Cycloalkylidene Compounds As Selective Estrogen Receptor Modulators

Abstract

The present invention relates to compounds of formula (I) with a variety of therapeutic uses, more particularly the substituted cyclic alkylidene compounds are useful for selective estrogen receptor modulation.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         Including pharmaceutically acceptable salts thereof wherein 
         R 1  is H or F; 
         R 2  and R 4  each independently are selected from H, OH, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, or cyano; 
         R 3  is —(Y) z —R 8 ; 
         z is 0 or 1; 
         Y is —C≡C— or —CR e ═CR f —, 
         each R 5  is H; or 
         both R 5 s together combine to form a bridging alkylene chain —(CH 2 ) m —, where m is 2, 3, or 4, when each R 6  and each R 7  is H and X is —(CH 2 ) m-2 —; 
         each of R 6  and R 7  are selected from H or alkyl; or 
         when X is —(CH 2 ) m —, both R 6 s are H, and both R 7 s together combine to form a bridging alkylene chain —(CH 2 ) m —, where each m is the same and is as defined; or 
         when X is —(CH 2 ) m —, both R 7 s are H, and both R 6 s together combine to form a bridging alkylene chain —(CH 2 ) m —, where each m is the same and is as defined; 
         when z is 0, then R 8  is alkyl, alkenyl, alkynyl, alkoxy, aryl, heterocyclyl, heterocyclyl substituted with one or more alkyl, cyano, —O(CH 2 ) t CN, —CO 2 H, —(CH 2 ) t CO 2 H, —O(CH 2 ) t CO 2 H, —(CH 2 ) t OH, —O(CH 2 ) t OH, —O(CH 2 ) t O(CH 2 ) t OH, —C(O)NR a R b , —O(CH 2 ) t C(O)NR a R b ; —NR a SO 2 R d , or —NR a C(O)R c ; 
         when z is 1, then R 8  is, —CO 2 H, —(CH 2 ) t CO 2 H, —(CH 2 ) t OH, —C(O)NR a R b , or —PO 3 HR a ; 
         each t independently is 1 to 8; 
         X is —(CH 2 ) n — where n is 0, 1, 2, or 3, —C(R h ) 2 —, —O—, —S(O) p  where p is 0, 1, or 2, —C(R g ) 2 OC(R g ) 2 —, or —C(CH 2 ) v — where v is 2 to 7 and forms a spirocycle with the depicted ring that contains X; 
         R a  is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl; 
         R b  is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl; 
         R c  is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl; 
         R d  is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl; or 
         R a  and R b , R a  and R c , or R a  and R d  may combine with the atoms to which they are bound to form an optionally substituted heterocyclyl; and 
         R e  and R f  each are independently selected from H, alkyl, halogen, and haloalkyl; 
         R g  is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl; 
         R h  is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl; 
         wherein each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted. 
       
     
     
         2 . A compound of formula (I-A): 
       
         
           
           
               
               
           
         
         including pharmaceutically acceptable salts thereof wherein 
         R 1  is H or F; 
         R 3  is —(Y) z —R 8 ; 
         z is 0 or 1; 
         Y is —CH═CH—; 
         each of R 6  and R 7  are selected from H or alkyl; 
         when z is 0, then R 8  is heterocyclyl, heterocyclyl substituted with one or more alkyl, —O(CH 2 ) t CN, —CO 2 H, —(CH 2 ) t CO 2 H, —O(CH 2 ) t CO 2 H, —O(CH 2 ) t OH, —O(CH 2 ) t O(CH 2 ) t OH, or —O(CH 2 ) t C(O)NH 2 ; 
         when z is 1, then R 8  is —CO 2 H or —CONH 2 ; 
         each t independently is 1 to 8; and 
         X is —(CH 2 ) n —, where n is 0, 1, or 2, or O. 
       
     
     
         3 . A compound selected from:
 (2E)-3-{4-[Cycloheptylidene(phenyl)methyl]phenyl}prop-2-enoic acid;   (2E)-3-{4-[Cycloheptylidene(phenyl)methyl]phenyl}prop-2-enamide;   2-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethanol;   2-{[2-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;   ({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic acid;   4-({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic acid;   ({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetonitrile;   2-({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethanol;   (2E)-3-{4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid;   4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoic acid;   3,5-Dimethyl-4-{4-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}isoxazole;   1-Methyl-4-{4-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-1H-pyrazole;   4-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-3,5-dimethylisoxazole;   3-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}furan;   2-{[2-({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;   2-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}furan;   4-{4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-1-methyl-1H-pyrazole;   4-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-1-butanol;   2-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetamide;   ({2-Methyl-5-[phenyl (3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic acid;   2-({2-Methyl-5-[phenyl (3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethanol;   ({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetonitrile;   4-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic acid;   4-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-1-butanol;   5-[({2-Methyl-5-[phenyl (3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)methyl]-1H-tetrazole;   2-{[2-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;   4-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic acid;   ({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic acid;   (2E)-3-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid;   (2E)-3-{4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoic acid;   (2E)-3-{4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoic acid;   4-{4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}butanoic acid;   4-{4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}butanoic acid;   2-({4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethanol;   2-({4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethanol;   2-{[2-({4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;   2-{[2-({4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;   4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoic acid;   4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoic acid; and   4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoic acid,   including pharmaceutically acceptable salts thereof.   
     
     
         4 . The compound of  claim 1 : 
       
         
           
           
               
               
           
         
         including pharmaceutically acceptable salts thereof. 
       
     
     
         5 . The compound of  claim 1 : 
       
         
           
           
               
               
           
         
         including pharmaceutically acceptable salts thereof. 
       
     
     
         6 . (canceled) 
     
     
         7 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         8 . A compound according to  claim 1  for use as an active therapeutic substance. 
     
     
         9 . A compound according to  claim 1  for use in the treatment of conditions or disorders affected by selective estrogen receptor modulation. 
     
     
         10 . The compound of  claim 9  wherein treatment relates to osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochondrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age-related functional decline (“ARFD”), sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and ulcerative colitis, obesity, eating disorders including anorexia associated with cachexia or aging, hypercortisolism and Cushing's syndrome, cardiovascular disease or cardiac dysfunction, congestive heart failure, high blood pressure, breast cancer, malignant tumore cells containing the androgen receptor including breast, brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate, hyperinsulinemia, insulin resistance, diabetes, syndrome X, dyslipidemia, urinary incontinence, artherosclerosis, libido enhancement, sexual dysfunction, depression, depressive symptoms, nervousness, irritability, stress, reduced mental energy and low self-esteem, improvement of cognitive function, endometriosis, polycystic ovary syndrome, counteracting preeclampsia, premenstral syndrome, contraception, uterine fibroid disease, and/or aortic smooth muscle cell proliferation, vaginal dryness, pruritis, dyspareunia, dysuria, frequent urination, urinary tract infections, hypercholesterolemia, hyperlipidemia, peripheral vascular disease, restenosis, vasospasm, vascular wall damage due to immune responses, Alzheimer's disease, bone disease, aging, inflammation, rheumatoid arthritis, respiratory disease, emphysema, reperfusion injury, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, stroke, CNS trauma, dementia, neurodegeneration, breast pain and dysmenorrhea, menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, for enhancing libido, for the treatment of hypoactive sexual disorder, sexual arousal disorder, for increasing the frequency and intensity of orgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatic hypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto's thyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, or reperfusion damage of ischemic myocardium. 
     
     
         11 . The compound of  claim 10  wherein treatment relates to menopausal or postmenopausal disorders, -vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A method for the treatment related to osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochondrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age-related functional decline (“ARFD”), sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and ulcerative colitis, obesity, eating disorders including anorexia associated with cachexia or aging, hypercortisolism and Cushing's syndrome, cardiovascular disease or cardiac dysfunction, congestive heart failure, high blood pressure, breast cancer, malignant tumore cells containing the androgen receptor including breast, brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine, pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate, hyperinsulinemia, insulin resistance, diabetes, syndrome X, dyslipidemia, urinary incontinence, artherosclerosis, libido enhancement, sexual dysfunction, depression, depressive symptoms, nervousness, irritability, stress, reduced mental energy and low self-esteem, improvement of cognitive function, endometriosis, polycystic ovary syndrome, counteracting preeclampsia, premenstral syndrome, contraception, uterine fibroid disease, and/or aortic smooth muscle cell proliferation, vaginal dryness, pruritis, dyspareunia, dysuria, frequent urination, urinary tract infections, hypercholesterolemia, hyperlipidemia, peripheral vascular disease, restenosis, vasospasm, vascular wall damage due to immune responses, Alzheimer's disease, bone disease, aging, inflammation, rheumatoid arthritis, respiratory disease, emphysema, reperfusion injury, viral hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, amyotrophic lateral sclerosis, stroke, CNS trauma, dementia, neurodegeneration, breast pain and dysmenorrhea, menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, for enhancing libido, for the treatment of hypoactive sexual disorder, sexual arousal disorder, for increasing the frequency and intensity of orgasms, vaginismus, osteopenia, endometriosis, BPH (benign prostatic hypertrophy), dysmenorrhea, autoimmune diseases, Hashimoto's thyroiditis, SLE (systemic lupus erythematosus), myasthenia gravis, or reperfusion damage of ischemic myocardium comprising the administration of a compound according to  claim 1 . 
     
     
         17 . The method of  claim 16  wherein the condition or disorder is menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.