Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety

• US 9,682,960 B2
• Filed: 12/11/2014
• Issued: 06/20/2017
• Est. Priority Date: 12/19/2013
• Status: Active Grant

• Current Assignee: Endorecherche
• Original Assignee: Endorecherche
• Inventors: Labrie, Fernand, Singh, Shankar Mohan, Labrecque, Richard, Ciobanu, Liviu Constantin
• Primary Examiner(s): REESE, HEIDI L
• Application Number:
  US14/567,970
• Publication Number:
  US 20150175576A1
• Time in Patent Office: 922 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• 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 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 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• 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 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/26 : Androgens
• CPC Class Codes: A61P 5/28 : Antiandrogens
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds having the structure or their salts:

are used to treat or reduce the likelihood of acquiring androgen-dependent diseases, such as prostate cancer, benign prostatic hyperplasia, polycystic ovarian syndrome, acne, hirsutism, seborrhea, androgenic alopecia, male baldness, muscle atrophy and weakness, sarcopenia, male hypogonadism, erectile dysfunction, female sexual dysfunction and osteoporosis. They can be formulated together with pharmaceutically acceptable diluent or carrier or otherwise made into any pharmaceutical dosage form. Combinations with other active pharmaceutical agents are also disclosed.

Claims

1. A compound of the formula

2. A compound according to claim 1 having the following formula:

3. A compound according to claim 2 wherein said compound is selected from the group consisting of:

4. A compound according to claim 2 wherein said compound is selected from the group consisting of:

5. A compound according to claim 1 wherein m is 0;

wherein n is 3;

wherein J is an oxygen;

wherein G₁, G₈ and G₁₀ are carbon or methine;

wherein Y is a direct bond;

wherein J and Y are in para position from each other; and

wherein G₆ or G₇ or G₉ is a nitrogen or nitrogen-oxide.

6. A compound according to claim 1 wherein said compound is selected from the group consisting of

8. A pharmaceutical composition comprising at least one compound as defined in claim 1 and a pharmaceutically acceptable diluent or carrier.

9. The pharmaceutical composition of claim 8 wherein said diluent or carrier is suitable for oral administration.

10. A method of treating or reducing the risk of developing prostate cancer, comprising administering to a patient in need of such treatment or reduction of risk a therapeutically effective amount of at least one compound as defined in claim 1.

11. The method of claim 10, further comprising administering to said patient a therapeutically effective amount of at least one inhibitor of androgen-synthesizing enzymes selected from the group consisting of an inhibitor of type 15 17β

-hydroxysteroid dehydrogenase, an inhibitor of type 5 17β

-hydroxysteroid dehydrogenase, an inhibitor of 5α

-reductase, and an inhibitor of 17α

-hydroxylase/17,20-lyase.

12. The method of claim 11, wherein an inhibitor of 5α

-reductase and an inhibitor of type 15 17β

-hydroxysteroid dehydrogenase are administered.

13. The method of claim 10, further comprising orchiectomy or administering an LHRH agonist or antagonist.

14. The method of claim 11, further comprising orchectomy or administering an LHRH agonist or antagonist.

15. The method of claim 12, further comprising orchiectomy or administering an LHRH agonist or antagonist.

16. A method of treating or reducing the risk of developing benign prostatic hyperplasia, comprising administering to a patient in need of such treatment or reduction of risk a therapeutically effective amount of at least one compound as defined in of claim 1.

17. The method of claim 16, further comprising administering to said patient a therapeutically effective amount of at least one inhibitor selected from the group consisting of an antiestrogen, an inhibitor of aromatase, an inhibitor of type 15 17β

-hydroxysteroid dehydrogenase, an inhibitor of type 5 17β

-hydroxysteroid dehydrogenase, an inhibitor of 5α

-reductase, an inhibitor of 17α

-hydroxylase/17,20-lyase, and an inhibitor of androgen-synthesizing enzymes.

18. The method of claim 17, wherein an inhibitor of 5α

-reductase and an inhibitor of type 15 17β

-hydroxysteroid dehydrogenase are administered.

19. A method of treating or reducing the risk of developing prostate cancer or benign prostatic hyperplasia, comprising administering to a patient in need of such treatment or reduction of risk a therapeutically effective amount of at least one compound as defined in claim 1.

20. A method according to claim 10, wherein said compound is formulated for administration to a patient in a pharmaceutically acceptable diluent or carrier.

21. A kit comprising a first container containing a therapeutically effective amount of at least one compound as defined in claim 1 and further comprising a second container containing a therapeutically effective amount of at least one LHRH agonist or LHRH antagonist.

22. A method according to claim 16 wherein said compound is formulated for administration to a patient in a pharmaceutically acceptable diluent or carrier.

23. A method according to claim 19 wherein said compound is formulated for administration to a patient in a pharmaceutically acceptable diluent or carrier.

24. A method according to claim 19 wherein said compound is formulated for administration to a patient in a pharmaceutically acceptable diluent or carrier.

7. A compound having the following structure: