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US 5,877,219 AGranted
Non-steroidal ligands for the estrogen receptor
AssigneeGlaxo WellcomeInc.
InventorTimothy Mark Willson
Life of this patent
Estimating the term…
Abstract
Described herein are non-steroidal ligands for the estrogen receptor which possess tissue-dependent estrogenic and antiestrogenic activity as well as methods for making the same and their applications in treating a variety of disease states.
Claims14
A compound of Formula I:
- ##STR12## wherein:
- ##STR13## R.sup.1 is --(CH.sub.2).sub.n CR.sup.5 .dbd.CR.sup.6 R.sup.7 !;
- --(CH.sub.2).sub.m C(X)NR.sup.8 R.sup.9 ;
- or
- R.sup.2 and R.sup.3 are independently H, --CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3 or --CH.sub.2 (CH.sub.3).sub.2 !--CH(CH.sub.3).sub.2 ;
- R.sup.4 is --CN, --NO.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 --Y or --Y;
- R.sup.5 and R.sup.6 are independently H, --C.sub.1-4 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --X--C.sub.1-3 alkyl, --X--C.sub.2-4 alkenyl, --X--C.sub.2-4 alkynyl or --Y;
- R.sup.7 is --CN, --C.sub.1-4 alkyl-OH, --C(O)O(CH.sub.3).sub.3, --C(O)NR.sup.10 R.sup.11, --C(O)NR.sup.12 R.sup.13, --C.sub.1-4 alkyl-NR.sup.10 R.sup.11, --C(O)R.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12 OR.sup.13, --C(O)NHC(O)R.sup.12, --C(O)NHCH.sub.2 R.sup.12, --C(NH.sub.2)(NOR.sup.12), --S(O)R.sup.12, --S(O)(O)(OR.sup.12), --S(O)(O)(NHCO.sub.2 R.sup.12), --PO.sub.3 R.sup.12, --P(O)(NR.sup.12 R.sup.13)(NR.sup.12 R.sup.13), --P(O)(NR.sup.12 R.sup.13)(OR.sup.14), --CONR.sup.12 (CH.sub.2).sub.q OCH.sub.3, --CONR.sup.12 (CH.sub.2).sub.q NR.sup.8 R.sup.9 or oxadiazole substituted with methyl;
- R.sup.8 and R.sup.9 are independently hydrogen, --C.sub.1-7 alkyl, --C.sub.3-7 cycloalkyl, --O--C.sub.1-7 alkyl, --C.sub.1-7 alkyl-Y or phenyl;
- R.sup.10 and R.sup.11 are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;
- R.sup.12, R.sup.13 and R.sup.14 are independently H, --C.sub.1-12 alkyl, --C.sub.2-12 alkenyl, --C.sub.2-12 alkynyl, --O--C.sub.1-12 alkyl, --O--C.sub.2-12 alkenyl, --O--C.sub.2-12 alkynyl, --C.sub.3-7 cycloalkyl, --C.sub.3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;
- X is oxygen or sulfur;
- Y is a halogen;
- n is an integer selected from 0, 1 and 2;
- m is the integer 1 or 2;
- p is an integer selected from 1 to 4;
- and
- q is an integer from 1-12.
15 more elements
A method of treating a mammal for arthritic diseases which comprises administering to said mammal an effective amount of the compound:
- ##STR14## wherein:
- R.sup.1 is --(CH.sub.2).sub.n CR.sup.5 .dbd.CR.sup.6 R.sup.7 ;
- R.sup.2 and R.sup.3 are independently H, --CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3 or --CH(CH.sub.3).sub.2 ;
- R.sup.4 is --CN, --NO.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 --Y or --Y;
- R.sup.5 and R.sup.6 are independently H, --C.sub.1-4 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --X--C.sub.1-3 alkyl, --X--C.sub.2-4 alkenyl, --X--C.sub.2-4 alkynyl or --Y;
- R.sup.7 is --CN, --C.sub.1-4 alkyl-OH, --C(O)NR.sup.10 R.sup.11,--C(O)NR.sup.12 R.sup.13, --C.sub.1-4 alkyl-NR.sup.10 R.sup.11, --C(O)R.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12 OR.sup.3, --C(O)NHC(O)R.sub.12, --C(O)NHCH.sub.2 R.sup.12, --C(NH.sub.2)(NOR.sup.12), --S(O)R.sup.12, --S(O)(O)(OR.sup.12), --S(O)(O)(NHCO.sub.2 R.sup.12), PO.sub.3 R.sup.12, --P(O)(NR.sup.12 R.sup.13)(NR.sup.12 R.sup.13), --P(O)(NR.sup.12 R.sup.13)(OR.sup.14), --CONR.sup.12 (CH.sub.2).sub.q OCH.sub.3, --CONR.sup.12 (CH.sub.2).sub.q NR.sup.8 R.sup.9 or oxadiazole substituted with methyl;
- R.sup.8 and R.sup.9 are independently hydrogen, --C.sub.1-7 alkyl, --C.sub.3-7 cycloalkyl, --O--C.sub.7-1 alkyl, --C.sub.1-7 alkyl-Y or phenyl;
- R.sup.10 and R.sup.11 are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;
- R.sup.12, R.sup.13 and R.sup.14 are independently H, --C.sub.1-2 alkyl, --C.sub.2-12 alkenyl, --C.sub.2-12 alkynyl, --O--C.sub.1-12 alkyl, --O--C.sub.2-12 alkenyl, --O--C.sub.2-12 alkynyl, --C.sub.3-7 cycloalkyl, --C.sub.3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;
- X is oxygen or sulfur;
- Y is a halogen;
- n is an integer selected from 0, 1 or 2;
- q is an integer from 1-12.
10 more elements
A method of treating a mammal for breast cancer which comprises administering to said mammal an effective amount of the compound:
- ##STR15## wherein:
- R.sup.1 is --(CH.sub.2).sub.n CR.sup.5 .dbd.CR.sup.6 R.sup.7 ;
- R.sup.2 and R.sup.3 are independently H, --CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3 or --CH(CH.sub.3).sub.2 ;
- R.sup.4 is --CN, --NO.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 --Y or --Y;
- R.sup.5 and R.sup.6 are independently H, --C.sub.4-1 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --X--C.sub.1-3 alkyl, --X--C.sub.2-4 alkenyl, --X--C.sub.2-4 alkynyl or --Y;
- R.sup.7 is --CN, --C.sub.1-4 alkyl--OH, --C(O)NR.sup.10 R.sup.11, --C(O)NR.sup.12 R.sup.13, --C.sub.1-4 alkyl-NR.sup.10 R.sup.11, --C(O)R.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12 OR.sup.13, --C(O)NHC(O)R.sup.12, --C(O)NHCH.sub.2 R.sup.12, --C(NH.sub.2)(NOR.sup.12 ), --S(O)R.sup.12, --S(O)(O)(OR.sup.12), --S(O)(O)(NHCO.sub.2 R.sup.12), PO.sub.3 R.sup.12, --P(O)(NR.sup.12 R.sup.13)(NR.sup.12 R.sup.13), --P(O)(NR.sup.12 R.sup.13)(OR.sup.14), --CONR.sup.12 (CH.sub.2).sub.q OCH.sub.3, --CONR.sup.12 (CH.sub.2).sub.q NR.sup.8 R.sup.9 or oxadiazole substituted with methyl;
- R.sup.8 and R.sup.9 are independently hydrogen, --C.sub.1-7 alkyl, --C.sub.3-7 cycloalkyl, --O--C.sub.1-7 alkyl, --C.sub.1-7 alkyl-Y or phenyl;
- R.sup.10 and R.sup.11 are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;
- R.sup.12, R.sup.13 and R.sup.14 are independently H, --C.sub.1-12 alkyl, --C.sub.2-12 alkenyl, --C.sub.2-12 alkynyl, --O--C.sub.1-12 alkyl, --O--C.sub.2-12 alkenyl, --O--C.sub.2-12 alkynyl, --C.sub.3-7 cycloalkyl, --C.sub.3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;
- X is oxygen or sulfur;
- Y is a halogen;
- n is an integer selected from 0, 1 and 2;
- q is an integer from 1-12.
10 more elements
A method of treating a mammal for cardiovascular disease which comprises administering to said mammal an effective amount of the compound:
- ##STR16## wherein:
- R.sup.1 is --(CH.sub.2).sub.n CR.sup.5 .dbd.CR.sup.6 R.sup.7 ;
- R.sup.2 and R.sup.3 are independently H, --CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3 or --CH(CH.sub.3).sub.2 ;
- R.sup.4 is --CN, --NO.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 --Y or --Y;
- R.sup.5 and R.sup.6 are independently H, --C.sub.1-4 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --X--C.sub.1-3 alkyl, --X--C.sub.2-4 alkenyl, --X--C.sub.2-4 alkynyl or --Y;
- R.sup.7 is --CN, --C.sub.1-4 alkyl-OH, --C(O)NR.sup.10 R.sup.11, --C(O)NR.sup.12 R.sup.13, --C.sub.1-4 alkyl-NR.sup.10 R.sup.11, --C(O)R.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12 OR.sup.13, --C(O)NHC(O)R.sup.12, --C(O)NHCH.sub.2 R.sup.12, --C(NH.sub.2)(NOR.sup.12), --S(O)R.sup.12, --S(O)(O)(OR.sup.12), --S(O)(O)(NHCO.sub.2 R.sup.12), PO.sub.3 R.sup.12, --P(O)(NR.sup.12 R.sup.13)(NR.sup.12 R.sup.13), --P(O)(NR.sup.12 R.sup.13)(OR.sup.14), --CONR.sup.12 (CH.sub.2).sub.q OCH.sub.3, --CONR.sup.12 (CH.sub.2).sub.q NR.sup.8 R.sup.9 or oxadiazole substituted with methyl;
- R.sup.8 and R.sup.9 are independently hydrogen, --C.sub.1-7 alkyl, --C.sub.3-7 cycloalkyl, --O--C.sub.1-7 alkyl, --C.sub.1-7 alkyl-Y or phenyl;
- R.sup.10 and R.sup.11 are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;
- R.sup.12, R.sup.13 and R.sup.14 are independently H, --C.sub.1-12 alkyl, --C.sub.2-12 alkenyl, --C.sub.2-12 alkynyl, --O--C.sub.1-12 alkyl, --O--C.sub.2-12 alkenyl, --O--C.sub.2-12 alkynyl, --C.sub.3-7 cycloalkyl, --C.sub.3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;
- X is oxygen or sulfur;
- Y is a halogen;
- n is an integer selected from 0, 1 and 2;
- q is an integer from 1-12.
10 more elements
A method of preventing arthritic diseases in a mammal which comprises administering to said mammal an effective amount the compound:
- ##STR17## wherein:
- R.sup.1 is --(CH.sub.2).sub.n CR.sup.5 .dbd.CR.sup.6 R.sup.7 ;
- R.sup.2 and R.sup.3 independently H, --CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3 or --CH(CH.sub.3).sub.2 ;
- R.sup.4 is --CN, --NO.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 --Y or --Y;
- R.sup.5 and R.sup.6 independently H, --C.sub.1-4 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --X--C.sub.1-3 alkyl, --X--C.sub.2-4 alkenyl, --X--C.sub.2-4 alkynyl or --Y;
- R.sup.7 is --CN, --C.sub.1-4 alkyl-OH, --C(O)NR.sup.10 R.sup.11, --C(O)NR.sup.12 R.sup.13, --C.sub.1-4 alkyl-NR.sup.10 R.sup.11, --C(O)R.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12 OR.sup.13, --C(O)NHC(O)R.sup.12, --C(O)NHCH.sub.2 R.sup.12, --C(NH.sub.2)(NOR.sup.12), --S(O)R.sup.12, --S(O)(O)(OR.sup.12), --S(O)(O)(NHCO.sub.2 R.sup.12), PO.sub.3 R.sup.12, --P(O)(NR.sup.12 R.sup.13)(NR.sup.12 R.sup.13), --P(O)(NR.sup.12 R.sup.13)(OR.sup.14), --CONR.sup.12 (CH.sub.2).sub.q OCH.sub.3, --CONR.sup.12 (CH.sub.2).sub.q NR.sup.8 R.sup.9 or oxadiazole substituted with methyl;
- R.sup.8 and R.sup.9 are independently hydrogen, --C.sub.1-7 alkyl, --C.sub.3-7 cycloalkyl, --O--C.sub.1-7 alkyl, --C.sub.1-7 alkyl-Y or phenyl;
- R.sup.10 and R.sup.11 are independently methyl or ethyl or, taken together form a morpholino group bounded via its nitrogen atom;
- R.sup.12, R.sup.13 and R.sup.14 are independently H, --C.sub.1-12 alkyl, --C.sub.2-12 alkenyl, --C.sub.2-12 alkynyl, --O--C.sub.1-12 alkyl, --O--C.sub.2-12 alkenyl, --O--C.sub.2-12 alkynyl, --C.sub.3-7 cycloalkyl, --C.sub.3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;
- X is oxygen or sulfur;
- Y is a halogen;
- n is an integer selected from 0, 1 and 2;
- q is an integer from 1-12.
10 more elements
A method of preventing cardiovascular disease in a mammal which comprises administering to said mammal an effective amount the compound:
- ##STR18## wherein:
- R.sup.1 is --(CH.sub.2).sub.n CR.sup.5 .dbd.CR.sup.6 R.sup.7 ;
- R.sup.2 and R.sup.3 are independently H, --CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3 or --CH(CH.sub.3).sub.2 ;
- R.sup.4 is --CN, --NO.sub.2, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 --Y or --Y;
- R.sup.5 and R.sup.6 are independently H, --C.sub.1-4 alkyl, --C.sub.2-4 alkenyl, --C.sub.2-4 alkynyl, --X--C.sub.1-3 alkyl, --X--C.sub.2-4 alkenyl, --X--C.sub.2-4 alkynyl or --Y;
- R.sup.7 is --CN, --C.sub.1-4 alkyl-OH, --C(O)NR.sup.10 R.sup.11, --C(O)NR.sup.12 R.sup.13, --C.sub.1-4 alkyl-NR.sup.10 R.sup.11, --C(O)R.sup.12, --C(O)OR.sup.12, --C(O)NR.sup.12 OR.sup.13, --C(O)NHC(O)R.sup.12, --C(O)NHCH.sub.2 R.sup.12, --C(NH.sub.2)(NOR.sup.12), --S(O)R.sup.12, --S(O)(O)(OR.sup.12), --S(O)(O)(NHCO.sub.2 R.sup.12), PO.sub.3 R.sup.12, --P(O)(NR.sup.12 R.sup.13)(NR.sup.12 R.sup.13), --P(O)(NR.sup.12 R.sup.13)(OR.sup.14), --CONR.sup.12 (CH.sub.2).sub.q OCH.sub.3, --CONR.sup.12 (CH.sub.2).sub.q NR.sup.8 R.sup.9 or oxadiazole substituted with methyl;
- R.sup.8 and R.sup.9 are independently hydrogen, --C.sub.1-7 alkyl, --C.sub.3-7 cycloalkyl, --O--C.sub.1-7 alkyl, --C.sub.1-7 alkyl-Y or phenyl;
- R.sup.10 and R.sup.11 are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;
- R.sup.12, R.sup.13 and R.sup.14 are independently H, --C.sub.1-12 alkyl, --C.sub.2-12 alkenyl, --C.sub.2-12 alkynyl, --O--C.sub.1-12 alkyl, --O--C.sub.2-12 alkenyl, --O--C.sub.2-12 alkynyl, --C.sub.3-7 cycloalkyl, --C.sub.3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or --Y;
- X is oxygen or sulfur;
- Y is a halogen;
- n is an integer selected from 0, 1 and 2;
- q is an integer from 1-12.
10 more elements
Dependencies are inferred from the claim text.