -OH, -NR12R13, -NR12-C(O)-(C1-C4)alkyl, -CN, -(C0-C2)alkyl-het, -O-(C1-C3)alkyl-C(O)-NR12R13, NR12-(C0-C2)alkyl-C(O)-NR12R13, -(C0-C2)alkyl-NR12-SO2-R13, -NR12-SO2-het, -O-C(O)-(C1-C4)alkyl or -O-SO2-(C1-C4)alkyl; het is selected from the group comprising a) pyridinyl, unsubstituted or substituted with methyl, b) pyrimidinyl, c) pyrazinyl, d) morphonyl, e) oxadiazolyl, f) pyrrolidinyl, g) piperidinyl and h) triazolyl; R2 is -OH; R3 is a) -(C1-C6) alkyl, unsubstituted or substituted with one of the following substituents: -CF3, -CN, -(C3-C6)cycloalkyl, phenyl or -N3, b) -C [triple bond] C-, substituted with one of the following substituents: -(C1-C5)alkyl, Cl, -CF3, (C3-C6)cycloalkyl, phenyl or benzyl, c) -CH2OH, d) -CH2O-(C1-C5)alkyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, e) CH2O-(C2-C5)alkenyl, f) CH2O-(C2-C5)alkynyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, g) -CH2ORy, h) -CN or i) -CF3; wherein Ry is a) -(C1-C3)alkyl-CF3, b) -(C3-C6)cycloalkyl, c) phenyl or d) benzyl; R10 is -C(O)NH-Z-het, wherein het is selected from the group comprising a) pyridinyl, unsubstituted or substituted with methyl, b) pyrimidinyl, c) pyrazinyl, d) morphonyl and e) oxadiazolyl; Z is (C1-C6)alkyl; R12 and R13 are independently a) -H or b) -(C1-C6)alkyl. 4. A compound according to claim 3 of formula II: an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is phenyl, unsubstituted or substituted with one of the following substituents: -OH, -NR12R13, -NR12-C(O)-(C1-C4)alkyl, -CN, -(C0-C2)alkyl-het, -O-(C1-C3)alkyl-C(O)-NR12R13, NR12-(C0-C2)alkyl-C(O)-NR12R13, -(C0-C2)alkyl-NR12-SO2-R13, -NR12-SO2-het, -O-C(O)-(C1-C4)alkyl or, -O-SO2-(C1-C4)alkyl; R2 is -OH; R3 is a) -(C1-C6)alkyl, unsubstituted or substituted with one of the following substituents: -CF3, -CN, -(C3-C6)cycloalkyl, phenyl or -N3, b) -C [triple bond] C-, substituted with one of the following substituents: -(C1-C5)alkyl, Cl, -CF3, (C3-C6)cycloalkyl, phenyl or benzyl, c) -CH2OH, d) -CH2O-(C1-C5)alkyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, e) CH2O-(C2-C5)alkenyl, f) CH2O-(C2-C5)alkynyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be substituted with 1 oxygen atom, g) -CH2ORy, h) -CN or i) -CF3; wherein Ry is a) -(C1-C3)alkyl-CF3, b) -(C3-C6)cycloalkyl, c) phenyl or d) benzyl; R10 is -C (O) NH-Z-het, het is selected from the group comprising a) pyridinyl, unsubstituted or substituted with methyl, b) pyrimidinyl, c) pyrazinyl, d) morphonyl and e) oxadiazolyl; Z is (C1-C6)alkyl; R12 and R13 are independently a) -H or b) -(C1-C6)alkyl. 5. A compound according to claim 4 of formula II: an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is phenyl, unsubstituted or substituted with one of the following substituents: -OH, -NR12R13, -NR12-C(O)-(C1-C4)alkyl, -CN, -(C0-C2)alkyl-het, -O-(C1-C3)alkyl-C(O)-NR12R13, NR12-(C0-C2)alkyl-C(O)-NR12R13, -(C0-C2)alkyl-NR12-SO2-R13, -NR12-SO2-het, -O-C(O)-(C1-C4)alkyl or, -O-SO2-(C1-C4)alkyl; R2 is -OH; R3 is a) -(C1-C6) alkyl, unsubstituted or substituted with -CF3, b) -C [triple bond] C-CH3, c) -C [triple bond] C-Cl, d) C [triple bond] C-CF3, e) -CH2O(C1-C3)alkyl, unsubstituted or substituted with -CF3 or f) -CF3; R10 is -C (O) NH-Z-het, het is selected from the group comprising a) pyridinyl, unsubstituted or substituted with methyl, b) pyrimidinyl, c) pyrazinyl, d) morphonyl and e) oxadiazolyl; Z is (C1-C6)alkyl; R12 and R13 are independently a) -H or b) -(C1-C6)alkyl. 6. A compound according to claim 5 of formula II: an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is phenyl; R2 is -OH; R3 is a) -(C1-C6) alkyl, unsubstituted or substituted with -CF3, b) -C [triple bond] C-CH3, c) -C [triple bond] C-Cl, d) C [triple bond] C-CF3, e) -CH2O(C1-C3)alkyl, unsubstituted or substituted with -CF3 or f) -CF3; R10 is -C(O)NH-Z-het, het is selected from the group comprising a) pyridinyl, unsubstituted or substituted with methyl, b) pyrimidinyl, c) pyrazinyl, d) morphonyl and e) oxadiazolyl; Z is (C1-C6)alkyl. 7. A compound according to claim 6 of formula III: an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R3 is a) -(C1-C6) alkyl, unsubstituted or substituted with -CF3, b) -C [triple bond] C-CH3, c) -C [triple bond] C-Cl, d) C [triple bond] C-CF3, e) -CH2O(C1-C3)alkyl, unsubstituted or substituted with -CF3 or f) -CF3. 8. A compound of claim 7 selected from the group consisting of: 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4(phenylmethyl)-7-(1-propynyl)-N-(4-pyridinylmethyl)-,[4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4(phenylmethyl)-7-(1-propynyl)-N-(2-pyridinylmethyl)-, [4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4(phenylmethyl)-7-(1-propynyl)-N-(3-pyridinylmethyl)-,[4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-, [4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9, 10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl) methyl]-4b-(phenylmethyl)-7-propyl-, [4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-N-(2-pyridinylmethyl)-, [4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-N-(4-pyridinylmethyl)-, [4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-N-(3-pyridinylmethyl)-, [4bS-(4balpha, 7alpha, 8abeta)]-; 2-phenanthrenecarboxamide, 4b, 5,6,7,8,8a, 9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(3,3-trifluoropropyl)-, [