Claims for Patent: 10,471,023

Summary for Patent: 10,471,023

Title:	Bisphenol ether derivatives and methods for using the same
Abstract:	Compounds having a structure of Formula I, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R.sup.1, R.sup.2, L.sup.1, L.sup.2, L.sup.3, X, a, b, c, n, and m are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity and uses as therapeutics as well as methods for treatment of subjects in need thereof, including prostate cancer are also provided. ##STR00001##
Inventor(s):	Andersen; Raymond John (Vancouver, CA), Jian; Kunzhong (Vancouver, CA), Sadar; Marianne Dorothy (West Vancouver, CA), Mawji; Nasrin R. (Burnaby, CA), Banuelos; Carmen Adriana (Richmond, CA)
Assignee:	British Columbia Cancer Agency Branch (Vancouver, CA) The University of British Columbia (Vancouver, CA)
Application Number:	15/557,726
Patent Claims:	1. A compound having a structure of Formula (I): ##STR00033## or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: X is --O--, --S(O).sub.0-2--, --C(.dbd.O)--, --C(OR.sup.5).sub.2--, --C(OR.sup.5)(OC(.dbd.O)R.sup.13)--, --C(R.sup.3R.sup.4)--, --C(.dbd.CR.sup.3R.sup.4)--, --N(R.sup.5)--, --N(COR.sup.4)--, --CHNR.sup.5R.sup.6--, --C(.dbd.NR.sup.5)--, --C(.dbd.NOR.sup.5)--, --C(.dbd.N--NHR.sup.7)--; R.sup.1 and R.sup.2 are each independently H, halogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, --OH, --OR.sup.5, --O(C.sub.1-C.sub.6)alkyl, --OC(.dbd.O)R.sup.13, C.sub.1-C.sub.10 acyl, --S(O).sub.0-2R.sup.5, --NO.sub.2, --CN, --NH.sub.2, --NHR.sup.5, --N(R.sup.5R.sup.6), --CO.sub.2H, CO.sub.2R.sup.14, or CONR.sup.5R.sup.6; R.sup.3 and R.sup.4 are each independently H, halogen, --S(O).sub.0-2R.sup.14, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, aralkyl, C.sub.1-C.sub.10 acyl, or --NR.sup.5R.sup.6, or R.sup.3 and R.sup.4 may join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; R.sup.5 and R.sup.6 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, or C.sub.2-C.sub.10 alkynyl; R.sup.7 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, aminocarbonyl, C.sub.1-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenylcarbonyl, C.sub.2-C.sub.10 alkynylcarbonyl, C.sub.1-C.sub.10 alkylaminocarbonyl, C.sub.2-C.sub.10 alkenylaminocarbonyl, or C.sub.2-C.sub.10 alkynylaminocarbonyl; R.sup.13 is each independently C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, or C.sub.2-C.sub.10 alkynyl; R.sup.14 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, or aryl; L.sup.1 is hydroxyl or --OC(.dbd.O)R.sup.13; L.sup.2 and L.sup.3 are each independently H, halogen, hydroxyl, --OC(.dbd.O)R.sup.13, --OC.sub.1-C.sub.10 alkyl, --OC.sub.2-C.sub.10 alkenyl, --OC.sub.2-C.sub.10 alkynyl, --OR.sup.15, --SR.sup.5, --NR.sup.5R.sup.6, --O(C.sub.1-C.sub.10 acyl), --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.2-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.2-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.1-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, carbocyclyl, aryl, or heteroaryl; R.sup.15 is each independently selected from the group consisting of ##STR00034## ##STR00035## ##STR00036## ##STR00037## wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and wherein each L.sup.2 and L.sup.3 is optionally substituted with one or more of halogen, hydroxyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylene-C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenylene-C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkynylene-C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylene-OH, C.sub.2-C.sub.6 alkenylene-OH, or C.sub.2-C.sub.6 alkynylene-OH; a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6; m and n are each independently 0, 1, 2, 3, or 4; and p is 1, 2, 3, or 4. 2. The compound of claim 1, wherein R.sup.1 and R.sup.2 are each independently H or halogen. 3. The compound of claim 1, wherein X is --C(R.sup.3R.sup.4)--. 4. The compound of claim 1, wherein R.sup.3 and R.sup.4 are each C.sub.1-C.sub.10 alkyl. 5. The compound of claim 1, wherein R.sup.3 and R.sup.4 are each methyl. 6. The compound of claim 3, wherein R.sup.3 and R.sup.4 are both C.sub.1 alkyl, and wherein R.sup.3 and R.sup.4 are joined together to form a cyclopropyl ring. 7. The compound of claim 1, wherein R.sup.5 is H or C.sub.1-C.sub.10 alkyl. 8. The compound of claim 1, wherein L.sup.1 is hydroxyl or --OC(.dbd.O)CH.sub.3. 9. The compound of claim 1, wherein L.sup.2 and L.sup.3 are each independently H, hydroxyl, --OC.sub.1-C.sub.10 alkyl, or --OC(.dbd.O)C.sub.1-C.sub.10 alkyl. 10. The compound of claim 1, wherein at least one of L.sup.2 and L.sup.3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, triazine, and tetrazine. 11. The compound of claim 1, wherein a is 1. 12. The compound of claim 1, wherein b is 1. 13. The compound of claim 1, wherein c is 1. 14. The compound of claim 1, wherein the compound has one of the following structures (Ia), (Ib), (Ic) or (Id): ##STR00038## 15. The compound of claim 1 selected from one or more of: ##STR00039## ##STR00040## 16. A pharmaceutical composition, comprising: a compound of formula (I): ##STR00041## or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: X is --O--, --S(O).sub.0-2--, --C(.dbd.O)--, --C(OR.sup.5).sub.2--, --C(OR.sup.5)(OC(.dbd.O)R.sup.13)--, --C(R.sup.3R.sup.4)--, --C(.dbd.CR.sup.3R.sup.4)--, --N(R.sup.5)--, --N(COR.sup.4)--, --CHNR.sup.5R.sup.6--, --C(.dbd.NR.sup.5)--, --C(.dbd.NOR.sup.5)--, --C(.dbd.N--NHR.sup.7)--; R.sup.1 and R.sup.2 are each independently H, halogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, --OH, --OR.sup.5, --O(C.sub.1-C.sub.6)alkyl, --OC(.dbd.O)R.sup.13, C.sub.1-C.sub.10 acyl, --S(O).sub.0-2R.sup.5, --NO.sub.2, --CN, --NH.sub.2, --NHR.sup.5, --N(R.sup.5R.sup.6), --CO.sub.2H, CO.sub.2R.sup.14, or CONR.sup.5R.sup.6; R.sup.3 and R.sup.4 are each independently H, halogen, --S(O).sub.0-2R.sup.14, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, aralkyl, C.sub.1-C.sub.10 acyl, or --NR.sup.5R.sup.6, or R.sup.3 and R.sup.4 may join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; R.sup.5 and R.sup.6 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, or C.sub.2-C.sub.10 alkynyl; R.sup.7 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, aminocarbonyl, C.sub.1-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenylcarbonyl, C.sub.2-C.sub.10 alkynylcarbonyl, C.sub.1-C.sub.10 alkylaminocarbonyl, C.sub.2-C.sub.10 alkenylaminocarbonyl, or C.sub.2-C.sub.10 alkynylaminocarbonyl; R.sup.13 is each independently C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, or C.sub.2-C.sub.10 alkynyl; R.sup.14 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, or aryl; L.sup.1 is hydroxyl or --OC(.dbd.O)R.sup.13; L.sup.2 and L.sup.3 are each independently H, halogen, hydroxyl, --OC(.dbd.O)R.sup.13, --OC.sub.1-C.sub.10 alkyl, --OC.sub.2-C.sub.10 alkenyl, --OC.sub.2-C.sub.10 alkynyl, --OR.sup.15, --SR.sup.5, --NR.sup.5R.sup.6, --O(C.sub.1-C.sub.10 acyl), --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.2-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.2-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.1-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, carbocyclyl, aryl, or heteroaryl; R.sup.15 is each independently selected from the group consisting of ##STR00042## ##STR00043## ##STR00044## ##STR00045## wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and wherein each L.sup.2 and L.sup.3 is optionally substituted with one or more of halogen, hydroxyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylene-C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenylene-C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkynylene-C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylene-OH, C.sub.2-C.sub.6 alkenylene-OH, or C.sub.2-C.sub.6 alkynylene-OH; a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6; m and n are each independently 0, 1, 2, 3, or 4; and p is 1, 2, 3, or 4. 17. The pharmaceutical composition of claim 16, further comprising a pharmaceutically acceptable carrier. 18. The pharmaceutical composition of claim 16, further comprising a pharmaceutically acceptable carrier and an additional therapeutic agent. 19. The pharmaceutical composition of claim 18, wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age-related macular degeneration, or combinations thereof. 20. The pharmaceutical composition of claim 18, wherein the additional therapeutic agent is enzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, radium 233, or related compounds thereof. 21. A method for modulating androgen receptor activity, comprising: administering a pharmaceutical composition according to claim 16 to a patient in need thereof. 22. A method for treating a condition or disease that is responsive to modulation of androgen receptor activity, comprising: administering a pharmaceutical composition according to claim 16 to a patient in need thereof, wherein said condition or disease is selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. 23. The method of claim 22, wherein the condition or disease is prostate cancer. 24. The method of claim 22, wherein the condition or disease is castration resistant prostate cancer. 25. The method of claim 22, wherein the condition or disease is androgen-dependent prostate cancer. 26. A method for treating a condition or disease selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration, comprising: administering to a patient in need thereof a compound having the following structure (I): ##STR00046## or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: X is --O--, --S(O).sub.0-2--, --C(.dbd.O)--, --C(OR.sup.5).sub.2--, --C(OR.sup.5)(OC(.dbd.O)R.sup.13)--, --C(R.sup.3R.sup.4)--, --C(.dbd.CR.sup.3R.sup.4)--, --N(R.sup.5)--, --N(COR.sup.4)--, --CHNR.sup.5R.sup.6--, --C(.dbd.NR.sup.5)--, --C(.dbd.NOR.sup.5)--, --C(.dbd.N--NHR.sup.7)--; R.sup.1 and R.sup.2 are each independently H, halogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, --OH, --OR.sup.5, --O(C.sub.1-C.sub.6)alkyl, --OC(.dbd.O)R.sup.13, C.sub.1-C.sub.10 acyl, --S(O).sub.0-2R.sup.5, --NO.sub.2, --CN, --NH.sub.2, --NHR.sup.5, --N(R.sup.5R.sup.6), --CO.sub.2H, CO.sub.2R.sup.14, or CONR.sup.5R.sup.6; R.sup.3 and R.sup.4 are each independently H, halogen, --S(O).sub.0-2R.sup.14, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, aralkyl, C.sub.1-C.sub.10 acyl, or --NR.sup.5R.sup.6, or R.sup.3 and R.sup.4 may join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; R.sup.5 and R.sup.6 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, or C.sub.2-C.sub.10 alkynyl; R.sup.7 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, aminocarbonyl, C.sub.1-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenylcarbonyl, C.sub.2-C.sub.010 alkynylcarbonyl, C.sub.1-C.sub.10 alkylaminocarbonyl, C.sub.2-C.sub.10 alkenylaminocarbonyl, or C.sub.2-C.sub.10 alkynylaminocarbonyl; R.sup.13 is each independently C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, or C.sub.2-C.sub.10 alkynyl; R.sup.14 is each independently H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, or aryl; L.sup.1 is hydroxyl or --OC(.dbd.O)R.sup.13; L.sup.2 and L.sup.3 are each independently H, halogen, hydroxyl, --OC(.dbd.O)R.sup.13, --OC.sub.1-C.sub.10 alkyl, --OC.sub.2-C.sub.10 alkenyl, --OC.sub.2-C.sub.10 alkynyl, --OR.sup.15, --SR.sup.5, --NR.sup.5R.sup.6, --O(C.sub.1-C.sub.10 acyl), --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, --OC.sub.1-C.sub.10 alkylene-(-O--C.sub.2-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.2-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkenylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.1-C.sub.10 alkyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.1-C.sub.10 alkenyl).sub.p, --OC.sub.2-C.sub.10 alkynylene-(-O--C.sub.2-C.sub.10 alkynyl).sub.p, carbocyclyl, aryl, or heteroaryl; R.sup.15 is each independently selected from the group consisting of ##STR00047## ##STR00048## ##STR00049## ##STR00050## wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and wherein each L.sup.2 and L.sup.3 is optionally substituted with one or more of halogen, hydroxyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylene-C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenylene-C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkynylene-C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylene-OH, C.sub.2-C.sub.6 alkenylene-OH, or C.sub.2-C.sub.6 alkynylene-OH; a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6; m and n are each independently 0, 1, 2, 3, or 4; and p is 1, 2, 3, or 4. 27. The method of claim 26, wherein the condition or disease is prostate cancer. 28. The method of claim 26, wherein the condition or disease is castration resistant prostate cancer or androgen-dependent prostate cancer.

Details for Patent 10,471,023

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2035-03-12
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2035-03-12