Non-steroidal ligands for the estrogen receptor

• US 5,877,219 A
• Filed: 06/18/1997
• Issued: 03/02/1999
• Est. Priority Date: 04/25/1994
• Status: Expired due to Term

• Current Assignee: Glaxo Wellcome Incorporated (GSK plc)
• Original Assignee: Glaxo Wellcome Incorporated (GSK plc)
• Inventors: Willson, Timothy Mark
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US08/877,665
• Time in Patent Office: 622 Days
• Field of Search: 564/181, 564/74, 564/265, 564/305, 514/617, 514/364, 514/599, 514/520, 514/532, 514/570, 514/640, 514/648, 544/176, 548/131, 558/401, 560/101, 562/491
• US Class Current: 514/617
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 211/28 having amino groups linked to the six-membered aromatic ring by unsaturated carbon chains
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/22 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/40 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/58 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 251/40 to carbon atoms of an unsaturated carbon skeleton
• CPC Class Codes: C07C 255/34 with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 327/44 to carbon atoms of an unsaturated carbon skeleton
• CPC Class Codes: C07C 327/48 having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 33/28 Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
• CPC Class Codes: C07C 45/45 : by condensation
• CPC Class Codes: C07C 45/59 : in five-membered rings from ozonides C07C45/40
• CPC Class Codes: C07C 47/548 : having unsaturation outside the six-membered aromatic rings
• CPC Class Codes: C07C 49/796 : polycyclic
• CPC Class Codes: C07C 57/42 : having unsaturation outside the rings
• CPC Class Codes: C07C 57/48 : having unsaturation outside the aromatic rings
• CPC Class Codes: C07C 69/618 : having unsaturation outside the six-membered aromatic ring
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07F 9/4006 : Esters of acyclic acids which can have further substituents on alkyl

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.

Claims

1. A compound of Formula I:

##STR12## wherein;

##STR13## R¹ is --(CH₂)_n CR⁵ ═

CR⁶ R⁷ !;

--(CH₂)_m C(X)NR⁸ R⁹ ;

or

R² and R³ are independently H, --CH₃, --OH, --OCH₃, --OCH₂ CH₃ or --CH₂ (CH₃)₂ !--CH(CH₃)₂ ;

R⁴ is --CN, --NO₂, --CH₃, --CH₂ CH₃, --CH₂ CH₂ --Y or --Y;

R⁵ and R⁶ are independently H, --C_1-4 alkyl, --C_2-4 alkenyl, --C_2-4 alkynyl, --X--C_1-3 alkyl, --X--C_2-4 alkenyl, --X--C_2-4 alkynyl or --Y;

R⁷ is --CN, --C_1-4 alkyl-OH, --C(O)O(CH₃)₃, --C(O)NR¹⁰ R¹¹, --C(O)NR¹² R¹³, --C_1-4 alkyl-NR¹⁰ R¹¹, --C(O)R¹², --C(O)OR¹², --C(O)NR¹² OR¹³, --C(O)NHC(O)R¹², --C(O)NHCH₂ R¹², --C(NH₂)(NOR¹²), --S(O)R¹², --S(O)(O)(OR¹²), --S(O)(O)(NHCO₂ R¹²), --PO₃ R¹², --P(O)(NR¹² R¹³)(NR¹² R¹³), --P(O)(NR¹² R¹³)(OR¹⁴), --CONR¹² (CH₂)_q OCH₃, --CONR¹² (CH₂)_q NR⁸ R⁹ or oxadiazole substituted with methyl;

R⁸ and R⁹ are independently hydrogen, --C_1-7 alkyl, --C_3-7 cycloalkyl, --O--C_1-7 alkyl, --C_1-7 alkyl-Y or phenyl;

R¹⁰ and R¹¹ are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;

R¹², R¹³ and R¹⁴ are independently H, --C_1-12 alkyl, --C_2-12 alkenyl, --C_2-12 alkynyl, --O--C_1-12 alkyl, --O--C_2-12 alkenyl, --O--C_2-12 alkynyl, --C_3-7 cycloalkyl, --C_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.

2. A compound according to claim 1 wherein the compound is selected from one of the following:

3- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!-N,N-diethyl propionamide; and

2- 4-(1,2-Diphenyl-but-1-enyl)-phenyl!cyclopropanecarboxylic acid diethylamide.

3. A method of treating a mammal for arthritic diseases which comprises administering to said mammal an effective amount of a compound according to claim 1.

4. A method of treating a mammal for breast cancer which comprises administering to said mammal an effective amount of a compound according to claim 1.

5. A method of treating a mammal for cardiovascular disease which comprises administering to said mammal an effective amount of a compound according to claim 1.

6. A method of preventing arthritic diseases in a mammal which comprises administering to said mammal an effective amount of a compound according to claim 1.

7. A method of preventing cardiovascular disease in a mammal which comprises administering to said mammal an effective amount of a compound according to claim 1.

13. A method of treating a mammal for osteoporosis comprising administering to said mammal an effective amount of a compound according to claim 1.

14. A method of preventing osteoporosis in a mammal comprising administering to said mammal an effective amount of a compound according to claim 1.

8. A method of treating a mammal for arthritic diseases which comprises administering to said mammal an effective amount of the compound:

##STR14## wherein;

R¹ is --(CH₂)_n CR⁵ ═

CR⁶ R⁷ ;

R² and R³ are independently H, --CH₃, --OH, --OCH₃, --OCH₂ CH₃ or --CH(CH₃)₂ ;

R⁴ is --CN, --NO₂, --CH₃, --CH₂ CH₃, --CH₂ CH₂ --Y or --Y;

R⁵ and R⁶ are independently H, --C_1-4 alkyl, --C_2-4 alkenyl, --C_2-4 alkynyl, --X--C_1-3 alkyl, --X--C_2-4 alkenyl, --X--C_2-4 alkynyl or --Y;

R⁷ is --CN, --C_1-4 alkyl-OH, --C(O)NR¹⁰ R¹¹,--C(O)NR¹² R¹³, --C_1-4 alkyl-NR¹⁰ R¹¹, --C(O)R¹², --C(O)OR¹², --C(O)NR¹² OR³, --C(O)NHC(O)R₁₂, --C(O)NHCH₂ R¹², --C(NH₂)(NOR¹²), --S(O)R¹², --S(O)(O)(OR¹²), --S(O)(O)(NHCO₂ R¹²), PO₃ R¹², --P(O)(NR¹² R¹³)(NR¹² R¹³), --P(O)(NR¹² R¹³)(OR¹⁴), --CONR¹² (CH₂)_q OCH₃, --CONR¹² (CH₂)_q NR⁸ R⁹ or oxadiazole substituted with methyl;

R⁸ and R⁹ are independently hydrogen, --C_1-7 alkyl, --C_3-7 cycloalkyl, --O--C_7-1 alkyl, --C_1-7 alkyl-Y or phenyl;

R¹⁰ and R¹¹ are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;

R¹², R¹³ and R¹⁴ are independently H, --C_1-2 alkyl, --C_2-12 alkenyl, --C_2-12 alkynyl, --O--C_1-12 alkyl, --O--C_2-12 alkenyl, --O--C_2-12 alkynyl, --C_3-7 cycloalkyl, --C_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.

9. A method of treating a mammal for breast cancer which comprises administering to said mammal an effective amount of the compound:

##STR15## wherein;

R¹ is --(CH₂)_n CR⁵ ═

CR⁶ R⁷ ;

R² and R³ are independently H, --CH₃, --OH, --OCH₃, --OCH₂ CH₃ or --CH(CH₃)₂ ;

R⁴ is --CN, --NO₂, --CH₃, --CH₂ CH₃, --CH₂ CH₂ --Y or --Y;

R⁵ and R⁶ are independently H, --C_4-1 alkyl, --C_2-4 alkenyl, --C_2-4 alkynyl, --X--C_1-3 alkyl, --X--C_2-4 alkenyl, --X--C_2-4 alkynyl or --Y;

R⁷ is --CN, --C_1-4 alkyl--OH, --C(O)NR¹⁰ R¹¹, --C(O)NR¹² R¹³, --C_1-4 alkyl-NR¹⁰ R¹¹, --C(O)R¹², --C(O)OR¹², --C(O)NR¹² OR¹³, --C(O)NHC(O)R¹², --C(O)NHCH₂ R¹², --C(NH₂)(NOR¹² ), --S(O)R¹², --S(O)(O)(OR¹²), --S(O)(O)(NHCO₂ R¹²), PO₃ R¹², --P(O)(NR¹² R¹³)(NR¹² R¹³), --P(O)(NR¹² R¹³)(OR¹⁴), --CONR¹² (CH₂)_q OCH₃, --CONR¹² (CH₂)_q NR⁸ R⁹ or oxadiazole substituted with methyl;

R⁸ and R⁹ are independently hydrogen, --C_1-7 alkyl, --C_3-7 cycloalkyl, --O--C_1-7 alkyl, --C_1-7 alkyl-Y or phenyl;

R¹⁰ and R¹¹ are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;

R¹², R¹³ and R¹⁴ are independently H, --C_1-12 alkyl, --C_2-12 alkenyl, --C_2-12 alkynyl, --O--C_1-12 alkyl, --O--C_2-12 alkenyl, --O--C_2-12 alkynyl, --C_3-7 cycloalkyl, --C_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. A method of treating a mammal for cardiovascular disease which comprises administering to said mammal an effective amount of the compound:

##STR16## wherein;

R¹ is --(CH₂)_n CR⁵ ═

CR⁶ R⁷ ;

R² and R³ are independently H, --CH₃, --OH, --OCH₃, --OCH₂ CH₃ or --CH(CH₃)₂ ;

R⁴ is --CN, --NO₂, --CH₃, --CH₂ CH₃, --CH₂ CH₂ --Y or --Y;

R⁵ and R⁶ are independently H, --C_1-4 alkyl, --C_2-4 alkenyl, --C_2-4 alkynyl, --X--C_1-3 alkyl, --X--C_2-4 alkenyl, --X--C_2-4 alkynyl or --Y;

R⁷ is --CN, --C_1-4 alkyl-OH, --C(O)NR¹⁰ R¹¹, --C(O)NR¹² R¹³, --C_1-4 alkyl-NR¹⁰ R¹¹, --C(O)R¹², --C(O)OR¹², --C(O)NR¹² OR¹³, --C(O)NHC(O)R¹², --C(O)NHCH₂ R¹², --C(NH₂)(NOR¹²), --S(O)R¹², --S(O)(O)(OR¹²), --S(O)(O)(NHCO₂ R¹²), PO₃ R¹², --P(O)(NR¹² R¹³)(NR¹² R¹³), --P(O)(NR¹² R¹³)(OR¹⁴), --CONR¹² (CH₂)_q OCH₃, --CONR¹² (CH₂)_q NR⁸ R⁹ or oxadiazole substituted with methyl;

R⁸ and R⁹ are independently hydrogen, --C_1-7 alkyl, --C_3-7 cycloalkyl, --O--C_1-7 alkyl, --C_1-7 alkyl-Y or phenyl;

R¹⁰ and R¹¹ are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;

R¹², R¹³ and R¹⁴ are independently H, --C_1-12 alkyl, --C_2-12 alkenyl, --C_2-12 alkynyl, --O--C_1-12 alkyl, --O--C_2-12 alkenyl, --O--C_2-12 alkynyl, --C_3-7 cycloalkyl, --C_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.

11. A method of preventing arthritic diseases in a mammal which comprises administering to said mammal an effective amount the compound:

##STR17## wherein;

R¹ is --(CH₂)_n CR⁵ ═

CR⁶ R⁷ ;

R² and R³ independently H, --CH₃, --OH, --OCH₃, --OCH₂ CH₃ or --CH(CH₃)₂ ;

R⁴ is --CN, --NO₂, --CH₃, --CH₂ CH₃, --CH₂ CH₂ --Y or --Y;

R⁵ and R⁶ independently H, --C_1-4 alkyl, --C_2-4 alkenyl, --C_2-4 alkynyl, --X--C_1-3 alkyl, --X--C_2-4 alkenyl, --X--C_2-4 alkynyl or --Y;

R⁷ is --CN, --C_1-4 alkyl-OH, --C(O)NR¹⁰ R¹¹, --C(O)NR¹² R¹³, --C_1-4 alkyl-NR¹⁰ R¹¹, --C(O)R¹², --C(O)OR¹², --C(O)NR¹² OR¹³, --C(O)NHC(O)R¹², --C(O)NHCH₂ R¹², --C(NH₂)(NOR¹²), --S(O)R¹², --S(O)(O)(OR¹²), --S(O)(O)(NHCO₂ R¹²), PO₃ R¹², --P(O)(NR¹² R¹³)(NR¹² R¹³), --P(O)(NR¹² R¹³)(OR¹⁴), --CONR¹² (CH₂)_q OCH₃, --CONR¹² (CH₂)_q NR⁸ R⁹ or oxadiazole substituted with methyl;

R⁸ and R⁹ are independently hydrogen, --C_1-7 alkyl, --C_3-7 cycloalkyl, --O--C_1-7 alkyl, --C_1-7 alkyl-Y or phenyl;

R¹⁰ and R¹¹ are independently methyl or ethyl or, taken together form a morpholino group bounded via its nitrogen atom;

R¹², R¹³ and R¹⁴ are independently H, --C_1-12 alkyl, --C_2-12 alkenyl, --C_2-12 alkynyl, --O--C_1-12 alkyl, --O--C_2-12 alkenyl, --O--C_2-12 alkynyl, --C_3-7 cycloalkyl, --C_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.

12. A method of preventing cardiovascular disease in a mammal which comprises administering to said mammal an effective amount the compound:

##STR18## wherein;

R¹ is --(CH₂)_n CR⁵ ═

CR⁶ R⁷ ;

R² and R³ are independently H, --CH₃, --OH, --OCH₃, --OCH₂ CH₃ or --CH(CH₃)₂ ;

R⁴ is --CN, --NO₂, --CH₃, --CH₂ CH₃, --CH₂ CH₂ --Y or --Y;

R⁵ and R⁶ are independently H, --C_1-4 alkyl, --C_2-4 alkenyl, --C_2-4 alkynyl, --X--C_1-3 alkyl, --X--C_2-4 alkenyl, --X--C_2-4 alkynyl or --Y;

R⁷ is --CN, --C_1-4 alkyl-OH, --C(O)NR¹⁰ R¹¹, --C(O)NR¹² R¹³, --C_1-4 alkyl-NR¹⁰ R¹¹, --C(O)R¹², --C(O)OR¹², --C(O)NR¹² OR¹³, --C(O)NHC(O)R¹², --C(O)NHCH₂ R¹², --C(NH₂)(NOR¹²), --S(O)R¹², --S(O)(O)(OR¹²), --S(O)(O)(NHCO₂ R¹²), PO₃ R¹², --P(O)(NR¹² R¹³)(NR¹² R¹³), --P(O)(NR¹² R¹³)(OR¹⁴), --CONR¹² (CH₂)_q OCH₃, --CONR¹² (CH₂)_q NR⁸ R⁹ or oxadiazole substituted with methyl;

R⁸ and R⁹ are independently hydrogen, --C_1-7 alkyl, --C_3-7 cycloalkyl, --O--C_1-7 alkyl, --C_1-7 alkyl-Y or phenyl;

R¹⁰ and R¹¹ are independently methyl or ethyl or, taken together form a morpholino group bonded via its nitrogen atom;

R¹², R¹³ and R¹⁴ are independently H, --C_1-12 alkyl, --C_2-12 alkenyl, --C_2-12 alkynyl, --O--C_1-12 alkyl, --O--C_2-12 alkenyl, --O--C_2-12 alkynyl, --C_3-7 cycloalkyl, --C_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.