Heterocyclic compounds for cancer imaging and treatment and methods for their use
10654811 ยท 2020-05-19
Assignee
- The University Of British Columbia (Vancouver, CA)
- British Columbia Cancer Agency Branch (Vancouver, CA)
Inventors
- Raymond John Andersen (Vancouver, CA)
- Javier Garcia Fernandez (Asturias, ES)
- Kunzhong JIAN (Vancouver, CA)
- Marianne Dorothy Sadar (West Vancouver, CA)
- Nasrin R. Mawji (Burnaby, CA)
- Carmen Adriana Banuelos (Richmond, CA)
Cpc classification
A61K45/06
HUMAN NECESSITIES
A61K51/0459
HUMAN NECESSITIES
A61K51/0453
HUMAN NECESSITIES
A61K51/0465
HUMAN NECESSITIES
C07D295/084
CHEMISTRY; METALLURGY
C07D249/04
CHEMISTRY; METALLURGY
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
C07D233/60
CHEMISTRY; METALLURGY
A61K51/0463
HUMAN NECESSITIES
International classification
C07D249/04
CHEMISTRY; METALLURGY
C07B59/00
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
C07D233/60
CHEMISTRY; METALLURGY
C07D295/084
CHEMISTRY; METALLURGY
Abstract
Compounds having a structure of Formula I: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.11a, R.sup.11b, R.sup.11c, R.sup.11d, X, n.sup.1, n.sup.2, and n.sup.3 are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of subjects in need thereof, including prostate cancer are also provided. ##STR00001##
Claims
1. A compound having the following structure (I): ##STR00309## or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: X is O, S(O).sub.0-2, C(O), C(OR.sup.5).sub.2, C(OR.sup.5)(OC(O)R.sup.13), C(R.sup.8R.sup.9), C(CR.sup.8R.sup.9), N(R.sup.9), N(COR.sup.9), CHNR.sup.8R.sup.9, C(NR.sup.9), C(NOR.sup.5), or C(NNHR.sup.5); R.sup.1 is H, hydroxyl, O-heterocyclyl, or OC(O)R.sup.13; R.sup.2 is hydroxyl, O-heterocyclyl, or OC(O)R.sup.13; R.sup.3 is N.sub.3 or heteroaryl, each R.sup.3 is optionally substituted with one or more R.sup.6; R.sup.5 is each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.6 is each independently selected from the group consisting of H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, and C.sub.6-C.sub.12 aryl, wherein each R.sup.6 is optionally substituted with one or more of halogen, .sup.123I, .sup.18F, hydroxyl, OS(O).sub.2-aryl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.8 and R.sup.9 are each independently H, halogen, S(O).sub.0-2R.sup.5, 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.5, or R.sup.8 and R.sup.9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; R.sup.11a, R.sup.11b, R.sup.11c, and R.sup.11d are each independently H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, OR.sup.5, OC(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, or N(R.sup.5).sub.2; R.sup.13 is each independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; n.sup.1 and n.sup.2 are each independently 0, 1, or 2; and n.sup.3 is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1, wherein X is C(R.sup.8R.sup.9).
3. The compound of claim 1, wherein R.sup.8 and R.sup.9 are C.sub.1-C.sub.10 alkyl.
4. The compound of claim 1, wherein R.sup.8 and R.sup.9 are methyl.
5. The compound of claim 1, wherein R.sup.3 is 5-6 membered heteroaryl, wherein the heteroaryl comprises at least one N atom in the ring.
6. The compound of claim 1, wherein R.sup.3 is selected from the group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, triazine, azepine, and tetrazine.
7. The compound of claim 1, wherein R.sup.3 is substituted with at least one .sup.123I or I.
8. The compound of claim 1, wherein R.sup.3 is substituted with at least one R.sup.6, wherein at least one R.sup.6 is further substituted with at least one of .sup.123I, I, or .sup.18F.
9. The compound of claim 1, wherein at least one R.sup.6 is C.sub.1-C.sub.6 alkyl, wherein at least one R.sup.6 is further substituted with at least one of .sup.123I, I, or .sup.18F.
10. The compound of claim 1, wherein each R.sup.13 is independently methyl, ethyl or propyl.
11. The compound of claim 1, wherein each R.sup.13 is methyl.
12. The compound of claim 1, wherein at least one of R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is Cl, Br, I or .sup.123I.
13. The compound of claim 1, wherein at least one of R.sup.6, R.sup.11aR.sup.11b, R.sup.11c and R.sup.11d is I; and at least one of R.sup.6, R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is .sup.123I.
14. The compound of claim 1, wherein n.sup.3 is 0, 1, or 2.
15. The compound of claim 1, wherein the compound has one of the following structures: ##STR00310## ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
16. The compound of claim 1, wherein the compound has one of the following structures: ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
17. A pharmaceutical composition, comprising: a compound of formula (I): ##STR00360## or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: X is O, S(O).sub.0-2, C(O), C(OR.sup.5).sub.2, C(OR.sup.5)(OC(O)R.sup.13), C(R.sup.8R.sup.9), C(CR.sup.8R.sup.9), N(R.sup.9), N(COR.sup.9), CHNR.sup.8R.sup.9, C(NR.sup.9), C(NOR.sup.5), or C(NNHR.sup.5); R.sup.1 is H, hydroxyl, O-heterocyclyl, or OC(O)R.sup.13; R.sup.2 is hydroxyl, O-heterocyclyl, or OC(O)R.sup.13; R.sup.3 is N.sub.3 or heteroaryl, each R.sup.3 is optionally substituted with one or more R.sup.6; R.sup.5 is each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.6 is each independently selected from the group consisting of H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, and C.sub.6-C.sub.12 aryl, wherein each R.sup.6 is optionally substituted with one or more of halogen, .sup.123I, .sup.18F, hydroxyl, OS(O).sub.2-aryl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.8 and R.sup.9 are each independently H, halogen, S(O).sub.0-2R.sup.5, 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.5, or R.sup.8 and R.sup.9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are each independently H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, OR.sup.5, OC(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, or N(R.sup.5).sub.2; R.sup.13 is each independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; n.sup.1 and n.sup.2 are each independently 0, 1, or 2; and n.sup.3 is 0, 1, 2, 3, 4, or 5.
18. The pharmaceutical composition of claim 17, further comprising a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 17, further comprising a pharmaceutically acceptable carrier and an additional therapeutic agent.
20. The pharmaceutical composition of claim 19, 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, or age-related macular degeneration.
21. The pharmaceutical composition of claim 19, 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, 5-alpha reductase inhibitor, darolutamide, radium 233, or related compounds thereof.
22. A method for modulating androgen receptor activity, comprising: administering a pharmaceutical composition according to claim 17 to a patient in need thereof.
23. 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 17 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.
24. The method of claim 23, wherein the condition or disease is prostate cancer.
25. The method of claim 23, wherein the condition or disease is castration resistant prostate cancer.
26. The method of claim 23, wherein the condition or disease is androgen-dependent prostate cancer.
27. 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): ##STR00361## or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: X is O, S(O).sub.0-2, C(O), C(OR.sup.5).sub.2, C(OR.sup.5)(OC(O)R.sup.13), C(R.sup.8R.sup.9), C(CR.sup.8R.sup.9), N(R.sup.9), N(COR.sup.9), CHNR.sup.8R.sup.9, C(NR.sup.9), C(NOR.sup.5), or C(NNHR.sup.5); R.sup.1 is H, hydroxyl, O-heterocyclyl, or OC(O)R.sup.13; R.sup.2 is hydroxyl, O-heterocyclyl, or OC(O)R.sup.13; R.sup.3 is N.sub.3 or heteroaryl, each R.sup.3 is optionally substituted with one or more R.sup.6; R.sup.5 is each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.6 is each independently selected from the group consisting of H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, and C.sub.6-C.sub.12 aryl, wherein each R.sup.6 is optionally substituted with one or more of halogen, .sup.123I, .sup.18F, hydroxyl, OS(O).sub.2-aryl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.8 and R.sup.9 are each independently H, halogen, S(O).sub.0-2R.sup.5, 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.5, or R.sup.8 and R.sup.9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are each independently H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, OR.sup.5, OC(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, or N(R.sup.5).sub.2; R.sup.13 is each independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; n.sup.1 and n.sup.2 are each independently 0, 1, or 2; and n.sup.3 is 0, 1, 2, 3, 4, or 5.
28. The method of claim 27, wherein the condition or disease is prostate cancer.
29. The method of claim 27, wherein the condition or disease is castration resistant prostate cancer or androgen-dependent prostate cancer.
30. A method of imaging cancer, the method comprising administering a compound of claim 1 to a subject and detecting the presence or absence of cancer by use of SPECT or PET.
31. The method of claim 30, wherein the method identifies the presence or absence of a tumor.
32. The method of claim 30, wherein the method identifies the location of a tumor.
33. The method of claim 30, wherein the cancer is prostate cancer.
34. The method of claim 30, wherein the compound of claim 1 is selected from the group consisting of: ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
35. A method of imaging cancer, the method comprising administering the pharmaceutical composition of claim 17 to a subject and detecting the presence or absence of cancer by use of SPECT or PET.
36. The compound of claim 1, wherein the compound has one of the following structures: ##STR00388## or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R.sup.11c is H, Cl, Br, I, F, or C.sub.1-C.sub.6 alkyl.
37. The compound of claim 1, wherein the compound has one of the following structures: ##STR00389## or a pharmaceutically acceptable salt thereof; wherein R.sup.11c is H, Cl, Br, I, F, or C.sub.1-C.sub.6 alkyl.
Description
BRIEF DESCRIPTION OF THE FIGURES
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DETAILED DESCRIPTION
I. Definitions
(18) In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word comprise and variations thereof, such as, comprises and comprising are to be construed in an open, inclusive sense, that is, as including, but not limited to. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
(19) Reference throughout this specification to one embodiment or an embodiment means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases in one embodiment or in an embodiment in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms a, an, and the include plural referents unless the content clearly dictates otherwise. It should also be noted that the term or is generally employed in its sense including and/or unless the content clearly dictates otherwise.
(20) The terms below, as used herein, have the following meanings, unless indicated otherwise:
(21) Amino refers to the NH.sub.2 radical.
(22) Cyano refers to the CN radical.
(23) Halo or halogen refers to bromo, chloro, fluoro or iodo radical.
(24) Hydroxy or hydroxyl refers to the OH radical.
(25) Imino refers to the NH substituent.
(26) Nitro refers to the NO.sub.2 radical.
(27) Oxo refers to the O substituent.
(28) Thioxo refers to the S substituent.
(29) Alkyl or alkyl group refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C.sub.1-C.sub.12 alkyl, an alkyl comprising up to 10 carbon atoms is a C.sub.1-C.sub.10 alkyl, an alkyl comprising up to 6 carbon atoms is a C.sub.1-C.sub.6 alkyl and an alkyl comprising up to 5 carbon atoms is a C.sub.1-C.sub.5 alkyl. A C.sub.1-C.sub.5 alkyl includes C.sub.5 alkyls, C.sub.4 alkyls, C.sub.3 alkyls, C.sub.2 alkyls and C.sub.1 alkyl (i.e., methyl). A C.sub.1-C.sub.6 alkyl includes all moieties described above for C.sub.1-C.sub.5 alkyls but also includes C.sub.6 alkyls. A C.sub.1-C.sub.10 alkyl includes all moieties described above for C.sub.1-C.sub.5 alkyls and C.sub.1-C.sub.6 alkyls, but also includes C.sub.7, C.sub.8, C.sub.9 and C.sub.10 alkyls. Similarly, a C.sub.1-C.sub.12 alkyl includes all the foregoing moieties, but also includes C.sub.11 and C.sub.12 alkyls. Non-limiting examples of C.sub.1-C.sub.12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
(30) Alkylene or alkylene chain refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C.sub.1-C.sub.12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
(31) Alkenyl or alkenyl group refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C.sub.2-C.sub.12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C.sub.2-C.sub.10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C.sub.2-C.sub.6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C.sub.2-C.sub.5 alkenyl. A C.sub.2-C.sub.5 alkenyl includes C.sub.5 alkenyls, C.sub.4 alkenyls, C.sub.3 alkenyls, and C.sub.2 alkenyls. A C.sub.2-C.sub.6 alkenyl includes all moieties described above for C.sub.2-C.sub.5 alkenyls but also includes C.sub.6 alkenyls. A C.sub.2-C.sub.10 alkenyl includes all moieties described above for C.sub.2-C.sub.5 alkenyls and C.sub.2-C.sub.6 alkenyls, but also includes C.sub.7, C.sub.8, C.sub.9 and C.sub.10 alkenyls. Similarly, a C.sub.2-C.sub.12 alkenyl includes all the foregoing moieties, but also includes C.sub.11 and C.sub.12 alkenyls. Non-limiting examples of C.sub.2-C.sub.12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
(32) Alkenylene or alkenylene chain refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C.sub.2-C.sub.12 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.
(33) Alkynyl or alkynyl group refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C.sub.2-C.sub.12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C.sub.2-C.sub.10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C.sub.2-C.sub.6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C.sub.2-C.sub.5 alkynyl. A C.sub.2-C.sub.5 alkynyl includes C.sub.5 alkynyls, C.sub.4 alkynyls, C.sub.3 alkynyls, and C.sub.2 alkynyls. A C.sub.2-C.sub.6 alkynyl includes all moieties described above for C.sub.2-C.sub.5 alkynyls but also includes C.sub.6 alkynyls. A C.sub.2-C.sub.10 alkynyl includes all moieties described above for C.sub.2-C.sub.5 alkynyls and C.sub.2-C.sub.6 alkynyls, but also includes C.sub.7, C.sub.8, C.sub.9 and C.sub.10 alkynyls. Similarly, a C.sub.2-C.sub.12 alkynyl includes all the foregoing moieties, but also includes C.sub.11 and C.sub.12 alkynyls. Non-limiting examples of C.sub.2-C.sub.12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
(34) Alkynylene or alkynylene chain refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C.sub.2-C.sub.12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
(35) Alkoxy refers to a radical of the formula OR.sub.a where R.sub.a is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
(36) Alkylamino refers to a radical of the formula NHR.sub.a or NR.sub.aR.sub.a where each R.sub.a is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.
(37) Alkylcarbonyl refers to the C(O)R.sub.a moiety, wherein R.sub.a is an alkyl, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl (acetal) moiety. Alkylcarbonyl groups can also be referred to as Cw-Cz acyl where w and z depicts the range of the number of carbon in R.sub.a, as defined above. For example, C.sub.1-C.sub.10 acyl refers to alkylcarbonyl group as defined above, where R.sub.a is C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkenyl, or C.sub.1-C.sub.10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
(38) Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term aryl is meant to include aryl radicals that are optionally substituted.
(39) Aralkyl refers to a radical of the formula R.sub.bR.sub.c where R.sub.b is an alkylene, alkenylene or alkynylene group as defined above and R, is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
(40) Carbocyclyl, carbocyclic ring or carbocycle refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
(41) Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
(42) Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2. I]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
(43) Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
(44) Cycloalkylalkyl refers to a radical of the formula R.sub.bR.sub.d where R.sub.b is an alkylene, alkenylene, or alkynylene group as defined above and R.sub.d is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.
(45) Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.
(46) Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
(47) Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
(48) Heterocyclyl, heterocyclic ring or heterocycle refers to a stable 3- to 20-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclyl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.
(49) N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.
(50) Heterocyclylalkyl refers to a radical of the formula R.sub.bR.sub.c where R.sub.b is an alkylene, alkenylene, or alkynylene chain as defined above and R.sub.c is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to the alkyl, alkenyl, alkynyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.
(51) Heteroaryl refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.
(52) N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.
(53) Heteroarylalkyl refers to a radical of the formula R.sub.bR.sub.f where R.sub.b is an alkylene, alkenylene, or alkynylene chain as defined above and R.sub.f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.
(54) .sup.123I refers to the radioactive isotope of iodine having atomic mass 123. The compounds of Formula I can comprise at least one .sup.123I moiety. Throughout the present application, where structures depict a .sup.123I moiety at a certain position it is meant that the I moiety at this position is enriched for .sup.123I. In other words, the compounds contain more than the natural abundance of .sup.123I at the indicated position(s). It is not required that the compounds comprise 100% .sup.123I at the indicated positions, provided .sup.123I is present in more than the natural abundance. Typically the .sup.123I isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 80% or greater than 90%, relative to .sup.127I.
(55) .sup.18F refers to the radioactive isotope of fluorine having atomic mass 18. F or .sup.19F refers to the abundant, non-radioactive fluorine isotope having atomic mass 19. The compounds of Formula I can comprise at least one .sup.18F moiety. Throughout the present application, where structures depict a .sup.18F moiety at a certain position it is meant that the F moiety at this position is enriched for .sup.18F. In other words, the compounds contain more than the natural abundance of .sup.18F at the indicated position(s). It is not required that the compounds comprise 100% .sup.18F at the indicated positions, provided .sup.18F is present in more than the natural abundance. Typically the .sup.18F isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90%, relative to .sup.19F.
(56) Thioalkyl refers to a radical of the formula SR.sub.a where R.sub.a is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
(57) The term substituted used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, substituted includes any of the above groups in which one or more hydrogen atoms are replaced with NR.sub.gR.sub.h, NR.sub.gC(O)R.sub.h, NR.sub.gC(O)NR.sub.gR.sub.h, NR.sub.gC(O)OR.sub.h, NR.sub.gSO.sub.2R.sub.h, OC(O)NR.sub.gR.sub.h, OR.sub.g, SR.sub.g, SOR.sub.g, SO.sub.2R.sub.g, OSO.sub.2R.sub.g, SO.sub.2OR.sub.g, NSO.sub.2R.sub.g, and SO.sub.2NR.sub.gR.sub.h. Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with C(O)R.sub.g, C(O)OR.sub.g, C(O)NR.sub.gR.sub.h, CH.sub.2SO.sub.2R.sub.g, CH.sub.2SO.sub.2NR.sub.gR.sub.h. In the foregoing, R.sub.g and R.sub.h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. Substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.
(58) As used herein, the symbol
(59) ##STR00003##
(hereinafter can be referred to as a point of attachment bond) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example,
(60) ##STR00004##
indicates that the chemical entity XY is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound CH.sub.3R.sup.3, wherein R.sup.3 is H or
(61) ##STR00005##
infers that when R.sup.3 is XY, the point of attachment bond is the same bond as the bond by which R.sup.3 is depicted as being bonded to CH.sub.3.
(62) Fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring can be replaced with a nitrogen atom.
(63) The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products can result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
(64) Stable compound and stable structure are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
(65) As used herein, a subject can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. The subject can be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of ordinary skill in the art.
(66) Mammal includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
(67) Optional or optionally means that the subsequently described event of circumstances can or can not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, optionally substituted aryl means that the aryl radical can or can not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
(68) Pharmaceutically acceptable carrier, diluent or excipient includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
(69) Pharmaceutically acceptable salt includes both acid and base addition salts.
(70) Pharmaceutically acceptable acid addition salt refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
(71) Pharmaceutically acceptable base addition salt refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
(72) Often crystallizations produce a solvate of the compound of the invention. As used herein, the term solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention can be true solvates, while in other cases, the compound of the invention can merely retain adventitious water or be a mixture of water plus some adventitious solvent.
(73) A pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
(74) An effective amount refers to a therapeutically effective amount or a prophylactically effective amount. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a compound can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to a castration-resistant form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount can be less than a therapeutically effective amount.
(75) Treating or treatment as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
(76) (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;
(77) (ii) inhibiting the disease or condition, i.e., arresting its development;
(78) (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or
(79) (iv) relieving the symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition. As used herein, the terms disease and condition can be used interchangeably or can be different in that the particular malady or condition can not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
(80) The compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
(81) A stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes enantiomers, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
(82) A tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.
(83) The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program, ChemDraw Ultra Version 11.0.1 and/or ChemDraw Ultra Version 14.0 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
(84) Throughout the present specification, the terms about and/or approximately can be used in conjunction with numerical values and/or ranges. The term about is understood to mean those values near to a recited value. For example, about 40 [units] can mean within 25% of 40 (e.g., from 30 to 50), within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, less than 1%, or any other value or range of values therein or therebelow. Furthermore, the phrases less than about [a value] or greater than about [a value] should be understood in view of the definition of the term about provided herein. The terms about and approximately can be used interchangeably.
(85) Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range from 50 to 80 includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range can be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
II. Compounds and Pharmaceutical Compositions
(86) As noted above, certain embodiments of the present invention are directed to compounds useful for treatment of various cancers, including various types of prostate cancers. While not wishing to be bound by theory, it is believed that binding of the compounds to the androgen receptor (for example at the N-terminal domain) can contribute to the activity of the disclosed compounds. The compounds of the present invention include novel heteroaryl, aryl, heterocyclyl, or carbocyclyl groups (i.e., R.sup.3 in Formula I) which impart improved properties to the compounds compared to compounds lacking the described R.sup.3 moiety. For example, the improved properties include improved drug-like properties such as improved activity (e.g., androgen receptor (AR) modulation), longer half-life (e.g., in vivo); decreased toxicity; better solubility, improved formulation, better bioavailability, better pharmacokinetic profile; reduction in unwanted metabolites and the like.
(87) In one embodiment the invention includes compounds which form covalent bonds with the androgen receptor (AR) (e.g., at the N-terminal domain), thus resulting in irreversible (or substantially irreversible) inhibition of the same. In this regard, the certain compounds of the present invention are designed to include functional groups capable of forming covalent bonds with a nucleophile under certain in vivo conditions. For example, in some embodiments the reactivity of compounds of the present invention is such that they will not substantially react with various nucleophiles (e.g., glutathione) when the compounds are free in solution. However, when the free mobility of the compounds is restricted, and an appropriate nucleophile is brought into close proximity to the compound, for example when the compounds associate with, or bind to, the androgen receptor, the compounds are capable of forming covalent bonds with certain nucleophiles (e.g., thiols).
(88) The present invention includes all compounds which have the above described properties (i.e., binding to androgen receptor (AR)). In one embodiment, the present invention is directed to a compound having a structure of Formula I:
(89) ##STR00006##
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
(90) X is O, S(O).sub.0-2, C(O), C(OR.sup.5).sub.2, C(OR.sup.5)(OC(O)R.sup.13), C(R.sup.8R.sup.9), C(CR.sup.8R.sup.9), N(R.sup.9), N(COR.sup.9), CHNR.sup.8R.sup.9, C(NR.sup.9), C(NOR.sup.5), C(NNHR.sup.5);
(91) R.sup.1 and R.sup.2 are each independently H, hydroxyl, O-heterocyclyl, or OC(O)R.sup.13;
(92) R.sup.3 is N.sub.3, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R.sup.6;
(93) R.sup.5 is each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(94) R.sup.6 is each independently selected from the group consisting of H, F, Cl, Br, I, .sup.123I, hydroxyl, oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.12 aryl, wherein each R.sup.6 is optionally substituted with one or more of halogen, .sup.123I, .sup.18F, hydroxyl, OS(O).sub.2-aryl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(95) R.sup.8 and R.sup.9 are each independently H, halogen, S(O).sub.0-2R.sup.5, 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.5, or R.sup.8 and R.sup.9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms;
(96) R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are each independently H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; OR.sup.5, OC(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, or N(R.sup.5).sub.2;
(97) R.sup.13 is each independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(98) n.sup.1 and n.sup.2 are each independently 0, 1, or 2; and
(99) n.sup.3 is 0, 1, 2, 3, 4, or 5.
(100) Accordingly, certain embodiments of the present invention are directed to compounds that bind to the AR NTD and are useful for imaging of tumors with splice variants using SPECT and/or methods of modulating AR NTD activity. Other embodiments are directed to compound and methods useful for imaging and/or treating benign prostate conditions or diseases. In one embodiment, the present disclosure provides a compound having a structure of Formula I:
(101) ##STR00007##
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
(102) X is O, S(O).sub.0-2, C(O), C(OR.sup.5).sub.2, C(OR.sup.5)(OC(O)R.sup.13), C(R.sup.8R.sup.9), C(CR.sup.8R.sup.9), N(R.sup.9), N(COR.sup.9), CHNR.sup.8R.sup.9, C(NR.sup.9), C(NOR.sup.5), C(NNHR.sup.5);
(103) R.sup.1 and R.sup.2 are each independently H, hydroxyl, O-heterocyclyl, or OC(O)R.sup.13;
(104) R.sup.3 is N.sub.3, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R.sup.6;
(105) R.sup.5 is each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(106) R.sup.6 is each independently selected from the group consisting of H, F, Cl, Br, I, .sup.123I, hydroxyl, oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.12 aryl, wherein each R.sup.6 is optionally substituted with one or more of halogen, .sup.123I, .sup.18F, hydroxyl, OS(O).sub.2-aryl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(107) R.sup.8 and R.sup.9 are each independently H, halogen, S(O).sub.0-2R.sup.5, 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.5, or R.sup.8 and R.sup.9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms;
(108) R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are each independently H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; OR.sup.5, OC(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, or N(R.sup.5).sub.2;
(109) R.sup.13 is each independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(110) n.sup.1 and n.sup.2 are each independently 0, 1, or 2; and
(111) n.sup.3 is 0, 1, 2, 3, 4, or 5.
(112) In various embodiments, different stereoisomers of the compound of structure (I) are provided, for example in some embodiments the compound has one of the following structures (Ia), (Ib), (Ic) or (Id):
(113) ##STR00008##
(114) In still other embodiments, the compound has one of the following structures (Ie), (If), (Ig) or (Ih):
(115) ##STR00009##
(116) In some embodiments, X is O. In other embodiments, X is S(O).sub.0-2. In some embodiments, X is C(O). In one embodiment, X is C(OR.sup.5).sub.2. In one embodiment, X is C(OR.sup.5)(OC(O)R.sup.13). In some embodiments, X is C(R.sup.8R.sup.9). In some embodiments, X is C(CR.sup.8R.sup.9). In other embodiments, X is N(R.sup.9). In one embodiment, X is N(COR.sup.9). In one embodiment, X is CHNR.sup.8R.sup.9. In another embodiment, X is C(NR.sup.9). In some embodiments, X is C(NOR.sup.5). In other embodiments, X is C(NNHR.sup.5).
(117) In some embodiments, X is C(R.sup.8R.sup.9) wherein R.sup.8 and R.sup.9 are 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. In some embodiments, X is C(R.sup.8R.sup.9) wherein R.sup.8 and R.sup.9 are each independently H or C.sub.1-C.sub.10 alkyl, In other embodiments, X is C(R.sup.8R.sup.9) wherein R.sup.8 and R.sup.9 are each independently C.sub.1-C.sub.10 alkyl. In some embodiments, X is C(R.sup.8R.sup.9) wherein R.sup.8 and R.sup.9 are each independently C.sub.1-C.sub.5 alkyl. In one embodiment, X is C(R.sup.8R.sup.9) wherein R.sup.8 and R.sup.9 are each independently C.sub.1 alkyl. In another embodiment, X is C(R.sup.8R.sup.9) wherein R.sup.8 and R.sup.9 are each independently a methyl.
(118) In certain of the foregoing embodiments, R.sup.3 is 5-6 membered heteroaryl or 3-7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl comprises at least one N atom in the ring.
(119) In another embodiment, R.sup.3 is selected from the group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine. In one embodiment R.sup.3 is selected form the group consisting of triazole, morpholine, thiomorpholine, pyrazole, and imidazole.
(120) In one embodiment, R.sup.3 is substituted with at least one R.sup.6. In some embodiments, R.sup.3 is substituted with at least one .sup.123I, I, Br, Cl, or F. In another embodiment, R.sup.3 is substituted with at least one .sup.123I or I.
(121) In one embodiment, R.sup.3 is substituted with at least one R.sup.6 which is further substituted with at least one .sup.123I, I, or F. In another embodiment, R.sup.3 is substituted with at least one R.sup.6 which is C.sub.1-C.sub.6 alkyl, and said C.sub.1-C.sub.6 alkyl is further substituted with at least one .sup.123I, I, or F. In some embodiments, R.sup.3 is substituted with at least one R.sup.6 which is C.sub.1-C.sub.6 alkyl, and said C.sub.1-C.sub.6 alkyl is further substituted with at least one .sup.123I. In other embodiments, R.sup.3 is substituted with at least one R.sup.6 which is C.sub.1-C.sub.6 alkyl, and said C.sub.1-C.sub.6 alkyl is further substituted with at least one .sup.18F.
(122) In one embodiment, at least one of R.sup.5, R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is I. In another embodiment, at least one of R.sup.5, R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is .sup.123I. In some embodiments, at least one of R.sup.5, R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is I and at least one of R.sup.5, R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is .sup.123I.
(123) In some embodiments, R.sup.13 is C.sub.1-C.sub.3 alkyl. In other embodiments, R.sup.13 is methyl, ethyl, or propyl. In one embodiment, R.sup.13 is a methyl.
(124) In one embodiment, n.sup.3 is 0, 1, or 2.
(125) The compounds for use in the imaging and treatment methods described herein. In some embodiments, the compounds comprise one F, Cl, Br, I, .sup.18F or .sup.123I substitution. For example in certain other embodiments, three of R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are H, and the remaining R.sup.11a, R.sup.11b, R.sup.11c or R.sup.11d is F, Cl, Br, I or .sup.123I. In some embodiments, the compounds comprise two F, Cl, Br, I or .sup.123I substitutions on the phenyl rings (i.e., two of R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are H, and the other two of R.sup.11a, R.sup.11b, R.sup.11c or R.sup.11d are F, Cl. Br, I or .sup.123I). In other embodiments, the compounds comprise three F, Cl. Br, I or .sup.123I substitutions (i.e., one of R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d is H, and the remaining R.sup.11a, R.sup.11b, R.sup.11c or R.sup.11d is F, Cl. Br, I or .sup.123I) and in other embodiments the compounds comprise four F, Cl. Br, I or .sup.123I substitutions (i.e., each of R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are F, Cl. Br, I or .sup.123I).
(126) In another embodiment, the compound comprise one or more F, Cl, Br, I or .sup.123I substitutions for R.sup.3. In one embodiment, the compound comprise one or more I or 123I substitutions for R.sup.3.
(127) In some embodiments, the compound comprises at least one R.sup.6 substituent on R.sup.3, wherein at least one R.sup.6 is further substituted with at least one of .sup.123I, I, or .sup.18F.
(128) Favorable imaging and/or AR NTD modulating results can be obtained by substitution with F, Cl. Br, I or .sup.123I at any of the R.sup.11 positions. In some of the foregoing embodiments, R.sup.11a is .sup.123I. In other embodiments, R.sup.11c is .sup.123I.
(129) In some more specific embodiments of the compound of Formula I, the compound has one of the following structures from Table 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
(130) TABLE-US-00001 TABLE 1 Compounds No. Structure Name 1
(131) In some more specific embodiments of the compound of Formula I, the compound has one of the following structures, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof including all 4 distinct stereoisomers e.g., (S,R), (R,S), (R,R), and (S,S):
(132) ##STR00170## ##STR00171## ##STR00172## ##STR00173##
(133) In some more specific embodiments of the compound of Formula I, the compound has one of the following structures from Table 2, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
(134) TABLE-US-00002 TABLE 2 .sup.123I Compounds No. Structure Name 33
(135) In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof including all 4 distinct stereoisomers e.g., (S,R), (R,S), (R,R), and (S,S), has one of the following structures:
(136) ##STR00264## ##STR00265##
(137) In some embodiments of the compound of Formula I, the compound has one of the following structures from Table 3, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
(138) TABLE-US-00003 TABLE 3 .sup.18F Compounds No. Structure Name 51
(139) In some embodiments of the compound of Formula I, the compound has one of the following structures, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof including all 4 distinct stereoisomers e.g., (S,R), (R,S), (R,R), and (S,S):
(140) ##STR00296##
wherein R.sup.11c is H, Cl, Br, I, F, or C.sub.1-C.sub.6 alkyl.
(141) In some embodiments of the compound of Formula I, the compound has one of the following structures, or a pharmaceutically acceptable salt thereof:
(142) ##STR00297##
wherein R.sup.11c is H, Cl, Br, I, F, or C.sub.1-C.sub.6 alkyl.
(143) In one embodiment, the present invention is directed to a pharmaceutical composition, comprising a compound having a structure of Formula I:
(144) ##STR00298##
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
(145) X is O, S(O).sub.0-2, C(O), C(OR.sup.5).sub.2, C(OR.sup.5)(OC(O)R.sup.13), C(R.sup.8R.sup.9), C(CR.sup.8R.sup.9), N(R.sup.9), N(COR.sup.9), CHNR.sup.8R.sup.9, C(NR.sup.9), C(NOR.sup.5), C(NNHR.sup.5);
(146) R.sup.1 and R.sup.2 are each independently H, hydroxyl, O-heterocyclyl, or OC(O)R.sup.13;
(147) R.sup.3 is N.sub.3, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R.sup.6;
(148) R.sup.5 is each independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(149) R.sup.6 is each independently selected from the group consisting of H, F, Cl, Br, I, .sup.123I, hydroxyl, oxo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.12 aryl, wherein each R.sup.6 is optionally substituted with one or more of halogen, .sup.123I, .sup.18F, hydroxyl, OS(O).sub.2-aryl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(150) R.sup.8 and R.sup.9 are each independently H, halogen, S(O).sub.0-2R.sup.5, 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.5, or R.sup.8 and R.sup.9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms;
(151) R.sup.11a, R.sup.11b, R.sup.11c and R.sup.11d are each independently H, F, Cl, Br, I, .sup.123I, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; OR.sup.5, OC(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, or N(R.sup.5).sub.2;
(152) R.sup.13 is each independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl;
(153) n.sup.1 and n.sup.2 are each independently 0, 1, or 2; and
(154) n.sup.3 is 0, 1, 2, 3, 4, or 5.
(155) In some embodiment, the pharmaceutical composition comprising a compound having a structure of Formula I further comprises a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising a compound having a structure of Formula I further comprises an additional therapeutic agent. In one embodiment, the pharmaceutical composition comprising a compound having a structure of Formula I further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.
(156) In another embodiment, the pharmaceutical composition comprising a compound having a structure of Formula I further comprises an additional therapeutic agent which 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, or age-related macular degeneration.
(157) Accordingly, one embodiment comprises the use of the disclosed compounds in combination therapy with one or more currently-used or experimental pharmacological therapies which are utilized for treating the above disease states irrespective of the biological mechanism of action of such pharmacological therapies, including without limitation pharmacological therapies which directly or indirectly inhibit the androgen receptor, pharmacological therapies which are cyto-toxic in nature, and pharmacological therapies which interfere with the biological production or function of androgen (hereinafter, an additional therapeutic agent). By combination therapy is meant the administration of any one or more of a compound of Formula I with one or more of another therapeutic agent to the same patient such that their pharmacological effects are contemporaneous with one another, or if not contemporaneous, that their effects are synergistic with one another even though dosed sequentially rather than contemporaneously.
(158) Such administration includes without limitation dosing of one or more of a compound of Formula I and one or more of the additional therapeutic agent(s) as separate agents without any comingling prior to dosing, as well as formulations which include one or more other androgen-blocking therapeutic agents mixed with one or more compound of Formula I as a pre-mixed formulation. Administration of the compound(s) of Formula I in combination with the additional therapeutic agents for treatment of the above disease states also includes dosing by any dosing method including without limitation, intravenous delivery, oral delivery, intra-peritoneal delivery, intra-muscular delivery, or intra-tumoral delivery.
(159) In another aspect of the present disclosure, the one or more of the additional therapeutic agents can be administered to the patient before administration of the compound(s) of Formula I. In another embodiment, the compound(s) of Formula I can be co-administered with one or more of the additional therapeutic agents. In yet another aspect, the one or more additional therapeutic agents can be administered to the patient after administration of the compound(s) of Formula I.
(160) The ratio of the doses of compound(s) of Formula I to that of the one or more additional therapeutic agents can be about 1:1 or can vary, e.g., about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, and can be varied accordingly to achieve the optimal therapeutic benefit.
(161) The compound(s) of Formula I that are combined with the one or more additional therapeutic agents for improved treatment of the above disease states can comprise, but are not limited to any compound having a structure of Formula I, including those compounds shown in Tables 1, 2, or 3.
(162) The additional therapeutic agents include without limitation any pharmacological agent which is currently approved by the FDA in the U.S. (or elsewhere by any other regulatory body) for use as pharmacological treatment of any of the above disease states, or which is currently being used experimentally as part of a clinical trial program that relates to the above disease states. Non-limiting examples of the Other Pharmacological Agents comprise, without limitation: the chemical entity known as ODM-201 (also known as BAY1841788) and related compounds; which appears to bind to the AR and blocks its cellular function, and is currently in clinical development as a treatment for prostate cancer); the chemical entity known as enzalutamide (4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide) and related compounds, which appears to be a blocker of the androgen receptor (AR) LBD and a FDA-approved treatment for prostate cancer; the chemical entity known as Galeterone and related compounds which appears to be a blocker of the androgen receptor (AR) LBD, and a CYP17 lyase inhibitor, and also appears to decrease overall androgen receptor levels in prostate cancer cells. Galeterone is currently in development as a treatment for prostate cancer; the chemical entity known as ARN-509 (4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide) and related compounds which appears to be a blocker of the androgen receptor (AR) LBD and is currently in development as a treatment for prostate cancer; the chemical entity known as abiraterone (or CB-7630; (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) 2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol), and related molecules, which appears to block the production of androgen and FDA-approved treatment for prostate cancer; the chemical entity known as bicalutamide (N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide) and related compounds, which appears to be a blocker of the androgen receptor (AR) LBD and which is currently used to treat prostate cancer, the chemical entity known as nilutamide (5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl] imidazolidine-2,4-dione) and related compounds, which appears to be a blocker of the AR LBD and which is currently used to treat prostate cancer, the chemical entity known as flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide) and related compounds, which appears to be a blocker of the androgen receptor (AR) LBD and which is currently used to treat prostate cancer, the chemical entities known as cyproterone acetate (6-chloro-1,2-dihydro-17-hydroxy-3H-cyclopropa[1,2]pregna-4,6-diene-3,20-dione) and related compounds, which appears to be a blocker of the androgen receptor (AR) LBD and which is currently used to treat prostate cancer, the chemical entity known as docetaxel (Taxotere; 1,7,10-trihydroxy-9-oxo-5,20-epoxytax-11-ene-2,4,13-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}) and related compounds, which appears to be a cytotoxic antimicrotubule agent and is currently used in combination with prednisone to treat prostate cancer, the chemical entity known as Bevacizumab (Avastin), a monoclonal antibody that recognizes and blocks vascular endothelial growth factor A (VEGF-A) and can be used to treat prostate cancer, the chemical entity known as OSU-HDAC42 ((S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide), and related compounds, which appears to act as a histone deacetylase inhibitor, and is currently being developed as a treatment for prostate cancer, the chemical entity known as VITAXIN which appears to be a monoclonal antibody against the vascular integrin 3 to prevent angiogenesis, and which can be used to treat prostate cancer, the chemical entity known as sunitumib (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) and related compounds, which appears to inhibit multiple receptor tyrosine kinases (RTKs) and can be used for treatment of prostate cancer, the chemical entity known as ZD-4054 (N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridin-3-sulfonamid) and related compounds, which appears to block the edta receptor and which can be used for treatment of prostate cancer; the chemical entity known as Cabazitaxel (XRP-6258), and related compounds, which appears to be a cytotoxic microtubule inhibitor, and which is currently used to treat prostate cancer; the chemical entity known as MDX-010 (Ipilimumab), a fully human monoclonal antibody that binds to and blocks the activity of CTLA-4 which is currently in development as an immunotherapeutic agent for treatment of prostate cancer; the chemical entity known as OGX 427 which appears to target HSP27 as an antisense agent, and which is currently in development for treatment of prostate cancer; the chemical entity known as OGX 011 which appears to target clusterin as an antisense agent, and which is currently in development as a treatment for prostate cancer; the chemical entity known as finasteride (Proscar, Propecia; N-(1,1-dimethylethyl)-3-oxo-(5,17)-4-azaandrost-1-ene-17-carboxamide), and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone, and can be used to treat prostate cancer; the chemical entity known as dutasteride (Avodart; 5, 17)-N-{2,5 bis(trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide) and related molecules, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone, and can be used in the treatment of prostate cancer; the chemical entity known as turosteride ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxo-N-(propan-2-yl)-N-(propan-2 ylcarbamoyl)hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide), and related molecules, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and can be used in the treatment of prostate cancer; the chemical entity known as bexlosteride (LY-191,704; (4aS,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one), and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and can be used in the treatment of prostate cancer; the chemical entity known as izonsteride (LY-320,236; (4aR,10bR)-8-[(4-ethyl-1,3-benzothiazol-2-yl)sulfanyl]-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one) and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and can be used for the treatment of prostate cancer; the chemical entity known as FCE 28260 and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and can be used for the treatment of prostate cancer; the chemical entity known as SKF105,111, and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and can be used for treatment of prostate cancer.
(163) Accordingly, in some embodiments, the pharmaceutical composition comprising a compound having a structure of Formula I further comprises an additional therapeutic agent selected form the group consisting of 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.
(164) In some embodiments, compounds of Formula I which result in unstable structures and/or unsatisfied valences are not included within the scope of the invention.
(165) In another embodiment, the present disclosure provides a pharmaceutical composition comprising any of the foregoing compounds of Formula I and a pharmaceutically acceptable carrier.
(166) Compounds as described herein can be in the free form or in the form of a salt thereof. In some embodiments, compounds as described herein can be in the form of a pharmaceutically acceptable salt, which are known in the art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent compound and which are not biologically and/or otherwise undesirable). Compounds as described herein having one or more functional groups capable of forming a salt can be, for example, formed as a pharmaceutically acceptable salt. Compounds containing one or more basic functional groups can be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid. Pharmaceutically acceptable salts can be derived from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lactic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonic acid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid, picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaric acid, thiocyanic acid or undecanoic acid. Compounds containing one or more acidic functional groups can be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion-exchange resins. Pharmaceutically acceptable salts can be derived from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N-ethylpiperidine, theobromine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine, N-ethylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine or polyamine resins. In some embodiments, compounds as described herein can contain both acidic and basic groups and can be in the form of inner salts or zwitterions, for example, and without limitation, betaines. Salts as described herein can be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts can occur in situ during isolation and purification of the compounds or preparation of salts can occur by separately reacting an isolated and purified compound.
(167) In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, polymorphs, isomeric forms) as described herein can be in the solvent addition form, for example, solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent in physical association the compound or salt thereof. The solvent can be, for example, and without limitation, a pharmaceutically acceptable solvent. For example, hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.
(168) In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, isomeric forms) as described herein can include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors including recrystallization solvent, rate of crystallization and storage temperature can cause a single crystal form to dominate.
(169) In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, polymorphs) as described herein include isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for the sake of convenience.
III. Methods
(170) The present compounds find use in any number of methods. For example, in some embodiments the compounds are useful in methods for modulating androgen receptor (AR). Accordingly, in one embodiment, the present disclosure provides the use of any one of the foregoing compounds of Formula I for modulating androgen receptor (AR) activity. For example in some embodiments, modulating androgen receptor (AR) activity is in a mammalian cell. Modulating androgen receptor (AR) can be in a subject in need thereof (e.g., a mammalian subject) and for treatment of any of the described conditions or diseases.
(171) In other embodiments, modulating androgen receptor (AR) activity is for treatment of at least one indication 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, age related macular degeneration, and combinations thereof. For example in some embodiments, the indication is prostate cancer. In other embodiments, the prostate cancer is castration resistant prostate cancer (also referred to as hormone refractory, androgen-independent, androgen deprivation resistant, androgen ablation resistant, androgen depletion-independent, castration-recurrent, anti-androgen-recurrent). While in other embodiments, the prostate cancer is androgen dependent prostate cancer. In other embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.
(172) In some embodiments, compounds as described herein can be administered to a subject. In one embodiment, the present invention is directed to a method of treating castration resistant prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I. In some embodiments, the present invention is directed to a method of treating androgen-dependent prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I. In other embodiments, the present invention is directed to a method of treating androgen-independent prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I.
(173) In other embodiments, the present disclosure provides a method of modulating androgen receptor (AR) activity, the method comprising administering any one of the foregoing compounds of Formula I, pharmaceutically acceptable salt thereof, or pharmaceutical composition of Formula I as described herein (including compositions comprising a compound of Formula I and an additional therapeutic agent), to a subject (e.g., mammal) in need thereof. In some embodiments, modulating androgen receptor (AR) activity is in a mammalian cell. In other embodiments, modulating androgen receptor (AR) activity is in a mammal. In one embodiment, modulating androgen receptor (AR) activity is in a human.
(174) The modulating androgen receptor (AR) activity can be for inhibiting AR N-terminal domain activity. The modulating androgen receptor (AR) activity can be for inhibiting androgen receptor (AR) activity. The modulating can be in vivo. The modulating androgen receptor (AR) activity can be for treatment of at least one indication 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 (e.g., Kennedy's disease), and age related macular degeneration. The indication can be prostate cancer. The prostate cancer can be castration-resistant prostate cancer. The prostate cancer can be androgen dependent prostate cancer.
(175) In accordance with another embodiment, there is provided a use of the compounds of Formula I, pharmaceutically acceptable salt thereof, or pharmaceutical composition of Formula I as described herein for preparation of a medicament for modulating androgen receptor (AR).
(176) Alternatively, in one embodiment, a method of modulating androgen receptor activity, comprising administering Formula I, pharmaceutically acceptable salt thereof, or pharmaceutical composition of Formula I as described herein, is provided. In some embodiments, the administration can be to a mammal. In other embodiments, the administering can be to a mammal in need thereof and in an effective amount for the treatment of at least one indication 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 (e.g., Kennedy's disease), age related macular degeneration, and combinations thereof.
(177) As noted above, the presently disclosed compounds can find utility in a number of medical imaging applications, including imaging of the prostate. Many currently available imaging agents tend to accumulate in the bladder, which decreases their effectiveness as imaging tools specifically for the prostate. While not wishing to be bound by theory, the present applicants believe the disclosed compounds are unexpectedly effective for imaging of the prostate due to their ability to accumulate in the prostate, rather than the bladder, allowing the prostate gland to be seen. Accordingly, the compounds can be used in methods for imaging the prostate, for example to image benign prostate diseases. In other embodiments, the compounds can be used in methods to image cancerous prostate diseases, such as tumors of the prostate.
(178) Androgen ablation therapy causes a temporary reduction in prostate cancer tumor burden, but the malignancy will begin to grow again in the absence of testicular androgens to form castrate resistant prostate cancer (CRPC). A rising titer of serum prostate-specific antigen (PSA) after androgen ablation therapy indicates biochemical failure, the emergence of CRPC, and re-initiation of an androgen receptor (AR) transcription program. Most patients succumb to CRPC within two years of biochemical failure.
(179) AR is a transcription factor and a validated target for prostate cancer therapy. Current therapies include androgen ablation and administration of antiandrogens. Most CRPC is suspected to be AR-dependent. AR has distinct functional domains that include the C-terminus ligand-binding domain (LBD), a DNA-binding domain (DBD), and an amino-terminal domain (NTD). AR NTD contains the activation function-1 (AF-1) that contributes most of the activity to the AR. Recently, splice variants of the AR that lack the LBD have been reported in prostate cancer cell lines (VCaP and 22Rv1), and in CRPC tissues. To date more than 20 splice variants of AR have been detected. Splice variants V7 and V567es are clinically relevant with levels of expression correlated to poor survival and CRPC. AR V567es is solely expressed in 20% of metastases. Abiraterone resistance is associated with expression of AR splice variants. Enzalutamide also increases levels of expression of these constitutively active AR splice variants. These splice variants lack LBD and thereby would not be inhibited by current therapies that target the AR LBD such as antiandrogens or androgen ablation therapy. A single patient with advanced prostate cancer can have many lesions throughout the body and skeleton and each tumor can have differing levels of expression of AR.
(180) Biopsy of metastatic tumors in a patient to determine AR species is neither widely accessible nor feasible to sample tumors in a patient that can have multiple metastases. Thus it is essential to develop approaches to detect the expression of all AR species for the molecular classification of tumors based on the level and extent of expression of AR splice variants, or other AR species that cannot be detected using an imaging agent that interacts with the LBD, to identify patients with potentially aggressive disease and poor prognosis, or to identify patients that will not respond to hormone therapies that target the AR LBD. Accordingly, certain embodiments of the present invention provide a AR NTD-targeted molecular imaging probe (e.g., compound of formula I) which can be used to monitor response to therapy and provide insight into the role of AR in resistance mechanisms.
(181) One current approach to image AR in prostate cancer uses positron emission tomography (PET) with 16-[.sup.18F]-fluoro-5 dihydrotestosterone (.sup.18F-FDHT) that binds to AR LBD. Unfortunately this imaging agent cannot detect splice variants lacking LBD. In some embodiments, the invention employs sequential imaging with .sup.18F-FDHT to detect full-length AR and gamma radiation emitting probes to specifically detect the AR NTD which would be the sum of both full-length AR and variant AR. In other embodiments, the invention employs sequential imaging with two different PET imaging agents to detects only full-length AR and another to specifically detect the AR NTD which would be the sum of both full-length AR and variant AR. Together these data reveal patients with tumors that express variant AR (NTD of variant plus full-length AR detected with NTD isotope minus full-length AR detected with .sup.18F-FDHT). By using sequential imaging, a discordant distribution or discordant level of uptake between .sup.18F-FDHT and a radiolabeled compound of this invention (i.e., compound of Formula I) indicates the presence of overexpression of splice variants lacking the LBD.
(182) As described above, radioactive .sup.18F labeled compounds have found use as imaging agents not only to image AR in prostate cancer but for imaging various organs and various tumors. Similarly, radioactive .sup.123I labeled compounds have been known for the use as imaging agents. In one embodiment, the compounds of the present disclosure comprise at least one .sup.18F and/or .sup.123I.
(183) In one embodiment, the present invention is directed to a method of imaging cancer by administering a compound having a structure of Formula I to a subject. In another embodiment, the present invention is directed to a method of imaging cancer by administering a pharmaceutical composition comprising a compound having a structure of Formula I to a subject.
(184) In some embodiment, the method of imaging cancer by administering a compound having a structure of Formula I or a pharmaceutical composition comprising Formula I to a subject and detecting the presence or absence of cancer by use of SPECT or PET. In other embodiments, the method of imaging cancer by administering a compound having a structure of Formula I to a subject and the method identifies the presence or absence of a tumor. In one embodiment, the method of imaging cancer by administering a compound having a structure of Formula I to a subject and the method identifies the location of a tumor. In one embodiment, the method of imaging cancer by administering a compound having a structure of Formula I to a subject and the method identifies a presence of a prostate cancer. In other embodiments, the prostate cancer is androgen-dependent prostate cancer. In some embodiments, the subject is a mammal such as a human.
(185) In some other embodiments, the method is useful for detecting the presence of AR splice variants or other AR species that cannot be detected by imaging agents that interact with the AR LBD (i.e., mutations, truncations). Without wishing to be bound by any particular theory, since the present compounds bind to the AR N-terminal domain (NTD), even mutants or variants which lack the AR LBD can be imaged employing the present compounds. Thus, the present methods can be useful for detecting AR species, including mutants and variants, which lack the LBD or have LBD mutations, but do comprise the AR NTD. In other embodiments the method detects the presence or overexpression of AR splice variants lacking the ligand binding domain. For example, the method can include sequential imaging with .sup.18F-FDHT and a compound of the invention and a discordant distribution or discordant level of uptake between .sup.18F-FDHT and the compound of the invention indicates the presence or overexpression of splice variants lacking the ligand binding domain.
(186) In other embodiments, the compounds of the invention are used in single photon emission computed tomography methods to monitor a patient's response to therapy. In other embodiments, the methods comprise use of a compound of the invention to detect the AR NTD.
(187) In accordance with a further embodiment, the method of imaging a cancer is by administering a compound as described anywhere herein. In one embodiment, the method of imaging a cancer is by administering a compound represented in Table 2, Table 3 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In some embodiments, the imaging is in a mammalian cell. In one embodiment, the imaging is in a mammal. In other embodiments, the imaging is in a human patient.
(188) The administering and imaging can be to a mammal in need of diagnosis of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, benign prostatic hyperplasia, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy (e.g., Kennedy's disease), and age-related macular degeneration. The imaging can be for imaging AR splice variants, mutants or other AR species which comprise the AR NTD.
(189) In some embodiments, the compounds as described herein or pharmaceutically acceptable salts thereof can be used for imaging and diagnosis of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, benign prostatic hyperplasia, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. In some embodiments, the compounds as described herein or acceptable salts thereof above can be used in the preparation of a medicament or a composition for imaging the prostate, for example for imaging benign prostate conditions or for imaging prostate cancer in a subject in need of such imaging (for example for diagnosis and/or location of prostate tumors).
(190) In some embodiments, pharmaceutical compositions useful in modulating androgen receptor (AR) activity or useful for imaging, in accordance with this invention can comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt. Pharmaceutical preparations will typically comprise one or more carriers, excipients or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents are those known in the art for use in such modes of administration.
(191) Suitable pharmaceutical compositions can be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound can be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound can be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule can be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant can be employed to provide release over a prolonged period of time. Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20.sup.th ed., Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration can, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation can contain excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can be oily solutions for administration in the form of nasal drops, or as a gel.
(192) In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein, and an additional therapeutic agent and/or a pharmaceutically acceptable carrier. In some embodiments, 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 or age related macular degeneration. In other embodiments, the additional therapeutic agent is enzalutamide, galeterone, ARN-509, ODN-201 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, or related compounds thereof.
(193) Compounds described herein can also be used in assays and for research purposes. Definitions used include ligand dependent activation of the androgen receptor (AR) by androgens such as dihydrotestosterone (DHT) or the synthetic androgen (R1881) used for research purposes. Ligand-independent activation of the androgen receptor (AR) refers to transactivation of the full length androgen receptor (AR) in the absence of androgen (ligand) by, for example, stimulation of the cAMP dependent protein kinase (PKA) pathway with forskolin (FSK). Some compounds and compositions of this invention can inhibit both FSK and androgen (e.g. R1881, a synthetic androgen) induction of ARE luciferase (ARE-luc). Constitutive activity of the androgen receptor (AR) refers to splice variants lacking the androgen receptor (AR) ligand-binding domain. Such compounds can block a mechanism that is common to both ligand dependent and ligand independent activation of the androgen receptor (AR), as well as constitutively active splice variants of the androgen receptor (AR) that lack ligand-binding domain. This could involve any step in activation of the androgen receptor (AR) including dissociation of heatshock proteins, essential posttranslational modifications (e.g., acetylation, phosphorylation), nuclear translocation, protein-protein interactions, formation of the transcriptional complex, release of co repressors, and/or increased degradation. Some compounds and compositions of this invention can inhibit ligand-only activity and can interfere with a mechanism specific to ligand dependent activation (e.g., accessibility of the ligand binding domain (LBD) to androgen). Numerous disorders in addition to prostate cancer involve the androgen axis (e.g., acne, hirsutism, alopecia, benign prostatic hyperplasia) and compounds interfering with this mechanism can be used to treat such conditions. Some compounds and compositions of this invention can only inhibit FSK induction and can be specific inhibitors to ligand independent activation of the androgen receptor (AR). These compounds and compositions can interfere with the cascade of events that normally occur with FSK and/or PKA activity or any downstream effects that can play a role on the androgen receptor (AR) (e.g. FSK increases MAPK activity which has a potent effect on androgen receptor (AR) activity). Examples can include an inhibitor of cAMP and or PKA or other kinases. Some compounds and compositions of this invention can induce basal levels of activity of the AR (no androgen or stimulation of the PKA pathway). Some compounds and compositions of this invention can increase induction by R1881 or FSK. Such compounds and compositions can stimulate transcription or transactivation of the AR. Some compounds and compositions of this invention can inhibit activity of the androgen receptor. Interleukin 6 (IL 6) also causes ligand independent activation of the androgen receptor (AR) in LNCaP cells and can be used in addition to FSK.
(194) Compounds or pharmaceutical compositions in accordance with this invention or for use in this invention can be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Also, implants can be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
(195) It is to be noted that dosage values can vary with the exact imaging protocol. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that can be selected by medical practitioners. The amount of active compound(s) in the composition can vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum imaging result. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the imaging results. It can be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
(196) In general, compounds of the invention should be used without causing substantial toxicity. Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances, such as in severe disease conditions, substantial excesses of the compositions can be administered for therapeutic effects. Some compounds of this invention can be toxic at some concentrations. Titration studies can be used to determine toxic and non-toxic concentrations. Toxicity can be evaluated by examining a particular compound's or composition's specificity across cell lines using PC3 or DU145 cells as possible negative controls since these cells do not express functional AR. Animal studies can be used to provide an indication if the compound has any effects on other tissues. Systemic therapy that targets the AR will not likely cause major problems to other tissues since antiandrogens and androgen insensitivity syndrome are not fatal.
(197) Compounds for use in the present invention can be obtained from medical sources or modified using known methodologies from naturally occurring compounds. In addition, methods of preparing or synthesizing compounds of the present invention will be understood by a person of skill in the art having reference to known chemical synthesis principles. For example, Auzou et al 1974 European Journal of Medicinal Chemistry 9(5), 548-554 describes suitable synthetic procedures that can be considered and suitably adapted for preparing compounds of any one of the compounds of structure (I) as set out above. Other references that can be helpful include: Debasish Das, Jyh-Fu Lee and Soofin Cheng Sulfonic acid functionalized mesoporous MCM-41 silica as a convenient catalyst for Bisphenol-A synthesis Chemical Communications, (2001) 2178-2179; U.S. Pat. No. 2,571,217 Davis, Orris L.; Knight, Horace S.; Skinner, John R. (Shell Development Co.) Halohydrin ethers of phenols. (1951); and Rokicki, G.; Pawlicki, J.; Kuran, W. Reactions of 4-chloromethyl-1,3-dioxolan-2-one with phenols as a new route to polyols and cyclic carbonates. Journal fuer Praktische Chemie (Leipzig) (1985) 327, 718-722.
(198) In some embodiments, compounds and all different forms thereof as described herein can be used, for example, and without limitation, in combination with other treatment methods for at least one indication 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. For example, compounds and all their different forms as described herein can be used as neoadjuvant (prior), adjunctive (during), and/or adjuvant (after) therapy with surgery, radiation (brachytherapy or external beam), or other therapies (eg. HIFU), and in combination with chemotherapies, androgen ablation, antiandrogens or any other therapeutic approach.
(199) In an exemplary embodiment for imaging the prostate, a dose of the disclosed compounds in solution (typically 5 to 10 millicuries or 200 to 400 MBq) is typically injected rapidly into a saline drip running into a vein, in a patient. Then, the patient is placed in the SPECT for a series of one or more scans which can take from 20 minutes to as long as an hour (often, only about one quarter of the body length can be imaged at a time). Methods for SPECT scanning are well known in the art.
(200) The compounds described herein can be used for in vivo or in vitro research uses (i.e. non-clinical) to investigate the mechanisms of orphan and nuclear receptors (including steroid receptors such as androgen receptor (AR)). Furthermore, these compounds can be used individually or as part of a kit for in vivo or in vitro research to investigate signal transduction pathways and/or the activation of orphan and nuclear receptors using recombinant proteins, cells maintained in culture, and/or animal models.
(201) For example, exemplary compounds of the present invention can be prepared with reference to the following General Reaction Scheme I:
(202) ##STR00299## ##STR00300##
(203) It should be noted that, although General Reaction Scheme I depicts a certain stereochemistry in the products, one skilled in the art would recognize that other stereoisomers can be synthesized by using starting materials of different stereochemistry, such as for step a and step d.
(204) Referring to General Reaction Scheme I, (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol can toslyated under basic conditions as shown in step a. In step b, tosly group (p-toulenesulfonate) can be displaced with bisphenol derivatives under basic conditions. Optionally, in step c, the bisphenol derivative is halogenated on the phenyl ring. In step d, the unreacted phenol portion undergoes another elimination reaction to afford a stereospecific bisphenol derivative with an epoxide on one side and a protected diol on the other. In step e, epoxide is opened using CeCl3.7H.sub.2O and the diol is deprotected in situ. In step f, primary alcohol is selectively tosylated then in step g, the tosyl group is displaced with an azide using sodium azide. Lastly, Click chemistry provides triazole containing products in steps h and i. Tosyl leaving groups have been found to be particularly useful in the synthesis outlined in General Scheme I.
(205) The radioactive iodine moiety (.sup.123I) can be installed by step c with an appropriate iodinating reagent, for example Na.sup.123I and a suitable oxidant (e.g., NaClO). It should be noted that, although General Reaction Scheme I depicts iodination at only one position, other compounds of structure (I) with .sup.123I at different positions and/or multiple .sup.123I substitutions can be prepared according to analogous methods known to those of ordinary skill in the art. Further, .sup.123I atoms can be introduced via any number of reagents, and iodination is not limited to those methods depicted or described above. Methods for such iodination are well known in the art. Methodologies for preparation of specific exemplary compounds of structure I are described in more detail in the following examples.
(206) One skilled in the art will recognize that variations to the order of the steps and reagents discussed in reference to the above General Synthetic Schemes I are possible. For example, epoxidation can precede dioxalone formation.
(207) In addition, protecting group strategies can be employed for preparation of the compounds disclosed herein. Such strategies are well known to those of skill in the art. Exemplary protecting groups and related strategies are disclosed in Greene's Protective Groups in Organic Synthesis, Wiley-InterScience; 4 edition (Oct. 30, 2006), which is hereby incorporated by reference in its entirety. In certain embodiments, a protecting group is used to mask an alcohol moiety while performing other chemical transformations. After removal of the protecting group, the free hydroxyl is obtained. Such protecting groups and strategies are well known in the art.
(208) Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention. The following examples are provided for purposes of illustration, not limitation.
EXAMPLES
(209) All non-aqueous reactions were performed in flame-dried round bottomed flasks. The flasks were fitted with rubber septa and reactions were conducted under a positive pressure of argon unless otherwise specified. Stainless steel syringes were used to transfer air- and moisture-sensitive liquids. Flash column chromatography was performed as described by Still et al. (Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layer chromatography was performed using aluminum plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light and a Seebach staining solution (700 mL water, 10.5 g Cerium (IV) sulphate tetrahydrate, 15.0 g molybdato phosphoric acid, 17.5 g sulphuric acid) followed by heating (1 min) with a heating gun (250 C.). Organic solutions were concentrated on Bchi R-114 rotatory evaporators at reduced pressure (15-30 torr, house vacuum) at 25-40 C.
(210) Commercial regents and solvents were used as received. All solvents used for extraction and chromatography were HPLC grade. Normal-phase Si gel Sep Paks were purchased from waters, Inc. Thin-layer chromatography plates were Kieselgel 60F.sub.254. All synthetic reagents were purchased from Sigma Aldrich and Fisher Scientific Canada.
Example 1
Synthesis of (S)-1-(4-(2-(3-bromo-4-((R)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propan-2-ol (1a) and (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (25a)
(211) ##STR00301##
Compound i-H (XH)
(212) p-Toluenesulfonyl chloride (1.5 equiv) was added portionwise over a period of approximately 10 min to a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (1 equiv) and DMAP (0.01 equiv) in anhydrous pyridine (1M) in a water bath. The resulting solution was stirred at room temperature. The pyridine was removed under reduced pressure, and the residue was diluted with ethyl acetate, washed subsequently with water (2), cold aqueous 1 M HCl, saturated NaHCO.sub.3 and water. The organic layer was dried over Mg.sub.2SO.sub.4, filtered and concentrated the crude product. The crude product was purified by column chromatography (eluent: ethyl acetate/hexane) to afford Compound i-H. .sup.1H NMR and .sup.13C NMR spectra are shown in
(213) Compound ii-H (XH)
(214) Sodium azide (1.5 equiv) was added to a solution of Compound i-H (1 equiv) in anhydrous dimethyl formamide, at room temperature. The reaction mixture was heated at 60 C. Once the reaction is complete, any excess sodium azide was quenched using common laboratory procedures. The product was extracted with ethyl acetate (3). The organic layer was washed with saturated NaHCO.sub.3 and water, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound ii-H. .sup.1H NMR and .sup.13C NMR spectra are shown in
(215) Compounds 1a and 25a
(216) CuI and NIS was added to a solution of Compound ii-H (1 equiv) and propargyl alcohol (1.5 equiv) in DMF and triethylamine. The reaction mixture is stirred at room temperature. Once the reaction was complete, any excess reagents were quenched using common laboratory procedures. The product was extracted with ethyl acetate (3). The organic layer was washed with saturated NaHCO.sub.3 and water, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound 1a and Compound 25a.
(217) Compound 1a: .sup.1H NMR and .sup.13C NMR spectra are shown in
(218) Compound 25a: .sup.1H NMR and .sup.13C NMR spectra are shown in
Example 2
Synthesis of (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol (4a) and (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-iodo-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)-2-iodophenoxy)propan-2-ol (28a)
(219) ##STR00302##
Compounds 4a and 28a
(220) Compound 4a and Compound 28a were synthesized according to Example 1 from (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)-3-iodophenyl)propan-2-yl)phenoxy)propane-1,2-diol.
(221) Compound i-I (XI): .sup.1H NMR and .sup.13C NMR spectra are shown in
(222) Compound ii-I (XI): .sup.1H NMR and .sup.13C NMR spectra are shown in
(223) Compound 4a: .sup.1H NMR and .sup.13C NMR spectra are shown in
(224) Compound 28a: .sup.1H NMR and .sup.13C NMR spectra are shown in
Example 3
Synthesis of (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-5-(iodo-.SUP.123.I)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (33a) and (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-4-(iodo-.SUP.123.I)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (41a)
(225) ##STR00303##
Compounds 37a and 45a
(226) CuCl.sub.2 and Na.sup.123I are added to a solution of Compound ii-H (1 equiv) and propargyl alcohol (1.5 equiv) in acetonitrile and triethylamine. The reaction mixture is stirred at room temperature. Once the reaction is complete, any excess reagents are quenched using common laboratory procedures. The product is extracted with ethyl acetate (3). The organic layer is washed with saturated NaHCO.sub.3 and water, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue is purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound 37a and Compound 45a.
Example 4
Synthesis of (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (5a) and (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (29a)
(227) ##STR00304##
Compounds 5a and 29a
(228) CuCl.sub.2 and NIS is added to a solution of Compound ii-H (1 equiv) and propargyl alcohol (1.5 equiv) in DMF and triethylamine. The reaction mixture is stirred at room temperature. Once the reaction is complete, any excess reagents are quenched using common laboratory procedures. The product is extracted with ethyl acetate (3). The organic layer is washed with saturated NaHCO.sub.3 and water, dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue is purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound 5a and Compound 29a.
Example 5
Synthesis of 1-chloro-3-(4-(2-(4-(2-hydroxy-3-morpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (13)
(229) ##STR00305##
Compound 13
(230) To a solution of 2,2-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(oxirane) (1.0 equiv) and morpholine (1 equiv) in acetonitrile/water (9:1) was added CeCl.sub.3.7H.sub.2O (0.5 equiv) and the mixture was refluxed. The resulting crude mixture was filtered and washed with ethyl acetate, and the resulting suspension was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide the title Compound 13. .sup.1H NMR spectrum is shown in
Example 6
Synthesis of (S)-1-chloro-3-(4-(2-(4-((R)-2-hydroxy-3-morpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (13a)
(231) ##STR00306##
Compound 13a
(232) To a solution of (2R,2R)-2,2-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(oxirane) (1.0 equiv) and morpholine (1 equiv) in acetonitrile/water (9:1) is added CeCl.sub.3.7H.sub.2O (0.5 equiv) and the mixture is refluxed. The resulting crude mixture is filtered and washed with ethyl acetate, and the resulting suspension is concentrated under reduced pressure. The resulting residue is purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound 13a and Compound 13b.
Example 7
Synthesis of 1-chloro-3-(4-(2-(4-(2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (9)
(233) ##STR00307##
Compound 9
(234) To a solution of 2,2-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(oxirane) (1 equiv) and 1H-imidazole (1 equiv) in acetonitrile/water (9:1) were added CeCl.sub.3. 7H.sub.2O (0.5 equiv) and the mixture was refluxed. The resulting crude mixture was filtered and washed with ethyl acetate, and the resulting suspension was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound 9.
Example 8
Synthesis of (S)-1-chloro-3-(4-(2-(4-((R)-3-(4-((fluoro-.SUP.18.F)methyl)-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (51a)
(235) ##STR00308##
Compound iii-H (XH)
(236) p-Toluenesulfonyl chloride (1.5 equiv) is added portion wise over a period of approximately 10 min to a solution of Compound 5a (1 equiv) and TEA in DCM (1M) in a water bath. The resulting solution is stirred at room temperature. The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed subsequently with water (2), cold aqueous 1 M HCl, saturated NaHCO.sub.3 and water. The organic layer was dried over Mg.sub.2SO.sub.4, filtered and concentrated the crude product. The crude product is purified by column chromatography (eluent: ethyl acetate/hexane) to afford Compound iii-H.
(237) Compound iv-H (XH)
(238) 3,4-Dihydro-2H-pyran and PPTS is added to a solution of Compound iii-H (1 equiv) in DCM. The resulting solution is stirred until reaction is complete. The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed subsequently with saturated NaHCO.sub.3 and water. The organic layer was dried over Mg.sub.2SO.sub.4, filtered and concentrated the crude product. The crude product is purified by column chromatography (eluent: ethyl acetate/hexane) to afford Compound iv-H.
(239) Compound 51a
(240) To a solution of Compound iv-H (1 equiv) in MeCN is added K.sup.18F and K.sub.2CO.sub.3, and the reaction mixture is heated at 110 C. Once the reaction is complete, concentrated HCl is added and stirred. The product is extracted with ethyl acetate, and the resulting suspension is concentrated under reduced pressure. The resulting residue is purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane) to provide Compound 51a.
Example 9
(241) Compound Activity
(242) LNCaP cells were transiently transfected with PSA (6.1 kb)-luciferase for 24 h prior to pre-treatment with compounds of the invention (e.g., compounds 1a, 9, 13) ranging in concentration from 62.5 ng/ml to 1.5 ug/ml for 1 hour before the addition of vehicle, or synthetic androgen, R1881 (1 nM) to induce luciferase production. After 24 h of incubation with R1881, the cells were harvested, and relative luciferase activities were determined. To determine the IC.sub.50, treatments were normalized to the predicted maximal activity induction (in the absence of test compounds, vehicle only).
(243) TABLE-US-00004 TABLE 4 IC.sub.50 values for selected compounds (M) with standard error Compound Number of Trials Average IC.sub.50 1a 4 3.23 +/ 0.37 9 6 8.45 +/ 3.14 13 3 12.84 +/ 1.95
(244) Although various embodiments of the invention are disclosed herein, many adaptations and modifications can be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word comprising is used herein as an open-ended term, substantially equivalent to the phrase including, but not limited to, and the word comprises has a corresponding meaning. As used herein, the singular forms a, an and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a thing includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.