Triphenylethylene Compounds Useful as Selective Estrogen Modulators

• US 20080306036A1
• Filed: 11/22/2006
• Published: 12/11/2008
• Est. Priority Date: 11/22/2005
• Status: Abandoned Application

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Katamreddy, Subba Reddy
• Application Number:
  US12/093,997
• Publication Number:
  US 20080306036A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/06 : for tuberculosis
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07C 217/20 : by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
• CPC Class Codes: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/10 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/088 : to an acyclic saturated chain

Abstract

Triphenylethylene compounds of formula (I) are provided. The compounds are particularly useful for selective estrogen receptor modulation.

Claims

1. A compound of Formula I

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—

R⁶, —

SO—

R⁶, and —

SO₂—

R⁶;

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 —

O—

R^a—

R⁸;

R⁵ is selected from hydrogen, —

OH, C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, and C₁-C₆ haloalkyl;

R^a is selected from C₁-C₆ alkylene;

R⁶ is a substituted or unsubstituted C₁-C₆ alkyl group;

R⁸ is selected from NR⁹R¹⁰; and

R⁹ and R¹⁰ are independently selected from H, C₁-C₆ alkyl, hydroxy (C₁-C₆) alkyl, and methoxy (C₁-C₆) alkyl, or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle, optionally substituted with one or more halogen and/or one or more C₁-C₆ alkyl;

with the proviso that R⁴ is —

O—

CH₂—

CH₂—

NCH₃CH₃ only if R⁵ is C₁-C₆ alkoxy.

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is selected from —

NCH₃CH₃,

3. The compounds of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is a C_1-6 alkyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt or solvate thereof wherein R¹ is ethyl.

5. The compounds of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R³ is hydrogen.

6. The compounds of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein each R² is —

OH.

9. A pharmaceutical composition comprising the compounds according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, diluent or excipient.

14. A pharmaceutical composition comprising the compounds 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-HT_D 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.

17. 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 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.

18. The method of claim 17 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.

7. A compound of Formula I

or a pharmaceutically acceptable salt or solvate, or physiologically thereof, wherein

R¹ is selected from the group consisting of C₁-C₆ alkyl and C₁-C₆ haloalkyl;

each R² is —

OH;

each R³ is hydrogen;

R⁴ is selected from —

O—

R^a—

R⁸;

R⁵ is selected from hydrogen and C₁-C₆ alkoxy;

R^a is selected from C₁-C₆ alkylene;

R⁸ is selected from NR⁹R¹⁰; and

R⁹ and R¹⁰ are independently selected from H and C₁-C₆ alkyl, or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle;

with the proviso that R⁴ is —

O—

CH₂—

CH₂—

NCH₃CH₃ only if R⁵ is C₁-C₆ alkoxy.

8. A compound selected from the group consisting of:

4,4′

-[2-(3-{[2-(Dimethylamino)ethyl]oxy}phenyl)-1-butene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-Piperidinyl)ethyl]oxy}phenyl)-1-hexene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-Pyrrolidinyl)ethyl]oxy}phenyl)-1-butene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-Piperidinyl)ethyl]oxy}phenyl)-1-butene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(Hexahydro-1H-azepin-1-yl)ethyl]oxy}phenyl)-1-butene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-pentene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-pyrrolidinyl)ethyl]oxy}phenyl)-1-pentene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-piperidinyl)ethyl]oxy}phenyl)-1-pentene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-1-hexene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-pyrrolidinyl)ethyl]oxy}phenyl)-1-hexene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(Hexahydro-1H-azepin-1-yl)ethyl]oxy}phenyl)-1-pentene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(Hexahydro-1H-azepin-1-yl)ethyl]oxy}phenyl)-1-hexene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(Dimethylamino)ethyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-Pyrrolidinyl)ethyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-Piperidinyl)ethyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(Hexahydro-1H-azepin-1-yl)ethyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol;

4,4′

-{2-[3-{[2-(Dimethylamino)ethyl]oxy}-4-(methyloxy)phenyl]-1-butene-1,1-diyl}diphenol;

4,4′

-{2-[3-{[2-(Dimethylamino)ethyl]oxy}-4-(methyloxy)phenyl]-1-pentene-1,1-diyl}diphenol;

4,4′

-{2-[3-{[2-(Dimethylamino)ethyl]oxy}-4-(methyloxy)phenyl]-1-hexene-1,1-diyl}diphenol;

4,4′

-{2-[3-({2-[(3S)-3-Fluoro-1-pyrrolidinyl]ethyl}oxy)phenyl]-1-heptene-1,1-diyl}diphenol;

4,4′

-[2-(3-{[2-(3,3-Difluoro-1-pyrrolidinyl)ethyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol;

4,4′

-[2-(3-{[2-(1-Pyrrolidinyl)propyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol;

and,

4,4′

-[2-(3-{[2-(2-Methyl-1-pyrrolidinyl)ethyl]oxy}phenyl)-1-heptene-1,1-diyl]diphenol

or a pharmaceutically acceptable salt or solvate thereof.

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

15. (canceled)

16. (canceled)