Patent ID: 6506766
Filing Date: 2003-01-14
Classification: A61P,C07D

Abstract:
A pharmaceutical composition for use in selectively modulating the activation, repression, agonism, and antagonism effects of glucocorticoid receptors and not progesterone, androgen, estrogen, or mineralocorticoid receptors, in a mammal comprising an effective amount of a compound of the Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier, where the symbol, , represents a single bond or a double bond,R1 is â€”L1â€”RA where L1 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 is O or S, (5) â€”N(R7)â€” 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 (i) aryl and (ii) cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (j) alkynyl of three to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (6) â€”N(R8)C(X)N(R9)â€” where X is O or S and 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, â€ƒprovided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (g) alkynyl of three to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (7) â€”Xâ€²C(X)â€” where X is previously defined and Xâ€² is O or S, (8) â€”C(X)Xâ€²â€”, (9) â€”Xâ€²C(X)Xâ€³â€” where X and Xâ€² are previously defined and Xâ€³ is O or S, â€ƒprovided that when X is O, at least one of Xâ€² or Xâ€³ is O, (10) â€”N(R8)C(X)â€”, (11) â€”C(X)N(R8)â€”, (12) â€”N(R8)C(X)Xâ€²â€”, (13) â€”Xâ€²C(X)N(R8)â€”, (14) â€”SO2N(R8)â€”, (15) â€”N(R8)SO2â€”, and (16) â€”N(R8)SO2N(R9)â€”â€ƒwhere (6)-(16) are drawn with their right ends attached to RA, and RA is selected from (1) â€”OH, (2) â€”OG where G is a â€”OH protecting group, (3) â€”SH, (4) â€”CO2R20 where R20 is hydrogen or alkyl of one to twelve carbons, (5) alkoxylcarbonyl, (6) â€”CN, (7) halo, (8) haloalkoxy of one to twelve carbons, (9) perfluoroalkoxy of one to twelve carbons, (10) â€”CHO, (11) â€”NR7R7â€² where R7â€² is the same as defined for R7, (12) â€”C(X)NR8R9, (13) 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, â€ƒprovided that when RA is (1)-(13), L1 is a covalent bond, (14) alkyl of one to twelve carbons, (15) alkenyl of two to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon double bond is not attached directly to L1 when L1 is other than a covalent bond, (16) alkynyl of two to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon triple bond is not attached directly to L1 when L1 is other than a covalent bond, â€ƒwhere (14), (15), and (16) can be substituted with 1, 2, or 3 substituents independently selected from (a) alkoxy of one to twelve carbons, (b) â€”OH, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (c) â€”SH, (d) thioalkoxy of one to twelve carbons, â€ƒprovided that no two â€”SH groups are attached to the same carbon, (e) â€”CN, (f) halo, (g) â€”CHO, (h) â€”NO2, (i) haloalkoxy of one to twelve carbons, (j) perfluoroalkoxy of one to twelve carbons, (k) â€”NR7RR7, (1) &boxH;NNR7R7, (m) â€”NR7NR7â€²R7â€³ where R7â€³ is the same as defined for R7, (n) â€”CO2R10 where R10 is selected from (i) hydrogen, (ii) aryl, (iii) aryl substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (iv) cycloalkyl of three to twelve carbons, (v) alkyl of one to twelve carbons, and (vi) alkyl of one to twelve carbons substituted with aryl or cycloalkyl of three to twelve carbons, (o) â€”C(X)NR8R9, (p) &boxH;Nâ€”OR10, (q) &boxH;NR10, (r) â€”S(O)tR10, (s) â€”Xâ€²C(X)R10, (t) (&boxH;X), (u) â€”OSO2R11, and (v) aryl, (17) cycloalkyl of three to twelve carbons, (18) cycloalkenyl of four to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon double bond is not attached directly to L1 when L1 is other than a covalent bond, â€ƒwhere (17) and (18) can be 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, (e) alkoxycarbonyl where the alkyl group is one to twelve carbons, and (f) â€”OH, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (19) perfluoroalkyl of one to twelve carbons, (20) aryl, and (21) heterocycle â€ƒwhere (20) and (21) can be 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, â€ƒprovided 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€”NR7R7â€², (j) â€”CO2R10, (k) â€”OSO2R11, and (l) (&boxH;X); R2, R3, and R4 are independently hydrogen or R1; 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€”, â€”CH2Oâ€”, â€”CH2N(R7)â€”, â€”N(R7)â€”, and â€”Oâ€”; L2 is selected from (1) a covalent bond, (2) alkylene of one to twelve carbons, (3) alkylene of one 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, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (4) alkynylene of two to twelve carbons, (5) â€”N(R7)â€”, (6) â€”C(X)â€”, (7) â€”Oâ€”, and (8) â€”S(O)tâ€”; and R5 is selected from (1) halo, (2) hydrogen, (3) â€”C(&boxH;NR7)OR10, (4) â€”CN, â€ƒprovided that when R5 is (1), (2), or (3), L2 is a covalent bond, (5) alkyl of one to twelve carbons, (6) alkynyl two to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon triple bond is not attached directly to L2 when L2 is other than a covalent bond, (7) cycloalkyl of three to twelve carbons, (8) heterocycle, (9) aryl â€ƒprovided that when R5 is (9), L2 is other than â€”N(R7)â€” or â€”Oâ€”, and where (5)-(9) can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from (a) â€”OH, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (b) â€”SH, â€ƒprovided 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 I 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, aryl, and alkoxycarbonyl where the alkyl group is one to twelve carbons, (viii) alkenyl of three to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon double bond is not directly attached to nitrogen, (ix) alkynyl of three to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon triple bond is not directly attached to nitrogen, (x) â€”C(O)NRxRy where Rx and Ry are independently selected from hydrogen and alkyl of one to twelve carbons, (xi) alkoxy of one to twelve carbons, (xii) aryl, and (xiii) 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 -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 â€ƒR8â€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) phthalimide, (viii) thiomorpholine, and (ix) thiomorpholine sulfone â€ƒwhere (i)-(ix) can be substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (j) &boxH;NNR8â€²R9â€², (k) â€”N(R7)NR8â€²R9â€², (l) â€”CO2R8, (m) â€”C(X)NR8â€²R9â€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)tâ€”, and (iv) â€”C(X)â€” and â€ƒR30 is selected from (i) alkyl of one to twelve carbons, (ii) alkenyl of one to twelve carbons, â€ƒprovided 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 one to twelve carbons, â€ƒprovided that a carbon of a carbon-carbon triple bond is not attached directly to LB when LB is other than a covalent bond, â€ƒwhere (i), (ii), and (iii) can be substituted with cycloalkyl of three to twelve carbons, â€”OH, provided that no two â€”OH groups are attached to the same carbon, halo, alkoxy of one to twelve carbons, thioalkoxy of one to twelve carbons, â€”NR8â€²R9â€², â€”Oâ€”(CH2)qâ€”Zâ€”R10, alkoxycarbonyl where the alkyl group is one to twelve carbons, alkanoyloxy where the alkyl group is one to twelve carbons, â€”N(R7)SO2-(alkyl of one to twelve carbons), â€”OSO2-(alkyl of one to twelve carbons), 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€”N(H)C(O)N(H)NH2, (z) alkenyl of two carbons, (aa) â€”C(&boxH;NR7)OR10, and (bb) â€”N(R7)C(X)NR8â€²R9â€², (10) â€ƒwhere the carbon-carbon double bond is in the Z or E configuration, and R19, R20, and R21, are independently selected from (a) hydrogen, (b) halo, (c) alkoxycarbonyl where the alkyl group is of one to twelve carbons, (d) alkyl of one to twelve carbons, and (e) alkyl of one to twelve carbons substituted with (i) alkoxy of one to twelve carbons, (ii) â€”OH, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (iii) â€”SH, â€ƒprovided 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) â€”NNR8â€²R9â€², (xii) â€”N(R7)NR8â€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€”N(R7)C(X)NR8â€²R9â€², or â€ƒR20 and R21 together are selected from (a) cycloalkyl of three to twelve carbon atoms, (b) cycloalkenyl of four to twelve carbon atoms, and (c) â€ƒ(allene) where R22 and R23 are independently hydrogen or alkyl of one to twelve carbons, and (11) cycloalkenyl of four to twelve carbons â€ƒwhere the cycloalkenyl group or the ring formed by R20 and R21 together can be substituted with one or two substituents independently selected from (a) alkoxy of one to twelve carbons, (b) â€”OH, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (c) â€”SH, â€ƒprovided 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) â€”NNR8â€²R9â€², (l) â€”N(R7)NR8â€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€”N(R7)C(X)NR8â€²R9â€²; R6 is hydrogen or alkyl of one to twelve carbon atoms; or â€”L2â€”R5 and R6 together are selected from (1) &boxH;O, (2) 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€”N(R7)â€”, and (3) â€ƒwhere the carbon-carbon double bond can be in the E or Z configuration and R26 and R26â€² are independently selected from (a) hydrogen, (b) alkenyl of three to twelve carbons, (c) aryl, (d) heterocycle, (e) alkyl of one to twelve carbons, (e) cycloalkyl of three to twelve carbons, (g) cycloalkenyl of four to twelve carbons, and (h) cycloalkenyl of four to twelve carbons where (a)-(f) can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from (i) alkoxy of one to twelve carbons, (ii) â€”OH, â€ƒprovided that no two â€”OH groups are attached to the same carbon, (iii) â€”SH, â€ƒprovided 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€”N(R7)NR8â€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, (xxii) alkanoyloxy where the alkyl group is one to twelve carbons, (xxiii) â€”OSO2R11, and (xxiv) â€”N(R7)(X)NR8â€²R9â€²; R16 and R16â€² are independently hydrogen or alkyl of one to six carbons; or R16 and R16â€² together are &boxH;CH2; a broken line represents the optional presence of a double bond, provided that when R16 and R16â€² together are alkenyl of two carbons forming an exocyclic double bond, the endocyclic double bond is not present; Y is carbon; R17 is hydrogen or alkyl of one to six carbons; and R18 and R18â€² are independently hydrogen or alkyl of one to six carbons; or R18 and R18â€² together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons.