Sulfonylpyrrolidine modulators of androgen receptor function and method

• US 20050187267A1
• Filed: 02/01/2005
• Published: 08/25/2005
• Est. Priority Date: 02/04/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Hamann, Lawrence G., Sutton, James C., Nirschl, Alexandra A., Bi, Yingzhi, Manfredi, Mark C.
• Granted Patent: US 7,820,702 B2
• Time in Patent Office: Days
• US Class Current: 514/362
• CPC Class Codes: C07D 207/48 Sulfur atoms
• CPC Class Codes: C07D 285/14 condensed with carbocyclic rings or ring systems

Abstract

Compounds are provided which are useful in the treatment of androgen receptor-associated conditions, such as age-related diseases, which compounds have the structure wherein

• • R₁ is hydrogen (H), alkyl or substituted alkyl, alkenyl or substituted alkenyl, arylalkyl or substituted arylalkyl, CO₂R_4a, CONR_4aR_4b, and CH₂OR_4a;
  • R₂ is hydrogen (H), OR₃, SR₃, halo, NHR₃, NHCOR_4c1, NHCO₂R_4c1, NHCONR_4cR_4d and NHSO₂R_4c;
  • R₃ in each functional group is hydrogen (H), alkyl or substituted alkyl, CHF₂, CF₃ and CON_4e;
  • R₄, R_4a, R_4b, R_4c, R_4c1, R_4d, R_4e, R_4f, R_4g, or R_4h in each functional group are the same or different and are hydrogen(H), alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl;
  • R₅ and R₅′ are the same or different and are hydrogen(H), alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl, wherein at least one of R₅ and R₅′ is hydrogen, or R₅ and R₅′ taken together form a double bond with oxygen (O), sulfur (S), NR₇ or CR₇R₇′;
  • where R₇ and R₇′ are as defined herein; G is an aryl, heterocyclo or heteroaryl group, wherein said group is mono- or polycyclic, and which is optionally substituted; and n is an integer of 1 or 2, m is an integer of 1 or 2,
  • Z is oxygen (—O—) or NR_4h, a prodrug ester, all stereoisomers thereof and a pharmaceutically acceptable salt. A method for treating androgen receptor-associated conditions such as age-related diseases is also provided.

Claims

1. A compound having the formula

2. The compound as defined in claim 1 having the formula

3. The compound as defined in claim 1 having the formula II

4. The compound as defined in claim 2 wherein

R₁ is H or alkyl,

R₂ is OH;

R₅ and R₅′

are each H or R₅ and R₅′

are taken together form a double bond with oxygen or sulfur;

n is 1;

m is 2.

5. The compound as defined in claim 2 wherein G is selected from:

6. The compound as defined in claim 5 wherein R₈ is CN.

7. The compound as defined in claim 1 having the structure

8. The compound as defined in claim 1 having the structure

9. The compound as defined in claim 1 having the name and structure

4-[(3aS,4R)-4-Hydroxy-1,1,3-trioxohexahydrothia-2,6a-diazapentalen-2-yl]-2-chloro-3-methylbenzonitrile

10. A method for treating androgen receptor-associated conditions, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

11. The method as defined in claim 10 wherein the compounds employed are selective agonists, partial agonists, antagonists or partial antagonists of the androgen receptor.

12. The method as defined in claim 10 wherein the compounds employed are agonists of the androgen receptor.

13. The method as defined in claim 12 wherein the compounds are used in maintenance of muscle strength and function;

reversal or prevention of frailty or age-related functional decline (“

ARFD”

) in the elderly;

prevention of catabolic side effects of glucocorticoids;

prevention and treatment of reduced bone density or growth in the treatment of osteoporosis, and osteopenia;

treatment of chronic fatigue syndrome (CFS);

chronic myalgia;

treatment of acute fatigue syndrome and muscle loss following elective surgery;

acceleration of wound healing;

accelerating bone fracture repair;

treatment of wasting secondary to fractures and wasting in connection with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic state, coma, eating disorders, anorexia, and chemotherapy.

14. The method as defined in claim 10 wherein the compounds employed are in a composition employing such compounds and a pharmaceutically acceptable carrier therefor.

15. The method as defined in claim 10 comprising administering a therapeutically effective amount of the compound alone or in combination with another therapeutic agent.

16. A method for preventing, inhibiting or treating the progression or onset of diseases or disorders associated with nuclear hormone receptors, wherein a therapeutically effective amount of a compound as defined in claim 1 is administered to a mammalian patient in need of treatment.

17. A method for the maintenance of muscle strength and function;

reversal or prevention of frailty or age-related functional decline;

treatment of catabolic side effects of glucocorticoids;

prevention and/or treatment of reduced bone mass, density or growth;

osteoporosis and osteopenia;

treatment of chronic fatigue syndrome (CFS);

chronic myalgia;

treatment of acute fatigue syndrome and muscle loss following elective surgery;

accelerating of wound healing;

accelerating bone fracture repair;

accelerating healing of complicated fractures, distraction osteogenesis;

in joint replacement;

prevention of post-surgical adhesion formation;

acceleration of tooth repair or growth;

maintenance of sensory function;

treatment of periodontal disease;

treatment of wasting secondary to fractures and wasting in connection with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic state;

eating disorders;

treatment of cardiomyopathy;

treatment of thrombocytopenia;

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

treatment of short bowel syndrome;

treatment of irritable bowel syndrome;

treatment of inflammatory bowel disease;

treatment of Crohn'"'"'s disease and ulcerative colits;

treatment of complications associated with transplantation;

treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness;

treatment of obesity and growth retardation associated with obesity;

treatment of anorexia;

treatment of hypercortisolism and Cushing'"'"'s syndrome;

Paget'"'"'s disease;

treatment of osteoarthritis;

induction of pulsatile growth hormone release;

treatment of osteochondrodysplasias;

treatment of depression, nervousness, irritability and stress;

treatment of reduced mental energy and low self-esteem;

improvement of cognitive function, the treatment of dementia, Alzheimer'"'"'s disease and short term memory loss;

treatment of catabolism in connection with pulmonary dysfunction and ventilator dependency;

treatment of cardiac dysfunction associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure;

lowering blood pressure;

protection against ventricular dysfunction or prevention of reperfusion events;

treatment of adults in chronic dialysis;

reversal or slowing of the catabolic state of aging;

attenuation or reversal of protein catabolic responses following trauma, reversal of the catabolic state associated with surgery, congestive heart failure, cardiac myopathy, bums, cancer, COPD;

reducing cachexia and protein loss due to chronic illness such as cancer or AIDS;

treatment of hyperinsulinemia including nesidioblastosis;

treatment of immunosuppressed patients;

treatment of wasting in connection with multiple sclerosis or other neurodegenerative disorders;

promotion of myelin repair;

maintenance of skin thickness;

treatment of metabolic homeostasis and renal homeostasis;

stimulation of osteoblasts, bone remodeling and cartilage growth;

regulation of food intake;

treatment of insulin resistance, including NIDDM, in mammals;

treatment of insulin resistance in the heart;

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

treatment of hypothermia;

treatment of congestive heart failure;

treatment of lipodystrophy;

treatment of muscular atrophy;

treatment of musculoskeletal impairment;

improvement of the overall pulmonary function;

treatment of sleep disorders; and

the treatment of the catabolic state of prolonged critical illness;

treatment of hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy, adenomas and neoplasies of the prostate and malignant tumor cells containing the androgen receptor, as is the case for breast, brain, skin, ovarian, bladder, lymphatic, liver and kidney cancers;

cancers of the skin, pancreas, endometrium, lung and colon;

osteosarcoma;

hypercalcemia of malignancy;

metastatic bone disease;

treatment of spermatogenesis, endometriosis and polycystic ovary syndrome;

conteracting preeclampsia, eclampsia of pregnancy and preterm labor;

treatment of premenstrual syndrome;

treatment of vaginal dryness;

age related decreased testosterone levels in men, male menopause, hypogonadism, male hormone replacement, male and female sexual dysfunction, erectile dysfunction, decreased sex drive, sexual well-being, decreased libido, urinary incontinence, male and female contraception, hair loss, Reaven'"'"'s Syndrome and the enhancement of bone and muscle performance/strength, and “

Syndrome X”

or Metabolic Syndrome, which comprises treating a human patient in need of treatment with a therapeutic amount of a compound as defined in claim 1 alone or in combination with another therapeutic agent.

18. The method as defined in claim 17 wherein the other therapeutic agent is an antibiotic, or growth promoting agent, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, zeranol, sulbenox, growth hormone secretagogues, GHRP-6, GHRP-1, GHRP-2, NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or with growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins, IGF-1 and IGF-2, or with alpha-adrenergic agonists, clonidine or serotinin 5-HT_D agonists, sumatriptan, or agents which inhibit somatostatin or its release, physostigmine and pyridostigmine, parathyroid hormone, PTH(1-34) or bisphosphonates, MK-217 (alendronate), testosterone, a selective estrogen receptor modulator, tamoxifen or raloxifene, other androgen receptor modulators, progesterone receptor agonist (“

PRA”

), which is levonorgestrel, medroxyprogesterone acetate (MPA), other modulators of nuclear hormone receptors, an anti-diabetic agent;

anti-osteoporosis agent;

anti-obesity agent;

anti-inflammatory agent;

anti-anxiety agent;

anti-depressant;

anti-hypertensive agent;

anti-platelet agent;

anti-thrombotic and thrombolytic agents;

cardiac glycoside;

cholesterol/lipid lowering agent;

mineralocorticoid receptor antagonist;

phospodiesterase inhibitor;

protein tyrosine kinase inhibitor;

thyroid mimetic and a thyroid receptor agonist;

anabolic agent;

HIV or AIDS therapy;

a therapy useful in the treatment of Alzheimer'"'"'s disease and other cognitive disorders;

a therapy useful in the treatment of sleeping disorders;

anti-proliferative agent; and

anti-tumor agent;

wherein the anti-diabetic agent is a biguanide, metformin, glucosidase inhibitor, acarbose, insulin, insulin secretagogue and insulin sensitizer, meglitinide, repaglinide, sulfonylurea, glimepiride, glyburide and glipizide, biguanide/glyburide combination, thiazolidinedione, troglitazone, rosiglitazone and pioglitazone, PPAR-alpha agonist, PPAR-gamma agonist, PPAR alpha/gamma dual agonist, SGLT2 inhibitor, glycogen phosphorylase inhibitor, inhibitors of fatty acid binding protein (aP2), glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitor, anti-osteoporosis agent which is alendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonins, steroidal or non-steroidal progesterone receptor agonists, RANK ligand antagonist, calcium sensing receptor antagonist, TRAP inhibitor, selective estrogen receptor modulator (SERM'"'"'s), estrogen and AP-1 inhibitor, anti-obesity agent which is aP2 inhibitor, PPAR gamma antagonist, PPAR delta agonist, beta 3 adrenergic agonist, AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer), a lipase inhibitor, orlistat or ATL-962 (Alizyme), a serotonin (and dopamine) reuptake inhibitor, sibutramine, topiramate or axokine, a thyroid receptor beta drug, a thyroid receptor ligand and GB98/284425 (KaroBio), and/or an anorectic agent, dexamphetamine, phentermine, phenylpropanolamine or mazindol, anti-inflammatory agent which is prednisone, dexamethasone, Enbrel®

, cyclooxygenase inhibitors, COX-1 and/or COX-2 inhibitors, NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen®

, Celebrex®

, Vioxx®

, CTLA4-Ig agonists/antagonist, CD40 ligand antagonist, IMPDH inhibitor, mycophenolate (CellCept®

), integrin antagonist, alpha-4 beta-7 integrin antagonist, cell adhesion inhibitor, interferon gamma antagonist, ICAM-1, tumor necrosis factor (TNF) antagonist, infliximab, OR1384, prostaglandin synthesis inhibitor, budesonide, clofazimine, CNI-1493, CD4 antagonist, priliximab, p38 mitogen-activated protein kinase inhibitor, protein tyrosine kinase (PTK) inhibitor, IKK inhibitor, and therapy for the treatment of irritable bowel syndrome, Zelmac® and

Maxi-K®

opener;

anti-anxiety agent which is diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine pamoate;

anti-depressant which is citalopram, fluoxetine, nefazodone, sertraline, and paroxetine;

anti-hypertensive agent which is beta adrenergic blocker, calcium channel blocker, L-type and T-type, diltiazem, verapamil, nifedipine, amlodipine and mybefradil, diuretic, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone, renin inhibitor, ACE inhibitor, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, AT-1 receptor antagonist, losartan, irbesartan, valsartan, ET receptor antagonist, sitaxsentan, atrsentan, Dual ET/AII antagonist, neutral endopeptidase (NEP) inhibitor, vasopepsidase inhibitor, dual NEP-ACE inhibitor, omapatrilat and gemopatrilat, and nitrates, anti-platelet agent which is a GPIIb/IIIa blocker, abciximab, eptifibatide, tirofiban, P2Y12 antagonist, clopidogrel, ticlopidine, CS-747, thromboxane receptor antagonist, ifetroban, aspirin, and PDE-III inhibitors, dipyridamole, cardiac glycoside which is digitalis and ouabain;

cholesterol/lipid lowering agent which is HMG-CoA reductase inhibitor, pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 or itavastatin, or nisvastatin or nisbastatin, ZD-4522 or rosuvastatin, or atavastatin or visastatin, squalene synthetase inhibitor, fibrate, bile acid sequestrant, ACAT inhibitor, MTP inhibitor, lipooxygenase inhibitor, cholesterol absorption inhibitor, and cholesterol ester transfer protein inhibitor, CP-529414, mineralocorticoid receptor antagonist which is spironolactone and eplerinone, phospodiesterase (PDE) inhibitor which is PDE-3 inhibitors, cilostazol, and phosphodiesterase-5 inhibitor (PDE-5 inhibitors, such as sildenafil;

thyroid mimetics which is thyrotropin, polythyroid, KB-130015, and dronedarone;

anabolic agent which is testosterone, TRH diethylstilbesterol, estrogen, β

-agonist, theophylline, anabolic steroid, dehydroepiandrosterone, an enkephalin, E-series prostagladin, retinoic acid, Zeranol®

, Sulbenox®

;

HIV or AIDS therapy which is indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir, lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate;

treatment of Alzheimer'"'"'s disease and cognitive disorders which is donepezil, tacrine, revastigmine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi-K blockers, and KCNQs blockers;

therapy for treatment of sleeping disorders which is a melatonin analog, melatonin receptor antagonist, ML1B agonist, and GABA/NMDA receptor antagonist;

anti-proliferative agents which is cyclosporin A, paclitaxel, FK-506, and adriamycin;

anti-tumor agent which is paclitaxel, adriamycin, epothilones, cisplatin and carboplatin;

a nutritional supplement which is whey protein or casein, an amino acid such as leucine, branched amino acid and hydroxymethylbutyrate, a triglyceride, vitamin A, B6, B12, folate, C, D and E, mineral which is selenium, magnesium, zinc, chromium, calcium and potassium, carnitine, lipoic acid, creatinine, B-hyroxy-B-methylbutyriate (Juven) and coenzyme Q-10;

a therapeutic agent used in the treatment of sexual dysfunction which is a PDE-5 inhibitor, sildenafil or IC-351;

an antiresorptive agent, hormone replacement therapy, vitamin D analogue, elemental calcium and calcium supplement, cathepsin K inhibitor, MMP inhibitor, vitronectin receptor antagonist, Src SH₂ antagonist, vacular—

H⁺-ATPase inhibitor, ipriflavone, fluoride, Tibolone, prostanoid, 17-beta hydroxysteroid dehydrogenase inhibitor and Src kinase inhibitor;

a male contraceptive which is nonoxynol 9, a therapeutic agent for the treatment of hair loss which is minoxidil and finasteride or a chemotherapeutic agent which is an LHRH agonist;

anti-cancer and cytotoxic agent which is alkylating agent, nitrogen mustard, alkyl sulfonate, nitrosourea, ethylenimine, and triazene;

antimetabolite which is a folate antagonist, purine analogue, and pyrimidine analogue;

antibiotic which is anthracycline, bleomycin, mitomycin, dactinomycin, and plicamycin;

an enzyme which is L-asparaginase;

farnesyl-protein transferase inhibitor;

5α

-reductase inhibitor;

inhibitor of 17β

-hydroxysteroid dehydrogenase type 3;

hormonal agent which is a glucocorticoid, estrogen/antiestrogen, androgen/antiandrogen, progestin, and luteinizing hormone-releasing hormone antagonist, octreotide acetate;

microtubule-disruptor agent which is an ecteinascidin or their analogs and derivative;

microtubule-stabilizing agent which is a taxane, paclitaxel (Taxol®

), docetaxel (Taxotere®

), and their analogs, and an epothilone which is epothilones A-F and their analogs;

a plant-derived product which is vinca alkaloids, epipodophyllotoxin, a taxane; and

a topiosomerase inhibitor;

prenyl-protein transferase inhibitor;

hydroxyurea, procarbazine, mitotane, hexamethylmelamine, a platinum coordination complex, cisplatin and carboplatin;

a biological response modifier, growth factor;

immune modulator and monoclonal antibody and radiation therapy;

an anti-cancer and cytotoxic agent which is mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vinblastine, vinorelbine tartrate, etoposide, etoposide phosphate, teniposide, paclitaxel, tamoxifen, estramustine, estramustine phosphate sodium, flutamide, buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethosone, gemcitabine hydrochloride, altretamine, and topoteca and any analogs or derivatives thereof;

an epothilone derivative;

cyclin dependent kinase inhibitors; and

prenyl-protein transferase inhibitor, NHR modulator, AR modulator, ER modulator, LHRH modulator, or with surgical castration.