Triphenylethylene Compounds Useful as Selective Estrogen Receptor Modulators
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Abstract
Triphenylethylene compounds of formula (I) are provided. The compounds are particularly useful for selective estrogen receptor modulation.
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Citations
32 Claims
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1. A compound of Formula I
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17, 19, 20, 25, 28, 29, 30, 31, 32)
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2. A compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; -
each R2 is the same and selected from the group consisting of —
OH, halogen, C1-C4 alkoxy, —
S—
R8, —
SO—
R8, —
SO2—
R8, and —
C≡
N;each R3 is the same and selected from hydrogen, —
OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl;R4 is selected from —
COOH, —
C≡
N, C≡
C—
Ra—
OH, —
C═
C—
COO—
R8, —
C═
NOH, —
C═
C—
R6, —
O—
Ra—
R10, —
N—
R11R12, —
N—
SO2—
R8, —
SO2—
R8, and a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms selected from N and O optionally substituted with one or more of C1-C6 alkyl, phenyl, and C1-C6 alkylphenyl;R5 is selected from hydrogen, —
OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl;R6 is selected from Ra—
COOH, COO—
R8, —
CONR8R9;R8 and R9 are independently selected from H and substituted or unsubstituted C1-C6 alkyl group; and R10 is selected from COOH, OH, O—
Rb—
OH, O—
Rb—
OCO—
R8, and COO—
R8R11 and R12 are independently selected from H, RaH, RaOH, and RaOMe; and Ra and Rb are independently selected from C1-C6 alkylene.
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3. The compound of claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from —
- COOH, —
C≡
N, —
C≡
C—
RaOH, —
C≡
C—
COO—
R8, —
C≡
NOH, —
C═
C—
R6, —
O—
Ra—
R10, and —
N—
R11R12.
- COOH, —
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4. The compound of claim 3 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C1-6 alkyl.
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5. The compound of claim 4 or a pharmaceutically acceptable salt or solvate thereof wherein R1 is ethyl.
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6. The compound of claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen.
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7. The compound of claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is —
- OH.
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8. The compound of claim 2 or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from —
- C═
C—
COOH, —
COOH, and —
O(CH2)2O(CH2)2OH.
- C═
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11. A compound of claim 1
or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; -
each R2 is the same and selected from the group consisting of —
OH, halogen, C1-C4 alkoxy, —
S—
R8, —
SO—
R8, —
SO2—
R8, and —
C≡
N;each R3 is the same and selected from hydrogen, —
OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl;R4 is selected from —
COOH, —
C≡
N, —
C═
C—
R6, —
O—
Ra—
R10, —
SO2—
R8, and a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms selected from N and O optionally substituted with one or more of C1-C6 alkyl, phenyl, and C1-C6 alkylphenyl;R5 is selected from hydrogen, —
OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl;R6 is selected from —
COOH, Ra—
COOH, COO—
R8, —
CONR8R9;Ra and Rb are independently selected from C1-C6 alkylene; R8 is selected from substituted or unsubstituted C1-C6 alkyl group; and R10 is selected from COOH, OH, O—
Rb—
OH, O—
Rb—
OCO—
R8, and COO—
R8.
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12. The compound of claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from —
- COOH, —
C≡
N, —
C═
C—
R6, and —
O—
R—
R10, and —
SO2—
R8.
- COOH, —
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13. The compound of claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a C1-6 alkyl.
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14. The compound of claim 13 or a pharmaceutically acceptable salt or solvate thereof wherein R1 is ethyl.
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15. The compound of claim 11 or a Pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen.
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16. The compound of claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is —
- OH.
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17. The compound of claim 11 or a
pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from — - COOH, —
C═
C—
COOH, and —
O(CH2)2O(CH2)2OH.
- COOH, —
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19. A compound of claim 1
or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; -
each R2 is the same and selected from the group consisting of —
OH, halogen, C1-C4 alkoxy, —
S—
R8, —
SO—
R8, —
SO2—
R8, and —
C≡
Neach R3 is the same and selected from hydrogen, —
OH, C1-C6 alkyl, halogen, C1-C6 alkoxy, and C1-C6 haloalkyl;R4 is selected from —
COOH, —
C≡
N, —
C═
C—
R6—
Ra—
R10, —
SO2—
R8, and a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms selected from N and O optionally substituted with one or more of C1-C6 alkyl, phenyl, and C1-C6 alkylphenyl;R5 is selected from hydrogen, —
OH, halogen, and C1-C6 alkoxy;R6 is selected from —
COOH, Ra—
COOH, COO—
R8;Ra and Rb are independently selected from C1-C6 alkylene; R8 is an unsubstituted C1-C6 alkyl group; and R10 is selected from COOH, OH, NH2, NHR8, O—
Rb—
OH, O—
Rb—
OCO—
R8, and COO—
R8.
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20. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
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25. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof in combination with other therapeutic agents selected from a bone building agent, anti-bone resorption agent, growth promoting agents, growth hormone secretagogues, growth hormone releasing factor and its analogs, growth hormone and its analogs, somatomedins, alpha-ardenergic agonists, serotonin 5-HTD agonists, selective serotonin reuptake inhibitors, agents that inhibit somatostatin or its release, 5-α
- -reductase inhibitors, aromatase inhibitors, GnRH inhibitors, parathyroid hormone, bisphosphonates, estrogen, testosterone, SERMs, progesterone receptor agonists, and other modulators of nuclear hormone receptors.
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28. A method of treatment for a condition or disorder affected by selective estrogen regulator modulation in a mammal in need thereof comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof
wherein the condition or disorder is selected from 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 tumor 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.
- ARFD”
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29. The method of claim 28 wherein the disorder or condition is selected from menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, and osteoporosis.
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30. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof according to claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.
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31. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof according to claim 11 and a pharmaceutically acceptable carrier, diluent or excipient.
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32. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof according to claim 19 and a pharmaceutically acceptable carrier, diluent or excipient.
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2. A compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein
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9. (canceled)
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10. (canceled)
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18. (canceled)
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21. (canceled)
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22. (canceled)
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23. (canceled)
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24. (canceled)
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26. (canceled)
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27. (canceled)
Specification
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Current AssigneeSubba Reddy Katamreddy
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Original AssigneeSubba Reddy Katamreddy
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InventorsKatamreddy, Subba Reddy
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Application NumberUS12/094,190Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/182CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/02 Stomatological preparations...A61P 1/04 for ulcers, gastritis or re...A61P 1/14 Prodigestives, e.g. acids, ...A61P 1/16 for liver or gallbladder di...A61P 11/00 Drugs for disorders of the ...A61P 13/02 of urine or of the urinary ...A61P 13/08 of the prostateA61P 13/10 of the bladderA61P 15/00 Drugs for genital or sexual...A61P 15/02 for disorders of the vaginaA61P 15/08 for gonadal disorders or fo...A61P 15/10 for impotenceA61P 15/12 for climacteric disordersA61P 15/16 Masculine contraceptivesA61P 15/18 Feminine contraceptivesA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/06 AntipsoriaticsA61P 17/08 AntiseborrheicsA61P 17/14 : for baldness or alopeciaA61P 19/02 : for joint disorders, e.g. a...A61P 19/08 : for bone diseases, e.g. rac...A61P 19/10 : for osteoporosisA61P 21/00 : Drugs for disorders of the ...A61P 21/04 : for myasthenia gravisA61P 25/00 : Drugs for disorders of the ...A61P 25/02 : for peripheral neuropathiesA61P 25/22 : AnxiolyticsA61P 25/24 : AntidepressantsA61P 25/28 : for treating neurodegenerat...A61P 29/00 : Non-central analgesic, anti...A61P 3/02 : Nutrients, e.g. vitamins, m...A61P 3/04 : Anorexiants; Antiobesity ag...A61P 3/06 : AntihyperlipidemicsA61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/06 : for tuberculosisA61P 31/12 : AntiviralsA61P 31/18 : for HIVA61P 35/00 : Antineoplastic agentsA61P 37/02 : ImmunomodulatorsA61P 37/04 : ImmunostimulantsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 5/14 : of the thyroid hormones, e....A61P 5/24 : of the sex hormonesA61P 5/38 : of the suprarenal hormonesA61P 7/00 : Drugs for disorders of the ...A61P 7/04 : Antihaemorrhagics; Procoagu...A61P 7/06 : AntianaemicsA61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/08 : Vasodilators for multiple i...A61P 9/10 : for treating ischaemic or a...A61P 9/12 : AntihypertensivesA61P 9/14 : Vasoprotectives; Antihaemor...C07C 251/48 : with the carbon atom of at ...C07C 255/53 : containing cyano groups and...C07C 255/57 : containing cyano groups and...C07C 2601/14 : The ring being saturatedC07C 317/22 : with sulfone or sulfoxide g...C07C 323/18 : having the sulfur atom of a...C07C 43/23 : containing hydroxy or O-met...C07C 59/48 : containing six-membered aro...C07C 59/56 : containing halogenC07C 59/68 : the oxygen atom of the ethe...C07C 59/70 : Ethers of hydroxy-acetic ac...C07D 261/08 : with only hydrogen atoms, h...C07D 307/42 : Singly bound oxygen atoms