Selective androgen receptor degrader (SARD) ligands and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9815776-B2
Application number	US-201615135151-A
Country	US
Kind code	B2
Filing date	Apr 21, 2016
Priority date	Apr 21, 2015
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

This invention provides novel 3-amino propanamide selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

First claim

What is claimed is:

1. A selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein
T is OH, OR, —NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is hydrogen, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, arylalkyl, benzyl, aryl, or C 3 -C 7 -cycloalkyl;
Q 1 , Q 4 , and Q 5 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted aryl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, or OCN;
Q 2 and Q 3 , are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted aryl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, C(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, NCS, SCN, NCO, or OCN;
wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are not hydrogens; or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring, and Q 3 , Q 4 , and Q 5 are as defined above; or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic ring or C 5 -C 8 substituted or unsubstituted heterocyclic ring, and Q 1 , Q 4 , and Q 5 are as defined above; and

wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

2. The SARD compound according to claim 1 , represented by the structure of formula III:

wherein
Z is NO 2 or CN;
Y is CF 3 , F, I, Br, Cl, or CN;
R 2 is hydrogen, C 1 -C 12 -alkyl, —SO 2 -aryl, —SO 2 -phenyl, —CO-aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted aryl, or substituted or unsubstituted C 3 -C 7 -cycloalkyl;
Q 1 is selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
Q 2 and Q 3 are each independently selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted phenyl, substituted or unsubstituted arylalkyl, F, Cl, Br, I, CF 3 , CN, NO 2 , substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
wherein at least one of Q 1 , Q 2 and Q 3 is a substituted aryl, substituted or unsubstituted arylalkyl, or substituted phenyl;
or
Q 1 and Q 2 are joined together to form a substituted or unsubstituted C 5 -C 8 carbocyclic or heterocyclic ring and Q 3 is as defined above;
or
Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic ring or a C 5 -C 8 heterocyclic ring and Q 1 is as defined above; and
wherein said formed carbocyclic or heterocyclic ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole.

3. The SARD compound of claim 1 , wherein Q 1 is CN.

4. The SARD compound of claim 1 wherein Q 2 and Q 3 are joined together to form a substituted or unsubstituted C 5 -C 8 non-aromatic carbocyclic or a substituted or unsubstituted C 5 -C 8 heterocyclic ring.

5. The SARD compound of claim 1 , represented by the structure of any one of the following compounds:

6. A pharmaceutical composition comprising a SARD compound according to claim 1 , or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 , wherein said composition is formulated for topical use.

8. The pharmaceutical composition of claim 7 , wherein said composition is in the form of a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soap or bar, emulsion, mousse, aerosol, shampoo, or any combination thereof.

9. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of prostate cancer (PCa) and its symptoms, or increasing the survival of a male subject suffering from prostate cancer comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 , or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

10. The method of claim 9 , wherein the prostate cancer is advanced prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), high-risk nmCRPC or any combination thereof.

11. The method of claim 9 , wherein said subject further receives androgen deprivation therapy (ADT).

12. The method of claim 9 , wherein said subject has failed androgen deprivation therapy (ADT).

13. The method of claim 9 , wherein said cancer is resistant to treatment with an androgen receptor antagonist.

14. The method of claim 9 , wherein said administering reduces the levels of AR, AR-full length (AR-FL), AR with antiandrogen resistance-conferring AR-LBD mutations, AR-splice variant (AR-SV), or any combination thereof, in said subject.

15. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of acne in a subject, comprising administering to said subject a therapeutically effective amount of the compound of claim 1 , or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

16. The method of claim 15 , wherein said acne is acne vulgaris.

17. A method of decreasing sebum production in a subject, comprising administering to said subject a therapeutically effective amount of a compound of claim 1 , or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

18. The method of claim 17 , wherein said subject suffers from a dermal disease.

19. The method of claim 18 , wherein said dermal disease is seborrhea, seborrheic dermatitis, acne, or any combination thereof.

20. The method of claim 18 , wherein said subject suffers from overactive sebaceous glands and/or is during the age of puberty.

21. A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of hirsutism in a subject, comprising administering to said subject a therapeutically effective amount of a compound o

Assignees

• Gtx Inc
• Univ Tennessee Res Found

Inventors

• Narayanan Ramesh
• Miller Duane D
• Ponnusamy Thamarai
• Hwang Dong-Jin
• Duke Charles B
• Coss Christopher C
• Jones Amanda
• Dalton James T

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/24

  of the sex hormones · CPC title