SELECTIVE ANDROGEN RECEPTOR MODULATORS (SARMS) AND USES THEREOF

• US 20100256129A1
• Filed: 12/12/2008
• Published: 10/07/2010
• Est. Priority Date: 12/21/2007
• Status: Active Grant

• Current Assignee: Lin Zhi
• Original Assignee: Ligand Pharmaceuticals, Inc.
• Inventors: Zhi, Lin
• Granted Patent: US 8,354,446 B2
• Time in Patent Office: Days
• US Class Current: 514/229.800
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 15/10 for impotence
• CPC Class Codes: A61P 15/12 for climacteric disorders
• 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 17/16 : Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• 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 21/06 : Anabolic agents androgens A61P5/26
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/26 : Androgens
• CPC Class Codes: A61P 5/28 : Antiandrogens
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 5/34 : Gestagens
• CPC Class Codes: A61P 5/46 : for decreasing, blocking or antagonising the activity of glucocorticosteroids
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided herein are compounds of formulae I to II that bind to androgen receptors and/or modulate activity of androgen receptors; and to methods for making and using such compounds. Also provided are compositions including such compounds and methods for making and using such compositions.

Claims

1. A compound of Formula I, II or III:

2. The compound of claim 1 that has formula I and is selected from among

the compound wherein R′

is CF₃, R² is H and R³ is H;

the compound wherein R′

is CF₃, R² is H and R³ is methyl;

the compound wherein R′

is CF₃, R² is methyl and R³ is hydrogen;

the compound wherein R′

is F, R² is H and R³ is H;

the compound wherein R′

is F, R² is H and R³ is methyl;

the compound wherein R′

is F, R² is methyl and R³ is hydrogen;

the compound wherein R′

is Cl, R² is H and R³ is H;

the compound wherein R′

is Cl, R² is H and R³ is methyl; and

the compound wherein R′

is Cl, R² is methyl and R³ is hydrogen.

4. The compound of claim 1 that has formula II and is selected from among:

the compound wherein R⁴ is Cl and R⁵ is methyl;

the compound wherein R⁴ is Cl and R⁵ is ethyl;

the compound wherein R⁴ is Cl and R⁵ is CF₃;

the compound wherein R⁴ is CF₃ and R⁵ is methyl;

the compound wherein R⁴ is CF₃ and R⁵ is ethyl; and

the compound wherein R⁴ is CF₃ and R⁵ is CF₃.

6. The compound of claim 1 that has formula III and is selected from among:

the compound wherein R⁵ is methyl;

the compound wherein R⁵ is ethyl; and

the compound wherein R⁵ is CF₃.

8. The compound of claim 1 selected from among:

R,R-4-(2-(1-Hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile;

4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-trifluoromethyl-benzonitrile;

R,R,R-4-(2-(1-Hydroxyl-2,2,2-trifluoroethyl)-5-methylpyrrolidinyl)-2-trifluoromethyl-benzonitrile;

4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)-5(R)-methylpyrrolidinyl)-2-trifluoro-methylbenzonitrile;

R,R-4-(2-(1-Hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-chlorobenzonitrile;

4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-chlorobenzonitrile;

R,R,R-4-(2-(1-hydroxyl-2,2,2-trifluoroethyl)-5-methylpyrrolidinyl)-2-chlorobenzonitrile;

4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)-5(R)-methylpyrrolidinyl)-2-chlorobenzonitrile;

R,R-4-(2-(1-hydroxyl-2,2,2-trifluoroethyl)pyrrolidinyl)-2-chloro-3-methylbenzonitrile;

4-(2(R)-(1(S)-hydroxyl-2,2,2-trifluoroethyl)-pyrrolidinyl)-2-chloro-3-methylbenzonitrile;

3-methyl-4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoro-methyl)benzonitrile;

3-methyl-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;

3-methyl-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;

2-fluoro-4-((2R,5R)-2-methyl-5)-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)-benzonitrile;

2-fluoro-3-methyl-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)benzonitrile;

2-fluoro-3-methyl-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-benzonitrile;

2-fluoro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)benzonitrile;

2-chloro-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)-benzonitrile;

2-chloro-3-methyl-4-((2R,5R)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-pyrrolidin-1-yl)benzonitrile;

2-chloro-3-methyl-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-benzonitrile;

2-chloro-4-((R)-2((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-benzonitrile;

(3R)-10-chloro-3-methyl-4-(3,3,3-trifluoro-2(R)-hydroxypropyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-10-chloro-3-ethyl-4-(3,3,3-trifluoro-2(R)-hydroxypropyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-10-chloro-4-(3,3,3-trifluoro-2(R)-hydroxypropyl)-3-(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-10-chloro-3-methyl-4-(3,3,3-trifluoro-2(S)-hydroxypropyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-10-chloro-3-ethyl-4-(3 3,3-trifluoro-2(S)-hydroxypropyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-10-chloro-4-(3,3,3-trifluoro-2(S)-hydroxypropyl)-3-(trifluoromethyl)-3,4-dihydro-2H-[1,4-f]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-3-ethyl-4-(3,3,3-trifluoro-2(R)-hydroxypropyl)-10-(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-3-methyl-4-(3,3,3-trifluoro-2(R)-hydroxypropyl)-10-(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-4-(3,3,3-trifluoro-2(R)-hydroxypropyl)-3,10-bis(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-3-ethyl-4-(3,3,3-trifluoro-2(S)-hydroxypropyl)-10-(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(3R)-3-methyl-4-(3,3,3-trifluoro-2(S)-hydroxypropyl)-10-(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino [2,3-f]quinolin-8(7H)-one;

(3R)-4-(3,3,3-trifluoro-2(S)-hydroxypropyl)-3,10-bis(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(R)-10-chloro-3-methyl-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]-quinolin-8(711)-one;

(R)-10-chloro-3-ethyl-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

(R)-10-chloro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinolin-8(7H)-one;

or a pharmaceutically acceptable salt, ester or prodrug thereof

9. The compound of claim 1, wherein the compound is a selective androgen receptor modulator.

10. The compound of claim 9, wherein the compound is a selective androgen receptor agonist or a selective androgen receptor partial agonist.

12. The compound of claim 10, wherein the compound is a tissue-specific androgen receptor agonist.

13. The compound of claim 9, wherein the compound is a selective androgen receptor antagonist.

14. The compound of claim 10, wherein the compound is a tissue-specific androgen receptor antagonist.

15. A pharmaceutical composition, comprising:

a compound of claim 1; and

a pharmaceutical acceptable carrier.

16. The composition of claim 15, further comprising one or more than one active ingredient selected from among an estrogen or an estrogen derivative, a progestin or a progestin derivative, an anti-estrogen or a selective estrogen receptor modulator compound, an α

_vβ

₃ integrin receptor antagonist, an activator of peroxisome proliferator-activated receptor gamma (PPARβ

), a calcium receptor antagonist, insulin-like growth factor, a cathepsin inhibitor, an HMG-CoA reductase inhibitor, a p38 protein kinase inhibitor, a prostaglandin derivative, a bisphosphonate, vitamin D or vitamin D derivative, vitamin K or vitamin K derivative, an osteoclast vacuolar ATPase inhibitor, an antagonist of VEGF binding to osteoclast receptors and calcitonin.

17. The composition of claim 15, wherein the composition is formulated for oral, rectal, transmucosal, intestinal, enteral, topical, transdermal, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular, parenteral, intravenous, intramuscular, intramedullary or subcutaneous administration.

19. A method for modulating an activity of an androgen receptor, comprising contacting an androgen receptor with a compound of claim 1, thereby modulating an activity of an androgen receptor.

20. The method of claim 19, wherein the androgen receptor is activated by the compound.

21. The method of claim 19, wherein the androgen receptor is deactivated by the compound.

22. The method of claim 19, wherein the androgen receptor is in a cell.

23. A method for identifying a compound that modulates an activity of an androgen receptor, comprising:

contacting a cell expressing an androgen receptor with a compound of claim 1; and

monitoring an effect of the compound upon the cell.

24. A method of treating a subject having a disease, disorder or condition caused by androgen deficiency or hypoactivity or subsensitivity of androgen receptor or a disease, disorder or condition ameliorated by androgen replacement or responsive to treatment with an AR agonist, comprising administering to the subject a therapeutically effective amount of a compound of any of claim 10, and thereby treating the disease, disorder or condition.

25. The method of claim 24, wherein the disease, disorder or condition is selected from among aging skin;

Alzheimer'"'"'s disease;

an anemia;

anorexia;

arthritis;

gout;

arteriosclerosis;

atherosclerosis;

bone disease;

bone damage or fracture;

distraction osteogenesis;

reduced bone mass, density or growth;

bone weakening;

musculoskeletal impairment;

cachexia;

breast cancer and osteosarcoma;

cardiac dysfunction;

myocardial infarction;

cardiac hypertrophy;

congestive heart failure;

cardiomyopathy;

catabolic side effects of glucocorticoids;

Crohn'"'"'s disease;

growth retardation in connection with Crohn'"'"'s disease;

short bowel syndrome;

irritable bowel syndrome;

inflammatory bowel disease;

ulcerative colitis;

cognitive decline and impairment;

dementia;

short term memory loss;

contraception (male and female);

chronic obstructive pulmonary disease (COPD);

chronic bronchitis;

decreased pulmonary function;

emphysema;

decreased libido in both men and women;

depression;

nervousness, irritability and/or stress;

reduced mental energy and low self-esteem;

reduced motivation/assertiveness;

dyslipidemia;

erectile dysfunction;

frailty;

age-related functional decline (“

ARFD”

) in the elderly;

growth hormone deficiency;

hematopoietic disorders;

hormone replacement (male and female);

hyper-cholesterolemia;

hyperinsulinemia;

hyperlipidemia;

hypertension;

hyperandrogenemia;

hypogonadism (including primary and secondary);

hypothermia (including hypothermia following anesthesia);

impotence;

insulin resistance;

type 2 diabetes;

lipodystrophy;

male menopause;

metabolic syndrome (syndrome X);

loss of muscle strength and/or function;

muscular dystrophies;

muscle loss following surgery;

muscular atrophy;

neurodegenerative diseases;

neuromuscular disease;

decreased platelet count;

platelet aggregation disorders;

obesity;

osteoporosis;

osteopenia;

glucocorticoid-induced osteoporosis;

osteochondrodysplasias;

periodontal disease;

premenstrual syndrome;

postmenopausal symptoms in women;

Reaven'"'"'s syndrome;

rheumatological disease;

sarcopenia;

male and female sexual dysfunction;

erectile dysfunction;

decreased sex drive;

decreased libido;

physiological short stature, including growth hormone deficient children and short stature associated with chronic illness and growth retardation associated with obesity;

tooth damage;

thrombo-cytopenia;

vaginal dryness;

atrophic vaginitis;

ventricular dysfunction; and

wasting.

26. The method of claim 24, wherein administration of the AR agonist compound produces an effect selected from among stimulation pulsatile growth hormone release;

improved bone strength, muscle strength and/or tone;

reduced subcutaneous fat in a subject;

increased athletic performance;

attenuation or reversal of protein catabolic responses following trauma;

improved sleep quality;

correction of the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency;

modification of lipid profile;

correction of female androgen deficiency; and

correction of male androgen decline.

27. A method of treating a subject having a disease, disorder or condition caused by hyperactivity of androgen receptor or a disease, disorder or condition responsive to treatment with an AR antagonist, comprising administering to the subject a therapeutically effective amount of a compound of claim 13, and thereby treating the disease, disorder or condition.

28. The method of claim 27, wherein the disease, disorder or condition is selected from among acanthosis nigricans;

acne;

adrenal hyperandrogenism; and

rogenetic alopecia (male-pattern baldness);

adenomas and neoplasias of the prostate;

advanced metastatic prostate cancer;

benign prostate hyperplasia;

cancer of the breast, bladder, brain, endometrium, kidney, lung (non-small cell lung cancer), ovaries, pancreas, prostate and skin;

lymphatic cancers;

bulimia nervosa;

chronic fatigue syndrome (CFS);

chronic myalgia;

acute fatigue syndrome;

counteracting preeclampsia, eclampsia of pregnancy and preterm labor;

delayed wound healing;

erythrocytosis;

gestational diabetes;

hirsutism;

hyper-insulinemia;

nesidioblastosis;

hyperandrogenism;

hypercortisolism;

Cushing'"'"'s syndrome;

hyperpilosity;

infertility;

menstrual irregularity;

ovarian hyperandrogenism;

polycystic ovarian syndrome;

seborrhea;

sleep disorders;

sleep apnea; and

visceral adiposity.

3. (canceled)

5. (canceled)

7. (canceled)

11. (canceled)

18. (canceled)

29-41. -41. (canceled)