Patent ID: 6380207
Filing Date: 2002-04-30
Classification: A61P,C07D

Abstract:
A method of selectively modulating the activation, repression, agonism, and antagonism effects of the glucocorticoid receptor and not progesterone, androgen, estrogen, or mineralocorticoid receptors, in a mammal comprising administering an effective amount of a compound of the Formula; or pharmaceutically acceptable salts, and a pharmaceutical carrier, where the symbolâ€”represents a single or double bond, provided that no two double bonds are in adjacent positions;R1, R2, R3, and R4 are each independently hydrogen, or E; or R1 and R2 together are â€”X*â€”Y*â€”Z*â€” where X* is â€”Oâ€” or â€”CH2â€”, Y* is â€”C(O)â€” or â€”(C(R12)(R13))vâ€” where R12 and R13 are independently hydrogen or alkyl of one to twelve carbons and v is 1, 2, or 3, and Z* is selected from â€”CH2â€”, â€”CH2S(O)tâ€” where t is 0, 1, or 2,â€”CH2Oâ€”, â€”CH2NR7â€”, â€”NR7â€”, and â€”Oâ€”;where E is â€”LEâ€”RE where LE is selected from(1) a covalent bond, (2) â€”Oâ€”, (3) â€”S(O)tâ€” where t is 0, 1, or 2, (4) â€”C(X)â€”, where X as used herein is selected from O or S, (5) â€”NR7â€” where R7 is selected from (a) hydrogen, (b) aryl, (c) cycloalkyl of three to twelve carbons, (d) alkanoyl where the alkyl part is one to twelve carbons, (e) alkoxycarbonyl where the alkyl part is one to twelve carbons, (f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups, (g) alkyl of one to twelve carbons, (h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (j) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (6) â€”NR8C(X)NR9â€” where R8 and R9 are independently selected from (a) hydrogen, (b) aryl, (c) cycloalkyl of three to twelve carbons, (d) alkyl of one to twelve carbons, (e) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons, (f) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (g) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (7) â€”Xâ€²C(X)â€”, where Xâ€² as used herein is selected from O or S, (8) â€”C(X)Xâ€²â€”, (9) â€”Xâ€²C(X)Xâ€³â€”, where Xâ€³ as used herein is selected from O or S, provided that when X is O, at least one of Xâ€² or Xâ€³ is O, (10) â€”NR8C(X)â€”, (11) â€”C(X)NR8â€”, (12) â€”NR8C(X)Xâ€²â€”, (13) â€”Xâ€²C(X)NR8â€”, (14) â€”SO2NR8â€”, (15) â€”NR8SO2â€”, and (16) â€”NR8SO2N9â€”where (6)-(16) are drawn with their right ends attached to RE and, RE is selected from (1) â€”OH, (2) â€”OG where G is a â€”OH protecting group, (3) â€”SH, (4) â€”CN (5) halo, (6) haloalkoxy of one to twelve carbons, (7) perfluoroalkoxy of one to twelve carbons, (8) â€”CHO, (9) â€”NR7R7, where R7 is defined previously and, R7, is selected from (a) hydrogen, (b) aryl, (c) cycloalkyl of three to twelve carbons, (d) alkanoyl where the alkyl part is one to twelve carbons, (e) alkoxycarbonyl where the alkyl part is one to twelve carbons, (f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups, (g) alkyl of one to twelve carbons, (h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (j) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (10) â€”C(X)NR8R9, (11) â€”OSO2R11 where R11 is selected from (a) aryl, (b) cycloalkyl of three to twelve carbons, (c) alkyl of one to twelve carbons, (d) alkyl of one to twelve carbons substituted with 1, 2, 3, or 4 halo substituents, and (e) perfluoroalkyl of one to twelve carbons, provided that when RE is (1)-(11), LE is a covalent bond, (12) alkyl of one to twelve carbons, (13) alkenyl of two to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to LE when LE is other than a covalent bond, (14) alkynyl of two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to LE when LE is other than a covalent bond, where (12), (13), and (14) can be optionally substituted with 1, 2, or 3 substituents independently selected from (a) alkoxy of one to twelve carbons, (b) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (c) â€”SH, provided that no two â€”SH groups are attached to the same carbon, (d) â€”CN, (e) halo, (f) â€”CHO, (g) â€”NO2, (h) haloalkoxy of one to twelve carbons, (i) perfluoroalkoxy of one to twelve carbons, (j) â€”NR7R7, (k) &boxH;NNR7R7â€², (l) â€”NR7NR7â€²R7â€³ where R7â€² and R7â€³ are defined previously and R7â€³ is selected from (i) hydrogen, (ii) aryl, (iii) cycloalkyl of three to twelve carbons, (iv) alkanoyl where the alkyl part is one to twelve carbons, (v) alkoxycarbonyl where the alkyl part is one to twelve carbons, (vi) alkoxycarbonyl where the alkyl part is one to twelve carbons substituted by 1 or 2 aryl groups, (vii) alkyl of one to twelve carbons, (viii) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons, (ix) alkenyl of three to twelve carbons, provided that a carbon-carbon double bond is not attached directly to nitrogen, and (x) alkynyl of three to twelve carbons, provided that a carbon-carbon triple bond is not attached directly to nitrogen, (m) â€”CO2R10 where R10 is selected from (i) aryl, (ii) aryl substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (iii) cycloalkyl of three to twelve carbons, (iv) alkyl of one to twelve carbons, and (v) alkyl of one to twelve carbons substituted with aryl or cycloalkyl of three to twelve carbons, (n) â€”C(X)NR8R9, (o) &boxH;Nâ€”OR10, (p) &boxH;NR10, (q) â€”S(O)tR10, (r) â€”Xâ€²C(X)R10, (s) (&boxH;X), and (t) â€”OSO2R11, (15) cycloalkyl of three to twelve carbons, (16) cycloalkenyl of four to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to LE when LE is other than a covalent bond, where (15) and (16) can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from (a) alkyl of one to twelve carbons, (b) aryl, (c) alkoxy of one to twelve carbons, (d) halo, and (e) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (17) perfluoroalkyl of one to twelve carbons, (18) aryl, and (19) heterocycle where (18) and (19) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (a) alkyl of one to twelve carbons, (b) alkanoyloxy where the alkyl part is one to twelve carbons, (c) alkoxycarbonyl where the alkyl part is one to twelve carbons, (d) alkoxy of one to twelve carbons, (e) halo, (f) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (g) thioalkoxy of one to twelve carbons, (h) perfluoroalkyl of one to twelve carbons, (i) â€”NR7R7, (j) â€”CO2R10, (k) â€”OSO2R11, and (l) (&boxH;X); L2 is selected from (1) a covalent bond, (2) alkylene of one to twelve carbons, (3) alkylene of two to twelve carbons substituted with 1 or 2 substituents independently selected from (a) spiroalkyl of three to eight carbon atoms, (b) spiroalkenyl of five or eight carbon atoms, (c) oxo, (d) halo, and (e) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (4) alkynylene of two to twelve carbons, (5) â€”NR7â€”, (6) â€”C(X)â€”, (7) â€”Oâ€”, and (8) â€”S(O)tâ€”; and R5 is selected from(1) halo, (2) â€”C(&boxH;NR7)OR10, (3) â€”CN, provided that when R5 is (1), (2), or (3), L2 is a covalent bond, (4) alkyl of one to twelve carbons, (5) alkynyl of two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to L2 when L2 is other than a covalent bond, (6) cycloalkyl of three to twelve carbons, (7) heterocycle, (8) aryl where (4)-(8) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (a) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (b) â€”SH, provided that no two â€”SH groups are attached to the same carbon, (c) â€”CN, (d) halo, (e) â€”CHO, (f) â€”NO2, (g) haloalkoxy of one to twelve carbons, (h) perfluoroalkoxy of one to twelve carbons, (i) â€”NR8â€²R9â€², where R8â€² and R9â€² are selected from (i) hydrogen, (ii) alkanoyl where the alkyl part is one to twelve carbons, (iii) alkoxycarbonyl where the alkyl part is one to twelve carbons, (iv) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted with 1 or 2 phenyl substituents, (v) cycloalkyl of three to twelve carbons, (vi) alkyl of one to twelve carbons, (vii) alkyl of one to twelve carbons substituted with 1, 2, or 3 substituents independently selected from alkoxy of one to twelve carbons, cycloalkyl of three to twelve carbons, and aryl, (viii) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not directly attached to nitrogen, (ix) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not directly attached to nitrogen, (x) aryl, (xi) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, alkanoyloxy where the alkyl part is one to twelve carbons, alkoxycarbonyl where the alkyl part is one to twelve carbons, alkoxy of one to twelve carbons, halo, â€”OH provided that no two â€”OH groups are attached to the same carbon, thioalkoxy of one to twelve carbons, perfluoroalkyl of one to twelve carbons, â€”NR7R7â€², â€”CO2R10, â€”OSO2R11, and (&boxH;X), or R8â€² and R9â€² together with the nitrogen atom to which they are attached form a ring selected from (i) aziridine, (ii) azetidine, (iii) pyrrolidine, (iv) piperidine, (v) pyrazine, (vi) morpholine, (vii) thiomorpholine, and (viii) thiomorpholine sulfone where (i)-(viii) can be optionally substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (j) &boxH;NNR8â€²R9â€², (k) â€”NR7NR8â€²R9â€², (l) â€”CO2R8, (m) â€”C(X)NR8â€²,R9â€². (n) &boxH;Nâ€”OR8, (o) &boxH;NR8, (p) â€”S(O)tR10, (q) â€”Xâ€²C(X)R8, (r) (&boxH;X), (s) â€”Oâ€”(CH2)qâ€”Zâ€”R10 where R10 is defined previously, q is 1, 2, or 3, and Z is O or â€”S(O)tâ€”, (t) â€”OC(X)NR8â€²R9â€², (u) â€”OSO2R11, (v) alkanoyloxy where the alkyl group is one to twelve carbons, (w) â€”LBR30 where LB is selected from (i) a covalent bond, (ii) â€”Oâ€”, (iii) â€”S(O)2â€”, and (iv) â€”C(X)â€” and R30 is selected from (i) alkyl of one to twelve carbons, (ii) alkenyl of two to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to LB when LB is other than a covalent bond, (iii) alkynyl of two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to LB when LB is other than a covalent bond, where (i), (ii), and (iii) can be optionally substituted with cycloalkyl of three to twelve carbons, â€”OH, provided that no two â€”OH groups are attached to the same carbon, aryl, and heterocycle, (iv) aryl, (v) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo, â€”NO2, and â€”OH, provided that no two â€”OH groups are attached to the same carbon, (vi) heterocycle, and (vii) heterocycle substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo, â€”NO2, and â€”OH, provided that no two â€”OH groups are attached to the same carbon, (x) â€”Xâ€²C(X)Xâ€³R10, (y) â€”C(&boxH;NR7)OR10, and (z) â€”NR7(X)NR8â€²R9â€², (9) provided that when R5 is (9), LB is other than â€”NR7â€” or â€”Oâ€”, where the carbon-carbon double bond is the Z or E configuration, and R19, R20, and R21 are independently selected from (a) hydrogen, (b) halo, (c) alkyl of one to twelve carbons, and (d) alkyl of one to twelve carbons substituted with (i) alkoxy of one to twelve carbons, (ii) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (iii) â€”SH, provided that no two â€”SH groups are attached to the same carbon, (iv) â€”CN, (v) halo, (vi) â€”CHO, (vii) â€”NO2, (viii) haloalkoxy of one to twelve carbons, (ix) perfluoroalkoxy of one to twelve carbons, (x) â€”NR8â€²R9â€², (xi) &boxH;NNR8â€²R9â€², (xii) â€”NR7NR8â€²R9â€², (xiii) â€”CO2R10, (xiv) â€”C(X)NR8â€²R9â€², (xv) &boxH;Nâ€”OR10, (xvi) &boxH;NR10, (xvii) â€”S(O)tR10, (xviii) â€”Xâ€²C(X)R10, (xix) (&boxH;X), (xx) â€”Oâ€”(CH2)qâ€”Zâ€”R10, (xxi) â€”OC(X)NR8â€²R9â€², (xxii) â€”LBR30, (xxiii) alkanoyloxy where the alkyl group is one to twelve carbons, (xxiv) â€”OSO2R11, and (xxv) â€”NR7(X)NR8â€²R9â€² or R20 and R21 together are selected from (a) cycloalkyl of three to twelve carbon atoms, (b) cycloalkenyl of four to twelve carbon atoms, and where R22 and R23 are independently hydrogen or alkyl of one to twelve carbons, and, (10) cycloalkenyl of four to twelve carbons where the cycloalkenyl group or the ring formed by R20 and R21 together can be optionally substituted with one or two substituents independently selected from (a) alkoxy of one to twelve carbons, (b) â€”OH, provided that no two â€”OH groups are attached to the same carbon, (c) â€”SH, provided that no two â€”SH groups are attached to the same carbon, (d) â€”CN, (e) halo, (f) â€”CHO, (g) â€”NO2, (h) haloalkoxy of one to twelve carbons, (i) perfluoroalkoxy of one to twelve carbons, (j) â€”NR8â€²R9â€², (k) &boxH;NNR8â€²R9â€², (l) â€”NR7NR8â€²R9â€², (m) â€”CO2R10, (n) â€”C(X)NR8â€²R9â€², (o) &boxH;Nâ€”OR10, (p) &boxH;NR10, (q) â€”S(O)tR10, (r) â€”Xâ€²C(X)R10, (s) (&boxH;X), (t) â€”Oâ€”(CH2)qâ€”Zâ€”R10, (u) â€”OC(X)NR8â€²R9â€², (v) â€”LBR30, (w) alkanoyloxy where the alkyl group is one to twelve carbons, (x) â€”OSO2R11, and (y) â€”NR7(X)NR8â€²R9â€², R6 is hydrogen or alkyl of one to twelve carbon atoms; or â€”L2â€”R5 and R6 together are â€ƒwhere d is 1, 2, 3, or 4 and A is selected from (a) â€”CH2â€”, (b) â€”Oâ€”, (c) â€”S(O)t, and (d) â€”NR7â€”, or where the carbon-carbon double bond can be in the E or Z configuration and R26 is selected from (a) aryl, (b) heterocycle, (c) alkyl of one to twelve carbons, (d) cycloalkyl of three to twelve carbons, (e) cycloalkenyl of four to twelve carbons, and (f) cycloalkenyl of four to twelve carbons where (a)-(f) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (i) alkoxy of one to twelve carbons, (ii) â€”OH, provided that no two â€”OH groups are attached to the sane carbon, (iii) â€”SH, provided that no two â€”SH groups are attached to the same carbon, (iv) â€”CN, (v) halo, (vi) â€”CHO, (vii) â€”NO2, (viii) haloalkoxy of one to twelve carbons, (ix) perfluoroalkoxy of one to twelve carbons, (x) â€”NR8â€²R9â€², (xi) &boxH;NNR8â€²R9â€², (xii) â€”NR7NR8â€²R9â€², (xiii) â€”CO2R10, (xiv) â€”C(X)NR8â€²R9â€², (xv) &boxH;Nâ€”OR10, (xvi) &boxH;NR10, (xvii) â€”S(O)tR10, (xviii) â€”Xâ€²C(X)R10, (xix) (&boxH;X), (xx) â€”Oâ€”(CH2)qâ€”Zâ€”R10, (xxi) â€”OC(X)NR8â€²R9â€², (xxii) â€”LBR30, (xxiii) alkanoyloxy where the alkyl group is one to twelve carbons, (xxiv) â€”OSO2R11, and (xxv) â€”NR7(X)NR8â€²R9â€².