Selective androgen receptor modulators

• US 9,920,044 B2
• Filed: 07/22/2015
• Issued: 03/20/2018
• Est. Priority Date: 09/28/2010
• Status: Active Grant

• Current Assignee: Radius Pharmaceuticals Inc. (Radius Health, Inc.)
• Original Assignee: Radius Pharmaceuticals Inc. (Radius Health, Inc.)
• Inventors: Miller, Chris P.
• Primary Examiner(s): SAEED, KAMAL A
• Application Number:
  US14/806,360
• Publication Number:
  US 20150322059A1
• Time in Patent Office: 972 Days
• Field of Search: None
• 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 1/14 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 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 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 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 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• 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 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/26 : Androgens
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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
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• CPC Class Codes: C07D 207/26 : 2-Pyrrolidones
• CPC Class Codes: C07D 233/36 : with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: G01N 2333/70567 : Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
• CPC Class Codes: G01N 33/74 : involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

This invention provides compounds of formula I, pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) and processes for making compounds and intermediates useful in the preparation of same.

Claims

1. A compound according to formula I:

2. The compound according to claim 1, wherein:

R_x is CN;

or

pharmaceutically acceptable salts thereof.

3. The compound according to claim 1, wherein:

R_y is CF₃ or Cl;

or

pharmaceutically acceptable salts thereof.

4. The compound according to claim 1, wherein:

R_z is H, CH₃, CF₃ or Cl;

or

pharmaceutically acceptable salts thereof.

5. The compound according to claim 1, wherein:

P₁ is hydrogen or (C═

O)—

C_1-6 alkyl;

or

pharmaceutically acceptable salts thereof.

6. The compound according to claim 1, wherein:

P₁ is hydrogen.

7. The compound according to claim 1, wherein:

R_a and R_b are each independently selected from hydrogen and CH₃;

or

pharmaceutically acceptable salts thereof.

8. The compound according to claim 1, wherein:

R_a is CH₃ and R_b is hydrogen;

or

R_a and R_b are each hydrogen;

or

pharmaceutically acceptable salts thereof.

9. The compound according to claim 1 wherein:

R_a is CH₃ and R_b is hydrogen;

or

a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein:

R_a and R_b are each hydrogen;

or

a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein the exocyclic stereochemical center is as shown in structure la below:

12. The compound according to claim 1 wherein the exocyclic stereochemical center is as shown in structure Ib below

15. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient.

16. A method of modulating an androgen receptor in a cell, comprising the administration of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. A method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to claim 1, and monitoring the effect of the compound on the cell.

18. A method of treating sarcopenia, frailty, multiple sclerosis, osteoporosis, muscular dystrophy, low body weight, anorexia nervosa, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, male hormone replacement therapy, myalgia, metabolic syndrome, dwarfism, lethargy, osteopenia, osteoarthritis, connective tissue disease or disorders, injury, burns, wounds, bone fracture, cachexia, and cancer cachexia, in a mammal in need thereof, comprising the administration to said mammal of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1.

13. A compound selected from the group consisting of

4-((R)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile,

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

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

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

and pharmaceutically acceptable salt of any of the foregoing.

14. A compound selected from the following:

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

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

or a pharmaceutically acceptable salt of any of the foregoing.

19. A compound selected from the following:

(R)-1-(3,4-dichlorophenyl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one,

(R)-1-(3,4-dichlorophenyl)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one,

or a pharmaceutically acceptable salt of any of the foregoing.