阅读说明：本技术 三部分组成的雄激素受体消除剂、其方法和用途 (Three-part androgen receptor eliminators, methods and uses thereof ) 是由 卓利·沙波斯尼克 于 2018-05-01 设计创作，主要内容包括：本说明书公开了三部分组成的雄激素受体消除剂(ARE)、包含这样的ARE的药物组合物和药物、这样的ARE和组合物和药物的方法和用途、以及ARE和组合物和药物用于治疗雄激素受体信号传导介导的状况、疾病或紊乱的方法和用途。(The present specification discloses three-part Androgen Receptor Eliminators (AREs), pharmaceutical compositions and medicaments comprising such AREs, methods and uses of such AREs and compositions and medicaments, and methods and uses of AREs and compositions and medicaments for treating androgen receptor signaling mediated conditions, diseases, or disorders.)

1. A compound of formula I wherein ARA is an AR antagonist, L is a linker molecule, and EE is an AR elimination facilitator or AR elimination enhancer element.

2. The compound of claim 1, wherein the AR antagonist comprises apalutamide, bicalutamide, canrenone, chlormadinone acetate, cimetidine, compound ARA1, cyproterone acetate, drospirenone, enzalutamide, flutamide, ketoconazole, megestrol acetate, methoxybenzyllactam, nilutamide, RU58841, spironolactone, or topilutamide (flurodil).

3. The compound of claim 1 or 2, wherein the linker molecule is:

formula II:

wherein R is¹And R²Each independently of the other is H, OH, COOH, NH₂、R³OH、R³COOH、OR³OH、OR³COOH、R³NH(CO)R⁴、R³NH(CO)R⁴OH、R³NH(CO)R⁴COOH；R³And R⁴Each independently is C_1-10Alkyl radical, C_2-10Alkenyl or C_2-10An alkynyl group; and n is any integer from 0 to 10;

formula III:

wherein n is any integer from 0 to 10;

formula IV:

wherein n is any integer from 0 to 10;

formula V:

wherein n is any integer from 0 to 10;

formula VI:

wherein n is any integer from 0 to 10;

formula VII:

wherein n is any integer from 0 to 10;

formula VIII:

wherein n is any integer from 0 to 10;

formula IX:

wherein n is any integer from 0 to 10;

formula X:

wherein n is any integer from 0 to 10.

4. The compound of any one of claims 1-3, wherein the AR elimination facilitator or enhancing element is a hydrophobic tag or E3 ligase recruiting portion.

5. The compound of claim 4, wherein the hydrophobic tag is an adamantane moiety, a Boc protected amino acid, or a hypoxia inducible factor 1 α (HIF-1 α) moiety.

6. The compound of claim 5, wherein the adamantane moiety is of formula XI:

wherein R is⁵Is H, OH, COOH, NH₂Halogen, R⁶OH、R⁶COOH、R⁶C(O)NH₂Or R⁶C(O)R⁷；R⁶Is C_1-10Alkyl radical, C_2-10Alkenyl or C_2-10An alkynyl group; and R is⁷Is a halogen.

7. The compound of claim 5, wherein the Boc protected amino acid comprises glutamine, arginine, glutamic acid, phenylalanine, aspartic acid, cysteine, lysine, or asparagine.

8. The compound of claim 5, wherein the HIF-1 α moiety is of formula XII:

wherein R is⁸Is H, OH, COOH, NH₂Halogen, R⁹OH、R⁹COOH、R⁹C(O)NH₂Or R⁹C(O)R¹⁰；R⁹Is C_1-10Alkyl radical, C_2-10Alkenyl or C_2-10An alkynyl group; and R is¹⁰Is a halogen.

9. The compound of claim 4, wherein the E3 ligase recruitment moiety is a Nutlin moiety, a Betadine moiety, or a phthalimide moiety.

10. The compound of claim 9, wherein the Nutlin moiety is of formula XIII:

wherein R is¹¹Is H, OH, COOH, NH₂Halogen, R¹²OH、R¹²COOH、R¹²C(O)NH₂Or R¹²C(O)R¹³；R¹²Is C_1-10Alkyl radical, C_2-10Alkenyl or C_2-10An alkynyl group; and R is¹³Is a halogen.

11. The compound of claim 9, wherein the betadine moiety is of formula XIV:

wherein R is¹⁴Is H, OH, COOH, NH₂Halogen, R¹⁵OH、R¹⁵COOH、R¹⁵C(O)NH₂Or R¹⁵C(O)R¹⁶；R¹⁵Is C_1-10Alkyl radical, C_2-10Alkenyl or C_2-10An alkynyl group; and R is¹⁶Is a halogen.

12. The compound of claim 9, wherein the phthalimide moiety is of formula XV:

wherein R is¹⁷Is H, OH, COOH, NH₂Halogen, R¹⁹OH、R¹⁹COOH、R¹⁹C(O)NH₂Or R¹⁹C(O)R²⁰、NHR¹⁹OH、NHR¹⁹COOH、NHR¹⁹C(O)NH₂Or NHR¹⁹C(O)R²⁰；R¹⁸Is H, OH, O, COOH or C_1-6；R¹⁹Is C_1-10Alkyl radical, C_2-10Alkenyl or C_2-10An alkynyl group; and R is²⁰Is a halogen.

13. The compound of any one of claims 1-12, wherein the compound has formula XX

Wherein n is any integer from 0 to 10.

14. The compound of any one of claims 1-12, wherein the compound has formula XXI

Wherein n is any integer from 0 to 10.

15. The compound of any one of claims 1-12, wherein the compound is of formula XXII below

Wherein n is any integer from 0 to 10.

16. The compound of any one of claims 1-12, wherein the compound is of formula XXIII below

Wherein n is any integer from 0 to 10.

17. A pharmaceutical composition comprising a compound according to any one of claims 1-16.

18. The pharmaceutical composition of claim 17, further comprising one or more pharmaceutically acceptable carriers and/or one or more pharmaceutically acceptable components.

19. The pharmaceutical composition according to claim 18, comprising 0.1% to 10% of the compound according to any one of claims 1-16, 20% to 40% denatured ethanol, 40% to 60% isopropyl myristate, and 10% to 30% Transcutol.

20. The pharmaceutical composition according to claim 19, comprising 0.5% to 5% of the compound according to any one of claims 1-16, 25% to 35% denatured ethanol, 45% to 55% isopropyl myristate, and 15% to 25% Transcutol.

21. A method of treating hair loss, hair thinning, hair depigmentation, conditions associated with degenerative hair follicle disorders, and/or improving hair appearance in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20.

22. A method of treating a skin condition in an individual comprising the step of administering to the individual a therapeutically effective amount of a compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20.

23. The method of claim 22, wherein the skin condition comprises acne, overproduction of sebum, scar formation after a wound, or a dermatological problem associated with polycystic ovarian disease.

24. A compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20 for use in treating hair loss, hair thinning, hair depigmentation, conditions associated with degenerative hair follicle disorders and/or improving hair appearance in a subject.

25. A compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20 for use in the treatment of a skin condition.

26. Use of a compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20 for treating hair loss, hair thinning, hair depigmentation, conditions associated with degenerative hair follicle disorders and/or improving hair appearance in a subject.

27. Use of a compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20 for the treatment of a skin condition.

28. Use of a compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20 in the manufacture of a medicament for treating hair loss, hair thinning, hair depigmentation, conditions associated with degenerative hair follicle disorders, and/or improving hair appearance in a subject.

29. Use of a compound as defined in any one of claims 1 to 16 or a pharmaceutical composition as defined in any one of claims 17 to 20 in the manufacture of a medicament for the treatment of a skin condition.

30. The use of any one of claims 25, 27, or 29, wherein the skin condition comprises acne, overproduction of sebum, scar formation after a wound, or a dermatological problem associated with polycystic ovarian disease.

Examples

The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the representative embodiments now contemplated. These examples should not be construed as limiting any of the embodiments described in this specification, including those relating to the compounds, pharmaceutical compositions, or methods and uses disclosed herein.