WO2017210771A1 - Compounds and compositions for radiation therapy and methods of using the same - Google Patents
Compounds and compositions for radiation therapy and methods of using the same Download PDFInfo
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- WO2017210771A1 WO2017210771A1 PCT/CA2017/000141 CA2017000141W WO2017210771A1 WO 2017210771 A1 WO2017210771 A1 WO 2017210771A1 CA 2017000141 W CA2017000141 W CA 2017000141W WO 2017210771 A1 WO2017210771 A1 WO 2017210771A1
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- compound
- cancer
- prostate cancer
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- alkyl
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
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- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
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- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/16—Acetic acid esters of dihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/18—Acetic acid esters of trihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Definitions
- the present disclosure relates to bisphenol ether derivatives and compositions comprising the same, which can be useful in imaging and treatment of diseases, such as prostate cancer.
- the disclosed compounds find utility in any number of imaging applications for androgen receptor (AR) including truncated AR splice variants in prostate cancers and radiation therapy applications for treatment of prostate cancers including, but not limited to, primary/localized prostate cancer (newly diagnosed), locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
- the compounds of the present disclosure containing a radiolabeled atom can be useful in targeted delivery of radionuclides for treatment of lesions, tumors, and/or cancer cells.
- the compound of the present disclosure can be useful in neoadjuvant and adjuvant therapies for various androgen-mediated or androgen-related diseases or conditions as well as in combination with different therapies, such as androgen ablation therapy.
- Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355 361 ( 1999); A. A. Thomson, Reproduction 121 , 187 195 (2001); N. Tanji, K. Aoki & M.
- Androgens also play a role in female diseases such as polycystic ovary syndrome as well as cancers.
- ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)).
- the AR has been detected in a majority of ovarian cancers (H. A.
- the AR has distinct functional domains that include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zinc finger motifs, and an N-terminus domain (NTD) that contains two transcriptional activation units (taul and tau5) within activation function- 1 (AF-1). Binding of androgen (ligand) to the LBD of the AR results in its activation such that the receptor can effectively bind to its specific DNA consensus site, termed the androgen response element (ARE), on the promoter and enhancer regions of androgen regulated genes, such as PSA, to initiate transcription.
- LBD carboxy-terminal ligand-binding domain
- DBD DNA-binding domain
- NTD N-terminus domain
- ARE transcriptional activation units
- the AR can be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 21 A, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 211, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
- PKA cAMP-dependent protein kinase pathway
- IL-6 interleukin-6
- Clinically available inhibitors of the AR include nonsteroidal antiandrogens such as bicalutamide (CasodexTM), nilutamide, flutamide, and enzalutamide. There is also a class of steroidal antiandrogens, such as cyproterone acetate and spironolactone.
- Both steroidal and non-steroidal antiandrogens target the LBD of the AR and predominantly fail presumably due to poor affinity, mutations that lead to activation of the AR by these same antiandrogens (Taplin, M.E., Bubley, G.J., Kom Y.J., Small E.J., Uptonm M., Rajeshkumarm B., Balkm S.P., Cancer Res., 59, 2511-2515 (1999)), and constitutively active AR splice variants.
- Antiandrogens have no effect on the constitutively active AR splice variants that lack the ligand-binding domain (LBD) and are associated with castration-recurrent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest.
- LBD ligand-binding domain
- AR antagonists other than the bisphenol ether derivatives previously reported see, WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2015/031984; WO 2016/058080; and WO 2016/058082
- AR degraders such as niclosamide (Liu C et al 2014), galeterone (Njar et al 2015; Yu Z at al 2014), and ARV- 330/Androgen receptor PROTAC (Neklesa et al 2016 J Clin Oncol 34 suppl 2S; abstr 267); AR DBD inhibitor VPC-14449 (Dalai K et al 2014 J Biol Chem.
- the AR-NTD is also a target for drug development (e.g. WO 2000/001813), since the NTD contains Activation-Function- 1 (AF-1) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404).
- AF-1 Activation-Function- 1
- the AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M.D. 1999 J. Biol. Chem. 21 A, 1111-1183; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol.
- the AR-NTD is important in hormonal progression of prostate cancer as shown by application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).
- PET positron emission tomography
- 18 F or 124 I a radioisotope
- R 1 and R 2 are each independently H or C 1 -C 10 alkyl, or R 1 and R 2 , together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
- R 3 , R 4 and R 5 are each independently H, C 1 -C 10 alkyl or C 1 -C 10 alkylcarbonyl; and [17] X 1 , X 2 , X 3 and X 4 are each independently H, F, CI, Br, I, 123 I, 124 I, or 125 I;
- X 1 , X 2 , X 3 or X 4 is 124 I. In one embodiment, X 3 is 124 I. In another embodiment of a compound of formula (I), at least one of X 1 , X 2 , X 3 or X 4 is 125 I. In one embodiment, X 3 is 125 I.
- R 1 and R 2 are each H or C 1 -C 3 alkyl. In another embodiment, R 1 and R 2 are each methyl.
- R 3 , R 4 and R 5 are each independently H or C 1 -C 4 alkylcarbonyl. In some embodiments, R 3 , R 4 and R 5 are each H. In another embodiment, R 3 , R 4 and R 5 are each methyl carbonyl.
- a compound of formula (I) the compound is selected from Table 2 or Table 3 or a pharmaceutically acceptable salt or stereoisomer thereof.
- a pharmaceutically composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), wherein at least one of X 1 , X 2 , X 3 or X 4 is 124 j or 125 j i s provided.
- the pharmaceutical composition further comprises at least one additional therapeutic agent.
- the at least one additional therapeutic agent is selected from: enzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC 4 2, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP- 6258), MDX-010 (Ipilimumab), OGX 427, OGX Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,1 1 1 , ODM-201 , ODM-204, radium 233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or related compounds thereof
- a method of modulating androgen receptor (AR) activity comprises administering a compound of formula (I) wherein at least one of X 1 , X 2 , X 3 or X 4 is 124 I or 125 I is administered to a subject in need tehreof.
- the modulating AR is inhibiting transactivation of AR N-terminal domain.
- the method of modulating AR activity is in a human.
- a method of modulating androgen receptor (AR) activity is for treating at least one indication selected from: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
- the indication is prostate cancer.
- prostate cancer is selected from primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
- a method of modulating androgen receptor (AR) activity is for neoadjuvant therapy.
- the method is for adjuvant therapy.
- the adjuvant therapy is following androgen ablation therapy.
- Some embodiments of the compounds described herein may be used for diagnostic purposes to investigate diseases of the prostate, including cancer.
- the compounds are useful for imaging diagnostics in cancer.
- imaging allows for the detection and/or location of cancer sites (e.g., tumor sites).
- cancer sites e.g., tumor sites.
- a use of a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, for radiation therapy is disclosed, wherein formula (I) is:
- R 1 and R 2 are each independently H or C 1 -C 10 alkyl, or R 1 and R 2 , together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
- R 3 , R 4 and R 5 are each independently H, C 1 -C 10 alkyl or C 1 -C 10 alkylcarbonyl; and [31] X 1 , X 2 , X 3 and X 4 are each independently H, F, CI, Br, I, 123 1, 124 I, or I25 I;
- a method of administering radiation therapy comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject in need thereof is provided, where formula (I) is as defined herein.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein X 3 is 125 I.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein R 1 and R 2 are each H or C 1 -C 3 alkyl. In another embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein R 1 and R 2 are each methyl.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein R 3 , R 4 and R 5 are each independently H or C 1 -C 4 alkylcarbonyl. In some embodiments, the use or the method disclosed herein utilizes the compound of formula (I), wherein R 3 , R 4 and R 5 are each H. In another embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein R 3 , R 4 and R 5 are each methyl carbonyl.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is selected from Table 5, or a pharmaceutically acceptable salt or stereoisomer thereof. [38] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is selected from:
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is an Auger emitter.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound comprises a radionuclide.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound comprises a radionuclide which emits alpha- or beta- particles.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the radiation therapy is for treating a cancer or a cancer cell.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the cancer is selected from prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma; or the cancer cell is selected from cells of prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
- the prostate cancer expresses full-length AR or truncated AR splice variant.
- the prostate cancer includes, but not limited to, primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
- primary/localized prostate cancer newly diagnosed or early stage
- recurrent prostate cancer e.g., prostate cancer which was not responsive to primary therapy
- metastatic prostate cancer e.g., advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
- CRPC metastatic castration-resistant prostate cancer
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the radiation therapy induces apoptosis of the cancer cells.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is distributed into the cancer cells upon administration.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound blocks transactivation of an androgen receptor (AR) N- terminal domain (NTD).
- the androgen receptor expresses a full- length AR or a constitutively active splice variant of AR (truncated AR splice variant).
- the use or the method disclosed herein utilizes the compound of formula (I), wherein the radiation therapy is an Auger therapy.
- the use or the method disclosed herein utilizes the compound of formula (I), wherein a progress of the radiation therapy is monitored by imaging the cancer cells using single-photon emission computed tomography (SPECT) or PET.
- SPECT single-photon emission computed tomography
- the imaging agent used for SPECT is selected from Table 1, or a pharmaceutically acceptable salt thereof.
- imaging agent used for PET is selected from Table 2, or a pharmaceutically acceptable salt thereof.
- the compounds of the present disclosure are useful for imaging and imaging diagnostics in androgen-related diseases and conditions.
- the disease or the condition is cancer.
- the cancer is prostate cancer.
- the prostate cancer includes, but not limited to, primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone- sensitive prostate cancer.
- a method of imaging cancer where a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof i administered to a subject in need thereof:
- R 1 and R 2 are each independently H or C 1 -C 10 alkyl, or R 1 and R 2 , together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
- R 3 , R 4 and R 5 are each independently H, O-Oo alkyl or C 1 -C 10 alkylcarbonyl; and [52] X 1 , X 2 , X 3 and X 4 are each independently H, F, CI, Br, I, 123 1, 124 I, or 125 I;
- the imaging method disclosed herein utilizes the compound of formula (I), wherein X 3 is 124 I.
- the imaging method disclosed herein utilizes the compound of formula (I), wherein R 1 and R 2 are each H or C 1 -C 3 alkyl. In another embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein R 1 and R 2 are each methyl.
- the imaging method disclosed herein utilizes the compound of formula (I), wherein R 3 , R 4 and R 5 are each independently H or C 1 -C 4 alkylcarbonyl. In some embodiments, the imaging method disclosed herein utilizes the compound of formula (I), wherein R 3 , R 4 and R 5 are each H. In another embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein R 3 , R 4 and R 5 are each methyl carbonyl.
- the imaging method disclosed herein utilizes the compound of formula (I), wherein the compound is selected from Table 5, or a pharmaceutically acceptable salt or stereoisomer thereof.
- the imaging method is for PET imaging.
- the compound of formula (I) useful for PET imaging is selected from Table 2, or a pharmaceutically acceptable salt thereof.
- Figure 1A shows dose-dependent inhibition of androgen induced transcriptional activity of endogenous full-length AR in LNCaP cells by Compound D ((R)-3-(4-(2-(4-((5>
- Figure IB shows the specific effects of Compound D on androgen-dependent proliferation of LNCaP cells (AR positive) treated with R1881 , while having no effect on
- Figure 2A shows the effects of Compounds B or D on androgen (R1881)-induced AR transcriptional activity in LNCaP cells.
- Figure 2B shows the lack of effects of Compounds B or D on 4-pregnene-3,20-dione (Progesterone, 10 nM) induced PR transcriptional activity in LNCaP cells to support specificity of Compounds B and D for AR.
- Figure 2C shows the lack of effects of Compounds B, D on dexamethasone (DEX, 10 nM) induced GR transcriptional activity in LNCaP cells, to support specificity of Compounds B and D for AR..
- Figure 2D shows the lack of effects of Compounds B, D on estradiol (E2, 10 nM) induced ER transcriptional activity in LNCaP cells, to support specificity of Compounds B and D for AR.
- Figure 3A shows a representative competition binding curve of displacement of 1 nM fluorescently labeled ligand from recombinant AR-LBD (25 nM) by enzalutamide and R1881 but not with Compounds B or D because these compounds do not bind to the AR-LBD.
- Figure 3B demonstrates that Compounds B and D did not inhibit ligand-binding to PR-LBD.
- Figure 3C demonstrates that Compounds B, D and enzalutamide did not inhibit ligand-binding to GR-LBD.
- Figure 3D demonstrates that Compounds B, D and enzalutamide did not inhibit ligand-binding to ERa-LBD.
- Figure 3E demonstrates that Compounds B, D and enzalutamide did not inhibit ligand-binding to ERp-LBD.
- Figure 3F demonstrates androgen-induced AR-transcriptional activity measured in LNCaP cells transfected with PSA(6.1kb)-luciferase reporter and treated with vehicle (DMSO), enzalutamide (ENZ, 5 ⁇ ), Compounds D (5 ⁇ ), or Compounds B (25 ⁇ ) and increasing concentrations of R1881.
- Figure 4A shows AR-driven PB-luciferase activity in LNCaP cells expressing solely full-length AR, full-length AR plus AR splice variant ARv567es, or full-length AR plus AR splice variant AR-V7 treated with Compounds B, D, or enzalutamide.
- Figure 4B is a Western blot showing protein levels of full-length AR, V567es and V7 from samples in Fig. 4A.
- Figure 4C shows proliferation of LNCaP95 cells treated with Compounds B, D, or enzalutamide for 2 days.
- Figure 4D shows proliferation of LNCaP95 cells treated with varying concentrations of Compounds D for 2 days.
- Figure 4E shows the distribution of cells in G2/M, S, and G0/G1 and inhibition of
- Figure 4F are Western blot analyses results showing the effect of Compounds B, D, or enzalutamide on cell cycle regulated proteins in LNCaP95 cells.
- Figure 5A shows binding of Compound Id to full-length AR protein.
- Figure 5B shows binding of Compound Id to AF-1.
- AF-1 was pre- incubated with Compound B.
- Figure 5C shows binding of Compound Id to endogenous AR in LNCaP95 cells incubated with Compound B.
- Figure 6A shows LNCaP95 tumor/blood and LNCaP95 tumor/muscle ratios in hosts carrying both LNCaP95 and PC 3 xenografts.
- Figure 6B shows the effects of Compound B co-treatment on Compound Id accumulation in blood, muscle, LNCaP95 and PC 3 xenografts.
- Figure 7A shows SPECT/CT images of castrated NOD-SCID mouse 2 hours after tail-vein injection of Compound Id unblocked or blocked with excess Compound B.
- Figure 7B shows the histology of harvested LNCaP95 and PC 3 xenografts at the end of the experiment.
- Figure 7C shows levels of full-length AR and AR-V7 proteins expressed from harvested xenografts shown in Fig. 7A and B.
- Amino refers to the -NH 2 radical.
- Halo or "halogen” refers to bromo, chloro, fluoro or iodo.
- Niro refers to the -N0 2 radical.
- Alkyl refers to a straight or branched saturated 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 1 -C 12 alkyl, an alkyl comprising up to 10 carbon atoms is a C 1 -C 10 alkyl, an alkyl comprising up to 6 carbon atoms is a C 1 -C 6 alkyl and an alkyl comprising up to 5 carbon atoms is a G -C 5 alkyl.
- a C 1 -C 5 alkyl includes C 5 alkyls, C 4 alkyls, C 3 alkyls, C 2 alkyls and C 1 alkyl (i.e., methyl).
- Non-limiting examples of C 1 -C 5 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n- pentyl and the like.
- a G-C 6 alkyl includes all moieties described above for C 1 -C 5 alkyls but also includes C 6 alkyls.
- a C 1 -C 10 alkyl includes all moieties described above for C 1 -C 5 alkyls and C 1 -C 6 alkyls, but also includes C7, Cs, C 9 and Go alkyls.
- a C 1 -G2 alkyl includes all the foregoing moieties, but also includes Cn and C 12 alkyls.
- an alkyl group may be optionally substituted.
- Alkylene or “alkylene chain” refers to a straight or branched divalent alkyl group having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, and n-butylene, and the like.
- the alkylene chain is attached to the rest of the molecule through a single bond and/or to a radical group through a single bond.
- the points of attachment of the alkylene chain to the rest of the molecule and/or 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 may be optionally substituted.
- Alkenyl refers to a straight or branched hydrocarbon chain radical which contains one or more double bonds, having from two to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkenyls comprising any number of carbon atoms from 2 to 12 are included.
- An alkenyl comprising up to 12 carbon atoms is a C 2 -C 12 alkenyl
- an alkenyl comprising up to 10 carbon atoms is a C 2 -C 10 alkenyl
- an alkenyl comprising up to 6 carbon atoms is a C 2 -C 6 alkenyl
- an alkenyl comprising up to 5 carbon atoms is a C 2 -C 5 alkenyl.
- a C 2 -C 5 alkenyl includes C 5 alkenyls, C 4 alkenyls, C 3 alkenyls, and C 2 alkenyls (i.e., vinyl).
- Non-limiting examples of C 2 -C 5 alkenyl include vinyl, allyl, isopropenyl, 1-propene- 2-yl, 1 -butene-l -yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, penteneyl and the like.
- a C 2 -C 6 alkenyl includes all moieties described above for C 2 -C 5 alkenyls but also includes C 6 alkenyls.
- a C 2 -C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
- a C 2 -C 12 alkenyl includes all the foregoing moieties, but also includes Cn and C 12 alkenyls. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted.
- alkenylene or “alkenylene chain” refers to a straight or branched divalent alkenyl group linking the rest of the molecule to and/or to a radical group, having from two to twelve carbon atoms, e.g., ethenylene, propenylene, butenylene, and the like.
- the alkyenlene chain is attached to the rest of the molecule through and/or 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 may be optionally substituted.
- Alkynyl refers to a straight or branched hydrocarbon chain radical which contains one or more triple bonds, having from two to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkynyls comprising any number of carbon atoms from 2 to 12 are included.
- An alkynyl comprising up to 12 carbon atoms is a C 2 -C 12 alkynyl
- an alkynyl comprising up to 10 carbon atoms is a C 2 -C 10 alkynyl
- an alkynyl comprising up to 6 carbon atoms is a C 2 -C 6 alkynyl
- an alkynyl comprising up to 5 carbon atoms is a C 2 -C 5 alkynyl.
- a C 2 -C 5 alkynyl includes C 5 alkynyls, C 4 alkynyls, C 3 alkynyls, and C 2 alkynyls (i.e., ethynyl).
- Non-limiting examples of C 2 -C 5 alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like.
- a C 2 -C 6 alkynyl includes all moieties described above for C 2 -C 5 alkynyls but also includes C 6 alkynyls.
- a C 2 -C 10 alkynyl includes all moieties described above for C 2 -C 5 alkynyls and C 2 -C 6 alkynyls, but also includes C 7 , C 8 , C 9 and Oo alkynyls.
- a C 2 -C 12 alkynyl includes all the foregoing moieties, but also includes C 1 1 and C 12 alkynyls.
- an alkenyl group may be optionally substituted.
- Alkynylene or "alkynylene chain” refers to a straight or branched divalent alkynyl group linking the rest of the molecule to and/or to a radical group, having from two to twelve carbon atoms, e.g. , ethynylene, propynylene, butynylene, and the like.
- the alkynlene chain is attached to the rest of the molecule through and/or 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.
- an alkynylene chain may be optionally substituted.
- Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.
- Alkylamino refers to a radical of the formula -NHRa or -NRaRa where each Ra 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 may be optionally substituted.
- a non-limiting example of an alkyl carbonyl is the methyl carbonyl ("acetal") moiety. Unless stated otherwise specifically in the specification, an alkyl carbonyl group may be optionally substituted.
- Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
- the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may 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, os-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
- aryl is meant to include aryl radicals that are optionally substituted.
- Aralkyl refers to a radical of the formula -Rb-Rc where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Rc 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 may be optionally substituted.
- Carbocyclyl or “carbocyclic ring” refers to a rings structure, wherein the the atoms which form the ring are each carbon. Carbocyclic rings may comprise from 3 to 18 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyls as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group may be optionally substituted.
- Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
- Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- Polycyclic 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 may be optionally substituted.
- Cycloalkylalkyl refers to a radical of the formula - R b R d where R b is an alkylene, alkenylene, or alkynylene chain as defined above and R d is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.
- 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 may be optionally substituted.
- Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
- Heterocyclyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, [1 1 1]
- Heterocyclyl or “heterocyclic ring” refers to a stable 3- to 18-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. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
- the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated.
- heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,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-thio
- 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 may be optionally substituted.
- Heterocyclylalkyl refers to a radical of the formula -RbRe where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene, alkenylene, or alkynylene radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.
- Heteroaryl refers to a 5- to 14-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.
- the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
- Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[3 ⁇ 4[l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl
- 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 may be optionally substituted.
- Heteroarylalkyl refers to a radical of the formula -RbRf where 3 ⁇ 4 is an alkylene, alkenylene, or alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.
- 123 l refers to the radioactive isotope of iodine having atomic mass 123.
- the compounds of formula (I) comprise at least one 123 I moiety. Throughout the present application, where structures depict a 123 I moiety at a certain position it is meant that the I moiety at this position is enriched for 123 I. In other words, the compounds contain more than the natural abundance of 123 I at the indicated position(s). It is not required that the compounds comprise 100% 123 I at the indicated positions, provided 123 I is present in more than the natural abundance.
- the 123 I isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 80% or greater than 90%, relative to 127 I.
- Thioalkyl refers to a radical of the formula -SRa where Ra 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 may be optionally substituted.
- substituted means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, 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, CI, 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, thi
- “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.
- R g and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, 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, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
- each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
- 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.
- the specific point of attachment to the non-depicted chemical entity may be specified by inference.
- fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
- 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 may be replaced with a nitrogen atom.
- the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may 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.
- Solid 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.
- “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.
- Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
- optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
- “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.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- “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-hydroxyethane
- “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 isoprop
- 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 may be water, in which case the solvate may be a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present invention may 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 may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
- 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.
- a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
- the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may 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 (5)-, or (D)- and (L)- isomers may 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).
- HPLC high pressure liquid chromatography
- 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 nonsuperimposeable mirror images of one another.
- 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.
- 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 and/or ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft).
- a substituent group is named before the group to which it attaches.
- cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent.
- 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.
- the present disclosure provides a compound having a structure of formula (I):
- R' and R 2 are each independently H or C 1 -C 10 alkyl, or R 1 and R 2 , together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
- R 3 , R 4 and R 5 are each independently H, O-C 10 alkyl or C 1 -C 10 alkylcarbonyl; and [141] X 1 , X 2 , X 3 and X 4 are each independently H, F, CI, Br, I, 123 I, !24 I, or 125 I;
- the compounds comprise one 123 I substitution, for example in certain other embodiments, three of X 1 , X 2 , X 3 and X 4 are independently selected from H, F, CI, Br, or I, and the remaining X 1 , X 2 , X 3 or X 4 is 123 I.
- the compounds comprise one 123 I substitution, for example in certain other embodiments, three of X 1 , X 2 , X 3 and X 4 are H, and the remaining X 1 , X 2 , X 3 or X 4 is 123 I.
- 123 I can be at any of the "X" positions.
- X 1 is 123 I.
- X 3 is 123 I.
- At least one of X 1 , X 2 , X 3 or X 4 is 124 I or 125 I.
- the compounds comprise one 124 I substitution, for example in certain other embodiments, three of X 1 , X 2 , X 3 and X 4 are independently selected from H, F, CI, Br, or I, and the remaining X 1 , X 2 , X 3 or X 4 is 124 I.
- the compounds comprise one 124 I substitution, for example in certain other embodiments, three of X 1 , X 2 , X 3 and X 4 are H, and the remaining X 1 , X 2 , X 3 or X 4 is 124 I.
- 124 I can be at any of the "X" positions.
- X 1 is 124 I.
- X 3 is 124 I.
- the compounds comprise one 125 I substitution, for example in certain other embodiments, three of X 1 , X 2 , X 3 and X 4 are independently selected from H, F, CI, Br, or I, and the remaining X 1 , X 2 , X 3 or X 4 is 125 I.
- the compounds comprise one 125 I substitution, for example in certain other embodiments, three of X 1 , X 2 , X 3 and X 4 are H, and the remaining X 1 , X 2 , X 3 or X 4 is 125 I.
- 125 I can be at any of the "X" positions.
- X 1 is 125 I.
- X 3 is 125 I.
- At least one of R 1 or R 2 is H.
- R 1 and R 2 are each H.
- R 1 or R 2 is C 1 -C 10 alkyl.
- R 1 and R 2 are each C 1 -Oo alkyl.
- C 1 -C 10 alkyl is C 1 -Go saturated alky such as methyl.
- Each R 1 may independently be C 1 -C 5 alkyl. Each R 1 may independently be C 1 -C 4 alkyl. Each R l may independently be C 1 -C 3 alkyl. Each R 1 may independently be C 1 -C 2 alkyl. Each R 1 may independently be methyl. Each R 1 may independently be C 2 alkyl. Each R 1 may independently be C 3 alkyl. Each R 1 may independently be C 4 alkyl. Each R 1 may independently be C 5 alkyl.
- Each R 2 may independently be C 1 -C 5 alkyl. Each R 2 may independently be C 1 -C 4 alkyl. Each R 2 may independently be C 1 -C 3 alkyl. Each R 2 may independently be C 1 -C 2 alkyl. Each R 2 may independently be methyl. Each R 2 may independently be C 2 alkyl. Each R 2 may independently be C 3 alkyl. Each R 2 may independently be C 4 alkyl. Each R 2 may independently be C 5 alkyl.
- R 3 , R 4 or R 5 is H. In certain embodiments, two of R 3 , R 4 and R 5 are H. In other embodiments, R 3 , R 4 and R 5 are each H.
- R 3 , R 4 or R 5 is C 1 -C 10 alkyl.
- two of R 3 , R 4 and R 5 are G- C 10 alkyl.
- R 3 , R 4 and R 5 are each G-C 10 alkyl.
- C 1 -C 10 alkyl is saturated C 1 -C 10 alkyl.
- the saturated G-C 10 alkyl is methyl, isopropyl or n-butyl.
- the C 1 -G0 alkyl is unsaturated C 1 -C 10 alkyl, for example propargyl.
- Each R 3 may independently be C 1 -C 5 alkyl. Each R 3 may independently be C 1 -C 4 alkyl. Each R 3 may independently be C 1 -C 3 alkyl. Each R 3 may independently be C 1 -C 2 alkyl. Each R 3 may independently be methyl. Each R 3 may independently be C 2 alkyl. Each R 3 may independently be C 3 alkyl. Each R 3 may independently be C 4 alkyl. Each R 3 may independently be C 5 alkyl.
- Each R 4 may independently be C 1 -C 5 alkyl. Each R 4 may independently be C 1 -C 4 alkyl. Each R 4 may independently be C 1 -C 3 alkyl. Each R 4 may independently be C 1 -C 2 alkyl. Each R 4 may independently be methyl. Each R 4 may independently be C 2 alkyl. Each R 4 may independently be C 3 alkyl. Each R 4 may independently be C 4 alkyl. Each R 4 may independently be C 5 alkyl.
- Each R 5 may independently be C 1 -C 5 alkyl. Each R 5 may independently be C 1 -C 4 alkyl. Each R 5 may independently be C 1 - C 3 alkyl. Each R 5 may independently be C 1 -C 2 alkyl. Each R 5 may independently be methyl. Each R 5 may independently be C 2 alkyl. Each R 5 may independently be C 3 alkyl. Each R 5 may independently be C 4 alkyl. Each R 5 may independently be C 5 alkyl.
- R 3 , R 4 or R 5 is C 1 -C 10 alkylcarbonyl.
- two of R 3 , R 4 and R 5 are C 1 -C 10 alkylcarbonyl.
- R 3 , R 4 and R 5 are each C 1 -C 10 alkylcarbonyl.
- the C 1 -C 10 alkylcarbonyl is methyl carbonyl (acetal).
- Each R 3 may independently be C 1 -C 5 alkylcarbonyl. Each R 3 may independently be G-C 4 alkylcarbonyl. Each R 3 may independently be C 1 -C 3 alkylcarbonyl. Each R 3 may independently be C 1 -C 2 alkylcarbonyl. Each R 3 may independently be methylcarbonyl. Each R 3 may independently be C 2 alkylcarbonyl. Each R 3 may independently be C 3 alkylcarbonyl. Each R 3 may independently be C 4 alkylcarbonyl. Each R 3 may independently be C 5 alkylcarbonyl.
- Each R 4 may independently be C 1 -C 5 alkylcarbonyl. Each R 4 may independently be C 1 - C 4 alkylcarbonyl. Each R 4 may independently be C 1 -C 3 alkylcarbonyl. Each R 4 may independently be C 1 -C 2 alkylcarbonyl. Each R 4 may independently be methylcarbonyl. Each R 4 may independently be C 2 alkylcarbonyl. Each R 4 may independently be C 3 alkylcarbonyl. Each R 4 may independently be C 4 alkylcarbonyl. Each R 4 may independently be C 5 alkylcarbonyl.
- Each R 5 may independently be C 1 -C 5 alkylcarbonyl. Each R 5 may independently be C 1 -C 4 alkylcarbonyl. Each R 5 may independently be C 1 -C 3 alkylcarbonyl. Each R 5 may independently be C 1 -C 2 alkylcarbonyl. Each R 5 may independently be methylcarbonyl. Each R 5 may independently be C 2 alkylcarbonyl. Each R 5 may independently be C 3 alkylcarbonyl. Each R 5 may independently be C 4 alkylcarbonyl. Each R 5 may independently be C 5 alkylcarbonyl.
- the compound of formula (I) has one of the following structures from Table 1, or a pharmaceutically acceptable salt thereof:
- the compound of formula (I) has one of the following structures from Table 2, or a pharmaceutically acceptable salt thereof:
- the compound of formula (I) has one of the following structures from Table 3, or a pharmaceutically acceptable salt thereof:
- the compound of formula (I) is one of the following:
- the compound of formula (I) is one of the following: [173] In one embodiment, the compound of formula (I) is one of the following:
- the present invention is directed to a pharmaceutical composition, comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as described herein.
- the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof further comprises a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof further comprises an additional therapeutic agent.
- the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.
- the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises an additional therapeutic agent which is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
- an additional therapeutic agent which is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
- 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").
- combination therapy is meant the administration of any one or more of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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.
- Such administration includes without limitation dosing of one or more of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as a pre-mixed formulation.
- Administration of the compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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.
- the one or more of the additional therapeutic agents can be administered to the patient before administration of the compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
- the compound(s) of formula (I) can be co-administered with one or more of the additional therapeutic agents.
- the one or more additional therapeutic agents can be administered to the patient after administration of the compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
- the ratio of the doses of compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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.
- the compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including those compounds shown in Table 1 , Table 2, or Table 3.
- 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.
- ODM-201 also known as BAY1841788
- 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) 2,3,4,7,8,9,10,1 1, 12,13, 14,15-dodecahydro-lH-cyclopenta[a]phenanthren-3-ol), and related molecules, which appears to block the production of androgen and FDA-approved treatment for prostate
- the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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- HDAC 4 2, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, radium 233, niclosamide, apa
- compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, which result in unstable structures and/or unsatisfied valences are not included within the scope of the invention.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising any of the foregoing compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier.
- Compounds as described herein can be in the free form or in the form of a salt thereof.
- 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.
- 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,
- 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.
- 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, theo
- 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.
- compounds and all different forms thereof 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.
- hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.
- compounds and all different forms thereof 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.
- compounds and all different forms thereof 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.
- the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used here includes subcutaneous, intravenous (IV), intramuscular, and intraarterial injections with a variety of infusion techniques.
- IV intravenous
- Intraarterial and intravenous injection as used herein includes administration through catheters.
- the compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
- the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- a suitable vehicle e.g., sterile pyrogen-free water
- suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
- a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as disclosed herein, combined with a pharmaceutically acceptable carrier.
- suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
- Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline.
- Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
- non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
- Oral carriers can be elixirs, syrups, capsules, tablets and the like.
- Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
- the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
- Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
- a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
- the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
- the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active compound.
- suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
- Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.
- Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
- Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
- the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
- Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle.
- Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
- microcrystalline cellulose e.g., AVICEL
- microfine cellulose e.g., lactose, starch, pregelatinized starch
- calcium carbonate calcium sulfate
- sugar dextrates
- dextrin dextrin
- dextrose dibasic calcium phosphate dihydrate
- a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates).
- a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
- Solid pharmaceutical compositions that are compacted into a dosage form may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
- carbomer e.g., carbopol
- the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition and/or combination.
- Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PR1MELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
- a disintegrant include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PR1MELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (
- Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing.
- Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
- a dosage form such as a tablet is made by the compaction of a powdered composition
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
- Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition and/or combination of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
- Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
- a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
- Liquid pharmaceutical compositions can be prepared using compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
- a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
- formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
- polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
- biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers can be useful excipients to control the release of active compounds.
- Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
- Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
- Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
- Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier.
- Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
- Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
- Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
- Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
- a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
- a pharmaceutical composition comprising the compound of the present disclosure is prepared for intravenous injection (IV).
- a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
- other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
- injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
- Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi- dose containers.
- Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
- Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3- butane-diol or prepared as a lyophilized powder.
- a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3- butane-diol or prepared as a lyophilized powder.
- sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3- butane-diol or prepared as a lyophilized powder.
- sterile fixed oils may conventionally be employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid may likewise be used in the preparation of injectables.
- Formulations for intravenous administration can
- the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent.
- the compound can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
- an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
- Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
- a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- suitable polymeric or hydrophobic materials for example an emulsion in an acceptable oil
- ion exchange resins for example an emulsion in an acceptable oil
- sparingly soluble derivatives for example, as a sparingly soluble salt.
- a pharmaceutical composition of the present invention comprises a delivery system.
- delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
- a pharmaceutical composition of the present invention comprises a co-solvent system.
- co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
- co-solvent systems are used for hydrophobic compounds.
- VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300.
- co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
- identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
- a pharmaceutical composition of the present invention comprises a sustained-release system.
- a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
- sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
- compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject.
- the manner in which the composition is administered is dependent, in part, upon the cause and/or location.
- One skilled in the art will recognize the advantages of certain routes of administration.
- the method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders.
- the route of administration is systemic, e.g., oral or by injection.
- agents or compounds, or pharmaceutically acceptable salts or derivatives thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, and parenterally.
- the route of administration is local, e.g., topical, intra-tumor and peri-tumor.
- the compound is administered orally.
- a pharmaceutical composition of the present disclosure is prepared for oral administration.
- a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
- Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- such a mixture is optionally ground and auxiliaries are optionally added.
- pharmaceutical compositions are formed to obtain tablets or dragee cores.
- disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate are added.
- dragee cores are provided with coatings.
- concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to tablets or dragee coatings.
- compositions for oral administration are push-fit capsules made of gelatin.
- Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers may be added.
- compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner.
- a pharmaceutical composition is prepared for transmucosal administration.
- penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
- a pharmaceutical composition is prepared for administration by inhalation.
- Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
- Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit may be determined with a valve that delivers a metered amount.
- capsules and cartridges for use in an inhaler or insufflator may be formulated.
- Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
- the compound of the present disclosure are administered by the intravenous route.
- the parenteral administration may be provided in a bolus or by infusion.
- a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema.
- Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
- a pharmaceutical composition is prepared for topical administration.
- Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams.
- ointments or creams include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions.
- suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.
- the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
- one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, are formulated as a prodrug.
- a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form.
- prodrugs are useful because they are easier to administer than the corresponding active form.
- a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
- a prodrug may have improved solubility compared to the corresponding active form.
- prodrugs are less water soluble than the corresponding active form.
- a prodrug is an ester.
- the ester is metabolically hydrolyzed to carboxylic acid upon administration.
- the carboxylic acid containing compound is the corresponding active form.
- a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
- the peptide is cleaved upon administration to form the corresponding active form.
- a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration.
- the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
- the amount of the compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or compounds disclosed in Table 1, Table 2 or Table 3, or a pharmaceutically acceptable salt or solvate thereof can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
- a dose of the disclosed compounds in solution (typically 5 to 30 millicuries or 200 to 1,100 MBq) is typically injected rapidly into a saline drip running into a vein, in a patient. Then, the patient is placed in the SPECT scanner to obtain a series of projections which may take about 15-20 minutes. Methods for SPECT scanning are well known in the art.
- 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 PET scanner for a series of one or more scans which may take from 20 minutes to as long as an hour (often, only about one quarter of the body length may be imaged at a time). Methods for PET scanning are well known in the art.
- the concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration.
- the agent may be administered in a single dose or in repeat doses.
- the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- compositions of the present disclosure may be manufactured and/or administered in single or multiple unit dose forms.
- compounds disclosed in Table 1 can be useful in methods for SPECT imaging.
- compounds of formula (I) wherein at least one of X 1 , X 2 , X 3 or X 4 is 123 I can be useful for SPECT imaging.
- the 123 I of the disclosed compounds can be useful as imaging agent.
- the ability for l23 I labeled compound of the disclosure to be useful in SPECT imaging applications is an important way to identify cell uptake and biodistribution of the compound selectively in the target cells, i.e., cancer cells.
- the compound of the present disclosure including compound comprising at least one ,23 I, selectively binds to androgen receptor (AR).
- AR androgen receptor
- the compound of the present disclosure selectively binds to AR N-terminal domain (NTD).
- compounds disclosed in Table 2 can be useful in methods for PET imaging.
- compounds of formula (I) wherein at least one of X 1 , X 2 , X 3 or X 4 is 124 I can be useful for PET imaging.
- the 124 I of the disclosed compounds can be useful as imaging agent.
- the ability for 124 I labeled compound of the disclosure to be useful in PET imaging applications is an important way to identify cell uptake and biodistribution of the compound selectively in the target cells, i.e., cancer cells.
- the compound of the present disclosure including compound comprising at least one 124 I, selectively binds to androgen receptor (AR).
- the compound of the present disclosure selectively binds to AR N-terminal domain (NTD).
- a method for imaging full-length AR and AR-Vs in CRPC patients using compounds of formula (I).
- administration of a compound of formula (I) to a subject in need thereof can enable specific visualization of xenografts that express full AR and AR-Vs using single-photon emission computed tomography-computed tomography (SPECT/CT) or PET.
- SPECT/CT single-photon emission computed tomography-computed tomography
- compound of formula (I) which can bind to AF-1 that is common to both full-length AR and AR-Vs, can be useful in revealing the expression of solely AR-Vs when compared to 16p-[ 18 F]-fluoro-5a dihydrotestosterone ( 18 F-FDHT) which binds only full-length AR, bind to AF-1 that is common to both full-length AR and AR-Vs.
- 18 F-FDHT 16p-[ 18 F]-fluoro-5a dihydrotestosterone
- a discordant distribution and/or discordant level of uptake between 18 F-FDHT and a compound of formula (I) would indicate the expression of solely AR-Vs.
- This imaging technique could reveal patients with lesions that are positive for AR-Vs who may not benefit from further therapies that target AR LBD.
- a compound of formula (I) can aid in monitoring treatment responses to significantly impact the clinical management of the disease as well as provide insight into the role of all AR species in resistance mechanisms.
- the compound of formula (I) can have favorable effects on blocking the transcriptional activity AR NTD without losing its specificity. That is, in one embodiment, when a compound of formula (I) bind to the AR NTD, the binding does not affect binding of ligand to AR-LBD.
- This specificity is an important attribute for this indication and molecular target because, imaging agents and/or radiolabeled compounds, such as compounds of formula (I), are applied at microdoses and hence highly susceptible to competing agents. For most applications, it is predicted that patients failing enzalutamide or other antiandrogens may have an AR LBD occupied by the antiandrogen.
- the present compounds find particular utility in methods for imaging the prostate using a compound of formula (I).
- a method for imaging benign conditions of the prostate comprising administering any of the foregoing compound or pharmaceutical compositions to a subject and detecting the prostate
- the present disclosure provides a method of imaging cancer, the method comprising administering the foregoing pharmaceutical composition to a subject and detecting the presence or absence of cancer by use of SPECT or PET.
- the present disclosure provides a method of imaging cancer and treating said cancer by radiotherapy with the use of a compound of the present disclosure of any of the forgoing pharmaceutical compositions.
- the method identifies the presence or absence of a tumor. For example, some embodiments the method identifies the location of a tumor.
- the cancer is prostate cancer, for example, castration resistant prostate cancer.
- the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone- sensitive prostate cancer.
- the subject is a mammal such as a human.
- the method identifies the presence of a tumor that expresses AR (both full-length and truncated AR lacking LBD) and then treats the tumor by radiotherapy.
- the imaging methods provide information to determine if a tumor expresses AR species.
- 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).
- the present compounds bind to the AR N- terminal domain (NTD)
- the present methods may be useful for detecting AR species, including mutants and variants, which lack the LBD or have LBD mutations, but do comprise the AR NTD.
- the method detects the presence or overexpression of AR splice variants lacking the ligand binding domain.
- the method may include sequential imaging with 18 F-FDHT and a compound of the invention and a discordant distribution or discordant level of uptake between 18 F-FDHT and the compound of the invention indicates the presence or overexpression of splice variants lacking the ligand binding domain.
- the present disclosure provides a method for detecting AR species, including mutants and variants, and emitting Auger electrons in the area of detection.
- the compounds of the invention are used in single photon emission computed tomography methods to monitor a patient's response to therapy.
- the methods comprise use of a compound of the invention to detect the AR NTD.
- the present disclosure provides the use of any one of the foregoing compounds of formula (I) for imaging cancer.
- the imaging is in a human patient.
- the present disclosure provides the use of a compound of formula (I) for imaging cancer and treating said cancer by radiotherapy.
- the imaging and treating is in a human patient.
- the present disclosure provides the use of any one of the foregoing compounds of formula (I) for imaging the prostate.
- the imaging is in a human patient.
- the present disclosure provides the use of a compound of formula (I) for imaging prostate cancer and treating said prostate cancer by radiotherapy.
- the imaging and treating is in a human patient.
- the imaging may be for imaging of benign prostate conditions of for imaging cancer (e.g., tumors), for example prostate cancer.
- the imaging may be by SPECT or PET.
- the imaging may be in a mammalian cell.
- the imaging may be in a mammal.
- the mammal may be a human.
- the present disclosure provides the use of a compound of formula (I) for imaging cancer by SPECT or PET and treating said cancer by radiotherapy.
- the imaging and treating is in a mammalian cell, in a mammal, or in a human.
- the cancer is prostate cancer or breast cancer.
- the compounds of formula (I) may be administered to a mammal for imaging purposes.
- the administering and imaging may 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 mammalian cell may be a human cell.
- the imaging may be for imaging AR splice variants, mutants or other AR species which contain AR NTD.
- the compounds of formula (I) may be administered to a mammal for imaging and/or treatment purposes.
- the administering, imaging, and/or treating may 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 mammalian cell may be a human cell.
- the imaging may be for imaging AR splice variants, mutants or other AR species which comprise the AR NTD.
- the treatment is by radiotherapy of cells where the compound of formula (I) have been distributed to.
- the compounds as described herein or pharmaceutically acceptable salts thereof may 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.
- the compounds as described herein or acceptable salts thereof above may 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).
- the compounds as described herein or pharmaceutically acceptable salts thereof may be used for imaging, diagnosis, and/or treatment 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.
- the compounds as described herein or a pharmaceutically acceptable salts thereof above may be used in the preparation of a medicament or a composition for imaging the prostate and/or treatment of the prostate, for example for imaging benign prostate conditions or for imaging and/or treating prostate cancer in a subject in need of such imaging (for example for diagnosis and/or location of prostate tumors).
- the imaging method disclosed herein is directed to imaging prostate cancer.
- the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
- the prostate cancer is CRPC.
- the imaging is for imaging benign prostate conditions such as benign prostatic hyperplasia. Methods of imaging and/or treating any of the indications described herein are also provided. Such methods may include administering a compound as described herein or a composition of a compound as described herein, or an effective amount of a compound as described herein or composition of a compound as described herein to a subject in need thereof.
- a pharmaceutical composition suitable for imaging is administered intravenously.
- the compound of the present disclosure finds utility in Auger therapy for treatment of cancer.
- the compound of the present disclosure finds utility in radiotherapy or radionuclide therapy for treatment of cancer.
- the presently disclosed compounds find utility in a number of medical imaging applications (e.g., PET and SPECT imaging), including imaging of the prostate, and also applications in radiotherapy for cancer, such as prostate cancer.
- compounds disclosed in Table 3 can be useful in Auger therapy.
- compounds of formula (I) wherein at least one of X 1 , X 2 , X 3 or X 4 is l25 I can be useful for Auger therapy.
- Auger therapy is a form of radiation therapy for treatment of cancer. Auger therapy differs from traditional radiation therapy in that it relies on a large number of low-energy electrons, emitted by the Auger effect (Auger electrons), to damage cancer cells, rather than the use of high-energy radiation. Like other radiation therapy, Auger therapy relies on radiation-induced apoptosis of cancer cells, damage to cancer cells (particularly DNA damage) such that cell division is stopped or attenuated, termination of tumor growth and metastasis.
- Auger therapy The major difference between Auger therapy and the traditional radiation therapy is that electrons emitted via the Auger effect are low energy but released in large numbers. Due to their low kinetic energy, the Auger electrons can only damage cells that are in very close range, in nanometer range. Thus, for an effective treatment, the radiation-emitting species/compounds/therapeutics must be inside the cell to which it is targeted. Accordingly, one of the challenges for Auger therapy is to find a compound that could selectively enter the targeted cell and bind to the specific sub-cellular components of said cell which also contains heavy atoms, which are capable of being an Auger emitter, such as 125 I. The Auger emitter would then release Auger electrons by radioactive decay or by external excitations.
- the compounds comprising a ,25 I can be useful as an Auger emitter.
- the targeted and selective delivery of the Auger emitter which can be established by SPECT and/or PET imaging using analogous compounds having 123 I or 124 I as described previously, is important for success of Auger therapy.
- the compound of the present disclosure selectively binds to androgen receptor (AR).
- AR androgen receptor
- NTD AR N-terminal domain
- the compounds of the present disclosure can be Auger emitters. In another embodiment, the compounds of the present disclosure can deliver alpha- or beta- emitting radionuclides to surrounding cells. In one embodiment, the compound of the present disclosure can deliver alpha- or beta-emitting radionuclides to cancer cells. In some embodiments, the compound of the present disclosure can deliver alpha- or beta-emitting radionuclides to lesions that express full-length AR and/or AR-Vs in patients with cancers. In another embodiment, the compound of the present disclosure can deliver alpha- or beta- emitting radionuclides to lesions that express full-length AR and/or AR-Vs in patients with metastatic castration-resistant prostate cancer (CRPC). In one embodiment, the compound of the present disclosure comprises a radionuclide which can emit alpha- or beta-particles.
- CRPC metastatic castration-resistant prostate cancer
- visceral metastases are positive for full-length AR they could benefit from hormone therapies that target AR LBD such as enzalutamide (Evans CP., et al. Eur Urol. 2016. doi: 10.1016/j.eururo.2016.03.017).
- the major mechanisms of resistance to these therapies include gain-of-function mutations in AR LBD and/or expression of constitutively active splice variants of AR (AR- Vs) that lack LBD ⁇ see, Antonarakis E.S., et al. N Engl J Med. 2014;371(11): 1028-1038; Nadiminty N., et al. Mol Cancer Ther. 2013;12(8): 1629-1637; Mostaghel E.A., et al. Clin Cancer Res. 2011 ; 17(18):5913-5925; Scher et al JAMA Oncol. 2016 doi: 10.1001).
- Full-length AR is a ligand-activated transcription factor with distinct functional domains that include: the C-terminal ligand-binding domain (LBD) to which androgens and antiandrogens bind; the hinge region which contains a nuclear translocation sequence; the DNA-binding domain (DBD) which binds to androgen response elements (AREs) in the enhancers/promoters of target genes; and the N-terminal domain (NTD) which contains activation function- 1 (AF-1) that is essential for AR transcriptional activity ⁇ see, Jenster G., et al. Mol Endocrinol. 1991;5(10): 1396-1404; Rundlett S.E., et al. Mol Endocrinol. 1990;4(5):708-714; Simental J.A., et al. J Biol Chem. 1991 ;266(1):510-518).
- LBD C-terminal ligand-binding domain
- DBD DNA-binding domain
- AR-Vs mediate a growth advantage for prostate cancer in androgen-deprived conditions and are detected in CRPC tissues (Guo et al. 2009; Hu R., et al. Cancer Res. 2009;69(l):16-22; Dehm S.M., et al. Cancer Res. 2008;68(13):5469-5477).
- AR-Vs that lack the LBD have been reported in prostate cancer cell lines (VCaP and 22Rvl), and in CRPC tissues.
- V7 and V567es are clinically relevant with levels of expression correlated to poor survival and CRPC (Hornberg E., et al. PLoS One.
- Detection of CTCs is dependent on tumor volume and the presence of a surface antigen, such as HER2 (human epidermal growth factor receptor 2), EpCAM (Epithelial cell adhesion molecule), CD45, and may not capture the entire CTC population.
- HER2 human epidermal growth factor receptor 2
- EpCAM EpCAM
- CD45 Circulating tumor-derived cell-free DNA (ctDNA) is also undergoing evaluation alongside CTCs for its utility in clinical practice (Dawson S.J., et al. TV Engl J 'Med. 2013;368(13):1199-1209; Haber D.A., et al. Cancer Discov. 2014;4(6):650-661).
- ctDNA and/or ctRNA may be derived from primary tumors, metastatic lesions, CTCs or from the plethora of benign tissues that are known to express AR-Vs (Hu D.G., et al. Horm Cancer. 2014;5(2):61-71). ctDNA analyses are restricted to measurable changes at the DNA level and to date the clinical relevance of genomic rearrangement to generate AR-Vs is lacking. Thus, there is a need to develop clinical methods to determine expression of AR-Vs in metastatic CRPC. One possible approach is application of molecular imaging agents to detect AR-Vs.
- Small molecule bisphenol ether derivatives previously developed and disclosed, provide an opportunity to develop such a prognostic imaging tool because they bind to AF-1 that is common to both full-length AR and AR-Vs (Andersen R.J., et al. Cancer Cell. 2010;17(6):535-546; Myung J.K., et al. J Clin Invest. 2013;123(7):2948-2960; De Mol E. et al 2016 ACS Chem Biol. doi : 10.102 l/acschembio.6b00182).
- AR NTD inhibitors such as Compound A and its stereoisomers (e.g., Compound B) and ester derivatives (e.g., Compound C) were developed as AF-1 inhibitors to block transactivation of both full-length AR and AR-Vs.
- Compound C received Investigational New Drug approval from the FDA and Health Canada (i.e., acceptable safety profile at therapeutic doses) and is currently in clinical trials in the USA and anada for CRPC atients that have failed abiraterone and/or enzalutamide.
- the compound of formula (I) can have favorable effects on blocking the transcriptional activity AR NTD without losing its specificity. That is, in one embodiment, when a compound of formula (I) bind to the AR NTD, the binding does not affect binding of ligand to AR-LBD.
- This specificity is an important attribute for this indication and molecular target because Auger emitters and/or radiolabeled compounds, such as compounds of formula (I), are applied at microdoses and hence highly susceptible to competing agents. For most applications, it is predicted that patients failing enzalutamide or other antiandrogens may have an AR LBD occupied by the antiandrogen.
- the present disclosure provides a method for treating cells, cancer cells, lesions, and the like by radiotherapy associated with the expression of AR and AR-Vs or to which the compounds of formula (I) modulates, binds, or inhibits.
- the method comprising administering a pharmaceutical composition comprising a compound as described herein to a subject in need thereof.
- the method for treatment by radiotherapy is 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.
- the indication is prostate cancer.
- the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone- sensitive prostate cancer.
- the spinal and bulbar muscular atrophy is Kennedy's disease.
- the prostate cancer is CRPC.
- the methods for treatment by radiotherapy may include administering a compound as described herein or a composition of a compound as described herein, or an effective amount of a compound as described herein or composition of a compound as described herein to a subject in need thereof.
- a pharmaceutical composition suitable for radiotherapy is administered intravenously.
- the present disclosure provides a method for modulating androgen receptor (AR) activity, the method comprising administering to a mammalian cell one or more of the present compounds.
- the modulating of androgen receptor (AR) activity is in a mammalian cell.
- the method comprising administering a compound of the present disclosure or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof.
- the method for 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, and age related macular degeneration.
- the indication is prostate cancer.
- the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
- the spinal and bulbar muscular atrophy is Kennedy's disease.
- the compound of the present disclosure can be used at various stages of the treatment of AR-related diseases or conditions, including prostate cancer.
- the compound of the present disclosure can be useful in a neoadjuvant therapy.
- the compound of the present disclosure can be useful in a primary therapy.
- the compound of the present disclosure can be useful alone or in combination with different therapies or with administration of additional pharmaceutical active agents.
- he compound of the present disclosure can be useful in an adjuvant therapy.
- An "adjuvant therapy” is a therapy that is administered in addition to a primary, main, or initial therapy in order to maximize the effectiveness of treatment.
- the compound of the present disclosure can be useful in an adjuvant therapy following an androgen ablation therapy. In another embodiment, the compound of the present disclosure can be useful in an adjuvant therapy to prevent recurrence of the disease after primary therapy or previous treatments.
- the compound of the present disclosure can be useful in combination with other treatments.
- the compound of the present disclosure can be useful in combination with therapeutic agents known for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
- the compound of the present disclosure can be useful in combination with therapeutic agents known for treating prostate cancer.
- the compound of the present disclosure can be useful in treating prostate cancer in combination with therapeutic agents selected from: enzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC 4 2, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, radium 233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10- AR441bsAb, sin
- therapeutic agents selected from
- the compound of the present disclosure can be useful in treating prostate cancer in combination with other therapies known to be effective in the treatment of prostate cancer.
- Compound Id can be prepared according to Scheme 1 involving three radiosynthetic steps.
- the [ 123 I]iodoacetonide (compound Hi) was prepared in 90 ⁇ 10% radiochemical yield via aromatic electrophilic iodination reaction using chloramines-T as the oxidizing reagent and the acetonide (compound ii) as the precursor.
- the isolated [ 123 I]iodoacetonide was subsequently coupled with (2i?)-(-)-glycidyl tosylate to form [ 123 I]iodoepoxide (compound iv) in 37 ⁇ 17% radiochemical yield.
- Na 123 I was purchased from Nordion (Vancouver, Canada). All other chemicals and solvents were obtained from commercial sources, and used without further purification. Purification and quality control of 123 I-labelled compounds were performed on an Agilent (Santa Clara, CA, USA) HPLC System equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector (set at 220 nm), and a Bioscan (Washington, DC, USA) Nal scintillation detector.
- the radio-detector was connected to a Bioscan B-FC-1000 Flow-count System, and the output from the Bioscan Flow-count system was fed into an Agilent 35900E Interface which converted the analog signal to digital signal.
- the operation of the Agilent HPLC system was controlled using the Agilent ChemStation software.
- the HPLC columns used were a semi-preparative column (Phenomenex Luna CI 8, 5 ⁇ , 250 x 10 mm) and an analytical column (Phenomenex Luna CI 8, 5 ⁇ , 250 x 4.6 mm). Radioactivity of 123 I-labelled compounds was measured using a Capintec (Ramsey, NJ) CRC ® -25R/W dose calibrator.
- LNCaP, PC 3 and DU145 cell lines as well as PSA(6.1 kb)-luciferase, probasin (PB)-luciferase, PRE- luciferase, GRE-Luciferase, ERE-Luciferase, AR-V7 and AR-V567es plasmids, and transfection of cells have been described previously (22, 23, 26, 29).
- LNCaP cells were obtained from Dr. Leland Chung (Cedars-Sinai Medical Center, Los Angeles, CA) in September 1993.
- DU145 cells were from Dr. Victor Ling (BC Cancer Agency, Integrative Oncology, Vancouver, BC) in October 1998.
- LNCaP95 an androgen-independent cell line that expresses full-length AR and AR-V7 was provided by Dr. Stephen R. Plymate (University of Washington, Seattle, WA) in February of 2012 and reported in previous studies (12, 14, 36, 37).
- PC 3 cells were purchased from American Type Culture Collection. LNCaP95 cells were not authenticated in our laboratory, but were regularly tested to ensure mycoplasma-free (VenorTMGeM Mycoplasma Detection kit, Sigma-Aldrich, St. Louis, MO). LNCaP, PC 3 and DU145 cells were authenticated by short tandem repeat (STR) analysis and tested to ensure mycoplasma-free by DDC Medical (Fairfield, OH) in September 2013. All cells used in the experiments were passaged in our laboratory for fewer than 3 months after resurrection.
- STR short tandem repeat
- PC 3 (2,000 cells/well), DU145 (2,000 cells/well) and LNCaP cells (5,000 cells/well) were plated in 96-well plates in respective media plus 0.5% FBS. The next day, PC 3 and DU145 cells were treated with DMSO (vehicle control) and Compound D for 3 days, and LNCaP cells were pretreated with vehicle and Compound D for 1 hour before treating with 0.1 nM R1881 for 4 days. Proliferation and cell viability was measured using alamarBlue® Cell Viability Assay (Invitrogen) following the manufacturer's protocol.
- BrdU incorporation experiments LNCaP95 cells (8,000 cells/well) were seeded in 96-well plates for 48 hr before in RPMI with 10 % charcoal stripped serum and changed to serum-free media 24 hr before treating with 5 ⁇ enzalutamide, 25 uM Compound B, 2 ⁇ Compound D or serial concentration of Compound D. BrdU incorporation was measured after 2 days using BrdU ELISA kit (Roche Diagnostics) according to the manufacturer's protocol.
- LNCaP95 cells (75,000 cells/dish) were plated in 10 cm dishes and were treated with inhibitors under serum-free and phenol red-free conditions for 48 hours. Cells were pulse labeled with 10 ⁇ BrdU for 2 hours and fixed in 70 % ethanol. BrdU- labeled cells were probed with anti-BrdU-FITC antibody (BD Biosciences) and DNA was stained with 7-aminoactinomycin D (Sigma). Data was acquired using a FACS Calibur (BD Biosciences). Bivariate analysis was performed using Flow Jo 7 software (Ashland).
- Binding Assays The cell-free binding assay was performed with commercially available full-length AR recombinant protein or AR AF-1 recombinant protein that was expressed and purified as previously described (22, 38), with additional purification by size exclusion chromatography. Binding reaction between Compound B or DMSO (vehicle control) and the recombinant AR AF-1 (amino acid residues 142 - 485) or full-length AR were carried out by mixing 60 ⁇ Compound B or DMSO with 10 ⁇ AR AF-1; also 1 ⁇ Compound B or DMSO with 0.35 ⁇ full-length AR in equivalent amounts. Binding reaction was incubated at room temperature for 6 hours.
- Proteins were extracted from treated cells with RIPA buffer containing 50 mM tris (pH 8.0), 150 mM NaCl, 0.5% Na Deoxycholate, 1% NP-40, 0.1% SDS and EDTA-free protease inhibitors. Proteins bound to 123 I test compound were separated by SDS-PAGE and radioactivity was visualized using Fujifilm FLA-7000 image analyzer, and also subjected to Western blot analysis using anti- AR antibody.
- LNCaP95 cells (250,000 cells/well) were seeded in a 6-well plate for 48 hr, and serum- starved for 24hr, followed by treatment with DMSO, enzalutamide (5 ⁇ ), Compound B (25 ⁇ ) or Compound D (5 uM) for 48hr.
- Cells were harvested and whole-cell lysate (10 to 15 ⁇ g) was subjected to SDS-PAGE.
- Antibodies used were: AR N-20 (sc-816, Santa Cruz Biotech Inc., Santa Cruz, CA), AR-V7 (AG10008, Precision AntibodyTM, Columbia, MD).
- SPECT scans were acquired over 30 min and 2 frames at 15min each using 1.0 mm multi-pinhole collimator, after which CT scans were performed for anatomic reference (parameters ; 60 kV, 600 uA).
- SPECT imaging data were reconstructed using MI Labs reconstruction software (2 subsets, 30 iterations). PMOD software was used to analysis and view the images, and Gaussian filter was applied post reconstruction.
- the PSA-luciferase (6.1kb) reporter contains functional AREs to which AR binds in response to androgen to induce luciferase activity.
- LNCaP cells were transfected with the PSA(6.1 kb)-luciferase reporter for 24 h, and then treated with indicated concentration of Compound D (cold Iodine, not 123 I) with synthetic androgen, R1881 (1 nM) for 24 h. After 24 h of incubation with R1881 , the cells were harvested, and relative luciferase activities were determined. To determine the IC 5 0, treatments were normalized to the predicted maximal activity induction (in the absence of test compounds, vehicle only); n > 3 (Fig. 1A).
- Compound D had an IC 5 0 of approximately 1 uM to block AR-driven proliferation of LNCaP cells in response to androgen; n > 3 (Fig. IB). Compound D had no effect on proliferation or viability of PC 3 and DU145 human prostate cancer cells that do not express functional AR at up to 10X the IC 5 0 required to reduce AR-dependent proliferation thereby supporting its specificity for AR. Data disclosed in Fig. IB represents mean ⁇ SD. Compound D is 10X more potent than Compound B which has IC 5 0 in the range of 10 ⁇ for these cell- based assays (Andersen 2010; Myung 2013).
- Imaging agents and Auger emitters/agents are administered at micro-doses and thus must be highly specific for its target. Therefore, it was examined whether Compound D would potentially interact with most highly related proteins to AR in the human proteome which are the other steroid receptors: progesterone receptor (PR), glucocorticoid receptor (GR) and estrogen receptor (ER).
- PR progesterone receptor
- GR glucocorticoid receptor
- ER estrogen receptor
- CBP CREB binding protein
- SRC 1-3 A sensitive method to determine if Compound D interacts with any of these other receptors is to measure their transcriptional activities. Therefore, reporter gene assays were used to determine if Compound D would inhibit PR, GR or ER transcriptional activities.
- Compound D does not have general effects on transcription or translation because it did not inhibit induction of PRE (progesterone response element)-, GRE (glucocorticoid response element)- or ERE (estrogen response element)-luciferase reporters in response to ligand. Thus, Compound D appears to maintain specificity for AR.
- Fig. 2C shows the effect of Compounds B, D on dexamethasone (DEX, 10 nM) induced GR transcriptional activity in LNCaP cells that were transiently transfected with GRE-luciferase reporter and expression vector for GR.
- Fig. 2D shows the effect of Compounds B, D on estradiol (E2, 10 nM) induced ER transcriptional activity in LNCaP cells that were transiently transfected with ERE-luciferase reporter and expression vector for ER.
- Example 3 Effect on AR Ligand Binding Domain
- Bisphenol ether derivatives such as Compound B, bind specifically to AR AF-1 without being affected by or interfering with, ligand binding to AR LBD (Andersen 2010; Myung 2013). This is an important attribute for an imaging agent for CRPC because AR LBD may be occupied by antiandrogen or steroid/androgen thereby making an imaging agent that targets the LBD having to compete for the binding site.
- fluorescence polarization assay To test whether Compound D maintained this property and does not affect ligand binding to AR LBD.
- This assay measures competition of a test compound for binding of fluoromone to recombinant AR-LBD or other related steroid hormone receptor LBDs.
- R1881 and the antiandrogen enzalutamide both bound to the AR-LBD to compete with the fluoromone as expected (Fig. 3 A).
- enzalutamide inhibited full-length AR induced by androgen, as measured with AR-driven probasin (PB)-luciferase reporter (Fig. 4A, left panel). Consistent with previous studies, enzalutamide had no effect in blocking AR transcriptional activity, either in the presence or absence of androgen, when V567es or V7 were expressed (Fig. 4A, middle and right panels).
- Compound D showed good inhibition against full-length AR as well as mixed populations of full-length AR with variant V567es or V7 at 10X less concentrations than Compound B. This suggests that Compound D interacts with the truncated AR variants consistent with Compound B but with better potency.
- Compound D (2 ⁇ ) decreased proliferation of LNCaP95 cells as well as Compound B (25 ⁇ ) whereas enzalutamide (5 ⁇ ) had no effect (Fig.4C).
- Compound D had an IC 5 0 of 6.89 ⁇ 2.85 ⁇ for inhibition of LNCaP95 cell proliferation (Fig. 4D).
- cell cycle analysis revealed Compounds B and D caused G0/G1 arrest.
- Approximately 25-30% of cells treated with enzalutamide or DMSO vehicle were in S-phase (Fig. 4E).
- Compound D or Compound B decreased S-phase cells by approximately 2-fold or more with a concomitant increase of cells in Gl-phase.
- EPI analogues decreased the expression of: ubiquitin-conjugating enzyme E2C (UBE2C), an AR-V7 regulated protein; cyclinD3; and cyclin dependent kinases (CDKs).
- EPI analogues increased protein expression of the cyclin-dependent kinase inhibitor p27kipl.
- enzalutamide had no effect on the levels of expression of these proteins which was consistent with these cells being resistant to enzalutamide (Fig. 4F). Together these data support that Compound D targets full-length AR and AR-Vs.
- Fig. 4A cells were treated with 2 ⁇ Compound D, 25 ⁇ Compound B or 5 ⁇ enzalutamide for 1 hour prior to treatment with or without 1 nM R1881 for 24 hours. Data represent mean ⁇ SD from 4 independent experiments, each performed in triplicate.
- Fig. 4B protein levels were detected using AR-N20 antibody.
- Data represent mean ⁇ SEM. Proliferation was assessed by BrdU incorporation.
- Fig. 4D data represents mean ⁇ SEM.
- Fig. 4A cells were treated with 2 ⁇ Compound D, 25 ⁇ Compound B or 5 ⁇ enzalutamide for 1 hour prior to treatment with or without 1 nM R1881 for 24 hours. Data represent mean ⁇ SD from 4 independent experiments, each performed in triplicate.
- Fig. 4B protein levels were detected using AR
- Example 5 Compound Id binds to AF-1 in the AR NTD in cells
- Compound B and analogues bind to AR AF-1 (Andersen 2010; Myung 2013) and specifically to Tau-5 in the AF-1 region (De Mol, E. et al 2016 ACS Chem Biol.doi: 10.1021/acschembio.6b00182).
- Compound Id binds to recombinant full-length AR (Fig. 5A).
- Recombinant full-length AR protein was incubated with Compound Id for 16 hours at room temperature. Binding of Compound Id to AR was detected by SDS-PAGE followed by phosphorimaging. Coomassie blue staining was used to provide an indication of equal loading.
- AF-1 protein was pre-incubated with excess Compound B prior to addition of radioactive Compound Id probe. Excess Compound B displaced binding of Compound Id to AF-1 thereby suggesting they bind to the same site (Fig. 5B).
- Recombinant AF-1 protein were incubated with vehicle (DMSO) or Compound B (60 ⁇ ) for 6 hours at room temperature prior to addition of Compound Id (200 ⁇ ), and then incubated for 16 hours more prior to SDS-PAGE and phosphorimaging. Less binding of Compound Id was observed when AF-1 was pre- incubated with excess Compound B. Coomassie blue staining was used to provide an indication of equal loading.
- LNCaP95 cells were treated with Compound Id for 16 hours, followed by SDS-PAGE and Western blot analysis.
- Compound Id binds covalently and specifically to AR in the LNCaP95 cells (Fig. 5C). Binding of Compound Id to endogenous AR in LNCaP95 cells that were incubated with or without 25 ⁇ Compound B overnight at 37°C prior to harvesting cells. Whole cell lysates were used for SDS-PAGE to reveal Compound Id covalently bound to full-length AR in the LNCaP95 cells as detected by phosphorimage. Western blot analyses detection of bands correspond to AR for radiolabelled phosphonmaged bands. For Figs. 5A-5B, n > 3 for binding experiments.
- the cLogP of Compound Id is 4.2 which means it is highly lipophilic; a property that predicts it would be eliminated by the hepatobiliary system. Consistent with this projection, Compound Id accumulation was highest in the gallbladder, liver, and intestines (Table 2). At 4 hours after injection, 66 %ID/g of Compound Id was detected in the large intestine. Generally, there was low uptake and fast washout from non-specific tissues.
- Compound Id reached a maximum 2.2 ⁇ 0.5 %ID/g uptake in LNCaP95 tumors at 1 hour after injection. This was greater than the maximum achieved for 18 F-FDHT (0.432 ⁇ 0.183 %ID/g ⁇ SEM), in the target tissue of ventral prostate in rodents at 1 hour after injection (Liu A., et al. JNucl Med. 1992;33(5):724-734). Both Compound Id and 18 F-FDHT target the nuclear AR. Based on similar studies with l8 F-FDHT, the accumulation of Compound Id in AR-rich tissues is expected for an AR-mediated process (Bonasera T.A., et al. J Nucl Med.
- Fig. 6B shows the effects of Compound B co-treatment on Compound Id accumulation in blood, muscle, LNCaP95 and PC 3 xenografts (1 hour treatment).
- the accumulation of Compound Id in LNCaP95 xenograft was significantly decreased by blocking with Compound B.
- n 3-7.
- Data represent mean ⁇ SD. *** P ⁇ 0.001 based on One-way ANOVA Dunnett's multiple comparison test.
- Example 7 Micro SPECT/CT Imaging
- the thyroid uptake was approximately 2.31 ⁇ 0.59%ID/g and was not altered by blocking with Compound B (2.32 ⁇ 0.33%ID/g). These data suggest that Compound Id may not be metabolically stable and that the 123 I may fall off the compound to accumulate in the thyroid.
Abstract
The present disclosure relates to bisphenol ether derivatives and compositions thereof, which can be useful in radiation therapy for treatment of diseases, such as prostate cancer. In particular, the compounds of the present disclosure containing a radiolabeled atom can be useful in targeted delivery of radionuclides for treatment of lesions, tumors, and/or cancer cells.
Description
COMPOUNDS AND COMPOSITIONS FOR RADIATION THERAPY AND METHODS
OF USING THE SAME
CROSS REFERENCE TO RELATED APPLICATIONS
[ 1] This application claims the priority benefit of U.S. Provisional Application No. 62/346,308, filed June 6, 2016, the disclosure of which is incorporated by reference herein in its entirety.
STATEMENT OF GOVERNMENT INTEREST
[2] This invention was made in part with government support under Grant No. 2R01 CA105304 awarded by the National Cancer Institute. The United States Government has certain rights in this invention.
BACKGROUND
Technical Field
[3] The present disclosure relates to bisphenol ether derivatives and compositions comprising the same, which can be useful in imaging and treatment of diseases, such as prostate cancer. The disclosed compounds find utility in any number of imaging applications for androgen receptor (AR) including truncated AR splice variants in prostate cancers and radiation therapy applications for treatment of prostate cancers including, but not limited to, primary/localized prostate cancer (newly diagnosed), locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer. The compounds of the present disclosure containing a radiolabeled atom can be useful in targeted delivery of radionuclides for treatment of lesions, tumors, and/or cancer cells. Further, the compound of the present disclosure can be useful in neoadjuvant and adjuvant therapies for various androgen-mediated or androgen-related diseases or conditions as well as in combination with different therapies, such as androgen ablation therapy.
Description of the Related Art
[4] Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355 361 ( 1999); A. A.
Thomson, Reproduction 121 , 187 195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1 7 (2001)). Several lines of evidence show that androgens are associated with the development of prostate carcinogenesis. Firstly, androgens induce prostatic carcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929 1933 (1977); R. L. Noble, Oncology 34, 138 141 (1977)) and men receiving androgens in the form of anabolic steroids have a higher incidence of prostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742(1986); J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149, 2365 2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D. Alrenga & I. M. Bush, Am J Surg 131, 599 600 (1976)). Secondly, prostate cancer does not develop if humans or dogs are castrated before puberty (J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 1 13-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of prostatic epithelium while eliciting no effect on other male external genitalia (E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgens provides the underlying rationale for treating prostate cancer with chemical or surgical castration (androgen ablation).
[5] Androgens also play a role in female diseases such as polycystic ovary syndrome as well as cancers. One example is ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)). The AR has been detected in a majority of ovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998); B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogen receptor-alpha (ERa) and the progesterone receptor are detected in less than 50% of ovarian tumors.
[6] The only effective treatment available for advanced prostate cancer is the withdrawal of androgens which are essential for the survival of prostate luminal cells. Androgen ablation therapy causes a temporary reduction in tumor burden concomitant with a decrease in serum prostate-specific antigen (PSA). Unfortunately prostate cancer can eventually grow again in the absence of testicular androgens (castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol. 104, 33-39). Castration-resistant prostate cancer that is still driven by AR is biochemically characterized before the onset of symptoms by a rising titre of serum PSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomes castration-resistant most patients succumb to their disease within two years.
[7] The AR has distinct functional domains that include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zinc finger motifs, and an N-terminus domain (NTD) that contains two transcriptional activation units (taul and tau5) within activation function- 1 (AF-1). Binding of androgen (ligand) to the LBD of the AR results in its activation such that the receptor can effectively bind to its specific DNA consensus site, termed the androgen response element (ARE), on the promoter and enhancer regions of androgen regulated genes, such as PSA, to initiate transcription. The AR can be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 21 A, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 211, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
[8] Clinically available inhibitors of the AR include nonsteroidal antiandrogens such as bicalutamide (Casodex™), nilutamide, flutamide, and enzalutamide. There is also a class of steroidal antiandrogens, such as cyproterone acetate and spironolactone. Both steroidal and non-steroidal antiandrogens target the LBD of the AR and predominantly fail presumably due to poor affinity, mutations that lead to activation of the AR by these same antiandrogens (Taplin, M.E., Bubley, G.J., Kom Y.J., Small E.J., Uptonm M., Rajeshkumarm B., Balkm S.P., Cancer Res., 59, 2511-2515 (1999)), and constitutively active AR splice variants. Antiandrogens have no effect on the constitutively active AR splice variants that lack the ligand-binding domain (LBD) and are associated with castration-recurrent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest. 2010 120, 2715-30) and resistant to abiraterone and enzalutamide (Antonarakis et al, N Engl J Med. 2014, 371, 1028-38; Scher et al JAMA Oncol. 2016 doi: 10.1001).
[9] AR antagonists other than the bisphenol ether derivatives previously reported (see, WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2015/031984; WO 2016/058080; and WO 2016/058082) that bind to full-length AR and/or truncated AR splice variants that are currently being developed include: AR degraders such as niclosamide (Liu C et al 2014), galeterone (Njar et al 2015; Yu Z at al 2014), and ARV- 330/Androgen receptor PROTAC (Neklesa et al 2016 J Clin Oncol 34 suppl 2S; abstr 267); AR DBD inhibitor VPC-14449 (Dalai K et al 2014 J Biol Chem. 289(38):26417-29; Li H et
al 2014 J Med Chem. 57(15):6458-67); antiandrogens apalutamide (Clegg NJ et al 2012), ODM-201 (Moilanen AM et al 2015), ODM-204 (Kallio et al J Clin Oncol 2016 vol. 34 no. 2_suppl 230), TAS3681 (Minamiguchi et al 2015 J Clin Oncol 33, suppl 7; abstr 266); and AR NTD inhibitors 3E10-AR441bsAb (Goicochea NL et al 2015), and sintokamide (Sadar et al 2008; Banuelos et al 2016).
[ 10] The AR-NTD is also a target for drug development (e.g. WO 2000/001813), since the NTD contains Activation-Function- 1 (AF-1) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404). The AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M.D. 1999 J. Biol. Chem. 21 A, 1111-1183; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277, 38087-38094; Blaszczyk et al 2004 Clin Cancer Res. 10, 1860-9; Dehm et al 2006 J Biol Chem. 28, 27882-93; Gregory et al 2004 J Biol Chem. 219, 7119-30). The AR-NTD is important in hormonal progression of prostate cancer as shown by application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).
[11] While the crystal structure has been resolved for the AR C-terminus LBD, this has not been the case for the NTD due to its high flexibility and intrinsic disorder in solution (Reid et al 2002 J. Biol. Chem. 277, 20079-20086) thereby hampering virtual docking drug discovery approaches. Compounds that modulate AR include the bisphenol compounds disclosed in published PCT Nos: WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2015/031984; WO 2016/058080; and WO 2016/058082, which are hereby incorporated by reference in their entireties, to the British Columbia Cancer Agency Branch and The University of British Columbia.
[12] In addition to compounds which modulate AR, compounds and methods for imaging the prostate are useful research, diagnostic and prognostic tools. Such compounds are useful in many applications, including imaging of benign and/or malignant prostate cells and tissue. In this regard, positron emission tomography (PET) is an often used imaging technique for non-invasive identification of pathological state and tumors. In PET imaging, the distribution of a radioisotope (e.g., 18F or 124I) in the body can be determined. Thus incorporating 18F into compounds which concentrate in tumor sites (see e.g., WO 2013/028791) or ,24I offers potential for diagnosis, staging, and monitoring treatment of cancers by PET imaging. In addition, incorporation of 123I for improving methods for single-photon emission computed tomography-computed tomography (SPECT/CT) imaging AR-rich tissues such as the benign
prostate, and in particular prostate cancers and AR splice variants in castrate recurrent prostate cancers were previously disclosed by the inventors (see e.g., WO 2015/031984).
[13] While significant advances have been made in the field of imaging, there remains a need for improved targeted treatment of lesions, tumors, and/or cancer cells. The inventors have discovered a new utility of the imaging compounds for use in targeted radiation therapy for treatment of cancer, such as prostate cancer.
SUMMARY OF THE DISCLOSURE
[14] In one embodiment of the present disclosure compounds with at least one 124I or 125I is presented. In one embodim nt of the present disclosure, a compound of formula (I):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
wherein:
[15] R1 and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
[16] R3, R4 and R5 are each independently H, C1-C10 alkyl or C1-C10 alkylcarbonyl; and [17] X1 , X2, X3 and X4 are each independently H, F, CI, Br, I, 123I, 124I, or 125I;
[18] wherein at least one of X1, X2, X3 or X4 is 124I or 125I.
[19] In one embodiment of a compound of formula (I), at least one of X1, X2, X3 or X4 is 124I. In one embodiment, X3 is 124I. In another embodiment of a compound of formula (I), at least one of X1, X2, X3 or X4 is 125I. In one embodiment, X3 is 125I.
[20] In one embodiment of a compound of formula (I), R1 and R2 are each H or C1-C3 alkyl. In another embodiment, R1 and R2 are each methyl.
[21 ] In one embodiment of a compound of formula (I), R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl. In some embodiments, R3, R4 and R5 are each H. In another embodiment, R3, R4 and R5 are each methyl carbonyl.
[22] In one embodiment of a compound of formula (I), the compound is selected from Table 2 or Table 3 or a pharmaceutically acceptable salt or stereoisomer thereof.
[23] In one embodiment, a pharmaceutically composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), wherein at least one of X1, X2, X3 or X4 is 124 j or 125 j is provided. In another embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is selected from: 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 Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,1 1 1 , ODM-201 , ODM-204, radium 233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or related compounds thereof.
[24] In one embodiment of the present disclosure, a method of modulating androgen receptor (AR) activity is provided, where the method comprises administering a compound of formula (I) wherein at least one of X1, X2, X3 or X4 is 124I or 125I is administered to a subject in need tehreof. In one embodiment, the modulating AR is inhibiting transactivation of AR N-terminal domain. In another embodiment, the method of modulating AR activity is in a human.
[25] In one embodiment of the present disclosure, a method of modulating androgen receptor (AR) activity is for treating at least one indication selected from: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma. In one embodiment, the indication is prostate cancer. In another embodiment, prostate cancer is selected from primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
[26] In one embodiment, a method of modulating androgen receptor (AR) activity is for neoadjuvant therapy. In another embodiment, the method is for adjuvant therapy. In another embodiment, the adjuvant therapy is following androgen ablation therapy.
[27] Some embodiments of the compounds described herein may be used for diagnostic purposes to investigate diseases of the prostate, including cancer. In particular embodiments, the compounds are useful for imaging diagnostics in cancer. In some embodiments, such imaging allows for the detection and/or location of cancer sites (e.g., tumor sites).
[28] In one embodiment of the present disclosure, a use of a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, for radiation therapy is disclosed, wherein formula (I) is:
[29] R1 and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
[30] R3, R4 and R5 are each independently H, C1-C10 alkyl or C1-C10 alkylcarbonyl; and [31] X1 , X2, X3 and X4 are each independently H, F, CI, Br, I, 1231, 124I, or I25I;
[32] wherein at least one of X1, X2, X3 or X4 is 125I.
[33] In one embodiment of the present disclosure a method of administering radiation therapy comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject in need thereof is provided, where formula (I) is as defined herein.
[34] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein X3 is 125I.
[35] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein R1 and R2 are each H or C1-C3 alkyl. In another embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein R1 and R2 are each methyl.
[36] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl. In some embodiments, the use or the method disclosed herein utilizes the compound of formula (I), wherein R3, R4 and R5 are each H. In another embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein R3, R4 and R5 are each methyl carbonyl.
[37] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is selected from Table 5, or a pharmaceutically acceptable salt or stereoisomer thereof.
[38] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
[39] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is an Auger emitter.
[40] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound comprises a radionuclide. In another embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound comprises a radionuclide which emits alpha- or beta- particles.
[41] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the radiation therapy is for treating a cancer or a cancer cell.
[42] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the cancer is selected from prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma; or the cancer cell is selected from cells of prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma. In another embodiment, the prostate cancer expresses full-length AR or truncated AR splice variant. In one embodiment, the prostate cancer includes, but not limited to, primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
[43] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the radiation therapy induces apoptosis of the cancer cells.
[44] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound is distributed into the cancer cells upon administration.
[45] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the compound blocks transactivation of an androgen receptor (AR) N-
terminal domain (NTD). In another embodiment, the androgen receptor expresses a full- length AR or a constitutively active splice variant of AR (truncated AR splice variant).
[46] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein the radiation therapy is an Auger therapy.
[47] In one embodiment, the use or the method disclosed herein utilizes the compound of formula (I), wherein a progress of the radiation therapy is monitored by imaging the cancer cells using single-photon emission computed tomography (SPECT) or PET. In one embodiment, the imaging agent used for SPECT is selected from Table 1, or a pharmaceutically acceptable salt thereof. In another embodiment, imaging agent used for PET is selected from Table 2, or a pharmaceutically acceptable salt thereof.
[48] In one embodiment, the compounds of the present disclosure are useful for imaging and imaging diagnostics in androgen-related diseases and conditions. In some embodiment, the disease or the condition is cancer. In another embodiment, the cancer is prostate cancer. In one embodiment, the prostate cancer includes, but not limited to, primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), or metastatic castration-resistant prostate cancer (CRPC), and hormone- sensitive prostate cancer.
[49] In one embodiment of the present disclosure, a method of imaging cancer is provided where a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof i administered to a subject in need thereof:
[50] R1 and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
[51 ] R3, R4 and R5 are each independently H, O-Oo alkyl or C1-C10 alkylcarbonyl; and [52] X1, X2, X3 and X4 are each independently H, F, CI, Br, I, 1231, 124I, or 125I;
[53] wherein at least one of X1 , X2, X3 or X4 is 124I.
[54] In one embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein X3 is 124I.
[55] In one embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein R1 and R2 are each H or C1-C3 alkyl. In another embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein R1 and R2 are each methyl.
[56] In one embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl. In some embodiments, the imaging method disclosed herein utilizes the compound of formula (I), wherein R3, R4 and R5 are each H. In another embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein R3, R4 and R5 are each methyl carbonyl.
[57] In one embodiment, the imaging method disclosed herein utilizes the compound of formula (I), wherein the compound is selected from Table 5, or a pharmaceutically acceptable salt or stereoisomer thereof.
[58] In one embodiment, the imaging method is for PET imaging.
[59] In one embodiment, the compound of formula (I) useful for PET imaging is selected from Table 2, or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[60] In the figures, identical reference numbers identify similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale and some of these elements are arbitrarily enlarged and positioned to improve figure legibility. Further, the particular shapes of the elements as drawn are not intended to convey any information regarding the actual shape of the particular elements, and have been solely selected for ease of recognition in the figures.
[61] Figure 1A shows dose-dependent inhibition of androgen induced transcriptional activity of endogenous full-length AR in LNCaP cells by Compound D ((R)-3-(4-(2-(4-((5>
3-chloro-2-hydroxypropoxy)-3-iodophenyl)propan-2-yl)phenoxy)propane-l,2-diol).
[62] Figure IB shows the specific effects of Compound D on androgen-dependent proliferation of LNCaP cells (AR positive) treated with R1881 , while having no effect on
Dul45 and PC3 cells which do not express functional AR.
[63] Figure 2A shows the effects of Compounds B or D on androgen (R1881)-induced AR transcriptional activity in LNCaP cells.
[64] Figure 2B shows the lack of effects of Compounds B or D on 4-pregnene-3,20-dione (Progesterone, 10 nM) induced PR transcriptional activity in LNCaP cells to support specificity of Compounds B and D for AR.
[65] Figure 2C shows the lack of effects of Compounds B, D on dexamethasone (DEX, 10 nM) induced GR transcriptional activity in LNCaP cells, to support specificity of Compounds B and D for AR..
[66] Figure 2D shows the lack of effects of Compounds B, D on estradiol (E2, 10 nM) induced ER transcriptional activity in LNCaP cells, to support specificity of Compounds B and D for AR.
[67] Figure 3A shows a representative competition binding curve of displacement of 1 nM fluorescently labeled ligand from recombinant AR-LBD (25 nM) by enzalutamide and R1881 but not with Compounds B or D because these compounds do not bind to the AR-LBD.
[68] Figure 3B demonstrates that Compounds B and D did not inhibit ligand-binding to PR-LBD.
[69] Figure 3C demonstrates that Compounds B, D and enzalutamide did not inhibit ligand-binding to GR-LBD.
[70] Figure 3D demonstrates that Compounds B, D and enzalutamide did not inhibit ligand-binding to ERa-LBD.
[71] Figure 3E demonstrates that Compounds B, D and enzalutamide did not inhibit ligand-binding to ERp-LBD.
[72] Figure 3F demonstrates androgen-induced AR-transcriptional activity measured in LNCaP cells transfected with PSA(6.1kb)-luciferase reporter and treated with vehicle (DMSO), enzalutamide (ENZ, 5 μΜ), Compounds D (5 μΜ), or Compounds B (25 μΜ) and increasing concentrations of R1881.
[73] Figure 4A shows AR-driven PB-luciferase activity in LNCaP cells expressing solely full-length AR, full-length AR plus AR splice variant ARv567es, or full-length AR plus AR splice variant AR-V7 treated with Compounds B, D, or enzalutamide.
[74] Figure 4B is a Western blot showing protein levels of full-length AR, V567es and V7 from samples in Fig. 4A.
[75] Figure 4C shows proliferation of LNCaP95 cells treated with Compounds B, D, or enzalutamide for 2 days.
[76] Figure 4D shows proliferation of LNCaP95 cells treated with varying concentrations of Compounds D for 2 days.
[77] Figure 4E shows the distribution of cells in G2/M, S, and G0/G1 and inhibition of
DNA synthesis in LNCaP95 cells treated with Compounds B, D, or enzalutamide for 48 h.
[78] Figure 4F are Western blot analyses results showing the effect of Compounds B, D, or enzalutamide on cell cycle regulated proteins in LNCaP95 cells.
[79] Figure 5A shows binding of Compound Id to full-length AR protein.
[80] Figure 5B shows binding of Compound Id to AF-1. In lane 3, AF-1 was pre- incubated with Compound B.
[81] Figure 5C shows binding of Compound Id to endogenous AR in LNCaP95 cells incubated with Compound B.
[82] Figure 6A shows LNCaP95 tumor/blood and LNCaP95 tumor/muscle ratios in hosts carrying both LNCaP95 and PC3 xenografts.
[83] Figure 6B shows the effects of Compound B co-treatment on Compound Id accumulation in blood, muscle, LNCaP95 and PC3 xenografts.
[84] Figure 7A shows SPECT/CT images of castrated NOD-SCID mouse 2 hours after tail-vein injection of Compound Id unblocked or blocked with excess Compound B.
[85] Figure 7B shows the histology of harvested LNCaP95 and PC3 xenografts at the end of the experiment.
[86] Figure 7C shows levels of full-length AR and AR-V7 proteins expressed from harvested xenografts shown in Fig. 7A and B.
DETAILED DESCRIPTION
[87] I. Definitions
[88] 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 may 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.
[89] 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 may 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.
[90] The terms below, as used herein, have the following meanings, unless indicated otherwise:
[91 ] "Amino" refers to the -NH2 radical.
[92] "Cyano" refers to the -CN radical.
[93] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
[94] "Hydroxy" or "hydroxyl" refers to the -OH radical.
[95] "Imino" refers to the =NH substituent.
[96] "Nitro" refers to the -N02 radical.
[97] "Oxo" refers to the =0 substituent.
[98] "Thioxo" refers to the =S substituent.
[99] "Alkyl" refers to a straight or branched saturated 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 C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl and an alkyl comprising up to 5 carbon atoms is a G -C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and C1 alkyl (i.e., methyl). Non-limiting examples of C1-C5 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n- pentyl and the like. A G-C6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, Cs, C9 and Go alkyls. Similarly, a C1-G2 alkyl includes all the foregoing moieties, but also includes Cn and C12 alkyls. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted. "Alkylene" or "alkylene chain" refers to a straight or branched divalent alkyl group having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, and n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and/or to a radical group through a single bond. The points of attachment of the alkylene
chain to the rest of the molecule and/or 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 may be optionally substituted.
[100] "Alkenyl" refers to a straight or branched hydrocarbon chain radical which contains one or more double bonds, having from two to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkenyls comprising any number of carbon atoms from 2 to 12 are included. An alkenyl comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls (i.e., vinyl). Non-limiting examples of C2-C5 alkenyl include vinyl, allyl, isopropenyl, 1-propene- 2-yl, 1 -butene-l -yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, penteneyl and the like. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes Cn and C12 alkenyls. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted. "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent alkenyl group linking the rest of the molecule to and/or to a radical group, having from two to twelve carbon atoms, e.g., ethenylene, propenylene, butenylene, and the like. The alkyenlene chain is attached to the rest of the molecule through and/or 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 may be optionally substituted.
[101] "Alkynyl" refers to a straight or branched hydrocarbon chain radical which contains one or more triple bonds, having from two to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkynyls comprising any number of carbon atoms from 2 to 12 are included. An alkynyl comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls (i.e., ethynyl). Non-limiting examples of C2-C5 alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like. A C2-C6 alkynyl includes all moieties described above for C2-C5
alkynyls but also includes C6 alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, C8, C9 and Oo alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted. "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent alkynyl group linking the rest of the molecule to and/or to a radical group, having from two to twelve carbon atoms, e.g. , ethynylene, propynylene, butynylene, and the like. The alkynlene chain is attached to the rest of the molecule through and/or 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 may be optionally substituted.
[102] "Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.
[103] "Alkylamino" refers to a radical of the formula -NHRa or -NRaRa where each Ra 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 may be optionally substituted.
[104] "Alkylcarbonyl" refers to the -C(=0)Ra moiety, wherein Ra is an alkyl, alkenyl, or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl ("acetal") moiety. Unless stated otherwise specifically in the specification, an alkyl carbonyl group may be optionally substituted.
[105] "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 may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may 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, os-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.
[106] "Aralkyl" refers to a radical of the formula -Rb-Rc where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Rc 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 may be optionally substituted.
[ 107] "Carbocyclyl" or "carbocyclic ring" refers to a rings structure, wherein the the atoms which form the ring are each carbon. Carbocyclic rings may comprise from 3 to 18 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyls as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group may be optionally substituted.
[ 108] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic 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 may be optionally substituted.
[ 109] "Cycloalkylalkyl" refers to a radical of the formula - Rb Rd where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Rd is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.
[ 1 10] "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 may be optionally substituted. "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, [1 1 1] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-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. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the
nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,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, Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.
[1 12] "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 may be optionally substituted.
[1 13] "Heterocyclylalkyl" refers to a radical of the formula -RbRe where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene, alkenylene, or alkynylene radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.
[1 14] "Heteroaryl" refers to a 5- to 14-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 may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[¾[l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyi, 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- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrirnidinyl, 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 may be optionally substituted.
[115] "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 may be optionally substituted.
[116] "Heteroarylalkyl" refers to a radical of the formula -RbRf where ¾ is an alkylene, alkenylene, or alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.
[117] "123l" refers to the radioactive isotope of iodine having atomic mass 123. The compounds of formula (I) comprise at least one 123I moiety. Throughout the present application, where structures depict a 123I moiety at a certain position it is meant that the I moiety at this position is enriched for 123I. In other words, the compounds contain more than the natural abundance of 123I at the indicated position(s). It is not required that the compounds comprise 100% 123I at the indicated positions, provided 123I is present in more than the natural abundance. Typically the 123I isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 80% or greater than 90%, relative to 127I.
[118] "Thioalkyl" refers to a radical of the formula -SRa where Ra 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 may be optionally substituted.
[119] The term "substituted" used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, 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, CI, 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 -NRgRh, -NRgC(=0)Rh, -NRgC(-0)NRgRh,
-NRgC(=0)ORh, -NRgS02Rh, -OC(=0)NRgRh, -ORg, -SRg, -SORg, -S02Rg, -OS02Rg, -S02ORg, =NS02Rg, and -S02NRgRh. "Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=0)Rg, -C(=0)ORg, -C(=0)NRgRh,
-CH2S02NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, 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, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
[120] As used herein, the symbol "
" (hereinafter may 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, " 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 ma be specified by inference. For example, the compound
CH3-R3, wherein R3 is H or
infers that when R3 is "XY", the point of attachment bond is the same bond as the bond by which R3 is depicted as being bonded to CH3.
[121] "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 may be replaced with a nitrogen atom.
[122] The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may 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.
[123] "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.
[124] "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.
[125] "Optional" or "optionally" means that the subsequently described event of circumstances may or may 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 may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
[126] "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.
[127] "Pharmaceutically acceptable salt" includes both acid and base addition salts.
[128] "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.
[129] "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.
[130] 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 may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may 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 may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
[131] 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.
[132] The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may 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 (5)-, or (D)- and (L)- isomers may 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 centres 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.
[133] 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 nonsuperimposeable mirror images of one another.
[134] 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.
[135] 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 and/or ChemDraw Ultra Version 11.0.1 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.
[136] II. Compounds and Pharmaceutical Compositions
[137] In one embodiment, the present disclosure provides a compound having a structure of formula (I):
[138] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
[139] R' and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
[140] R3, R4 and R5 are each independently H, O-C10 alkyl or C1-C10 alkylcarbonyl; and [141] X1, X2, X3 and X4 are each independently H, F, CI, Br, I, 123I, !24I, or 125I;
[142] wherein at least one of X1, X2, X3 or X4 is 123I, 124I, or 125I.
[143] In various embodiments, different stereoisomers of the compound of formula (I) are provided, for example in some embodiments the compound has one of the following structures (la), (lb), (Ic) or (Id):
[145] In some embodiments, the compounds comprise one 123I substitution, for example in certain other embodiments, three of X1, X2, X3 and X4 are independently selected from H, F, CI, Br, or I, and the remaining X1, X2, X3 or X4 is 123I. In some embodiments, the compounds comprise one 123I substitution, for example in certain other embodiments, three of X1, X2, X3 and X4 are H, and the remaining X1, X2, X3 or X4 is 123I.
[146] In one embodiment, 123I can be at any of the "X" positions. In some of the foregoing embodiments, X1 is 123I. In other embodiments, X3 is 123I.
[147] In one embodiment of the compounds of formula (I), at least one of X1, X2, X3 or X4 is 124I or 125I.
[148] In some embodiments, the compounds comprise one 124I substitution, for example in certain other embodiments, three of X1, X2, X3 and X4 are independently selected from H, F, CI, Br, or I, and the remaining X1, X2, X3 or X4 is 124I. In some embodiments, the compounds comprise one 124I substitution, for example in certain other embodiments, three of X1, X2, X3 and X4 are H, and the remaining X1, X2, X3 or X4 is 124I.
[149] In one embodiment, 124I can be at any of the "X" positions. In some of the foregoing embodiments, X1 is 124I. In other embodiments, X3 is 124I.
[150] In some embodiments, the compounds comprise one 125I substitution, for example in certain other embodiments, three of X1, X2, X3 and X4 are independently selected from H, F, CI, Br, or I, and the remaining X1, X2, X3 or X4 is 125I. In some embodiments, the compounds comprise one 125I substitution, for example in certain other embodiments, three of X1, X2, X3 and X4 are H, and the remaining X1, X2, X3 or X4 is 125I.
[151] In one embodiment, 125I can be at any of the "X" positions. In some of the foregoing embodiments, X1 is 125I. In other embodiments, X3 is 125I.
[152] In various embodiments of any of the foregoing, at least one of R1 or R2 is H. For example, in some embodiments R1 and R2 are each H.
[153] In other embodiments of the foregoing, at least one of R1 or R2 is C1-C10 alkyl. For example, in some embodiments R1 and R2 are each C1-Oo alkyl. In some of these embodiments C1-C10 alkyl is C1-Go saturated alky such as methyl.
[154] In other embodiments, Each R1 may independently be C1-C5 alkyl. Each R1 may independently be C1-C4 alkyl. Each Rl may independently be C1-C3 alkyl. Each R1 may independently be C1-C2 alkyl. Each R1 may independently be methyl. Each R1 may independently be C2 alkyl. Each R1 may independently be C3 alkyl. Each R1 may independently be C4 alkyl. Each R1 may independently be C5 alkyl.
[155] In other embodiments, Each R2 may independently be C1-C5 alkyl. Each R2 may independently be C1-C4 alkyl. Each R2 may independently be C1-C3 alkyl. Each R2 may independently be C1-C2 alkyl. Each R2 may independently be methyl. Each R2 may independently be C2 alkyl. Each R2 may independently be C3 alkyl. Each R2 may independently be C4 alkyl. Each R2 may independently be C5 alkyl.
[156] In certain of the foregoing embodiments, at least one of R3, R4 or R5 is H. In certain embodiments, two of R3, R4 and R5 are H. In other embodiments, R3, R4 and R5 are each H.
[157] In still other embodiments of the foregoing compounds of formula (I), at least one of R3, R4 or R5 is C1-C10 alkyl. For example, in some embodiments two of R3, R4 and R5 are G- C10 alkyl. In other embodiments, R3, R4 and R5 are each G-C10 alkyl. In certain of the foregoing embodiments, C1-C10 alkyl is saturated C1-C10 alkyl. For example, in some embodiments the saturated G-C10 alkyl is methyl, isopropyl or n-butyl. In some different embodiments, the C1-G0 alkyl is unsaturated C1-C10 alkyl, for example propargyl.
[158] In other embodiments, Each R3 may independently be C1-C5 alkyl. Each R3 may independently be C1-C4 alkyl. Each R3 may independently be C1-C3 alkyl. Each R3 may
independently be C1-C2 alkyl. Each R3 may independently be methyl. Each R3 may independently be C2 alkyl. Each R3 may independently be C3 alkyl. Each R3 may independently be C4 alkyl. Each R3 may independently be C5 alkyl.
[159] In other embodiments, Each R4 may independently be C1-C5 alkyl. Each R4 may independently be C1-C4 alkyl. Each R4 may independently be C1-C3 alkyl. Each R4 may independently be C1-C2 alkyl. Each R4 may independently be methyl. Each R4 may independently be C2 alkyl. Each R4 may independently be C3 alkyl. Each R4 may independently be C4 alkyl. Each R4 may independently be C5 alkyl.
[160] In other embodiments, Each R5 may independently be C1-C5 alkyl. Each R5 may independently be C1-C4 alkyl. Each R5 may independently be C1- C3 alkyl. Each R5 may independently be C1-C2 alkyl. Each R5 may independently be methyl. Each R5 may independently be C2 alkyl. Each R5 may independently be C3 alkyl. Each R5 may independently be C4 alkyl. Each R5 may independently be C5 alkyl.
[161] In still other embodiments of some of the foregoing embodiments of the compound of formula (I), at least one of R3, R4 or R5 is C1-C10 alkylcarbonyl. In some of these embodiments, two of R3, R4 and R5 are C1-C10 alkylcarbonyl. In other of these embodiments, R3, R4 and R5 are each C1-C10 alkylcarbonyl. In some more specific embodiments, the C1-C10 alkylcarbonyl is methyl carbonyl (acetal).
[162] In other embodiments, Each R3 may independently be C1-C5 alkylcarbonyl. Each R3 may independently be G-C4 alkylcarbonyl. Each R3 may independently be C1-C3 alkylcarbonyl. Each R3 may independently be C1-C2 alkylcarbonyl. Each R3 may independently be methylcarbonyl. Each R3 may independently be C2 alkylcarbonyl. Each R3 may independently be C3 alkylcarbonyl. Each R3 may independently be C4 alkylcarbonyl. Each R3 may independently be C5 alkylcarbonyl.
[163] In other embodiments, Each R4 may independently be C1-C5 alkylcarbonyl. Each R4 may independently be C1- C4 alkylcarbonyl. Each R4 may independently be C1-C3 alkylcarbonyl. Each R4 may independently be C1-C2 alkylcarbonyl. Each R4 may independently be methylcarbonyl. Each R4 may independently be C2 alkylcarbonyl. Each R4 may independently be C3 alkylcarbonyl. Each R4 may independently be C4 alkylcarbonyl. Each R4 may independently be C5 alkylcarbonyl.
[164] In other embodiments, Each R5 may independently be C1-C5 alkylcarbonyl. Each R5 may independently be C1-C4 alkylcarbonyl. Each R5 may independently be C1-C3 alkylcarbonyl. Each R5 may independently be C1-C2 alkylcarbonyl. Each R5 may independently be methylcarbonyl. Each R5 may independently be C2 alkylcarbonyl. Each R5
may independently be C3 alkylcarbonyl. Each R5 may independently be C4 alkylcarbonyl. Each R5 may independently be C5 alkylcarbonyl.
[165] 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 thereof:
[166] Table 1. Representative 123I Compounds
[ 167] 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 thereof:
[169] In some more specific embodiments of the compound of formula (I), the compound has one of the following structures from Table 3, or a pharmaceutically acceptable salt thereof:
[ 170] Table 3. Representative 125I Compounds
[171] In one embodiment, the compound of formula (I) is one of the following:
[172] In one embodiment, the compound of formula (I) is one of the following:
[173] In one embodiment, the compound of formula (I) is one of the following:
[174] In one embodiment, the present invention is directed to a pharmaceutical composition, comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as described herein.
[175] In some embodiment, the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises an additional therapeutic agent. In one embodiment, the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.
[176] In another embodiment, the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises an additional therapeutic agent which is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
[177] 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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.
[178] Such administration includes without limitation dosing of one or more of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as a pre-mixed formulation. Administration of the compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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.
[179] 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
[180] The ratio of the doses of compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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.
[181] The compound(s) of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including those compounds shown in Table 1 , Table 2, or Table 3.
[182] 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) 2,3,4,7,8,9,10,1 1, 12,13, 14,15-dodecahydro-lH-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-i p,2p-dihydro-17-
hydroxy-3'H-cyclopropa[l,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 ,7β, 1 Οβ-trihydroxy- 9-oxo-5p,20-epoxytax-l l-ene-2a,4, 13a-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 ανβ3 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-lH-indol-3-ylidene)methyl]-2,4- dimethyl-lH-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 Oi l 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-(l , l-dimethylethyl)-3-oxo- (5a, l 7P)-4-azaandrost-l-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; 5a, 17P)-N-{2,5 bis(trifluoromethyl) phenyl} -3-oxo-4-azaandrost-l-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,l laR)-l,4a,6a-trimethyl-2-oxo-N-(propan-2- yl)-N-(propan-2 ylcarbamoyl)hexadecahydro- 1 H-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-l,2,4a,5,6,10b- hexahydrobenzo[fJquinolin-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, 1 Ob-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.
[183] Accordingly, in some embodiments, the pharmaceutical composition comprising a compound having a structure of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, 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 Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, radium 233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or related compounds thereof.
[184] In some embodiments, compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, which result in unstable structures and/or unsatisfied valences are not included within the scope of the invention.
[185] In another embodiment, the present disclosure provides a pharmaceutical composition comprising any of the foregoing compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier.
[ 186] 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^V- 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.
[187] 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.
[188] 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.
[189] 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.
[190] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous (IV), intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
[191] The compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
[192] In certain embodiments, a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
[193] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as disclosed herein, combined with a pharmaceutically acceptable carrier. In one embodiment, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous
solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
[ 194] Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.
[195] Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
[196] Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
[197] Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by
compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
[198] Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
[199] Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
[200] Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle. Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
[201] Additional embodiments relate to the pharmaceutical formulations wherein the formulation is selected from the group consisting of a solid, powder, liquid and a gel. In certain embodiments, a pharmaceutical composition of the present invention is a solid (e.g., a
powder, tablet, a capsule, granulates, and/or aggregates). In certain of such embodiments, a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[202] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
[203] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition and/or combination. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PR1MELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
[204] Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
[205] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
[206] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition and/or combination of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[207] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[208] In certain embodiments, a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
[209] Liquid pharmaceutical compositions can be prepared using compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
[210] For example, formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
[211] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
[212] Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
[213] Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
[214] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
[215] A liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
[216] In one embodiment, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In another embodiment, a pharmaceutical composition comprising the compound of the present disclosure is prepared for intravenous injection (IV). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi- dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or
dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
[217] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3- butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
[218] Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
[219] In certain embodiments, a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[220] In certain embodiments, a pharmaceutical composition of the present invention comprises a delivery system. Examples of delivery systems include, but are not limited to,
liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
[221] In certain embodiments, a pharmaceutical composition of the present invention comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
[222] In certain embodiments, a pharmaceutical composition of the present invention comprises a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
[223] Appropriate pharmaceutical compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject. The manner in which the composition is administered is dependent, in part, upon the cause and/or location. One skilled in the art will recognize the advantages of certain routes of administration. The method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders. In various aspects, the route of administration is systemic, e.g., oral or by injection. The agents or compounds, or pharmaceutically acceptable salts or derivatives thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, and parenterally. Alternatively or in addition, the route of
administration is local, e.g., topical, intra-tumor and peri-tumor. In some embodiments, the compound is administered orally.
[224] In certain embodiments, a pharmaceutical composition of the present disclosure is prepared for oral administration. In certain of such embodiments, a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical compositions are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.
[225] In certain embodiments, dragee cores are provided with coatings. In certain such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings.
[226] In certain embodiments, pharmaceutical compositions for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
[227] In certain embodiments, pharmaceutical compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner.
[228] In certain embodiments, a pharmaceutical composition is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[229] In certain embodiments, a pharmaceutical composition is prepared for administration by inhalation. Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
[230] In other embodiments the compound of the present disclosure are administered by the intravenous route. In further embodiments, the parenteral administration may be provided in a bolus or by infusion.
[231] In certain embodiments, a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema. Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
[232] In certain embodiments, a pharmaceutical composition is prepared for topical administration. Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions. Exemplary suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.
[233] In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
[234] In certain embodiments, one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, are formulated as a prodrug. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral
administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, a prodrug is an ester. In certain such embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is cleaved upon administration to form the corresponding active form.
[235] In certain embodiments, a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
[236] In various aspects, the amount of the compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or compounds disclosed in Table 1, Table 2 or Table 3, or a pharmaceutically acceptable salt or solvate thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
[237] In an exemplary embodiment for imaging the prostate, a dose of the disclosed compounds in solution (typically 5 to 30 millicuries or 200 to 1,100 MBq) is typically injected rapidly into a saline drip running into a vein, in a patient. Then, the patient is placed in the SPECT scanner to obtain a series of projections which may take about 15-20 minutes. Methods for SPECT scanning are well known in the art.
[238] 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 PET scanner for a series of one or more scans which may take from 20 minutes to as long as
an hour (often, only about one quarter of the body length may be imaged at a time). Methods for PET scanning are well known in the art.
[239] The concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. The agent may be administered in a single dose or in repeat doses. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
[240] The compounds or pharmaceutical compositions of the present disclosure may be manufactured and/or administered in single or multiple unit dose forms.
[241] Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
[242] III. Methods
Imaging Methods
[243] In one embodiment, compounds disclosed in Table 1 can be useful in methods for SPECT imaging. In another embodiment, compounds of formula (I) wherein at least one of X1, X2, X3 or X4 is 123I can be useful for SPECT imaging.
[244] In one embodiment, the 123I of the disclosed compounds can be useful as imaging agent. In one embodiment, the ability for l23I labeled compound of the disclosure to be useful in SPECT imaging applications is an important way to identify cell uptake and biodistribution of the compound selectively in the target cells, i.e., cancer cells. In one embodiment, the compound of the present disclosure, including compound comprising at least one ,23I, selectively binds to androgen receptor (AR). In one embodiment, the compound of the present disclosure selectively binds to AR N-terminal domain (NTD).
[245] In one embodiment, compounds disclosed in Table 2 can be useful in methods for PET imaging. In another embodiment, compounds of formula (I) wherein at least one of X1, X2, X3 or X4 is 124I can be useful for PET imaging.
[246] In one embodiment, the 124I of the disclosed compounds can be useful as imaging agent. In one embodiment, the ability for 124I labeled compound of the disclosure to be useful in PET imaging applications is an important way to identify cell uptake and biodistribution of the compound selectively in the target cells, i.e., cancer cells. In one embodiment, the compound of the present disclosure, including compound comprising at least one 124I, selectively binds to androgen receptor (AR). In one embodiment, the compound of the present disclosure selectively binds to AR N-terminal domain (NTD).
[247] In one embodiment, a method is provided for imaging full-length AR and AR-Vs in CRPC patients using compounds of formula (I). In one embodiment, administration of a compound of formula (I) to a subject in need thereof, can enable specific visualization of xenografts that express full AR and AR-Vs using single-photon emission computed tomography-computed tomography (SPECT/CT) or PET. In one embodiment, compound of formula (I), which can bind to AF-1 that is common to both full-length AR and AR-Vs, can be useful in revealing the expression of solely AR-Vs when compared to 16p-[18F]-fluoro-5a dihydrotestosterone (18F-FDHT) which binds only full-length AR, bind to AF-1 that is common to both full-length AR and AR-Vs. To specifically reveal AR-Vs, a discordant distribution and/or discordant level of uptake between 18F-FDHT and a compound of formula (I) would indicate the expression of solely AR-Vs. This imaging technique could reveal patients with lesions that are positive for AR-Vs who may not benefit from further therapies that target AR LBD. In one embodiment, a compound of formula (I) can aid in monitoring treatment responses to significantly impact the clinical management of the disease as well as provide insight into the role of all AR species in resistance mechanisms.
[248] In one embodiment, the compound of formula (I) can have favorable effects on blocking the transcriptional activity AR NTD without losing its specificity. That is, in one embodiment, when a compound of formula (I) bind to the AR NTD, the binding does not affect binding of ligand to AR-LBD. This specificity is an important attribute for this indication and molecular target because, imaging agents and/or radiolabeled compounds, such as compounds of formula (I), are applied at microdoses and hence highly susceptible to competing agents. For most applications, it is predicted that patients failing enzalutamide or other antiandrogens may have an AR LBD occupied by the antiandrogen. Washout of enzalutamide takes approximately 5 half-lives (ty2 = 6-9 days) or more than one month. Also
if there is steroid hormone breakthrough in castrated or abiraterone-treated patients or a mutation in AR LBD making the receptor promiscuous to binding other steroid, AR LBD could be occupied by steroid. Under these clinical conditions, an imaging agent and/or radiolabeled compounds that binds to AR NTD would theoretically not be affected, contrary to 18F-FDHT which competes for binding to LBD and shown to have diminished uptake at the tumor site in the presence of testosterone (Larson S.M., et al. J Nucl Med. 2004;45(3):366-373).
[249] The present compounds find particular utility in methods for imaging the prostate using a compound of formula (I). In some embodiments, a method for imaging benign conditions of the prostate (e.g., benign prostatic hyperplasia), comprising administering any of the foregoing compound or pharmaceutical compositions to a subject and detecting the prostate, is provided. Accordingly, in another embodiment, the present disclosure provides a method of imaging cancer, the method comprising administering the foregoing pharmaceutical composition to a subject and detecting the presence or absence of cancer by use of SPECT or PET.
[250] In one embodiment, the present disclosure provides a method of imaging cancer and treating said cancer by radiotherapy with the use of a compound of the present disclosure of any of the forgoing pharmaceutical compositions.
[251] In certain embodiments, the method identifies the presence or absence of a tumor. For example, some embodiments the method identifies the location of a tumor. In certain embodiments, the cancer is prostate cancer, for example, castration resistant prostate cancer. In other embodiments, the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone- sensitive prostate cancer. In some embodiments, the subject is a mammal such as a human.
[252] In one embodiment, the method identifies the presence of a tumor that expresses AR (both full-length and truncated AR lacking LBD) and then treats the tumor by radiotherapy. In another embodiment, the imaging methods provide information to determine if a tumor expresses AR species.
[253] 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 may 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 may include sequential imaging with 18F-FDHT and a compound of the invention and a discordant distribution or discordant level of uptake between 18F-FDHT and the compound of the invention indicates the presence or overexpression of splice variants lacking the ligand binding domain.
[254] In one embodiment, the present disclosure provides a method for detecting AR species, including mutants and variants, and emitting Auger electrons in the area of detection.
[255] 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.
[256] In another embodiment, the present disclosure provides the use of any one of the foregoing compounds of formula (I) for imaging cancer. For example in some embodiments, the imaging is in a human patient. In one embodiment, the present disclosure provides the use of a compound of formula (I) for imaging cancer and treating said cancer by radiotherapy. In one embodiment, the imaging and treating is in a human patient.
[257] In another embodiment, the present disclosure provides the use of any one of the foregoing compounds of formula (I) for imaging the prostate. For example in some embodiments, the imaging is in a human patient. In one embodiment, the present disclosure provides the use of a compound of formula (I) for imaging prostate cancer and treating said prostate cancer by radiotherapy. In one embodiment, the imaging and treating is in a human patient.
[258] In accordance with another embodiment, there is provided a use of the compounds of formula (I) as described anywhere herein for preparation of a medicament for imaging the prostate. The imaging may be for imaging of benign prostate conditions of for imaging cancer (e.g., tumors), for example prostate cancer. The imaging may be by SPECT or PET. The imaging may be in a mammalian cell. The imaging may be in a mammal. The mammal may be a human.
[259] In one embodiment, the present disclosure provides the use of a compound of formula (I) for imaging cancer by SPECT or PET and treating said cancer by radiotherapy. In one embodiment, the imaging and treating is in a mammalian cell, in a mammal, or in a human. In one embodiment, the cancer is prostate cancer or breast cancer.
[260] In one embodiment, the compounds of formula (I) may be administered to a mammal for imaging purposes. The administering and imaging may 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 mammalian cell may be a human cell. The imaging may be for imaging AR splice variants, mutants or other AR species which contain AR NTD.
[261 ] In one embodiment, the compounds of formula (I) may be administered to a mammal for imaging and/or treatment purposes. The administering, imaging, and/or treating may 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 mammalian cell may be a human cell. The imaging may be for imaging AR splice variants, mutants or other AR species which comprise the AR NTD. The treatment is by radiotherapy of cells where the compound of formula (I) have been distributed to.
[262] In some embodiments, the compounds as described herein or pharmaceutically acceptable salts thereof may 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 may 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).
[263] In some embodiments, the compounds as described herein or pharmaceutically acceptable salts thereof may be used for imaging, diagnosis, and/or treatment 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 a pharmaceutically acceptable salts thereof above may be used in the preparation of a medicament or a composition for imaging the prostate and/or treatment of the prostate, for example for imaging benign prostate conditions or for imaging and/or treating prostate cancer in a subject in need of such imaging (for example for diagnosis and/or location of prostate tumors).
[264] In one embodiment, the imaging method disclosed herein is directed to imaging prostate cancer. In some embodiments, the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer. In some embodiments the prostate cancer is CRPC. In other embodiments, the imaging is for imaging benign prostate conditions such as benign prostatic hyperplasia. Methods of imaging and/or treating any of the indications described herein are also provided. Such methods may include administering a compound as described herein or a composition of a compound as described herein, or an effective amount of a compound as described herein or composition of a compound as described herein to a subject in need thereof. In one embodiment, a pharmaceutical composition suitable for imaging is administered intravenously.
Radiation Therapy/Auger Therapy
[265] In one embodiment, the compound of the present disclosure finds utility in Auger therapy for treatment of cancer. In some embodiments, the compound of the present disclosure finds utility in radiotherapy or radionuclide therapy for treatment of cancer. In another embodiment, the presently disclosed compounds find utility in a number of medical imaging applications (e.g., PET and SPECT imaging), including imaging of the prostate, and also applications in radiotherapy for cancer, such as prostate cancer.
[266] In one embodiment, compounds disclosed in Table 3 can be useful in Auger therapy. In another embodiment, compounds of formula (I) wherein at least one of X1, X2, X3 or X4 is l25I can be useful for Auger therapy.
[267] Auger therapy is a form of radiation therapy for treatment of cancer. Auger therapy differs from traditional radiation therapy in that it relies on a large number of low-energy electrons, emitted by the Auger effect (Auger electrons), to damage cancer cells, rather than the use of high-energy radiation. Like other radiation therapy, Auger therapy relies on radiation-induced apoptosis of cancer cells, damage to cancer cells (particularly DNA
damage) such that cell division is stopped or attenuated, termination of tumor growth and metastasis.
[268] The major difference between Auger therapy and the traditional radiation therapy is that electrons emitted via the Auger effect are low energy but released in large numbers. Due to their low kinetic energy, the Auger electrons can only damage cells that are in very close range, in nanometer range. Thus, for an effective treatment, the radiation-emitting species/compounds/therapeutics must be inside the cell to which it is targeted. Accordingly, one of the challenges for Auger therapy is to find a compound that could selectively enter the targeted cell and bind to the specific sub-cellular components of said cell which also contains heavy atoms, which are capable of being an Auger emitter, such as 125I. The Auger emitter would then release Auger electrons by radioactive decay or by external excitations.
[269] In one embodiment, the compounds comprising a ,25I can be useful as an Auger emitter. In one embodiment, the targeted and selective delivery of the Auger emitter, which can be established by SPECT and/or PET imaging using analogous compounds having 123I or 124I as described previously, is important for success of Auger therapy. In one embodiment, the compound of the present disclosure selectively binds to androgen receptor (AR). In one embodiment, the compound of the present disclosure selectively binds to AR N-terminal domain (NTD).
[270] In one embodiment, the compounds of the present disclosure can be Auger emitters. In another embodiment, the compounds of the present disclosure can deliver alpha- or beta- emitting radionuclides to surrounding cells. In one embodiment, the compound of the present disclosure can deliver alpha- or beta-emitting radionuclides to cancer cells. In some embodiments, the compound of the present disclosure can deliver alpha- or beta-emitting radionuclides to lesions that express full-length AR and/or AR-Vs in patients with cancers. In another embodiment, the compound of the present disclosure can deliver alpha- or beta- emitting radionuclides to lesions that express full-length AR and/or AR-Vs in patients with metastatic castration-resistant prostate cancer (CRPC). In one embodiment, the compound of the present disclosure comprises a radionuclide which can emit alpha- or beta-particles.
[271] Most CRPC continues to be dependent on transcriptionally active androgen receptor (AR). Bone scans are routinely used for metastatic CRPC but they do not provide insight about the cancer itself or whether the lesions are AR positive to aid in treatment selection. Although bone metastates are the predominate site of dissemination, approximately 20-30% of metastatic CRPC patients have visceral metastases (Pond G.R., et al. Eur Urol. 2014;65(l):3-6; Goodman O.B., Jr., et al. Prostate Cancer Prostatic Dis. 2014;17(l):34-39).
If visceral metastases are positive for full-length AR they could benefit from hormone therapies that target AR LBD such as enzalutamide (Evans CP., et al. Eur Urol. 2016. doi: 10.1016/j.eururo.2016.03.017).
[272] Powerful agents in the arsenal of hormone therapies for advanced prostate cancer, such as abiraterone and enzalutamide, have been approved based upon 5-6 months improvements in overall survival. Approximately 20-40% of patients with metastatic CRPC have primary resistance to enzalutamide or abiraterone and patients that were originally responsive will all eventually fail {see, Scher H. I., et al. Lancet. 2010;375(9724): 1437-1446; Scher H. I., et al. N Engl J Med. 2012;367(13):1187-1 197; de Bono J.S, et al. N Engl J Med. 2011;364(21): 1995-2005; Ryan C.J., et al. NEnglJMed. 2013;368(2):138-148).
[273] The major mechanisms of resistance to these therapies include gain-of-function mutations in AR LBD and/or expression of constitutively active splice variants of AR (AR- Vs) that lack LBD {see, Antonarakis E.S., et al. N Engl J Med. 2014;371(11): 1028-1038; Nadiminty N., et al. Mol Cancer Ther. 2013;12(8): 1629-1637; Mostaghel E.A., et al. Clin Cancer Res. 2011 ; 17(18):5913-5925; Scher et al JAMA Oncol. 2016 doi: 10.1001).
[274] Full-length AR is a ligand-activated transcription factor with distinct functional domains that include: the C-terminal ligand-binding domain (LBD) to which androgens and antiandrogens bind; the hinge region which contains a nuclear translocation sequence; the DNA-binding domain (DBD) which binds to androgen response elements (AREs) in the enhancers/promoters of target genes; and the N-terminal domain (NTD) which contains activation function- 1 (AF-1) that is essential for AR transcriptional activity {see, Jenster G., et al. Mol Endocrinol. 1991;5(10): 1396-1404; Rundlett S.E., et al. Mol Endocrinol. 1990;4(5):708-714; Simental J.A., et al. J Biol Chem. 1991 ;266(1):510-518).
[275] All current hormone therapies target the AR LBD either directly with antiandrogens or indirectly by reducing levels of androgen that bind to AR LBD. Constitutively active AR- Vs, such as V7 and V567es, lack a full LBD, are non-responsive to both androgen and therapies targeting AR LBD (Guo Z., et al. Cancer Res. 2009;69(6):2305-2313; Hu R., et al. Cancer Res. 2012;72(14):3457-3462). Abiraterone and enzalutamide increase expression of V7 in prostate cancer cells and xenografts (Mostaghel et al. 2011; Hu et al. 2012; Li Y., et al. Cancer Res. 2013;73(2):483-489). AR-Vs mediate a growth advantage for prostate cancer in androgen-deprived conditions and are detected in CRPC tissues (Guo et al. 2009; Hu R., et al. Cancer Res. 2009;69(l):16-22; Dehm S.M., et al. Cancer Res. 2008;68(13):5469-5477). For example, AR-Vs that lack the LBD have been reported in prostate cancer cell lines (VCaP and 22Rvl), and in CRPC tissues. Of the more than 20 AR-Vs discovered, V7 and V567es
are clinically relevant with levels of expression correlated to poor survival and CRPC (Hornberg E., et al. PLoS One. 201 l;6(4):e!9059; Haile S., et al. Cell Mol Life Sci. 2011;68(24):3971-3981). AR V567es is solely expressed in 20% of metastases. Detection of V7 in circulating rumor cells (CTCs) of prostate cancer patients is prognostic of resistance to enzalutamide and abiraterone (Antonarakis 2014), whereas V7 positive patients respond to taxanes (Antonarakis E.S., et al. JAMA Oncol. 2015; 1(5):582-591). Thus the ability to determine AR-Vs status of CRPC patients is vital to their clinical management to prevent patients receiving futile treatments and the high costs of these related therapies (e.g., enzalutamide, $7,450/month and abiraterone $5,000/month).
[276] An important clinical example of resistance is drawn from a report using CTCs from CRPC patients which revealed that upon initiating enzalutamide treatment that those patients with CTCs that express V7 have a lower PSA response rate, shorter PSA-progression-free survival, shorter clinical or radiographic progression-free survival, and reduced overall survival compared to patients that had CTCs that were V7 negative (Antonarakis 2014). Compared to taxanes, hormone therapies are the preferred therapeutic due to low toxicity. However, taxanes are more efficacious than AR LBD targeting therapies in V7 positive CRPC patient (Antonarakis 2015). Therefore the ability to distinguish those patients that express AR-Vs that are resistant to AR LBD therapies would be a significant advance in the clinical management of CRPC.
[277] Approaches to determine if a patient harbors metastases that express AR-Vs are not well developed. Measurement of AR-Vs in CTCs is dependent on abilities to isolate/detect CTCs and the sensitivity of the assay to measure levels of AR-Vs. Current assays for AR-Vs in CTCs have limited reproducibility, sensitivity and specificity with the predictive value of the assay limited to only patients with detectable CTCs. This is because biopsy of the multiple lesions which predominate in the bone of CRPC patients is not viable making the comprehensive assessment of expression of AR-Vs in metastatic tissues unfeasible.
[278] Detection of CTCs is dependent on tumor volume and the presence of a surface antigen, such as HER2 (human epidermal growth factor receptor 2), EpCAM (Epithelial cell adhesion molecule), CD45, and may not capture the entire CTC population. Circulating tumor-derived cell-free DNA (ctDNA) is also undergoing evaluation alongside CTCs for its utility in clinical practice (Dawson S.J., et al. TV Engl J 'Med. 2013;368(13):1199-1209; Haber D.A., et al. Cancer Discov. 2014;4(6):650-661). Conceptually, ctDNA and/or ctRNA may be derived from primary tumors, metastatic lesions, CTCs or from the plethora of benign tissues that are known to express AR-Vs (Hu D.G., et al. Horm Cancer. 2014;5(2):61-71). ctDNA
analyses are restricted to measurable changes at the DNA level and to date the clinical relevance of genomic rearrangement to generate AR-Vs is lacking. Thus, there is a need to develop clinical methods to determine expression of AR-Vs in metastatic CRPC. One possible approach is application of molecular imaging agents to detect AR-Vs. Small molecule bisphenol ether derivatives, previously developed and disclosed, provide an opportunity to develop such a prognostic imaging tool because they bind to AF-1 that is common to both full-length AR and AR-Vs (Andersen R.J., et al. Cancer Cell. 2010;17(6):535-546; Myung J.K., et al. J Clin Invest. 2013;123(7):2948-2960; De Mol E. et al 2016 ACS Chem Biol. doi : 10.102 l/acschembio.6b00182).
[279] Clinical application of measurement of expression of AR-Vs using CTCs have several caveats that include abilities to isolate or detect CTCs and the sensitivity of the assay to measure levels of AR-Vs. Thus, a non-invasive imaging approach that could robustly reveal the presence of full-length AR and AR-Vs in all metastatic lesions is of importance to identify patients that may or may not benefit from further antiandrogen or androgen ablation therapies. The optimal qualities for a potentially useful imaging probe to provide a noninvasive approach to localize metastatic lesions that express full-length AR and AR-Vs are a high binding affinity to AR NTD, and low non-specific binding affinity.
[280] The fact that AR protein is commonly overexpressed in CRPC tissues supports the application of AR NTD-based imaging agents. AR NTD inhibitors such as Compound A and its stereoisomers (e.g., Compound B) and ester derivatives (e.g., Compound C) were developed as AF-1 inhibitors to block transactivation of both full-length AR and AR-Vs. Compound C received Investigational New Drug approval from the FDA and Health Canada (i.e., acceptable safety profile at therapeutic doses) and is currently in clinical trials in the USA and anada for CRPC atients that have failed abiraterone and/or enzalutamide.
[281] In one embodiment, the compound of formula (I) can have favorable effects on blocking the transcriptional activity AR NTD without losing its specificity. That is, in one embodiment, when a compound of formula (I) bind to the AR NTD, the binding does not affect binding of ligand to AR-LBD. This specificity is an important attribute for this indication and molecular target because Auger emitters and/or radiolabeled compounds, such as compounds of formula (I), are applied at microdoses and hence highly susceptible to competing agents. For most applications, it is predicted that patients failing enzalutamide or other antiandrogens may have an AR LBD occupied by the antiandrogen. Washout of enzalutamide takes approximately 5 half-lives (t¼ = 6-9 days) or more than one month. Also if there is steroid hormone breakthrough in castrated or abiraterone-treated patients or a mutation in AR LBD making the receptor promiscuous to binding other steroid, AR LBD could be occupied by steroid. Under these clinical conditions Auger emitters and/or radiolabeled compounds that binds to AR NTD would theoretically not be affected, contrary to 18F-FDHT which competes for binding to LBD and shown to have diminished uptake at the tumor site in the presence of testosterone (Larson S.M., et al. J Nucl Med. 2004;45(3):366-373).
[282] In another embodiment, the present disclosure provides a method for treating cells, cancer cells, lesions, and the like by radiotherapy associated with the expression of AR and AR-Vs or to which the compounds of formula (I) modulates, binds, or inhibits. In one embodiment, the method comprising administering a pharmaceutical composition comprising a compound as described herein to a subject in need thereof.
[283] In certain embodiments, the method for treatment by radiotherapy is 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. In certain embodiments, the indication is prostate cancer. In certain embodiments, the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced
prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone- sensitive prostate cancer. In certain embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease. In some embodiments the prostate cancer is CRPC.
[284] In other embodiments, the methods for treatment by radiotherapy may include administering a compound as described herein or a composition of a compound as described herein, or an effective amount of a compound as described herein or composition of a compound as described herein to a subject in need thereof. In one embodiment, a pharmaceutical composition suitable for radiotherapy is administered intravenously.
Other Therapies and Combination Treatments
[285] In other embodiments, the present disclosure provides a method for modulating androgen receptor (AR) activity, the method comprising administering to a mammalian cell one or more of the present compounds. In some embodiments the modulating of androgen receptor (AR) activity is in a mammalian cell. In one embodiment, the method comprising administering a compound of the present disclosure or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof.
[286] In certain embodiments, the method for 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, and age related macular degeneration. In certain embodiments, the indication is prostate cancer. In certain embodiments, the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer. In certain embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.
[287] In one embodiment, the compound of the present disclosure can be used at various stages of the treatment of AR-related diseases or conditions, including prostate cancer. In one embodiment, the compound of the present disclosure can be useful in a neoadjuvant therapy. In another embodiment, the compound of the present disclosure can be useful in a primary therapy. In other embodiments, the compound of the present disclosure can be useful alone or in combination with different therapies or with administration of additional pharmaceutical active agents. In one embodiment, he compound of the present disclosure can be useful in an
adjuvant therapy. An "adjuvant therapy" is a therapy that is administered in addition to a primary, main, or initial therapy in order to maximize the effectiveness of treatment.
[288] In one embodiment, the compound of the present disclosure can be useful in an adjuvant therapy following an androgen ablation therapy. In another embodiment, the compound of the present disclosure can be useful in an adjuvant therapy to prevent recurrence of the disease after primary therapy or previous treatments.
[289] In another embodiment, the compound of the present disclosure can be useful in combination with other treatments. In one embodiment, the compound of the present disclosure can be useful in combination with therapeutic agents known for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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 another embodiment, the compound of the present disclosure can be useful in combination with therapeutic agents known for treating prostate cancer.
[290] In one embodiment, the compound of the present disclosure can be useful in treating prostate cancer in combination with therapeutic agents selected from: 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 Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, radium 233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10- AR441bsAb, sintokamide or related compounds thereof.
[291] In another embodiment, the compound of the present disclosure can be useful in treating prostate cancer in combination with other therapies known to be effective in the treatment of prostate cancer.
EXAMPLES
[292] Synthesis of the compounds of the present disclosure is previously reported in WO 2015/031984, which is hereby incorporated in its entirety. For example, Scheme 1 describes the synthesis of Compound Id and Scheme 2 describes the synthesis of Compound D, which differs from Compound Id in that "cold", "regular", "nonradio labeled", or "unlabeled" iodine is present.
[293] Scheme 1: Synthesis of Compound Id
[294] Compound Id can be prepared according to Scheme 1 involving three radiosynthetic steps. First, the [123I]iodoacetonide (compound Hi) was prepared in 90 ± 10% radiochemical yield via aromatic electrophilic iodination reaction using chloramines-T as the oxidizing reagent and the acetonide (compound ii) as the precursor. The isolated [123I]iodoacetonide was subsequently coupled with (2i?)-(-)-glycidyl tosylate to form [123I]iodoepoxide (compound iv) in 37 ± 17% radiochemical yield. At the final step, compound Id was obtained in 70 ± 11% radiochemical yield by hydrolysis of the compound iv with CeCl3- 7H20. Due to multiple radiolabeling and HPLC purification steps, compound Id was isolated in an overall 14 ± 4% (n = 12) decay-corrected yield in 4.5 h synthesis time with > 99% radiochemical purity and 3.4 ± 1.0 Ci/umol specific activity at the end of synthesis.
[295] Scheme 2: Synthesis of Compound D
[296] 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 may be considered and suitably adapted for preparing compounds of any one of the compounds of formula (I) as set out above. Other references that may 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; US Patent 2571217 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-l,3-dioxolan-2-one with phenols as a new route to polyols and cyclic carbonates." Journal fuer Praktische Chemie (Leipzig) (1985) 327, 718-722.
[297] One skilled in the art will recognize that variations to the order of the steps and reagents discussed in above referenced protocols and Scheme 1 are possible. Further, 123I atoms may 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.
[298] Furthermore, protecting group strategies may 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 (October 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.
[299] Material and Methods. Na123I was purchased from Nordion (Vancouver, Canada). All other chemicals and solvents were obtained from commercial sources, and used without further purification. Purification and quality control of 123I-labelled compounds were performed on an Agilent (Santa Clara, CA, USA) HPLC System equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector (set at 220 nm), and a Bioscan (Washington, DC, USA) Nal scintillation detector. The radio-detector was connected to a Bioscan B-FC-1000 Flow-count System, and the output from the Bioscan Flow-count system was fed into an Agilent 35900E Interface which converted the analog signal to digital signal. The operation of the Agilent HPLC system was controlled using the Agilent ChemStation software. The HPLC columns used were a semi-preparative column (Phenomenex Luna CI 8, 5 μ, 250 x 10 mm) and an analytical column (Phenomenex Luna CI 8, 5 μ, 250 x 4.6 mm). Radioactivity of 123I-labelled compounds was measured using a Capintec (Ramsey, NJ) CRC®-25R/W dose calibrator.
[300] Fluorescence Polarization. Androgen, progesterone, estrogen and glucocorticoid receptor PolarScreen Competitor Assay kits (Invitrogen) were used according to the manufacturer's protocol. Serial dilution was done for each small molecule, and solvent was compensated to ensure equal volume of DMSO and ethanol in each sample. Fluorescence polarization at excitation wavelength 470 nm and emission at 530 nm were measured in Greiner 384 black clear-bottomed plates using Infinite Ml 000 (TEC AN).
[301] Cells, Plasmids, Transfections and Reporter Assays. The synthetic androgen, R1881 was purchased from Perkin-Elmer (Woodbridge, ON). Compound B was provided by NAEJA (Edmonton, Alberta). Enzalutamide was purchased from Omega Chem (St-Romuald, Quebec). Progesterone (4-pregnene- 3,20-dione) was from Steraloids Inc (Newport, RI). Dexamethasone and HEPES were obtained from Sigma-Aldrich (St. Louis, MO). LNCaP, PC3 and DU145 cell lines as well as PSA(6.1 kb)-luciferase, probasin (PB)-luciferase, PRE- luciferase, GRE-Luciferase, ERE-Luciferase, AR-V7 and AR-V567es plasmids, and
transfection of cells have been described previously (22, 23, 26, 29). LNCaP cells were obtained from Dr. Leland Chung (Cedars-Sinai Medical Center, Los Angeles, CA) in September 1993. DU145 cells were from Dr. Victor Ling (BC Cancer Agency, Integrative Oncology, Vancouver, BC) in October 1998. LNCaP95, an androgen-independent cell line that expresses full-length AR and AR-V7 was provided by Dr. Stephen R. Plymate (University of Washington, Seattle, WA) in February of 2012 and reported in previous studies (12, 14, 36, 37). PC3 cells were purchased from American Type Culture Collection. LNCaP95 cells were not authenticated in our laboratory, but were regularly tested to ensure mycoplasma-free (VenorTMGeM Mycoplasma Detection kit, Sigma-Aldrich, St. Louis, MO). LNCaP, PC3 and DU145 cells were authenticated by short tandem repeat (STR) analysis and tested to ensure mycoplasma-free by DDC Medical (Fairfield, OH) in September 2013. All cells used in the experiments were passaged in our laboratory for fewer than 3 months after resurrection.
[302] Viability and Proliferation Assays. PC3 (2,000 cells/well), DU145 (2,000 cells/well) and LNCaP cells (5,000 cells/well) were plated in 96-well plates in respective media plus 0.5% FBS. The next day, PC3 and DU145 cells were treated with DMSO (vehicle control) and Compound D for 3 days, and LNCaP cells were pretreated with vehicle and Compound D for 1 hour before treating with 0.1 nM R1881 for 4 days. Proliferation and cell viability was measured using alamarBlue® Cell Viability Assay (Invitrogen) following the manufacturer's protocol. For BrdU incorporation experiments, LNCaP95 cells (8,000 cells/well) were seeded in 96-well plates for 48 hr before in RPMI with 10 % charcoal stripped serum and changed to serum-free media 24 hr before treating with 5 μΜ enzalutamide, 25 uM Compound B, 2 μΜ Compound D or serial concentration of Compound D. BrdU incorporation was measured after 2 days using BrdU ELISA kit (Roche Diagnostics) according to the manufacturer's protocol.
[303] FACS Analysis. LNCaP95 cells (75,000 cells/dish) were plated in 10 cm dishes and were treated with inhibitors under serum-free and phenol red-free conditions for 48 hours. Cells were pulse labeled with 10 μΜ BrdU for 2 hours and fixed in 70 % ethanol. BrdU- labeled cells were probed with anti-BrdU-FITC antibody (BD Biosciences) and DNA was stained with 7-aminoactinomycin D (Sigma). Data was acquired using a FACS Calibur (BD Biosciences). Bivariate analysis was performed using Flow Jo 7 software (Ashland).
[304] Binding Assays. The cell-free binding assay was performed with commercially available full-length AR recombinant protein or AR AF-1 recombinant protein that was expressed and purified as previously described (22, 38), with additional purification by size
exclusion chromatography. Binding reaction between Compound B or DMSO (vehicle control) and the recombinant AR AF-1 (amino acid residues 142 - 485) or full-length AR were carried out by mixing 60 μΜ Compound B or DMSO with 10 μΜ AR AF-1; also 1 μΜ Compound B or DMSO with 0.35 μΜ full-length AR in equivalent amounts. Binding reaction was incubated at room temperature for 6 hours. 200 μθί of Compound Id was then mixed in each sample at room temperature for 16 hours prior to SDS-PAGE. Proteins were separated from free probes on 8% SDS-PAGE and radioactivity was visualized using Fujifilm FLA-7000 image analyzer (GE Healthcare). The same gel was stained with Coomassie blue R-250. To examine binding to the endogenous AR, LNCaP95 cells (60,000 cells/well) were seeded in 12-well plates and serum-starved for 24 hr before treating cells for 16 hours with DMSO or 25 μΜ Compound B, and with 400 μCi of Compound Id. Proteins were extracted from treated cells with RIPA buffer containing 50 mM tris (pH 8.0), 150 mM NaCl, 0.5% Na Deoxycholate, 1% NP-40, 0.1% SDS and EDTA-free protease inhibitors. Proteins bound to 123I test compound were separated by SDS-PAGE and radioactivity was visualized using Fujifilm FLA-7000 image analyzer, and also subjected to Western blot analysis using anti- AR antibody.
[305] Immunohistochemistry and Western Blot Analysis. Immunohistochemistry was performed as previously described (Andersen 2010; Myung 2013). For analysis of AR protein, concentrations of lysates of homogenized LNCaP95 and PC3 xenografts were measured by bicinchoninic acid (BCA) assay after albumin depletion. Proteins (20 μg) were resolved on a NuPAGE 4%-15% Bis Tris gradient gel, transferred to nitrocellulose membrane, and probed for AR species using antibodies to the AR NTD and AR-V7. LNCaP95 cells (250,000 cells/well) were seeded in a 6-well plate for 48 hr, and serum- starved for 24hr, followed by treatment with DMSO, enzalutamide (5 μΜ), Compound B (25 μΜ) or Compound D (5 uM) for 48hr. Cells were harvested and whole-cell lysate (10 to 15 μg) was subjected to SDS-PAGE. Antibodies used were: AR N-20 (sc-816, Santa Cruz Biotech Inc., Santa Cruz, CA), AR-V7 (AG10008, Precision Antibody™, Columbia, MD). UBE2C (A-650, BostonBiochem), CyclinDl, CyclinD3, p27kipl, CDK2, CDK4 and CDK6 from Cell Cycle Regulation Sampler Kit (9932 from Cell Signaling Technology, Danvers, MA), β-actin (ab6276, Abeam, Cambridge, MA) was used as a loading control.
[306] Xenografts and Animal Biodistribution Studies. Six to eight weeks old male NOD- SCID mice were castrated 2 weeks before inoculating LNCaP95 cells (10 million cells/tumor) and PC3 cells (2 million cells/tumor) subcutaneously. The mice bearing LNCaP95 and PC3 xenografts were injected with 370 kBq- 7.4 MBq (10- 200 μα) of
Compound Id in 200 μl of 30 % PEG solution via the tail vein. At 0, 1, 2, 4, 6, 12 hours after injection, blood, liver, kidney, spleen, lung, large intestine, small intestine, stomach, heart, muscle, bone, bladder, brain, gallbladder and tumor samples were collected, weighed, and their radioactivity content determined using an automated γ-spectrometer. The results were expressed as the percentage injected dose per gram (%ID/g). More than three animals per time point were used.
[307] Micro SPECT/CT Imaging. SPECT/CT studies were performed using the MILabs U- SPECT- II (Advanced Molecular Vision, Grantham, Lincolnshire, UK). LNCaP95 and PC-3 tumor-bearing mice (20-25 g) were anesthetized with isoflurane inhalation at 2% and placed on a heating pad to maintain body temperature. The mice were then injected with Compound Id (37-74 MBq; 1-2 mCi, in 200 μl of 30% PEG solution) via the tail vein. A competition experiment was performed by co-injection of the radiotracer with 50 mg/kg of EPI-002 in a total volume of 200 μl of 30% PEG solution. SPECT scans were acquired over 30 min and 2 frames at 15min each using 1.0 mm multi-pinhole collimator, after which CT scans were performed for anatomic reference (parameters ; 60 kV, 600 uA). SPECT imaging data were reconstructed using MI Labs reconstruction software (2 subsets, 30 iterations). PMOD software was used to analysis and view the images, and Gaussian filter was applied post reconstruction.
[308] Statistics. Statistical analysis was performed using GraphPad Prism (version 6.01 GraphPad Software, Inc. La Jolla, CA). Values are presented as mean ± SD or mean ± SEM. Except where specified, comparisons between groups were performed with One-way ANOVA Dunnett's multiple comparisons test, and differences were consider statistically significant at P values less than 0.05.
[309] Study Approval. All experiments involving animals conformed to the relevant regulatory and ethical standards, and the University of British Columbia Animal Care Committee approved the experiments.
[310]
[311] Example 1 : Compound Activity
[312] The PSA-luciferase (6.1kb) reporter contains functional AREs to which AR binds in response to androgen to induce luciferase activity. LNCaP cells were transfected with the PSA(6.1 kb)-luciferase reporter for 24 h, and then treated with indicated concentration of Compound D (cold Iodine, not 123I) with synthetic androgen, R1881 (1 nM) for 24 h. After 24 h of incubation with R1881 , the cells were harvested, and relative luciferase activities were
determined. To determine the IC50, treatments were normalized to the predicted maximal activity induction (in the absence of test compounds, vehicle only); n > 3 (Fig. 1A). From a representative experiment, it was determined that the Compound D has an IC50 of 1.17±0.22 μΜ for inhibition of AR transcriptional activity. This is comparable to that reported for the antiandrogen enzalutamide which is considered to have strong affinity for the AR. At 1 μΜ, enzalutamide caused 67% inhibition of ARE(4x)-luciferase activity (Tran C, et al. Science. 2009;324(5928):787-790).
Compound D
[313] Compound D had an IC50 of approximately 1 uM to block AR-driven proliferation of LNCaP cells in response to androgen; n > 3 (Fig. IB). Compound D had no effect on proliferation or viability of PC3 and DU145 human prostate cancer cells that do not express functional AR at up to 10X the IC50 required to reduce AR-dependent proliferation thereby supporting its specificity for AR. Data disclosed in Fig. IB represents mean ± SD. Compound D is 10X more potent than Compound B which has IC50 in the range of 10 μΜ for these cell- based assays (Andersen 2010; Myung 2013). Together these data support that Compound D has improved potency compared to Compound B and is consistent with saturation transfer difference (STD)-NMR data showing strong interaction of the bisphenyl rings of the tested compounds with Tau-5 of AR AF-1 (De Mol, E. "Structure, dynamics and interactions of the N- terminal domain of the androgen receptor", Doctoral Thesis, 2014).
[314] For Figs. 1A and IB, each independent experiment was performed in triplicate. NS: not statistically significant. ** P < 0.01. One-way ANOVA Dunnett's multiple comparison test was utilized.
[315] Example 2: Compound Specificity for AR
[316] Imaging agents and Auger emitters/agents are administered at micro-doses and thus must be highly specific for its target. Therefore, it was examined whether Compound D would potentially interact with most highly related proteins to AR in the human proteome which are the other steroid receptors: progesterone receptor (PR), glucocorticoid receptor (GR) and estrogen receptor (ER). In addition to high sequence identity in the LBD and DBD
of this class of receptors, they also interact with many of the same proteins such as CBP (CREB binding protein) and SRC 1-3. A sensitive method to determine if Compound D interacts with any of these other receptors is to measure their transcriptional activities. Therefore, reporter gene assays were used to determine if Compound D would inhibit PR, GR or ER transcriptional activities. Cells were co-transfected with expression plasmids for full- length human PRp, GR, ERa and their respective reporter, and then treated with ethanol vehicle, 4-pregnene-3,20 dione (progesterone) (PRP), dexamethasone (GR), or estradiol (E2) (ERa). At a concentration of ~2 μΜ, Compound D inhibited AR transcriptional activity to similar levels (75%) to that achieved with 25 μΜ Compound B; n = 5 (Fig. 2A). Data disclosed in Fig. 2A represents mean ± SEM. Importantly, Compound D did not inhibit the transcriptional activities of PR, GR, or ER in response to their cognant ligands (Figs. 2B-2D). These data provide evidence that Compound D does not have general effects on transcription or translation because it did not inhibit induction of PRE (progesterone response element)-, GRE (glucocorticoid response element)- or ERE (estrogen response element)-luciferase reporters in response to ligand. Thus, Compound D appears to maintain specificity for AR.
[317] Fig. 2B shows the effect of Compounds B and D on 4-pregnene-3,20-dione (Progesterone, 10 nM) induced PR transcriptional activity in LNCaP cells that were transiently transfected with PRE-luciferase reporter and expression vector for PRp. n = 5. Data represent mean ± SEM. Fig. 2C shows the effect of Compounds B, D on dexamethasone (DEX, 10 nM) induced GR transcriptional activity in LNCaP cells that were transiently transfected with GRE-luciferase reporter and expression vector for GR. Fig. 2D shows the effect of Compounds B, D on estradiol (E2, 10 nM) induced ER transcriptional activity in LNCaP cells that were transiently transfected with ERE-luciferase reporter and expression vector for ER.
[318] For Figs 2A and 2B, each independent experiment was performed in triplicate. NS: not statistically significant. ** P < 0.01. One-way ANOVA Dunnett's multiple comparison test was utilized.
[319] For Figs. 2C and 2D, values are shown as mean ± SEM from n = 5 for GR and n = 3 for ER with each experiment performed in triplicate. NS: not statistically significant. Oneway ANOVA Dunnett's multiple comparison test was performed.
[320] Example 3: Effect on AR Ligand Binding Domain
[321] Bisphenol ether derivatives, such as Compound B, bind specifically to AR AF-1 without being affected by or interfering with, ligand binding to AR LBD (Andersen 2010; Myung 2013). This is an important attribute for an imaging agent for CRPC because AR LBD may be occupied by antiandrogen or steroid/androgen thereby making an imaging agent that targets the LBD having to compete for the binding site. To test whether Compound D maintained this property and does not affect ligand binding to AR LBD, we employed fluorescence polarization assay. This assay measures competition of a test compound for binding of fluoromone to recombinant AR-LBD or other related steroid hormone receptor LBDs. R1881 and the antiandrogen enzalutamide both bound to the AR-LBD to compete with the fluoromone as expected (Fig. 3 A). Compound D behaved consistent to Compound B and did not prevent ligand-binding to the LBDs of AR (Fig. 3 A) or any steroid hormone receptors tested (Figs. 3B-3E). Consistent with these data, Compound D and Compound B maintained effective inhibition of AR transcriptional activity with increasing concentrations of androgen; n = 4 (Fig. 3F) unlike enzalutamide that significantly lost potency as expected for a competitive antiandrogen. These data support that imaging with a molecular probe targeted to AR AF-1 should not be affected by an occupied AR LBD.
[322] For Figs 3A and 3F, each independent experiment was performed in triplicate. NS: not statistically significant. ** P < 0.01. One-way ANOVA Dunnett's multiple comparison test was utilized. For Fig. 3F, values shown are the means ± SD.
[323] For Figs 3B-3E, representative competitive binding curves are shown from experiments that were repeated 3 times.
[324] Example 4: Targeting AR-Vs
[325] Constitutively active AR-Vs that lack LBD are detected in clinical samples of CRPC and levels of expression are correlated to poor prognosis and resistance to abiraterone and enzalutamide that target the AR LBD (Antonarakis 2014; Guo 2009; Hu 2009; Hornberg 2011; Sun 2010; Zhang 2011). To ensure that the addition of an iodine substituent to Compound B had no detrimental effect on its ability to interact with truncated AR-Vs, we performed direct comparison of Compound D, Compound B and enzalutamide on solely endogenous full-length AR or endogenous full-length AR combined with V567es or V7. In the absence of V567es or V7, enzalutamide inhibited full-length AR induced by androgen, as measured with AR-driven probasin (PB)-luciferase reporter (Fig. 4A, left panel). Consistent with previous studies, enzalutamide had no effect in blocking AR transcriptional activity, either in the presence or absence of androgen, when V567es or V7 were expressed (Fig. 4A,
middle and right panels). Compound D showed good inhibition against full-length AR as well as mixed populations of full-length AR with variant V567es or V7 at 10X less concentrations than Compound B. This suggests that Compound D interacts with the truncated AR variants consistent with Compound B but with better potency. Western blot analysis using an antibody against the AR NTD confirmed the approximate 1 : 1 ratio of endogenous full-length AR to ectopic V567es or V7 in whole cell lysates of cells treated with Compound D, Compound B and enzalutamide (Fig. 4B). Compound D was next tested to examine if it had effects on AR- V-driven proliferation. LNCaP95 cells are enzalutamide resistant (Hu 2012; Yang Y.C., et al. Clin Cancer Res. 2016. doi: 10.1158/1078-0432.CCR-15-2901) and increase proliferation in the absence of androgen by a mechanism driven by AR-Vs. Compound D (2 μΜ) decreased proliferation of LNCaP95 cells as well as Compound B (25 μΜ) whereas enzalutamide (5 μΜ) had no effect (Fig.4C). Compound D had an IC50 of 6.89 ± 2.85 μΜ for inhibition of LNCaP95 cell proliferation (Fig. 4D). Consistent with these data, cell cycle analysis revealed Compounds B and D caused G0/G1 arrest. Approximately 25-30% of cells treated with enzalutamide or DMSO vehicle were in S-phase (Fig. 4E). Whereas Compound D or Compound B decreased S-phase cells by approximately 2-fold or more with a concomitant increase of cells in Gl-phase. Western blot analysis of cell cycle Gl/S-related proteins revealed that EPI analogues decreased the expression of: ubiquitin-conjugating enzyme E2C (UBE2C), an AR-V7 regulated protein; cyclinD3; and cyclin dependent kinases (CDKs). EPI analogues increased protein expression of the cyclin-dependent kinase inhibitor p27kipl. Importantly, enzalutamide had no effect on the levels of expression of these proteins which was consistent with these cells being resistant to enzalutamide (Fig. 4F). Together these data support that Compound D targets full-length AR and AR-Vs.
[326] For Fig. 4A, cells were treated with 2 μΜ Compound D, 25 μΜ Compound B or 5 μΜ enzalutamide for 1 hour prior to treatment with or without 1 nM R1881 for 24 hours. Data represent mean ± SD from 4 independent experiments, each performed in triplicate. For Fig. 4B, protein levels were detected using AR-N20 antibody. For Fig. 4C, cells were treated with enzalutamide (5 uM), Compound B (25 μΜ) or Compound D (2 μΜ) for 2 days, n = 4. Data represent mean ± SEM. Proliferation was assessed by BrdU incorporation. For Fig. 4D, data represents mean ± SEM. For Fig. 4E, cells were treated by Compound D (5 μΜ), Compound B (25 μΜ) or enzalutamide (5 μΜ) for 48 hours. Bivariate plots show cell cycle distribution of a representative experiment. Stacked graph (below) represents the average results from 3 independent experiments. The percentage of cells in each phase of cell cycle was calculated. For Fig. 4F, LNCaP95 cells were serum-starved for 24 hr and then treated with DMSO,
enzalutamide (5 μΜ), Compound B (25 μΜ) or Compound D (5 μΜ) for 48 hours. For Figs. 4A-4F, ENZ: enzalutamide. NS: not statistically significant. *, **, *** and **** indicate statistical difference of P < 0.05, P < 0.01, P < 0.001 and P < 0.0001 respectively. One-way ANOVA Dunnett's multiple comparison test was utilized.
[327] Example 5: Compound Id binds to AF-1 in the AR NTD in cells
[328] Compound B and analogues bind to AR AF-1 (Andersen 2010; Myung 2013) and specifically to Tau-5 in the AF-1 region (De Mol, E. et al 2016 ACS Chem Biol.doi: 10.1021/acschembio.6b00182). Here we show that Compound Id binds to recombinant full-length AR (Fig. 5A). Recombinant full-length AR protein was incubated with Compound Id for 16 hours at room temperature. Binding of Compound Id to AR was detected by SDS-PAGE followed by phosphorimaging. Coomassie blue staining was used to provide an indication of equal loading.
[329] To determine if Compound Id binds the same site as Compound B, AF-1 protein was pre-incubated with excess Compound B prior to addition of radioactive Compound Id probe. Excess Compound B displaced binding of Compound Id to AF-1 thereby suggesting they bind to the same site (Fig. 5B). Recombinant AF-1 protein were incubated with vehicle (DMSO) or Compound B (60 μΜ) for 6 hours at room temperature prior to addition of Compound Id (200 μ^), and then incubated for 16 hours more prior to SDS-PAGE and phosphorimaging. Less binding of Compound Id was observed when AF-1 was pre- incubated with excess Compound B. Coomassie blue staining was used to provide an indication of equal loading.
[330] Ultimately to ensure specific binding of Compound Id to endogenous AR in cells, LNCaP95 cells were treated with Compound Id for 16 hours, followed by SDS-PAGE and Western blot analysis. Compound Id binds covalently and specifically to AR in the LNCaP95 cells (Fig. 5C). Binding of Compound Id to endogenous AR in LNCaP95 cells that were incubated with or without 25 μΜ Compound B overnight at 37°C prior to harvesting cells. Whole cell lysates were used for SDS-PAGE to reveal Compound Id covalently bound to full-length AR in the LNCaP95 cells as detected by phosphorimage. Western blot analyses detection of bands correspond to AR for radiolabelled phosphonmaged bands. For Figs. 5A-5B, n > 3 for binding experiments.
[331] There was no indication that Compound Id was a random alkylator; consistent with previous reports that Compound B or it's racemic mixture do not react with glutathione at
physiological pH (Myung 2013; Banuelos C.A., et al. PLoS One. 2014;9(9):el07991.). These data support the specificity of Compound Id binding to AR AF-1.
[332] Example 6: Biodistribution Study
[333] Biodistribution studies of Compound Id were conducted in male castrated non-obese diabetic severe-combined immunodeficient (NOD-SCID) mice that each carried both a LNCaP95 and a PC3 xenograft. The LNCaP95 cell line was selected as the target CRPC xenograft due to its high level of expression of endogenous full-length AR and AR-V7. PC3 was selected as the non-target xenograft because it has very low/negligible protein levels of AR. Table 2 outlines the in vivo tissue biodistribution results of Compound Id. The cLogP of Compound Id is 4.2 which means it is highly lipophilic; a property that predicts it would be eliminated by the hepatobiliary system. Consistent with this projection, Compound Id accumulation was highest in the gallbladder, liver, and intestines (Table 2). At 4 hours after injection, 66 %ID/g of Compound Id was detected in the large intestine. Generally, there was low uptake and fast washout from non-specific tissues.
[334] Accumulation of Compound Id in LNCaP95 tumors showed no support that it was binding irreversibily in this or any other tissues (Table 2). To date, covalent binding of bisphenol ether derivatives to AR NTD has only been shown in vitro and in closed systems over a long time (Andersen 2010; Myung 2013). Binding of Compound B is proposed as a two-step process of a quick reversible binding followed by a very slow covalent binding (Andersen 2010; Myung 2013). It may be plausible that the short t½ of bisphenol ether compounds in vivo (~3 hours) may result in negligible covalent binding because it is not around long enough for covalent binding to occur.
[335] Compound Id reached a maximum 2.2 ± 0.5 %ID/g uptake in LNCaP95 tumors at 1 hour after injection. This was greater than the maximum achieved for 18F-FDHT (0.432 ± 0.183 %ID/g ± SEM), in the target tissue of ventral prostate in rodents at 1 hour after injection (Liu A., et al. JNucl Med. 1992;33(5):724-734). Both Compound Id and 18F-FDHT target the nuclear AR. Based on similar studies with l8F-FDHT, the accumulation of Compound Id in AR-rich tissues is expected for an AR-mediated process (Bonasera T.A., et al. J Nucl Med. 1996;37(6): 1009-1015). At this time point, Compound Id uptake in AR- deficient PC3 tumors was only 0.7 ± 0.4 %ID/g providing a ratio of 3.2 for AR rich tissue (LNCaP95) compared to AR deficient tissues (PC3 ). LNCaP95 tumor to blood ratio was 3.58 ± 0.66 (Fig. 6A) which was similar to the 3.5 ratio achieved with 18F-FDHT that is used
clinically (Bonasera 1996). LNCaP95 tumor/blood and tumor/muscle ratios were greater than that of PC3 for all time points examined. For Fig. 6A, n = 3-8 at each time point. Data is shown as mean ± SEM.
[336] Blocking with excess Compound B (50 mg/kg body weight) caused a 74 % decrease (p < 0.001) in Compound Id accumulation in the LNCaP95 xenograft (Fig. 6B) suggesting the uptake of Compound Id was AR-mediated. This 74 % drop in LNCaP95 tumours by blocking with excess Compound B was similar to the 70 % drop achieved with testosterone to block 18F-FDHT (Bonasera 1996). Blocking with excess Compound B had no significant effect on levels of Compound Id uptake in blood, muscle and PC3 xenograft (Fig. 6B). These data suggest that the accumulation of Compound Id in LNCaP95 xenograft was specifically AR-mediated.
[337] Fig. 6B shows the effects of Compound B co-treatment on Compound Id accumulation in blood, muscle, LNCaP95 and PC3 xenografts (1 hour treatment). The accumulation of Compound Id in LNCaP95 xenograft was significantly decreased by blocking with Compound B. n = 3-7. Data represent mean ± SD. *** P < 0.001 based on One-way ANOVA Dunnett's multiple comparison test.
[338] Table 4: Biodistribution of Compound Id shown as % injected dose per gram (%ID/g)
[339] Example 7: Micro SPECT/CT Imaging
[340] On the basis of the results from the biodistribution study (Example 6) and ratios of target tissues to non-target tissues that were at similar levels to those achieved with clinically employed 18F-FDHT, a whole-body micro SPECT/CT study was performed to evaluate the specific tumor-targeting ability of Compound Id. To do this, male castrated NOD-SCID mice bearing both LNCaP95 and PC3 xenografts of approximately equal volumes were scanned using SPECT. Scanning at 2 hours post tail vein injection of Compound Id, when the tumor/blood and tumor/muscle ratios were sufficiently high, provided SPECT images shown in Figure 7A. Axial and coronal micro SPECT/CT images of castrated NOD-SCID mouse bearing LNCaP95 (arrow) and PC3 (arrowhead) xenografts 2 hours after co-injection of Compound Id with (Block) or without excess dose of Compound B (Unblock). The images are scaled to the same threshold. Color scale indicated the level of radioactivity, n = 2.
[341] Compound Id distinguished LNCaP95 tumors (arrow) from PC3 tumors (arrowhead), whereas the liver region had relatively higher uptake (Fig. 7 A; Unblock). The amount of radiopharmaceutical uptake seen in the liver with concurrent little gastrointestinal uptake, was likely due to the lipophilic nature of Compound Id, and was consistent with the in vivo biodistribution data. LNCaP95 tumor uptake was similar to the tumor uptake observed in the
biodistribution study, being 1.09 ± 0.41 % ID/g at 2 hours post injection (n = 3). In addition, the Compound Id tracer accumulation was absent from SPECT images when blocked with excess Compound B (Fig. 7A; Block). Importantly, the thyroid uptake was approximately 2.31 ± 0.59%ID/g and was not altered by blocking with Compound B (2.32 ± 0.33%ID/g). These data suggest that Compound Id may not be metabolically stable and that the 123I may fall off the compound to accumulate in the thyroid.
[342] Histological analysis showed that LNCaP95 xenografts have more necrotic centers than PC3 xenografts (Fig. 7B). This suggests that poor vascularization and consequent central necrosis may prevent optimal access of Compound Id to AR in LNCaP95 tumors. Hematoxylin and eosin (H&E) staining and immunohistochemistry (AR) of representative section of formalin-fixed, paraffin-embedded LNCaP95 and PC3 xenografts with lower magnification. Xenograft was extracted approximately 6 weeks after subcutaneous injection of LNCaP95 and PC3 cell lines. The histological analysis demonstrated LNCaP95 cells that expressing the AR formed a largely concentrated tumor, which resulted in a necrotic center. Scale bar represents 40 um.
[343] Western blot analysis using an antibody against the AR NTD and V7 confirmed the expression of full-length AR and V7 in LNCaP95 xenografts, which were undetectable in PC3 xenografts (Fig. 7C). Protein expression obtained from LNCaP95 and PC3 xenografts. Four xenografts from each cell line are shown. Western blot analysis of LNCaP95 xenograft showed both full-length AR and AR-V7 expression, but negative from PC3 xenograft, β-actin is shown as a protein loading control.
[344] These data support that Compound Id accumulation in the LNCaP95 tumor was specific to full-length AR and AR-Vs. Together all of these data support the feasibility of developing molecular imaging agents directed to AR AF-1 to detect the AR and AR-Vs to improve the clinical management of prostate cancer, including radiotherapy.
[345] Although various embodiments of the invention are disclosed herein, many adaptations and modifications may 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 by reference for all purposes as though fully set forth herein. The present claims are intended to and should be construed as including all embodiments and variations substantially as described herein and with reference to the examples and drawings.
Claims
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
wherein:
R1 and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
R3, R4 and R5 are each independently H, C1-C10 alkyl or C1-C10 alkylcarbonyl; and
X1, X2, X3 and X4 are each independently H, F, CI, Br, I, 1231, 124I or 125I, wherein at least one of X1, X2, X3 or X4 is ,24I or 125I.
2. The compound of claim 1 , wherein at least one of X1, X2, X3 or X4 is 124I.
3. The compound of claim 1 or 2, wherein X3 is 124I.
4. The compound of claim 1 , wherein at least one of X1, X2, X3 or X4 is 125I.
5. The compound of claim 1 or 4, wherein X3 is 125I.
6. The compound of any one of claims 1-5, wherein R1 and R2 are each H or C1-C3 alkyl.
7. The compound of any one of claims 1-6, wherein R1 and R2 are each methyl.
8. The compound of any one of claims 1-7, wherein R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl.
9. The compound of any one of claims 1-8, wherein R3, R4 and R5 are each H.
10. The compound of any one of claims 1-8, wherein R3, R4 and R5 are each methyl carbonyl.
11. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt or stereoisomer thereof.
13. A use of a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, for radiation therapy, wherein formula I) is:
wherein:
R1 and R2 are each independently H or G-Go alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
R3, R4 and R5 are each independently H, G-Go alkyl or G-Go alkylcarbonyl; and
X1, X2, X3 and X4 are each independently H, F, CI, Br, 1, 1231, 124I or 125I, wherein at least one of X1, X2, X3 or X4 is 125I.
14. The use of claim 13, wherein X3 is 125I.
15. The use of claim 13 or 14, wherein R1 and R2 are each H or C1-C3 alkyl.
16. The use of any one of claims 13-15, wherein R1 and R2 are each methyl.
17. The use of any one of claims 13-16, wherein R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl.
18. The use of any one of claims 13-17, wherein R3 , R4 and R5 are each H.
19. The use of any one of claims 13-17, wherein R3, R4 and R5 are each methyl carbonyl.
or a pharmaceutically acceptable salt or stereoisomer thereof.
21. The use of claim 13, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
22. The use of any one of claims 13-21, wherein the compound is an Auger emitter.
23. The use of any one of claims 13-22, wherein the compound comprises a radionuclide.
24. The use of claim 23, wherein the radionuclide emits alpha- or beta-particles.
25. The use of any one of claims 13-24, wherein the radiation therapy is for treating a cancer or a cancer cell.
26. The use of claim 25, wherein the cancer is selected from prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma; or the cancer cell is selected from cells of prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
27. The use of claim 26, wherein the cancer is prostate cancer.
28. The use of claim 27, wherein the prostate cancer is selected from primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration- resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
29. The use of any one of claims 25-28, wherein the radiation therapy induces apoptosis of the cancer cells.
30. The use of any one of claims 25-28, wherein the compound is distributed into the cancer cells upon administration.
31. The use of any one of claims 13-30, wherein the compound blocks transactivation of an androgen receptor (AR) N-terminal domain (NTD).
32. The use of claim 31, wherein the androgen receptor is a full-length AR or a constitutively active splice variant of AR.
33. The use of any one of claims 13-32, wherein the radiation therapy is an Auger therapy.
34. A method of administering radiation therapy comprising administering a therapeutically effective amount of a compound of formula (I),
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R1 and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
R3, R4 and R5 are each independently H, C1-C10 alkyl or C1-C10 alkylcarbonyl; and
X1, X2, X3 and X4 are each independently H, F, CI, Br, 1, 1231, 124I, or 125I, wherein at least one of X1, X2, X3 or X4 is 125I.
35. The method of claim 34, wherein X3 is 125I.
36. The method of claim 34 or 35, wherein R1 and R2 are each H or C1-C3 alkyl.
37. The method of any one of claims 34-36, wherein R1 and R2 are each methyl.
38. The method of any one of claims 34-37, wherein R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl.
39. The method of any one of claims 34-38, wherein R3, R4 and R5 are each H.
40. The method of any one of claims 34-38, wherein R3, R4 and R5 are each methyl carbonyl.
The method of claim 34, wherein the compound is selected from:
or a pharmaceutically acceptable salt or stereoisomer thereof.
or a pharmaceutically acceptable salt thereof.
43. The method of any one of claims 34-42, wherein the compound is an Auger emitter.
44. The method of any one of claims 34-43, wherein the compound comprises a radionuclide.
45. The method of claim 44, wherein the radionuclide emits alpha- or beta- particles.
46. The method of any one of claims 34-45, wherein the radiation therapy is for treating a cancer or a cancer cell.
47. The method of claim 46, wherein the cancer is selected from prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma; or the cancer cell is selected from cells of prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
48. The method of claim 47, wherein the cancer is prostate cancer.
49. The method of claim 48, wherein the prostate cancer is selected from primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration- resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
50. The method of any one of claims 46-49, wherein the radiation therapy induces apoptosis of the cancer cells.
51. The method of any one of claims 46-49, wherein the compound is distributed into the cancer cells upon administration.
52. The method of any one of claims 34-51, wherein the compound blocks transactivation of an androgen receptor (AR) N-terminal domain (NTD).
53. The method of claim 52, wherein the androgen receptor is a full-length AR or a constitutively active splice variant of AR.
54. The method of any one of claims 43-53, wherein the radiation therapy is an Auger therapy.
55. The method of anyone of claims 46-51, wherein a progress of the radiation therapy is monitored by imaging the cancer cells using single-photon emission computed tomography (SPECT) or PET imaging.
56. The method of claim 55, wherein the imaging by SPECT uses an imaging agent selected from:
57. The method of claim 55, wherein the imaging by PET uses an imaging agent selected from:
or a pharmaceutically acceptable salt or stereoisomer thereof.
58. A method of imaging cancer, the method comprises administering to a subject a compound of formula (I),
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R1 and R2 are each independently H or C1-C10 alkyl, or R1 and R2, together with the carbon atom to which they are bound, are taken together to form a carbocyclic or heterocyclic ring;
R3, R4 and R5 are each independently H, C1-C10 alkyl or C1-C10 alkylcarbonyl; and
X1, X2, X3 and X4 are each independently H, F, CI, Br, 1, 123I, 124I, or 125I, wherein at least one of X1, X2, X3 or X4 is 124I.
59. The method of claim 58, wherein X3 is 124I.
60. The method of claim 58 or 59, wherein R1 and R2 are each H or C1-C3 alkyl.
61. The method of any one of claims 58-60, wherein Rl and R2 are each methyl.
62. The method of any one of claims 58-61, wherein R3, R4 and R5 are each independently H or C1-C4 alkylcarbonyl.
63. The method of any one of claims 58-62, wherein R3, R4 and R5 are each H.
64. The method of any one of claims 58-62, wherein R3, R4 and R5 are each methyl carbonyl.
65. The method of any one of claims 58-64, wherein the method is PET imaging.
The method of any one of claims 58-65, wherein the method images prostate.
The method of any one of claims 58-67, wherein the method images prostate
or a pharmaceutically acceptable salt or stereoisomer thereof.
69. A pharmaceutical composition comprising a compound of any of claims 1 to 12, and a pharmaceutically acceptable carrier.
70. The pharmaceutical composition of claim 69, wherein the composition further comprises at least one additional therapeutic agent.
71. The pharmaceutical composition of claim 70, wherein the at least one additional therapeutic agent is selected from: enzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXTN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, radium 233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or related compounds thereof.
72. A method of modulating androgen receptor (AR) activity, the method comprising administering a compound of any of claims 1 to 12 to a subject in need thereof.
73. The method of claim 72, wherein the modulating AR is inhibiting transactivation of AR N-terminal domain (NTD).
74. The method of claim72 or 73, wherein the subject is human.
75. The method of any one of claim 72-74, wherein the modulating AR is for treating at least one indication selected from: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
76. The method of claim 75, wherein the cancer is prostate cancer.
77. The method of claim 76, wherein the prostate cancer is selected from primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration- resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
78. The method of any one of claims 72-77, wherein the method is for neoadjuvant therapy.
79. The method of any one of claims 72-77, wherein the method is for adjuvant therapy.
80. The method of claim 79, wherein the adjuvant therapy is following androgen ablation therapy.
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