Patent Application
20230416297
The present disclosure provides a new class of androgen receptor modulators and their use to treat androgen-dependent conditions, including androgen receptor-driven malignancies, such as prostate cancer.
The Androgen Receptor (AR) is a ligand-dependent transcription factor composed of an N-terminal domain, a DNA binding domain, and a C-terminal domain. The C-terminal domain includes a ligand binding domain (LBD). The AR is activated by androgen binding, which exposes the nuclear localization signal (NLS) thereby initiating translocation of the complex into the nucleus to exert transcriptional activity.
Several medical conditions are known to be dependent on, or sensitive to, the presence of androgenic activity. Such androgen-dependent conditions include acne, seborrhea, androgenic alopecia, hirsutism, hidradenitis suppurativa, precocious puberty in boys, hypersexuality, paraphilias, benign prostatic hyperplasia (BPH), prostate cancer, and hyperandrogenism in women such as in polycystic ovary syndrome (PCOS).
Prostate cancer is one of the most common cancers in men. Each year in the United States alone, nearly 200,000 new cases of prostate cancer will be diagnosed and about 33,000 deaths will be attributed to prostate cancer. It has been estimated that about 1 in 9 men will be diagnosed with prostate cancer during his lifetime.
Prostate cancer develops in the prostate and is typically slow growing; however, some prostate cancers are aggressive. Prostate cancer cells are typically androgen-dependent and may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes.
Thus, there remains a need for compounds that modulate androgen receptor activity and, particularly, androgen receptor modulators that possess anti-androgen properties.
The present disclosure relates to polycyclic (e.g., tetracyclic) compounds, including compounds that serve as androgen receptor modulators. In certain embodiments, the compounds have a C19 steroidal scaffold. In other embodiments, compounds having a C19 steroidal scaffold enable access to further compounds based on, or derived from, the C19 scaffold. In certain embodiments, the compounds are C9-α-alkyl as well as C13-β-alkyl steroidal tetracycles.
The present disclosure also relates to the use of such compounds as biologically active (e.g., therapeutic) components in, for example, pharmaceutical compositions and/or directly as human and/or animal therapeutics and medicines. In certain embodiments, the compounds are androgen receptor antagonists and/or may be used to treat or prevent androgen-dependent conditions, including proliferative diseases such as prostate cancer or BPH.
In one aspect, this disclosure provides a method for treating an androgen-dependent condition by administering a compound disclosed herein or a pharmaceutically acceptable salt or prodrug thereof to a patient in need thereof. In some embodiments, the compound is selected from Compounds 101-110. In some embodiments, the androgen-dependent condition is prostate cancer or BPH. In some embodiments, the compound is administered orally.
The compounds, pharmaceutical compositions comprising the compounds, and methods for treating or preventing conditions, disorders, or diseases by administering the compounds are further described herein.
These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.
For a better understanding of the invention, reference may be made to embodiments shown in the following drawings. The components in the drawings are not necessarily to scale and related elements may be omitted, or in some instances proportions may have been exaggerated, so as to emphasize and clearly illustrate the novel features described herein. In addition, system components can be variously arranged, as known in the art.
This detailed description is intended only to acquaint others skilled in the art with the present invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.
In certain aspects, the present disclosure relates to compounds (and methods of making such compounds, compositions comprising such compounds, and methods of using such compounds) comprising a generic tetracyclic steroidal (A, B, C, D) ring structure, as follows:
More particularly, the present disclosure relates to compounds (and methods of making such compounds, compositions comprising such compounds, and methods of using such compounds) comprising a generic C19 steroidal core skeleton of according to the following formulas, where additional substitution about these base structures is intended to be within the scope of the invention:
In one aspect, this disclosure provides compounds having a chemical structure including a C19 steroidal core skeleton, said C19 steroidal core skeleton having a quaternary center at each of carbon C9 and carbon C13. In certain embodiments, the “C19” group attached at C9 projects an electron density beyond the traditional bounds of the androgen receptor ligand binding pocket. In some such embodiments, the “C19” group is attached at C9a, where the bond is shown as .
The C19 steroidal core skeleton depicted above encompasses, inter alia, a C20 steroidal core skeleton, a C21 steroidal core skeleton, a C22 steroidal core skeleton, a C23 steroidal core skeleton, a C24 steroidal core skeleton, and a C25 steroidal core skeleton.
By way of example, the C19 steroidal core skeleton depicted above encompasses, inter alia, a steroidal core skeleton, such as:
The numbering convention throughout the present disclosure is in accordance with numbered structures above.
In reference to the generic tetracyclic steroidal (A, B, C, D) ring structure and the generic C19 and C20 steroidal core skeletons, it will be well appreciated that in view of the disclosure contained herein as well as the teachings in the relevant fields of art, the compounds, compositions, and methods of the present disclosure are not limited to any particular respective constituent (R) group(s) at the various numbered carbon atoms. For example, an R group may be hydrogen, a C1-10-aliphatic group, a C6-10 aromatic group, carboxylic acid, carboxylic acid ester, hydroxyl, or halogen. Moreover, it will be well appreciated that in view of the disclosure contained herein as well as the teachings in the relevant fields of art, the compounds, compositions, and methods of the present disclosure may comprise ones in which any of the rings (A, B, C, D) can be saturated, partially unsaturated, or completely unsaturated (i.e., aromatic); in particular, the A ring can be saturated, partially unsaturated, or completely unsaturated; the B ring can be saturated or partially unsaturated; the C ring can be saturated or partially unsaturated; and the D ring can be saturated or partially unsaturated.
Thus, the C19 steroidal core skeleton depicted above also encompasses, inter alia, a steroidal core skeleton, such as:
In an exemplary embodiment, with reference to any of the above formulae, each of C1, C2, C4, C6, C7, C10, C11, C12, and C17 is independently substituted with hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, oxo, hydroxy, C1-6-alkoxy, —O—C1-10-alkyl, —O—C2-10-alkenyl, —O—C2-10-alkynyl, —O—C1-10-haloalkyl, —O—C6-10-aryl, —O-5- to 10-membered heteroaryl, —OC(O)—C1-10-alkyl, —OC(O)—C6-10-aryl, —OC(O)-5- to 10-membered heteroaryl, C6-10-aryl, or 5- to 10-membered heteroaryl and R3, R9, R13, and RD are defined herein.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term “about” as used herein means approximately, and in most cases within 10% of the stated value.
The term “aliphatic” as used herein includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons. In some embodiments, an aliphatic group is optionally substituted with one or more functional groups. In some embodiments, one or more units (e.g., methylene units) of an aliphatic may be replaced with —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, or —NRZC(S)—, where RZ is hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, C3-7-cycloalkyl, and y is 0, 1, or 2. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl moieties.
The term “alkyl” as used herein includes linear or branched saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-6-alkyl, for example, includes C1, C2, C3, C4, C5, and C alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl. In particular embodiments, an alkyl of this invention is a C1-10-alkyl, C1-9-alkyl, C1-8-alkyl, C1-7-alkyl, C1-6-alkyl, C1-5-alkyl, C1-4-alkyl, C1-3-alkyl, or C1-2 alkyl.
The term “pharmaceutically acceptable” is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product for human use or as a part of a pharmaceutical product for human use.
The term “prodrug” refers to a compound that can be readily converted (e.g., metabolized) in vivo to yield a parent compound. Prodrugs include, but are not limited to, compounds having a substituent, such an ester moiety, attached to a hydroxy group at C3 (steroid numbering), which yield a parent compound having a phenolic A ring upon in vivo conversion. Suitable C3 substituents are identified in US2007/0015740 A1, which is herein incorporated by reference in its entirety. Exemplary ester moieties include, but are not limited to, an alkyl ester (e.g., —O—C1-6alkyl), a carbonate ester (e.g., —O—C(O)—O—C1-10-alkyl), a carbamate ester (e.g., —O—C(O)—NRZ1RZ2), and a sulfamate ester (e.g., —O—S(O)2NRZ1RZ2). Additionally or alternatively, prodrugs may have a substituent, such as an optionally substituted 5- to 10-membered heteroaryl, attached to carbon C17 (steroid numbering), such as those identified in US2014/0371181 A1, which is herein incorporated by reference in its entirety. Prodrugs also include, but are not limited to, di-steroidal prodrugs such as those disclosed in U.S. Pat. No. 7,067,505, which is herein incorporated by reference in its entirety.
The terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a condition, disorder, or disease and/or the attendant symptoms thereof.
In one aspect, compounds disclosed herein possess biological activity, for example, as a modulator of the androgen receptor. In some such embodiments, compounds disclosed herein possess potent anti-androgenic activity while substantially lacking agonistic activity. In another aspect, compounds disclosed herein provide a platform for development of analogs or derivatives possessing biological activity, for example, as modulators of the androgen receptor. Thus, in certain embodiments, a compound disclosed herein may be transformed by methods well known to those skilled in the art of synthetic organic chemistry into a derivative compound that possesses biological activity, for example, as a modulator of the androgen receptor.
In one aspect, compounds disclosed herein comprise a steroidal core, such as a C19 steroidal core. In certain embodiments, such compounds comprise an aliphatic group attached at C9 and positioned on the alpha (a) face. In some such embodiments, the aliphatic group attached at C9α projects an electron density beyond the traditional bounds of the androgen receptor ligand binding pocket. In certain embodiments, such compounds comprise a C8-C14 double bond in the C ring. In certain embodiments, such compounds comprise an alcohol or other group attached at C16 (rather than the typical C17 alcohol in other anti-androgen agents). In certain embodiments, such compounds comprise a C4-C5 double bond in the A ring. In particularly preferred embodiments, the compounds comprise an aliphatic group attached at C9α that projects an electron density beyond the traditional bounds of the androgen receptor ligand binding pocket, a C8-C14 double bond in the C ring, and an alcohol moiety attached at C16. In other particularly preferred embodiments, the compounds comprise an aliphatic group attached at C9α that projects an electron density beyond the traditional bounds of the androgen receptor ligand binding pocket, a C4-C5 double bond in the A ring, a C8-C14 double bond in the C ring, and an alcohol moiety attached at C16. Such compounds unexpectedly act as androgen receptor antagonists.
In certain embodiments, the compounds, with reference to the quaternary centers at C9 and C13, are anti-isomers (the quaternary center at C9 projects a substituent on the opposite face of the tetracycle as the substituent at C13). For example, the compounds may be C9-α-substituted and C13-β-substituted or, alternatively, C9-β-substituted and C13-α-substituted.
Exemplary generic formula include:
In certain embodiments, the ORD or —OH substituent attached to carbon C16 by has the alpha orientation (e.g.,
). In certain other embodiments the ORD or —OH substituent attached to carbon C16 by
has the beta orientation (e.g.,
).
In one aspect, this disclosure provides a compound or a salt thereof, wherein the compound either has a structure corresponding to Formula (I-A) or Formula (I-B):
The compounds of Formula (I-A) and Formula (I-B) optionally include a double bond between carbon C8 and carbon C14 (i.e., 8,14-unsaturated) or, alternatively, a double bond between carbon C14 and carbon C15, provided that if the bond between carbon C8 and carbon C14 or the bond between carbon C14 and carbon C15 is a double bond, then R14 is absent and provided that if the bond between carbon C14 and carbon C15 is a double bond, then one of R15A or R15B is absent.
The compounds of Formula (I-A) and Formula (I-B) optionally include a double bond between carbon C5 and carbon C6 (i.e., 5,6-unsaturated), provided that if the bond between carbon C5 and carbon C6 is a double bond, then one of R6A or R6B is absent.
In certain embodiments, the compound has a structure corresponding to Formula (I-A1) or Formula (I-B1):
In one aspect, this disclosure provides a compound or a salt thereof, wherein the compound either has a structure corresponding to Formula (II-A) or Formula (II-B):
The compounds of Formula (II-A) and Formula (II-B) optionally include a double bond between carbon C8 and carbon C14 (i.e., 8,14-unsaturated) or, alternatively, a double bond between carbon C14 and carbon C15, provided that if the bond between carbon C8 and carbon C14 or the bond between carbon C14 and carbon C15 is a double bond, then R14 is absent and provided that if the bond between carbon C14 and carbon C15 is a double bond, then one of R15A or R15B is absent.
The compounds of Formula (II-A) and Formula (II-B) optionally include a double bond between carbon C4 and carbon C5 (i.e., 4,5-unsaturated) or, alternatively, a double bond between carbon C5 and carbon C6, provided that if the bond between carbon C5 and carbon C6 is a double bond, then one of R6A or R6B is absent.
In certain embodiments, the compound has a structure corresponding to Formula (II-A1), Formula (II-A1.1), Formula (II-A1.2), Formula (II-A1.3), Formula (II-B1), Formula (II-B1.1), Formula (II-B1.2), or Formula (II-B1.3):
In one aspect, this disclosure provides a compound or a salt thereof, wherein the compound either has a structure corresponding to Formula (III-A) or Formula (III-B):
The compounds of Formula (III-A) and Formula (III-B) optionally include a double bond between carbon C8 and carbon C14 (i.e., 8,14-unsaturated) or, alternatively, a double bond between carbon C14 and carbon C15. The compounds of Formula (III-A) and Formula (III-B) optionally include a double bond between carbon C4 and carbon C5 (i.e., 4,5-unsaturated) or, alternatively, a double bond between carbon C5 and carbon C6.
In certain embodiments, the compound has a structure corresponding to Formula (III-A1), Formula (III-A1.1), Formula (III-A1.2), Formula (III-A1.3), Formula (III-1), Formula (III-B1.1), Formula (III-B1.2), or Formula (III-B1.3):
In one aspect, this disclosure provides a compound or a salt thereof, wherein the compound either has a structure corresponding to Formula (IV-A) or Formula (IV-B):
The compounds of Formula (IV-A) and Formula (IV-B) optionally include a double bond between carbon C8 and carbon C14 (i.e., 8,14-unsaturated) or, alternatively, a double bond between carbon C14 and carbon C15. The compounds of Formula (IV-A) and Formula (IV-B) optionally include a double bond between carbon C4 and carbon C5 (i.e., 4,5-unsaturated) or, alternatively, a double bond between carbon C5 and carbon C6.
In certain embodiments, the compound has a structure corresponding to Formula (IV-A1), Formula (IV-A1.1), Formula (IV-A1.2), Formula (IV-A1.3), Formula (IV-B1), Formula (IV-B1.1), Formula (IV-B1.2), or Formula (IV-B1.3):
In any aspect or embodiment described herein, a dashed or solid semi-circle (e.g., representing the A ring) represents a saturated or unsaturated carbocyclic or heterocyclic ring containing 5 or 6 ring atoms. In some such embodiments, the A ring is optionally substituted benzene. In other such embodiments, the A ring is an optionally substituted 6-membered carbocyclic ring that is saturated or partially unsaturated. In some such embodiments, the A ring is optionally substituted cyclohexene. In some such embodiments, the A ring is cyclohex-2-en-1-one. In some such embodiments, the A ring is optionally substituted cyclohexane. In some such embodiments, the A ring is cyclohexanone. In still other such embodiments, the A ring is a 5- or 6-membered heterocyclic ring, such as thiophene or furan.
In any aspect or embodiment described herein, variables shown in generic structures may have the following meanings:
In certain preferred embodiments, n is 1 or 2. In some such preferred embodiments, n is 1. In some such preferred embodiments, n is 2.
In certain preferred embodiments, m is 0 or 1. In some such preferred embodiments, m is 0. In some such preferred embodiments, m is 1.
In certain preferred embodiments, RA is —OH, —O—C1-6-alkyl, or oxo. In some such preferred embodiments, RA is —OH or oxo.
In certain preferred embodiments, n is 2 and one RA is —OH or —O—C1-6-alkyl and the other RA is C1-10-alkyl, such as methyl, or —ORAX wherein RAX is C1-6-alkyl, such as methyl.
In certain preferred embodiments, R3 is —OH or oxo. In some such preferred embodiments, R3 is oxo.
In certain preferred embodiments, the bond between C4-C5 is a double bond and the bond between C5-C6 is a single bond.
In certain preferred embodiments, the bond between C4-C5 is a double bond, the bond between C5-C6 is a single bond, and R3 is —OH or oxo. In some such preferred embodiments, the bond between C4-C5 is a double bond, the bond between C5-C6 is a single bond, and R3 is oxo.
In certain preferred embodiments, the bond between C5-C6 is a single bond and both R6A and R6B are hydrogen, R6A is hydrogen and R6B is C1-10-alkyl, and R6A is hydrogen and R6B is C1-10-haloalkyl. In some such preferred embodiments, both R6A and R6B are hydrogen.
In certain preferred embodiments, both R7A and R7B are hydrogen, R7A is hydrogen and R7B is C1-10-alkyl, and R7A is hydrogen and R7B is C1-10-haloalkyl. In some such preferred embodiments, both R7A and R7B are hydrogen.
In certain preferred embodiments, R9 is selected from the group consisting of C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —(CH2)m—C6-10-aryl, and —(CH2)m-5- to 10-membered heteroaryl. In some such preferred embodiments, R9 is C1-10-alkyl. For example, R9 may be methyl.
In certain preferred embodiments, R13 is an optionally substituted C1-10-aliphatic group, wherein one or more units (e.g., methylene units) of the aliphatic group is optionally replaced with —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, or —NRZC(S)—, where RZ is hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, C3-7-cycloalkyl, and y is 0, 1, or 2. In certain preferred embodiments, R13 is selected from the group consisting of C1-14-alkyl and C1-14-haloalkyl, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, and —NRZC(S)—. In some such preferred embodiments, R13 is C1-4-alkyl. For example, R13 may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl. In some embodiments, R13 is a C4-alkyl. In some embodiments, R13 is a C5-alkyl. In some embodiments, R13 is a C6-alkyl. In some embodiments, R13 is a C7-alkyl. In some embodiments, R13 is a C8-alkyl. In some embodiments, R13 is a C9-alkyl. In some embodiments, R13 is a C10-alkyl. In some embodiments, R13 is a C11-alkyl. In some embodiments, R13 is a C12-alkyl. In some embodiments, R13 is a C13-alkyl. In some embodiments, R13 is a C14-alkyl.
In certain preferred embodiments, the bond between C8-C14 is a double bond and the bond between C14-C15 is a single bond.
In certain preferred embodiments, the bond between C14-C15 is a single bond and both R15A and R15B are hydrogen, R15A is hydrogen and R15B is C1-10-alkyl, and R15A is hydrogen and R15B is C1-10-haloalkyl. In some such preferred embodiments, both R15A and R15B are hydrogen.
In certain preferred embodiments, R16 is —OH, —O—C1-6-alkyl, or —O—C(O)—C1-10-alkyl. In some such preferred embodiments, R16 is —OH or —O—C(O)—C1-10-alkyl. In certain preferred embodiments, R16 is —ORD and RD is selected from the group consisting of hydrogen, C1-10-alkyl, C1-10-haloalkyl, C2-10-alkenyl, C2-10-haloalkenyl, C2-10-alkynyl, C2-10-haloalkynyl, —(CH2)m—C6-10-aryl, and —(CH2)m-5- to 10-membered heteroaryl. In some such embodiments, RD is hydrogen, C1-6-alkyl, or C1-6-haloalkyl. In certain preferred embodiments, R16 is —O—C(O)RD and RD is selected from the group consisting of hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, —(CH2)m—C6-10-aryl, and —(CH2)m-5- to 10-membered heteroaryl. In some such embodiments, RD is hydrogen, C1-6-alkyl, or C1-6-haloalkyl.
In certain preferred embodiments, both R17A and R17B are hydrogen, R17A is hydrogen and R17B is C1-10-alkyl, and R17A is hydrogen and R17B is C1-10-haloalkyl. In some such preferred embodiments, both R17A and R17B are hydrogen. In certain preferred embodiments, neither R17A nor R17B are hydroxy.
It is to be understood that any preferred embodiment for a variable (e.g., n, RA, R6A, R6B, R7A, R7B, R9, R13, R15A, R15B, R16, R17A and R17B) may be combined with any preferred embodiment for any other variable(s) described herein. Exemplary combinations for compounds having a structure corresponding to formulae described herein include, but are not limited to: n is 0 or 1; RA, if present, is hydroxy or oxo; R3 is hydroxy or oxo; the bond between C4-C5 is a double bond and the bond between C5-C6 is a single bond; R6A and R6B are both hydrogen; R7A and R7B are both hydrogen; R9 is C1-6-alkyl; R13 is C1-10-alkyl; the bond between C8-C14 is a double bond and the bond between C14-C15 is a single bond; R15A and R15B are both hydrogen; R16 is —OH or —O—C(O)—C1-6-alkyl; and R17A and R17B are both hydrogen.
In one aspect, this disclosure provides a compound or salt or prodrug thereof, wherein the compound has a structure corresponding to one of the listed in Table A.
Data for select compounds are shown in Table A:
The following general scheme is representative of a particular embodiment of the method and allows for concise and stereoselective synthesis of “C19” tetracyclic compounds:
Step (i) is a metallacycle-mediated annulation reaction between readily available Enyne (a) and an optionally substituted alkyne (e.g., in the presence of Ti(Oi-Pr)4, n-BuLi, and PhMe) to provide Hydrindane (a), which possesses the C13 quaternary center. While step (i) depicts an optionally substituted trimethylsilypropyne, alternative compounds such as those having a simple internal alkyne (without a TMS) or an alternative to the silyl group (or stannyl group, for example) on the alkyne may also be used.
Step (ii) is a cyclization reaction through C9-C10 bond-formation, such as by an intramolecular regio- and stereoselective Friedel-Crafts cyclization of stereoselective Heck cyclization (for example, where the A ring of Hydrindane (a) further comprises a group suitable for an intramolecular Heck reaction such as halogen or —OTf).
In at least one aspect, the present disclosure includes a method for inhibiting androgen receptor activity. The method comprises exposing an androgen receptor to and/or contacting an androgen receptor with an effective amount of a compound described herein (including, but not limited to, Compounds 101-110) or a pharmaceutically acceptable salt or prodrug thereof.
In at least one aspect, the present disclosure includes a method for treating or preventing an androgen-dependent condition in a subject in need of such treatment or prevention. In certain embodiments, the androgen-dependent condition is a proliferative disease. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”) and benign neoplasms. In particular, exemplary proliferative diseases that may be treated or prevented include prostate cancer and benign prostatic hyperplasia (“BPH”). In certain embodiments, the androgen-dependent condition is cancer (e.g., prostate cancer), BPH, hypersexuality, acne, amenorrhea, seborrhea, hirsutism, androgenic alopecia, hidradenitis suppurativa, or hyperandrogenism.
Thus, one aspect of the present disclosure includes a method for treating prostate cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein (including, but not limited to, Compounds 101-110) or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the compound is a compound listed in Table A. In some embodiments, the compound is Compound 108. In some embodiments, the compound (or pharmaceutically acceptable salt thereof) is administered orally. In some embodiments, the compound (or pharmaceutically acceptable salt thereof) is administered parenterally, such as intramuscularly, subcutaneously, or transdermally. In at least one aspect, the present disclosure includes a compound disclosed herein or a pharmaceutically acceptable salt or prodrug thereof for use in a method for treating a cancer, particularly prostate cancer. In certain embodiments, the compound is a compound listed in Table A. In certain embodiments, a compound described herein (including, but not limited to, Compounds 101-110) or a pharmaceutically acceptable salt or prodrug thereof can be used in combination with one or more additional therapeutic agents. In certain embodiments, the prostate cancer is castration-resistant prostate cancer (“CRPC”), particularly metastatic CRPC.
Another aspect of the present disclosure includes a method for treating or preventing BPH in a subject in need of such treatment or prevention.
Still another aspect of the present disclosure includes a method for treating or preventing hypersexuality, acne, amenorrhea, seborrhea, hirsutism, androgenic alopecia, hidradenitis suppurativa, or hyperandrogenism in a subject in need of such treatment or prevention.
One aspect of the present disclosure includes a method for treating or preventing a disease or condition that is at least partially mediated or affected by an androgen receptor (AR) in a subject in need of such treatment or prevention.
Another aspect of the present disclosure includes a method for treating or preventing a disease or condition treatable or preventable by selectively modulating AR in a subject in need of such treatment or prevention.
In certain embodiments, for any of the aforementioned aspects, the subject is a mammal. In some such embodiments, the mammal is a human.
In certain embodiments, for any of the aforementioned aspects, the methods comprise administering to the subject a therapeutically effective amount of a compound described herein (including, but not limited to, Compounds 101-110) or a pharmaceutically acceptable salt or prodrug thereof as single agent or in combination with another therapeutic agent. In some such embodiments, the methods comprise administering to the subject a therapeutically effective amount of one of Compound 101-110 or a pharmaceutically acceptable salt or prodrug thereof, preferably one of Compound 101-110. For example, in one particular embodiment, the method comprises administering to the subject a therapeutically effective amount of Compound 108 or a pharmaceutically acceptable salt or prodrug thereof, preferably Compound 108. In certain embodiments, the compound is administered orally.
In some such embodiments, the compound has a structure corresponding to Formula (III-A1.1), (III-A1.2), (III-A1.3), (III-B1.1), (III-B1.2), or (III-B1.3):
In certain preferred embodiments, n is 0, 1, or 2. In some such preferred embodiments, n is 0.
In certain preferred embodiments, RA is C1-10-alkyl, such as methyl,
In certain preferred embodiments, R3 is oxo or —OH.
In certain preferred embodiments, R9 is an aliphatic group that projects an electron density beyond the traditional bounds of the androgen receptor ligand binding pocket. In some such preferred embodiments, R9 is C1-10-alkyl, C1-10-haloalkyl, or —(CH2)m—C6-10-aryl. In some such preferred embodiments, R9 is C1-10-alkyl, such as methyl, ethyl, or propyl. In some such preferred embodiments, R9 is —(CH2)m—C6-10-aryl, wherein m is 0 or 1. For example, R10 may be phenyl or benzyl.
In certain preferred embodiments, R13 is C1-10-alkyl, C1-10-haloalkyl, or —(CH2)m—C6-10-aryl. In some such preferred embodiments, R13 is C1-10-alkyl, such as methyl, ethyl, propyl, butyl (e.g., n-butyl or isobutyl), pentyl, or hexyl (e.g., n-hexyl or methylpentyl). In some such preferred embodiments, R13 is —(CH2)m—C6-10-aryl, wherein m is 0 or 1. For example, R13 may be phenyl or benzyl.
In certain preferred embodiments, R17A and R17B are both hydrogen.
In certain preferred embodiments, RD is hydrogen or —C(O)—C1-10-alkyl. In some such preferred embodiments, RD is hydrogen. In some such preferred embodiments, RD is —C(O)—C1-6-alkyl.
The preferred total daily dose of the compound or salt (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg of the compound or salt per kg body weight). In certain embodiments, dosage unit compositions contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. In certain embodiments, multiple doses per day typically may be used to increase the total daily dose, if desired.
Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular compound or salt used; whether a drug delivery system is utilized; and whether the compound or salt is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and therefore, can derive from the preferred dosage regimen set forth above.
The activity of a compound can be determined using various known methods. For example, AR assays can be used. Such AR assays include binding assays using, for example, cells transfected with the human androgen receptor. Several cell based model systems that allow sensitive detection and monitoring of steroids or other compounds with AR bioactivity are known. Most cell based AR reporter models use transgenic gene constructs that include an androgen response element (ARE) that controls reporter gene (e.g., lucifersrase) expression. For example, a human AR Reporter Assay System is commercially available from Indigo Biosciecnes. The principle application of such an assay product is to quantify functional activities, either agonist or antagonist, that a compound may exert against the human androgen receptor. An exemplary assay system or test kit includes reporter cells, a reference agonist (e.g., 6α-fluoro-testosterone), and a reference antagonist (e.g., bicalutamide or hydroxyflutamide). In addition, the anti-proliferative activity of a compound can be determined using various known methods, including in vitro and in vivo antiproliferative assays using cancer cell lines such as a prostate cancer cell line.
In at least one aspect, the present disclosure includes compositions comprising a compound described herein (including, but not limited to, Compounds 101-110) or a pharmaceutically acceptable salt or prodrug thereof. In certain embodiments, the composition comprises one or more conventional pharmaceutically acceptable excipients.
In at least one aspect, the present disclosure includes compositions comprising an enantiomeric compound described herein. In certain embodiments, the composition is enantiomerically pure or enriched. For example, the composition may comprise at least 85% of one enantiomer and not more than 15% of the other enantiomer; alternatively, at least 90% of one enantiomer and not more than 10% of the other enantiomer; alternatively, at least 95% of one enantiomer and not more than 5% of the other enantiomer; alternatively, at least 97% of one enantiomer and not more than 3% of the other enantiomer; or alternatively, at least 99% of one enantiomer and not more than 1% of the other enantiomer. In certain embodiments, the composition is substantially free of enantiomeric impurities. In some such embodiments, the composition is free of any detectable amount of an enantiomeric impurity.
Pharmaceutical compositions disclosed herein comprise a compound disclosed herein or a pharmaceutically acceptable salt or prodrug thereof, preferably, Compounds 101-110. In some embodiments, the pharmaceutical composition is an oral dosage form, preferably a solid oral dosage form (e.g., a tablet). In some such embodiments, the solid oral dosage form may comprise pharmaceutically acceptable excipients such as excipients that function as binders, glidants, lubricants, and fillers. Thus, a solid oral dosage form comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof further optionally comprises one or more conventional pharmaceutically acceptable excipients.
In some embodiments, a compound is co-administered with at least one additional therapeutic agent. In some such embodiments, the additional therapeutic agent is a corticosteroid, such as prednisone or prednisolone. In some such embodiments, the additional therapeutic agent is an estrogen, such as estradiol, ethinyl estradiol, or a conjugated estrogen. In some such embodiments, the additional therapeutic agent is a CYP17A1 inhibitor, such as abiraterone acetate or galeterone. In some such embodiments, the additional therapeutic agent is a nonsteroidal antiandrogen (NSAA) medication, such as flutamide, nilutamide, bicalutamide, topilutamide, apalutamide, enzalutamide, darolutamide, proxalutamide, or seviteronel.
In some embodiments, the additional therapeutic agent and the compound of the present disclosure are co-administered to the patient in a substantially simultaneous manner (e.g., or within about 5 min of each other), in a sequential manner, or both. It is contemplated, for example, that such combination therapies may include administering one therapeutic agent multiple times between the administrations of the other. The time period between the administration of each agent may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of each composition and active ingredient (e.g., potency, solubility, bioavailability, half-life, and kinetic profile), as well as the condition of the patient. In some embodiments, the additional therapeutic agent and the compound of the present disclosure are administered in separate pharmaceutical compositions. In some embodiments, the additional therapeutic agent and the compound of the present disclosure are administered in the same pharmaceutical composition.
In at least one aspect, the present disclosure includes a pharmaceutical composition for treating an androgen-dependent condition such as prostate cancer or BPH, the composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain embodiments, the compound is one of Compounds 101-110.
It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the compositions and methods of the invention described herein may be made using suitable equivalents without departing from the scope of the invention or the embodiments disclosed herein.
The compounds, compositions, and methods described herein will be better understood by reference to the following examples, which are included as an illustration of and not a limitation upon the scope of the invention.
Compound 101—(9R,10S,13R,16S)-9,13-dimethyl-3-oxo-2,3,6,7,9,10,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate
Compound 102—(9R,10S,13R,16S)-16-hydroxy-9,13-dimethyl-1,2,6,7,9,10,11,12,13,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
Compound 103—(9R,10S,13R,16R)-16-hydroxy-9,13-dimethyl-1,2,6,7,9,10,11,12,13,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
Compound 102 was prepared in 3 steps from Enyne 1, which is available from, for example, epichlorohydrin.
Preparation of Compound 102 from Enyne 1:
The first step was a titanium-mediated annulation reaction as generally described above to provide the stereodefined Hydrindane 2.
In the second step, Hydrindane 2, which is a silyl-substituted diene, was reacted with (S)-Binol and SnCl4 at −78° C. to deliver the intermediate tetracyclic steroid product.
In the third step, the aromatic A ring was converted to a cyclohexanone to provide Compound 102.
Compounds 101 and 103-110 were prepared in a similar manner.
Compounds were characterized by nuclear magnetic resonance (NMR) spectroscopy. 1H NMR and 13C NMR spectra for Compounds 101-110 are shown in
The activity of certain compounds were tested in a human AR agonist assay and a human AR antagonist assay (Indigo Biosciences).
Results from the human AR agonist assay for Compounds 101-103 are shown in
Results from the human AR antagonist assay for Compounds 101-103 are shown in
Results from the human AR antagonist assay for Compounds 108 and 110 are shown in
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof.
All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of those references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or prior art at all). Applicant reserves the right to challenge the accuracy and pertinence of the cited references.
This patent application claims priority to U.S. Provisional Patent Application No. 62/990,008, filed on Mar. 16, 2020 and U.S. Provisional Patent Application No. 63/037,318, filed on Jun. 10, 2020, the entire contents of which are fully incorporated herein by reference.
This invention was made with government support under R01 GM080266 awarded by the National Institutes of Health and R35 GM134725 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/22319 | 3/15/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62990008 | Mar 2020 | US | |
| 63037318 | Jun 2020 | US |
