compound, pharmaceutical composition and use of a compound

专利摘要:
COMPOUNDS, PHARMACEUTICALLY ACCEPTABLE SALES, PROPHARMACEUTICAL, PHARMACEUTICAL COMPOSITION AND USES OF A COMPOUND This disclosure is directed, in general, to neuroactive 19-alkoxy-17-substituted steroids, as referred to in this document, and pharmaceutically acceptable salts thereof. for use as, for example, an anesthetic, and / or in the treatment of disorders related to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions that comprise such compounds.
公开号:BR112015014397B1
申请号:R112015014397-0
申请日:2013-12-18
公开日:2021-02-02
发明作者:Douglas Covey；Albert Jean Robichaud
申请人:Washington University；Sage Therapeutics, Inc；
IPC主号:

专利说明:

GOVERNMENT SUPPORT
[001] The claimed matter was developed with support from the American Government under the NIH Concession # GM47969, granted by the National Institute of Health (National Institute of Health). Consequently, the American Government has certain rights in the matter claimed. CROSS REFERENCE TO RELATED REQUESTS
[002] This application claims the priority benefit of the Provisional Patent Application for Serial Number US 61 / 738,822, filed on December 18, 2012, the entire content of which is incorporated into this document as a reference. BACKGROUND OF THE REVELATION
[003] The present disclosure is directed, in general, to innovative compounds that are useful as an anesthetic and / or in the treatment of disorders related to the function and activity of GABA. More specifically, the present disclosure is directed to steroids that have a 19-alkoxy-17-substituted tetracyclic structure that is neuroactive and suitable for use as an anesthetic, as well as pharmaceutically acceptable salts and prodrugs thereof and pharmaceutical compositions containing the themselves.
[004] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA activates two types of receptors, the inotropic GABAA receptor and the metabotropic GABAB receptor. Activation of the GABAB receptor by GABA causes hyperpolarization and an inhibition resulting from neurotransmitter release. The GABAA receptor subtype regulates neuronal excitability and sudden mood swings, such as anxiety, panic and stress response. GABAA receptors are chloride ion channels; as a result, activation of the receptor induces a greater flow of chloride ion inward, resulting in membrane hyperpolarization and neuronal inhibition. Drugs that stimulate GABAA receptors, such as benzodiazepines and barbiturates, have anticonvulsant effects (reducing neuronal excitability and raising the seizure limit), as well as anxiolytic and anesthetic effects.
[005] The effect of certain steroids on GABAA receptors has been well demonstrated. As a result, researchers continue to seek the disclosure and synthesis of neuroactive steroids that can act as anesthetics and / or that can serve to provide treatment for disorders related to GABA function. For example, it is now widely accepted that the intravenous anesthetic alfaxalone (Compound A, below) causes general anesthesia in humans due to the fact that it allosterically increases GABA-mediated chloride currents that act on GABAA receptors in the brain. However, the various structural features that allow this compound to work the way it does have, to date, not been fully understood. For example, in contrast to alfaxalone, Δ16-alfaxalone (Compound B, below) has been found to significantly decrease allosteric activity at GABAA receptors and is not used as a general intravenous anesthetic in humans
[006] The difference in the performance of these two compounds, which some attributed to the presence of the carbon-carbon double bond in the D ring, attracted the attention of many researchers. In fact, it has recently been determined that the effect of this double bond has on anesthetic activity may depend on the group connected to C-17 in ring D. (See Bandyopadhyaya, AK, et al., “Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues. Bioorg. Med. Chem. Lett., 20: 6,680 to 6,684 (2010).)
[007] In addition to anesthetic properties, neuroactive steroids can be used to treat disorders related to GABA function. For example, neuroactive steroids, such as progesterone, can be used as hypnotic sedatives, which exhibit actions similar to benzodiazepine, inducing reduced sleep latency and increased non-REM sleep with only minor changes in slow wave and REM sleep. In addition, drugs that improve GABA responses are generally used to treat anxiety in humans. Thus, GABA-enhancing steroids can be expected to exhibit anxiolytic effects. Neuroactive steroids can also be used to treat depression, assuming that the accumulation of evidence suggests that patients with major depression have reduced levels of GABAergic neurosteroids and that certain treatments for depression alter levels of these steroids. Although GABA is not typically seen as playing an essential role in the biology of depression, there is evidence that low GABAergic activity can predispose a person to mood disorders. Finally, inhibition of NMDA receptors and enhancement of GABAA receptors appear to play important roles in mediating the acute effects of ethanol on the nervous system, while related studies suggest that GABAergic neurosteroids may be involved in some pharmacological effects of ethanol that neuroactive steroids may be useful. to treat ethanol withdrawal.
[008] In view of the foregoing, it is evident that there are numerous potentially beneficial uses of neurosteroids. As a result, there is still a need for additional synthesis and understanding of new neuroactive steroids, particularly those that are useful as an anesthetic and / or in the treatment of a disorder related to GABA function and activity. BRIEF DESCRIPTION OF THE REVELATION
[009] In one aspect, the present disclosure relates to a compound that has a structure of Formula (I):
or a pharmaceutically acceptable salt thereof; where: R1 is selected from (C1-C4 alkyl) -O, spiro-oxirane, cyano, = O, nitro, (C1-C4 alkyl) C (O) and HO (C1-C4 alkyl) C (O ), with R1 being preferably in the beta position when it is not = O, and / or in one or more preferred embodiments, C1-C4 alkyl being methyl, therefore, R1 is selected from methoxy, spiro-oxirane, cyan, = O , nitro, CH3C (O) - and OHCH2C (O) -; R2 is = O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl or optionally substituted aryl, with the proviso that when R2 is = O, R8 is not present; R3 is H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl or optionally substituted aryl; R4 is independently selected from H and unsubstituted C1-C4 alkyl; R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl (and in particular is substituted alkoxy methyl, or even more particularly is -CH2-ORb, where Rb is C1-C4 alkyl, or even more particularly it is -CH2-OCH3); R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; - - - denotes an additional and optional CC bond, which results in a C = C bond between C4-C5 or C5-C6, with the proviso that when present, the R5-H substituent is not present; and, - - - denotes an additional and optional DC link, which results in a C = C link between C16-C17, with the proviso that when present, R1 is not = O.
[010] The present disclosure relates to a pharmaceutically acceptable salt of the compounds observed, or alternatively to prodrugs thereof. In a particular embodiment, the present disclosure relates to a compound that has a structure of Formula (II):
or a pharmaceutically acceptable salt thereof; where: R1 is selected from (C1-C4 alkyl) -O, spiro-oxirane, cyano, = O, nitro, (C1-C4 alkyl) C (O) and HO (C1-C4 alkyl) C (O ), with R1 being preferably in the beta position when it is not = O, and / or in one or more preferred embodiments C1-C4 alkyl being methyl, therefore, R1 is selected from methoxy, spiro-oxirane, cyan, = O, nitro, CH3C (O) - and OHCH2C (O) -; R2 is = O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl or optionally substituted aryl, with the proviso that when R2 is = O, R8 is not present; Rx is = O or ORd, where Rd is H or C (O) Re, where Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl, with the proviso that when Rx is OH, it is in a beta configuration; R4 is independently selected from H and unsubstituted C1-C4 alkyl; R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl (and in particular is alkoxy-substituted methyl, or even more particularly is -CH2-ORb, where Rb is C1-C4 alkyl, or even more particularly it is -CH2-OCH3); R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; - - - denotes an additional and optional DC bond, which results in a C = C bond between C4-C5 or C5-C6, with the proviso that when present, the C5-H substituent is not present; and, - - - denotes an additional and optional CC bond, which results in a C = C bond between C16-C17, with the proviso that when present, R1 is not = O, with the proviso that the compound does not have one of the following structures:
or alternatively with the proviso that: (i) when Rx is = O, a C = C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spiro-oxirane, cyan, nitro , and CH3C (O) -; and / or (ii) when Rx is beta-OH, a C = C bond is present between C5-C6, and R5 is CH2OCH3, so R1 is selected from methoxy, spiro-oxirane, cyan, nitro, and HOCH2C ( O)-.
[011] The present disclosure further relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more steroids, or prodrugs, or pharmaceutically acceptable salts thereof, as noted above, and optionally a pharmaceutically acceptable carrier. The present disclosure also provides kits comprising steroids, salts thereof, prodrugs thereof and / or pharmaceutical compositions thereof.
[012] The present disclosure further provides methods for inducing anesthesia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of one or more steroids, or prodrugs, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof as noted above.
[013] The present disclosure additionally provides methods for treating disorders related to GABA function in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of one or more steroids, or prodrugs, or salts pharmaceutically acceptable compounds, or a pharmaceutical composition thereof, as noted above. In certain embodiments, the disorder is selected from the group consisting of insomnia, mood disorders, seizure disorders, anxiety, or ethanol withdrawal symptoms. DETAILED DESCRIPTION OF CERTAIN ACHIEVEMENTS
[014] According to the present disclosure, it has been revealed that compounds that have certain structures of 17-substituted steroids, more specifically certain structures of 19-alkoxy-17-substituted steroids, and even more specifically certain structures of 19-methoxy steroids Substituted, are neuroactive and are also suitable for use as anesthetics and in the treatment of disorders associated with GABA function, as well as pharmaceutically acceptable salts and prodrugs thereof. The compounds can be used, for example, as an effective continuous infusion sedative for non-surgical procedures (for example, colonoscopy). The compounds also offer advantages over anesthetics known in the art, such as a lower likelihood of bacterial contamination, as well as an improved relationship with solubilizing agents. 1. STEROID STRUCTURE
[015] In general, the steroid of the present disclosure has a tetracyclic fused ring structure, like a cyclopenta [a] phenanthrene ring system (the realization of which is illustrated and discussed in more detail below), in which the C3 position of the ring A has a hydroxyl substituent at position α, and position C17 of ring D has a substituent attached to it selected from the group consisting of methoxy, spiro-oxirane, cyano, = O, nitro, CH3C (O) -, and HOCH2C (O) - (with R1 being preferably in the beta position when it is not = O).
[016] More particularly, however, the present disclosure refers, in certain embodiments, to a steroid that has the formula (I) structure:
or a pharmaceutically acceptable salt thereof; where: R1 is selected from (C1-C4 alkyl) -O (e.g., methoxy, ethoxy, propoxy, butoxy), spiro-oxirane, cyano, = O, nitro, (C1- C4 alkyl) C (O ) (e.g. CH3C (O), CH3CH2C (O), CH3CH2 CH2C (O), CH3CH2 CH2 CH2C (O)) and HO (C1-C4 alkyl) C (O) (e.g. HOCH2C (O), HOCH2CH2C (O), HOCH2CH2 CH2C (O), HOCH2CH2 CH2 CH2C (O)), with R1 being preferably in the beta position when it is not = O, and / or in one or more preferred embodiments, C1-C4 alkyl being methyl, R1 is therefore selected from methoxy, spiro-oxirane, cyan, = O, nitro, CH3C (O) - and OHCH2C (O) -; R2 is = O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl or optionally substituted aryl, with the proviso that when R2 is = O, R8 is not present; R3 is H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl or optionally substituted aryl; R4 is independently selected from H and unsubstituted C1-C4 alkyl; R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl (and in particular is alkoxy-substituted methyl, or even more particularly is -CH2-ORb, where Rb is C1-C4 alkyl, or even more particularly it is -CH2-OCH3); R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; - - - denotes an additional and optional DC bond, which results in a C = C bond between C4-C5 or C5-C6, with the proviso that when present, the R5-H substituent is not present; and, - - - denotes an additional and optional DC link, which results in a C = C link between C16-C17, with the proviso that when present, R1 is not = O.
[017] As generally defined above, R1 is selected from (C1-C4 alkyl) -O, spiro-oxirane, cyano, = O, nitro, (C1-C4 alkyl) C (O) and HO (C1- alkyl) C4) C (O). In certain embodiments, R1 is preferably in the beta position (when it is not = O, or when a C = C is not present between C16-C17). In certain embodiments, R1 is selected from (C1-C4 alkyl) -O (e.g., methoxy, ethoxy, propoxy, butoxy), spiro-oxirane, cyano, = O, nitro, (C1-C4 alkyl) C ( O) (for example, CH3C (O), CH3CH2C (O), CH3CH2 CH2C (O), CH3CH2 CH2 CH2C (O)) and HO (C1-C4 alkyl) C (O) (for example, HOCH2C (O), HOCH2CH2C (O), HOCH2CH2 CH2C (O), HOCH2CH2 CH2 CH2C (O)). In certain embodiments, C1-C4 alkyl is methyl, so R1 is selected from methoxy, spiro-oxirane, cyano, = O, nitro, CH3C (O) - and OHCH2C (O) -.
[018] As generally defined above, R2 is = O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl or optionally substituted aryl, with the proviso that when R2 is = O, R8 is not present. In certain embodiments, R2 is = O and R8 is not present. In certain embodiments, R2 is H. In certain embodiments, R2 is ORa. In certain embodiments, R2 is ORa and Ra is optionally substituted C1, C2, C3, or C4 alkyl (e.g., methyl, ethyl), optionally substituted benzyl, or C1, C2, C3, or C4 alkyl substituted by O-aryl, like O-benzyl. In certain embodiments, R2 is ORa and Ra is optionally substituted aryl. In certain embodiments, R2 is ORa and Ra is H.
[019] As generally defined above, R3 is H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl or optionally substituted aryl. In certain embodiments, R3 is H. In certain embodiments, R3 is optionally substituted C1, C2, C3 or C4 alkyl (for example, methyl, ethyl, trifluoromethyl, difluoromethyl). In certain embodiments, R3 is methyl. In certain embodiments, R3 is trifluoromethyl. In certain embodiments, R3 is optionally substituted C2, C3 or C4 alkenyl (for example, optionally substituted allyl). In certain embodiments, R3 is C2 alkynyl, optionally substituted C3, or C4 alkynyl (for example, optionally substituted acetylene or optionally substituted propargyl). In certain embodiments, R3 is optionally substituted aryl (for example, optionally substituted phenyl, such as OH-substituted phenyl, methyl, or CORc, where Rc is optionally substituted C1-C22 alkyl or optionally substituted C2C22 alkenyl, including, for example, alkyl C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, or C22 or C2, C3, alkenyl C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, or optionally substituted C22).
[020] As generally defined above, R4 is H or unsubstituted C1C4 alkyl. In certain embodiments, R4 is H. In certain embodiments, R4 is unsubstituted C1, C2, C3 or C4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, or n-butyl).
[021] As generally defined above, R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl. In certain embodiments, R5 is substituted C1-C4 alkyl, and in particular is substituted C1-C4 alkoxy-alkyl. In other particular embodiments, R5 is substituted methyl, and more particularly is alkoxy-substituted methyl (or even more particularly is -CH2-ORb, where Rb is C1-C4 alkyl, or even more particularly is -CH2-OCH3). In other embodiments, R5 is optionally substituted C2-C4 alkenyl. In other embodiments, R5 is optionally substituted C2-C4 alkynyl.
[022] As generally defined above, R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy. In certain embodiments, R6 is H. In certain embodiments, R6 is optionally substituted C1, C2, C3, or C4 alkyl (for example, methyl). In certain embodiments, R6 is optionally substituted C1, C2, C3 or C4 alkoxy (for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In certain embodiments, when R6 is a non-hydrogen group, R6 is in the alpha (down) position. In certain preferred embodiments, however, when R6 is a non-hydrogen group, R6 is in the beta position (upward).
[023] As generally defined above, R7 is H, optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring. In certain embodiments, R7 is H. In certain embodiments, R7 is optionally substituted C1, C2, C3 or C4 alkoxy (for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In certain embodiments, R7 is an optionally substituted morpholinyl ring. In certain embodiments, when R7 is a non-hydrogen group, R7 is in the alpha (down) position. In certain preferred embodiments, however, when R7 is a non-hydrogen group, R7 is in the beta position (upward).
[024] As generally defined above, R8, when present, is H or optionally substituted C1-C4 alkyl. In certain embodiments, R8 is H. In certain embodiments, R8 is optionally substituted C1, C2, C3 or C4 alkyl (for example, methyl). In certain embodiments, when R8 is optionally substituted C1-C4 alkyl, R8 is in the alpha (down) position. In certain embodiments, when R8 is optionally substituted C1-C4 alkyl, R8 is in the beta (up) position.
[025] In certain embodiments, R2 and R8 are H. In certain embodiments, R2 is ORa and R8 is H.
[026] As generally defined above, - - - denotes an additional and optional DC bond, which results in a C = C bond between C4C5 or C5-C6, with the proviso that when present, the C5-H substituent is not gift. In certain embodiments, the additional C-C bond is absent, and the hydrogen in C5 is in the alpha or beta position. In certain embodiments, the additional C-C bond is absent, and the hydrogen in C5 is in the alpha (down) position. In certain embodiments, the additional C-C bond is absent, and the hydrogen in C5 is in the beta (up) position. In certain embodiments, - - - denotes an additional C-C bond, which results in a C = C bond between C4-C5. In certain embodiments, - - - denotes an additional C-C bond, which results in a C = C bond between C5-C6.
[027] As generally defined above, - - - denotes an additional and optional C-C bond, which results in a C = C bond, between C16-C17, with the proviso that when present, R1 is not = O. In certain embodiments, the additional C-C bond is absent (that is, there is no C = C bond) and therefore R1 can be in the alpha or beta position. In certain embodiments, the additional C-C bond is absent, and R1 is in the alpha (down) position. In certain embodiments, the additional C-C bond is absent, and R1 is in the beta (up) position.
[028] It will be appreciated that the present disclosure contemplates and is intended to cover all the various combinations and permutations (that is, combinations of options, locations and substituting stereochemical configurations) possible in the present document.
[029] For example, in various embodiments, the compounds of the present disclosure can be selected from those covered by the structure of Formula (I), where R2 is = O; alternatively, R2 can be H and R8 is H (for example, C11 which thus has two hydrogen atoms attached to it as substituents). In certain embodiments, R2 may be ORa, where Ra is methyl, optionally substituted benzyl, or C1-C4 alkyl substituted by O-aryl, such as O-benzyl. In certain embodiments, R3 can be H, methyl, trifluoromethyl, or substituted aryl (for example, substituted phenyl, which in turn can be optionally substituted, for example, with OH, methyl, or CORc, where Rc = C1 alkyl -C4); additionally, when R3 is something other than H, R3 is preferably in the β position. In certain embodiments, each R4 and R6 is independently selected from H and methyl, where R5 is in the β configuration and R6 is optionally in the α or β configuration (for example, when R6 is methyl), with the β configuration is preferred. In certain embodiments, R7 is selected from H, methoxy, ethoxy and an optionally substituted morpholinyl ring; additionally, when R7 is something other than H, R7 is preferably in the β position. In certain embodiments, R8, when present, is selected from H or optionally substituted C1-C4 alkyl. In certain embodiments, R8 is methyl (for example, methyl in the alpha configuration).
[030] In certain embodiments, C5-H is in the alpha configuration and R5 is, for example, a substituted methyl group (for example, alkoxy-substituted methyl, or in particular a methoxy-substituted methyl) in a beta configuration. In certain embodiments, C5-H is in a beta configuration and R5 is, for example, a substituted methyl group (for example, methoxy-substituted methyl) in a beta configuration. In certain embodiments, R6 is H. In certain embodiments, R4 is methyl. In certain embodiments, R2 is = O or methoxy.
[031] Consequently, as noted, the Formula (I) steroid can encompass numerous structures according to the present disclosure.
[032] In certain embodiments, where R1 is as defined above, R3 is in the beta position, R4 is methyl, R5 is substituted methyl in the beta position, and R6 is H, a compound of Formula (I-one is provided) ):
or a pharmaceutically acceptable salt thereof, wherein - - R2, R3, R7 and R8 are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each instance of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, each of - - - between C16-C17 is absent and R1 is in the beta position.
[033] In certain embodiments of Formula (I), where = O and R8 is absent, a compound of Formula (Ib) is provided:
or a pharmaceutically acceptable salt thereof, wherein R3 and R7 are as defined herein, and further, where optionally substituted C1-C4 alkyl. In certain embodiments, if - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[034] In certain embodiments of Formula (I), where R2 and R8 are H, a compound of Formula (Ic) is provided:
or a pharmaceutically acceptable salt thereof, wherein - - -, R2, R3, and R7 are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[035] In certain embodiments of Formula (I), where R2 is ORa and R8 is H, a compound of Formula (Id) is provided:
or a pharmaceutically acceptable salt thereof, wherein - - -, R3, R7, and Ra are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[036] In certain embodiments of Formula (I), where R7 is H, a compound of Formula (Ie) is provided:
or a pharmaceutically acceptable salt thereof, wherein - - -, R2, R3, and R8 are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[037] In certain embodiments of Formula (I), in which each case of - - - is absent and C5-H is in an alpha position, a compound of Formula (If) is provided:
or a pharmaceutically acceptable salt thereof, wherein R2, R3, R7 and R8 are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[038] In certain embodiments of Formula (I), where R7 is H, a compound of Formula (Ig) is provided:
or a pharmaceutically acceptable salt thereof, wherein R2, R3, and R8 are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[039] In certain embodiments of Formula (I), where R2 is = O, a compound of Formula (Ih) is provided:
or a pharmaceutically acceptable salt thereof, where R3 and R7 are as defined herein, and further, where Rb is optionally substituted C1C4 alkyl. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[040] In certain embodiments of Formula (I), where R2 is ORa, a compound of Formula (Ii) is provided:
or a pharmaceutically acceptable salt thereof, where Ra, R3, and R7 are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[041] In certain embodiments of Formula (I), where - - - represents an additional CC bond, which results in a C = C bond between C4-C5, a compound of Formula (Ij) is provided:
or a pharmaceutically acceptable salt thereof, wherein R3, R2, R7 and R8 are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[042] In certain embodiments of Formula (I), where - - - represents an additional CC bond, which results in a C = C bond between C5-C6, a compound of Formula (Ik) is provided:
or a pharmaceutically acceptable salt thereof, wherein R3, R2, R7 and R8 are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position.
[043] It will be noted that, in one or more of the preferred embodiments detailed above, R1 can, in particular, be selected from methoxy (or more generally lower alkoxy, for example, -O- (C1-C4)), or alternatively selected from CH3C (O) - or HOCH2C (O) - (or more generally substituted or unsubstituted lower alkylcarbonyl, for example, (C1-C4) C (O) -, where one or more carbon atoms are optionally substituted, such as, for example, by a hydroxyl group). Alternatively, R1 can be selected from nitro or cyan, with an optional C = C being present between C16-C17. In yet another alternative embodiment, C17 may be a carbonyl carbon (ie, R1 is = O), or it may be part of an oxirane ring fused to the D ring (ie, R1 being a spiro-oxirane substituent, where C17 is the carbon atom common to both rings).
[044] Exemplary compounds of Formula (I) include, but are not limited to, the following:
and pharmaceutically acceptable salts thereof, wherein in a preferred embodiment Rb is CH3.
[045] In certain embodiments, the Formula (I) steroid is selected from the group consisting of

and pharmaceutically acceptable salts thereof, where R3 is as defined above, and in a particular embodiment is H, and further, in that or another preferred embodiment Rb is CH3.
[046] In certain embodiments, the Formula (I) steroid is selected from the group consisting of:
and pharmaceutically acceptable salts thereof, where R3 is as defined above, and in a particular embodiment is H, and further, in that or another preferred embodiment Rb is CH3.
[047] In certain embodiments, the Formula (I) steroid is selected from the group consisting of:
and a pharmaceutically acceptable salt thereof, wherein R3 and / or R1 are as defined above, and in a particular embodiment R3 is H and R1 is methoxy, and further, in those or other preferred embodiments Rb is CH3.
[048] In certain embodiments, the Formula (I) steroid is selected from the group consisting of:
and a pharmaceutically acceptable salt thereof, where R3 is as defined above, and in a particular embodiment is H, and further, in that or another preferred embodiment Rb is CH3.
[049] In certain embodiments, the Formula (I) steroid is selected from the group consisting of:
and a pharmaceutically acceptable salt thereof, where R3 is as defined above, and in a particular embodiment is H, and further, in that or another preferred embodiment Rb is CH3.
[050] In this regard, it will be noted that the structures provided above are of various exemplary achievements. Therefore, they should not be seen in a limiting sense. 2. PRO-DRUG STRUCTURES
[051] In another particular embodiment, the present disclosure relates, in general, to prodrugs of the various steroids detailed above. In general, as used herein, a “prodrug” refers to an inactive, or significantly less active, form of the steroids detailed above (and in particular Formula (I) steroids) than after administration is metabolized in vivo to one or more active metabolites of the Formula (I) steroid. The prodrug can be formed using means generally known in the art and, therefore, can take essentially any form that could be recognized by an expert in the art. The prodrugs of the present disclosure can advantageously provide enhanced absorption, distribution, metabolism and / or excretion optimization, as well as improved oral bioavailability of the steroids detailed above (and, in particular, Formula (I) steroids).
[052] In another particular embodiment of the present disclosure, the prodrug of a steroid described in this document has a Formula (II) structure:
or a pharmaceutically acceptable salt thereof; where: R1 is selected from (C1-C4 alkyl) -O (e.g., methoxy, ethoxy, propoxy, butoxy), spiro-oxirane, cyano, = O, nitro, (C1- C4 alkyl) C (O ) (e.g. CH3C (O), CH3CH2C (O), CH3CH2 CH2C (O), CH3CH2 CH2 CH2C (O)) and HO (C1-C4 alkyl) C (O) (e.g. HOCH2C (O), HOCH2CH2C (O), HOCH2CH2 CH2C (O), HOCH2CH2 CH2 CH2C (O)), with R1 being preferably in the beta position when it is not = O, and / or in one or more preferred embodiments, C1-C4 alkyl being methyl, therefore, R1 is selected from methoxy, spiro-oxirane, cyano, = O, nitro, CH3C (O) - and OHCH2C (O) -; R2 is = O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl or optionally substituted aryl, with the proviso that when R2 is = O, R8 is not present; Rx is = O or ORd, where Rd is H or C (O) Re, where Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl, with the proviso that when Rx is OH, it is in a beta configuration; R4 is independently selected from H and unsubstituted C1-C4 alkyl; R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl (and in particular is alkoxy-substituted methyl, or even more particularly is -CH2-ORb, where Rb is C1-C4 alkyl, or even more particularly it is -CH2-OCH3); R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; - - - denotes an additional and optional DC bond, which results in a C = C bond between C4-C5 or C5-C6, with the proviso that when present, the C5-H substituent is not present; and, - - - denotes an additional and optional CC bond, which results in a C = C bond between C16-C17, with the proviso that when present, R1 is not = O, with the proviso that the compound does not have one of the following structures:
or alternatively with the proviso that: (i) when Rx is = O, a C = C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spiro-oxirane, cyan, nitro , and CH3C (O) -; and / or (ii) when Rx is beta-OH, a C = C bond is present between C5-C6, and R5 is CH2OCH3, so R1 is selected from methoxy, spiro-oxirane, cyano, nitro, and HOCH2C ( O)-.
[053] In this regard, it will be noted that the present disclosure contemplates and is intended to cover all the various combinations and permutations (that is, combinations of options, locations and substituting stereochemical configurations) possible in this document.
[054] As generally defined above, R1 is selected from (C1-C4 alkyl) -O, spiro-oxirane, cyano, = O, nitro, (C1-C4 alkyl) C (O) and HO (C1- alkyl) C4) C (O). In certain embodiments, R1 is preferably in the beta position (when it is not = O, or when a C = C is not present between C16-C17). In certain embodiments, R1 is selected from (C1-C4 alkyl) -O (e.g., methoxy, ethoxy, propoxy, butoxy), spiro-oxirane, cyano, = O, nitro, (C1-C4 alkyl) C ( O) (for example, CH3C (O), CH3CH2C (O), CH3CH2 CH2C (O), CH3CH2 CH2 CH2C (O)) and HO (C1-C4 alkyl) C (O) (for example, HOCH2C (O), HOCH2CH2C (O), HOCH2CH2 CH2C (O), HOCH2CH2 CH2 CH2C (O)). In certain embodiments, C1-C4 alkyl is methyl, so R1 is selected from methoxy, spiro-oxirane, cyano, = O, nitro, CH3C (O) - and OHCH2C (O) -.
[055] As generally defined above, Rx is = O or ORd, where Rd is H or C (O) Re, where Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl (including, for example, alkyl C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, or C22 or C2, C3 alkenyl , C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, or C22 optionally substituted), with the proviso that when Rx for OH, it is in the beta configuration (upwards). In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, Rx is ORd, Rd is C (O) Re, and Re is optionally substituted C1-C22 alkyl or optionally substituted C2-C22 alkenyl, for example, C (O) CH3 and, in such cases, the group Rx it is provided in alpha or beta configuration (with beta configuration being preferred). In certain embodiments, where Rx is ORd, and Rd is H, then Rx is OH in the beta (upward) configuration.
[056] As generally defined above, R2 is = O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl or optionally substituted aryl, with the proviso that when R2 is = O, R8 is not present. In certain embodiments, R2 is = O and R8 is not present. In certain embodiments, R2 is H. In certain embodiments, R2 is ORa. In certain embodiments, R2 is ORa and Ra is optionally substituted C1, C2, C3 or C4 alkyl (for example, methyl, ethyl), optionally substituted benzyl or C1, C2, C3 or C4 alkyl substituted by O-aryl, such as O- benzyl. In certain embodiments, R2 is ORa and Ra is optionally substituted aryl. In certain embodiments, R2 is ORa and Ra is H.
[057] As generally defined above, R4 is H or unsubstituted C1C4 alkyl. In certain embodiments, R4 is H. In certain embodiments, R4 is unsubstituted C1, C2, C3 or C4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl or n-butyl).
[058] As generally defined above, R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl. In certain embodiments, R5 is substituted C1-C4 alkyl and, in particular, is substituted C1-C4 alkoxy-alkyl. In other particular embodiments, R5 is substituted methyl, and more particularly is alkoxy-substituted methyl (or even more particularly is -CH2-ORb, where Rb is C1-C4 alkyl or even more particularly is -CH2-OCH3). In other embodiments, R5 is optionally substituted C2-C4 alkenyl. In other embodiments, R5 is optionally substituted C2-C4 alkynyl.
[059] As generally defined above, R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy. In certain embodiments, R6 is H. In certain embodiments, R6 is optionally substituted C1, C2, C3, or C4 alkyl (for example, methyl). In certain embodiments, R6 is optionally substituted C1, C2, C3 or C4 alkoxy (for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In certain embodiments, when R6 is a non-hydrogen group, R6 is in the alpha (down) position. In certain preferred embodiments, however, when R6 is a non-hydrogen group, R6 is in the beta position (upward).
[060] As generally defined above, R7 is H, optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring. In certain embodiments, R7 is H. In certain embodiments, R7 is optionally substituted C1, C2, C3 or C4 alkoxy (for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In certain embodiments, R7 is an optionally substituted morpholinyl ring. In certain embodiments, when R7 is a non-hydrogen group, R7 is in the alpha (down) position. In certain preferred embodiments, however, when R7 is a non-hydrogen group, R7 is in the beta position (upward).
[061] As generally defined above, R8, when present, is optionally substituted H or C1-C4 alkyl. In certain embodiments, R8 is H. In certain embodiments, R8 is optionally substituted C1, C2, C3 or C4 alkyl (for example, methyl). In certain embodiments, when R8 is optionally substituted C1-C4 alkyl, R8 is in the alpha (down) position. In certain embodiments when R8 is optionally substituted C1-C4 alkyl, R8 is in the beta (up) position.
[062] In certain embodiments, R2 and R8 are H. In certain embodiments, R2 is ORa and R8 is H.
[063] As generally defined above, - - - denotes an additional and optional DC bond, which results in a C = C bond between C4C5 or C5-C6, with the proviso that when present, the C5-H substituent is not gift. In certain embodiments, the additional C-C bond is absent, and the hydrogen in C5 is in the alpha or beta position. In certain embodiments, the additional C-C bond is absent, and the hydrogen in C5 is in the alpha (down) position. In certain embodiments, the additional C-C bond is absent, and the hydrogen in C5 is in the beta (up) position. In certain embodiments, - - - denotes an additional C-C bond, which results in a C = C bond between C4-C5. In certain embodiments, - - - denotes an additional C-C bond, which results in a C = C bond between C5-C6.
[064] As generally defined above, - - - denotes an additional and optional C-C bond, which results in a C = C bond, between C16-C17, with the proviso that when present, R1 is not = O. In certain embodiments, the additional C-C bond is absent (that is, there is no C = C bond) and therefore R1 can be in the alpha or beta position. In certain embodiments, the additional C-C bond is absent, and R1 is in the alpha (down) position. In certain embodiments, the additional C-C bond is absent, and R1 is in the beta (up) position.
[065] In certain embodiments, the prodrugs of the present disclosure can be selected from those covered by the structure of Formula (II), where R2 is = O. In certain embodiments, R2 is H and R8 is H, for example, C11 which thus has two hydrogen atoms attached to it as substituents. In certain embodiments, R2 may be ORa, where Ra is methyl, optionally substituted benzyl, or C1-C4 alkyl substituted by O-aryl, such as O-benzyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is β-hydroxy. In certain embodiments, Rx is ORd, where Rd is H or C (O) Re, where Re is optionally substituted C1-C4 alkyl (e.g., methyl). In certain embodiments, each R4 and R6 is independently selected from H and methyl. In certain embodiments, R6 is optionally substituted alkyl, for example, methyl, optionally in the alpha configuration when the carbon-carbon double bond between C5-C6 is absent. In certain embodiments, R6 is optionally substituted alkyl, for example, methyl, optionally in the beta configuration when the carbon-carbon double bond between C5-C6 is absent. In certain embodiments, R7 is selected from H, methoxy, ethoxy and an optionally substituted morpholinyl ring. In certain embodiments, R7 is a non-hydrogen group, R7 is in the β position. In certain embodiments, a carbon-carbon double bond (or unsaturated bond) may be present between the C4-C5 or C5-C6 carbon atoms. In certain embodiments, R8, when present, is selected from H or optionally substituted C1-C4 alkyl, preferably methyl and more preferably alpha-methyl.
[066] In certain embodiments, Rx is OH and in the beta position. In certain embodiments, a carbon-carbon double bond is present between the C4-C5 carbon atoms. In certain embodiments, a carbon-carbon double bond is present between the C5-C6 carbon atoms. In certain embodiments, R2 is = O. In certain embodiments, R2 is methoxy. In certain embodiments, R7 is H. In certain embodiments, R7 is β-met0xi. In certain embodiments, R7 is β-ethoxy.
[067] In certain embodiments, where R4 is methyl, R5 is methyl substituted in the beta position, and R6 is H, a compound of Formula (II-one) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, - - -, Rx, R2, R7 (preferably in a beta configuration) and R8 (preferably in a beta configuration) are as defined herein, and further, in which Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, - - - represents an additional DC bond, which results in a C = C bond between C4-C5 or C5-C6. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[068] In certain embodiments of Formula (II), where R2 is = O and R8 is absent, a compound of Formula (II-b) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, - - -, Rx, and R7 (preferably in a beta configuration) are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, - - - represents an additional DC bond, which results in a C = C bond between C4-C5 or C5-C6. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[069] In certain embodiments of Formula (II), where R2 is H and R8 is H, a compound of Formula (II-c) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, - - -, Rx, and R7 (preferably in a beta configuration) are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in an alpha position. In certain embodiments, each case of - - - between C5-C6 and C6-C7 is absent and C5-H is in the beta position. In certain embodiments, - - - represents an additional DC bond, which results in a C = C bond between C4-C5 or C5-C6. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[070] In certain embodiments of Formula (II), where R2 is ORa and R8 is H, a compound of Formula (II-d) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, - - -, R3, R7 (preferably in a beta configuration), and Ra are as defined herein, and further, where Rb is optionally substituted C1-C4 alkyl . In certain embodiments, each case of - - - is absent C5-H is in an alpha position. In certain embodiments, each case of - - - is absent C5-H is in the beta position. In certain embodiments, - - - represents an additional DC bond, which results in a C = C bond between C4-C5 or C5-C6. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[071] In certain embodiments of Formula (II), where R7 is H, a compound of Formula (II-e) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, - - -, Rx, R2 and R8 (preferably in a beta configuration) are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - is absent C5-H is in an alpha position. In certain embodiments, each case of - - - is absent C5-H is in the beta position. In certain embodiments, - - - represents an additional DC bond, which results in a C = C bond between C4-C5 or C5-C6. In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[072] In certain realizations of Formula (|), where each case of - - - is absent C5-H is in an alpha position, a compound of Formula (| -f) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, Rx, R2, R7 (preferably in the beta configuration) and R8 (preferably in the beta configuration) are as defined herein, and furthermore, where Rb is C1 alkyl -C4 optionally replaced. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C16C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16C17.
[073] In certain embodiments of Formula (II), where R7 is H, a compound of Formula (II-g) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, Rx, R2 and R8 (preferably in the beta configuration) are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[074] In certain embodiments of Formula (II), where R2 is = O, a compound of Formula (II-h) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, Rx and R7 (preferably in the beta configuration) are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[075] In certain embodiments of Formula (II), where R2 is ORa, a compound of Formula (II-i) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, Rx, Ra, and R7 (preferably in the beta configuration) are as defined herein, and furthermore, where Rb is optionally substituted C1-C4 alkyl. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C16-C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[076] In certain embodiments of Formula (II), where - - - represents an additional CC bond, which results in a C = C bond between C4-C5, a compound of Formula (II-j) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, Rx, R2, R7 (preferably in the beta configuration) and R8 (preferably in the beta configuration) are as defined herein, and furthermore, where Rb is C1 alkyl -C4 optionally replaced. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C16C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16-C17.
[077] In certain embodiments of Formula (II), where - - - represents an additional CC bond, which results in a C = C bond between C5-C6, a compound of Formula (II-k) is provided:
or a pharmaceutically acceptable salt thereof, wherein R1, Rx, R2, R7 (preferably in a beta configuration) and R8 (preferably in a beta configuration) are as defined herein, and furthermore, where Rb is C1 alkyl -C4 optionally replaced. In certain embodiments, Rx is = O. In certain embodiments, Rx is OH in the beta configuration (upwards). In certain embodiments, each case of - - - between C16C17 is absent and R1 is in the beta position. In certain embodiments, - - - represents an additional DC link, which results in a C = C between C16C17.
[078] It will be noted that, in one or more of the preferred embodiments detailed above, R1 can, in particular, be selected from methoxy (or more generally lower alkoxy, for example, -O- (C1-C4)), or alternatively selected from CH3C (O) - or HOCH2C (O) - (or more generally substituted or unsubstituted lower alkylcarbonyl, for example, (C1-C4) C (O) -, where one or more carbon atoms are optionally substituted, such as, for example, by a hydroxyl group). Alternatively, R1 can be selected from nitro or cyan, with an optional C = C present between C16-C17. In yet another alternative embodiment, C17 may be a carbonyl carbon (ie, R1 is = O), or it may be part of an oxirane ring fused to the D ring (ie, R1 being a spiro-oxirane substituent, where C17 is the carbon atom common to both rings).
[079] Exemplary compounds of Formula (II) include, but are not limited to:
and pharmaceutically acceptable salts thereof, wherein in a preferred embodiment Rb is CH3.
[080] In this sense, it will be noted that the structures provided above are of several exemplary achievements. Therefore, they should not be seen in a limiting sense. PREPARATION METHODS AND PHARMACEUTICAL COMPOSITIONS
[081] It is observed that the compounds or steroids of the present disclosure, or the prodrugs thereof, can, in various embodiments, be prepared or used according to means generally known in the art. For example, in certain embodiments, the steroids or prodrugs of the present disclosure can be prepared or used in a pharmaceutically acceptable salt form, for example, where R7 is an optionally substituted morpholinyl ring. Suitable salt forms include, for example, citrate or chloride salt forms.
[082] In various embodiments of the present disclosure, a described pharmaceutical composition can comprise a steroid, a prodrug, or a combination of two or more of them according to the formulas of the present disclosure. The compounds or steroids of the present disclosure (or the prodrugs thereof), as well as the various salt forms and other pharmaceutically acceptable forms, for example, solvates and / or hydrates of compounds described herein, and pharmaceutical compositions containing the same , can, in general, be prepared using known methods and techniques and / or as described in the Examples provided herein.
[083] Without sticking to any particular theory, the compounds or steroids of the present disclosure are useful to potentiate GABA in GABAA receptors, thereby inducing anesthesia or treating disorders related to GABA function (eg, insomnia, mood disorders, convulsive disorders, anxiety disorders, or ethanol withdrawal symptoms) in a subject, e.g., a human subject, and are preferably administered in the form of a pharmaceutical composition comprising an effective amount of a compound of the present disclosure and, optionally , a pharmaceutically or pharmacologically acceptable carrier.
[084] In one aspect, a method is provided to induce anesthesia in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of one or more steroids, or prodrugs, or pharmaceutically acceptable salts of them, or a pharmaceutical composition of the same as noted above.
[085] In another aspect, a method is provided to attract disorders related to the function of GABA in an individual in need of it, the method comprising administering to the individual a therapeutically effective amount of one or more steroids, or prodrugs. , or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof as noted above. In certain embodiments, the disorder is selected from the group consisting of insomnia, mood disorders, seizure disorders, anxiety or ethanol withdrawal symptoms.
[086] In one embodiment of the present disclosure, a therapeutically effective amount of compound is about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 18 mg / kg, about 5 mg / kg to about 16 mg / kg, about 5 mg / kg to about 14 mg / kg, about 5 mg / kg to about 12 mg / kg, about 5 mg / kg to about 10 mg / kg, about 6 mg / kg to about 10 mg / kg, about 6 mg / kg to about 9 mg / kg, about 7 mg / kg to about 9 mg / kg, or about 8 mg / kg kg to about 16 mg / kg. In certain embodiments, a therapeutically effective amount of the compound is about 8 mg / kg. It will be appreciated that the dose ranges as described herein provide guidance for the administration of pharmaceutical compositions administered to an adult. The amount that will be administered, for example, to a child or adolescent can be determined by a doctor or element skilled in the art and may be less than or equal to that administered to an adult.
[087] The exact amount of a compound required to obtain an effective amount will vary from individual to individual, depending, for example, on the species, age, and general condition of an individual, identity of the particular compound (s) ( (s), method of administration, and the like. The desired dosage can be administered three times a day, twice a day, once a day, on alternate days, every three days, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be administered using multiple administrations (for example, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
[088] It will also be appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents. The compounds or compositions can be administered in combination with additional therapeutically active agents that enhance their bioavailability, reduce and / or modify their metabolism, inhibit their excretion and / or modify their distribution within the body.
[089] The compound or composition can be administered simultaneously, before, or subsequent to one or more additional therapeutically active agents. In general, each agent will be administered at a dose and / or at a specific time for that agent. It will be further assessed that the additional therapeutically active agent used in that combination can be administered together in a single composition or administered separately in different compositions. The particular combination for use in a regimen will take into account the compatibility of the inventive compound with the additional therapeutically active agent and / or the desired therapeutic effect that will be obtained. In general, additional therapeutically active agents used in combination are expected to be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than those used individually. Exemplary therapeutically active agents include small organic molecules such as drug compounds (for example, compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins , mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
[090] The pharmaceutical composition can also be in combination with at least one pharmacologically acceptable carrier. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance that is pharmaceutically inert, gives an adequate consistency or shape to the composition, and does not reduce the therapeutic efficacy of the compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other unpleasant reaction when administered to a mammal or human, as appropriate.
[091] The pharmaceutical compositions containing the compounds or steroids of the present disclosure can be formulated in any conventional manner. The appropriate formulation is dependent on the route of administration selected. Developing compositions can be formulated for any route of administration, as long as the target tissue is available through that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal) administration , transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavitary, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopic, transmucosal, sublingual, and intestinal. In certain embodiments, the route of administration is oral. In certain embodiments, the route of administration is parenteral. In certain embodiments, the route of administration is intravenous.
[092] Pharmaceutically acceptable carriers for use in the compositions of the present disclosure are well known for elements skilled in the art and are selected based on a number of factors, including, for example: the particular compound used, and its intended concentration, stability and bioavailability; the disease, disorder or condition that will be treated with the composition; the individual, his age, size and general condition; and / or the route of administration. Suitable carriers can be easily determined by an expert in the art. (See, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (UM. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp.1492-1517.)
[093] The compositions can be formulated as tablets, dispersible powders, pills, capsules, gelatin capsules, tablets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, lozenges, pills, tablets, or any other form of dosage that can be administered orally. Techniques and compositions for producing oral dosage forms useful in the present disclosure are described in the following exemplary references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and, Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).
[094] The compositions of the present disclosure designed for oral administration comprise an effective amount of a disclosing compound in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other conventional substances that include lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, acid alginic, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate and stearic acid. In addition, such solid dosage forms may be uncoated or may be coated by known techniques (for example, to delay disintegration and absorption).
[095] The compounds, steroids, and prodrugs of the present disclosure can also be formulated for parenteral administration (for example, formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal). The compositions of the present disclosure for parenteral administration comprise an effective amount of the compound in a pharmaceutically acceptable carrier. Dosage forms for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form that can be administered parenterally. Techniques and compositions for producing parenteral dosage forms are known in the art. Typically, formulations for parenteral administration are sterile or are sterilized prior to administration.
[096] Suitable carriers used in the formulation of liquid dosage forms for oral or parenteral administration include pharmaceutically acceptable non-aqueous polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, solutions saline, dextrose solutions (eg, DW5), electrolyte solutions, or any other pharmaceutically acceptable aqueous liquid.
[097] Suitable pharmaceutically acceptable non-aqueous polar solvents include, but are not limited to, alcohols (for example, α-glycerol formal, β-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 atoms carbon as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol , fatty acid esters of fatty alcohols such as polyalkylene glycols (for example, polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (for example, dimethylacetamide (DMA), DMA benzyl benzoate, dimethylformamide, N- (β-hydroxyethyl) -lactamide, N, N-dimethylacetamide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (for example, 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters like monoacetin, diacetin and triacetin, aliphatic or aromatic esters like caprylate or ethyl octanoate, alkali oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), glycerin esters such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, sorbitan fatty acid esters, PEG esters fatty acid derivatives, glyceryl monostearate, glyceride esters like mono, di, or tri-glycerides, fatty acid esters like isopropyl myristate, PEG esters derived from fatty acid like PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone , pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly (ethoxylated) 30-60 poly (oleate) 2-4, poly (oxyethylene) monooleate 15-20, poly (oxyethylene) mono 12-hydroxystearate 15-20, and poly mono-ricinoleate ( oxyethylene) 15-20, polyoxyethylene sorbitan esters (such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate and Polisorbate® 20, 40, 60 or 80 from ICI Americas, Wilming , Del.), Polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters (such as hydrogenated polyoxyl 40 castor oil, modified cyclodextrins or cyclodextrins (for example, beta-hydroxypropyl-cyclodextrin)), esters of saccharide fatty acids (ie, the condensation product of a monosaccharide (for example, pentoses, such as ribose, ribulose, arabinose, xylose, lixose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharides (by sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture of these with a C4-C22 fatty acid (s) (for example, saturated fatty acids such as caprylic acid, capric acid ico, lauric acid, myristic acid, palmitic acid and stearic acid and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic esters having 2 to 30 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (polyethylene glycol tetrahydrofurfuryl alcohol ether); ketones having 3 to 30 carbon atoms (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms (eg benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfone, tetramethylsulfoxide, toluene, dimethylsulfoxide DMSO), or tetramethylsulfoxide); mineral, vegetable, animal, essential or synthetic oils (for example, mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, aliphatic and mixed aromatic hydrocarbons, and refined paraffin oil, vegetable oils such as linseed oil , tung, saffron, soy, castor, cottonseed, walnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persimmon and peanut and glycerides such as mono-, di-triglycerides, animal oils such as fish, marine, sperm, cod liver, haliver, squalene, squalane, and shark liver oil, oleic oils and polyoxyethylated castor oil); alkyl or aryl halides that have 1 to 30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzine; trolamine; omega-3 polyunsaturated fatty acids (for example, alpha-linolenic acid, eicosapentanoic acid, docosapentanoic acid, or docosahexanoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germani); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.
[098] Other pharmaceutically acceptable solvents for use in the disclosure are well known to those skilled in the art and are identified in the Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical Society of Great Britain, London, England, 1968 ), Modern Pharmaceutics, (G. Banker et al., Eds., 3d ed.) (Marcel Dekker, Inc., New York, NY, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing) , Pharmaceutical Dosage Forms, (H. Lieberman et al., Eds.) (Marcel Dekker, Inc., New York, NY, 1980), Remington's Pharmaceutical Sciences (UM. Gennaro, ed., 19th ed.) (Mack Publishing , Easton, Pa., 1995), The United States Pharmacopeia 24, The National Formula 19, (National Publishing, Philadelphia, Pa., 2000), UM. J. Spiegel et al., And Use of Nonaqueous Solvents in Parenteral Products, J. of Pharm. Sciences, Vol. 52, No. 10, pp. 917-927 (1963).
[099] Preferred solvents include cyclodextrins or modified cyclodextrins (for example, beta-hydroxypropyl-cyclodextrin) as well as oils rich in triglycerides, for example safflower oil, soy oil or mixtures thereof and alkyleneoxy modified fatty acid esters as hydrogenated polyoxyl 40 castor oil. Commercially available triglycerides include emulsified soybean oil Intralipid® (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), 20% Liposyn® II emulsion (a fatty emulsion solution 20% containing 100 mg of safflower oil, 100 mg of soybean oil, 12 mg of egg phosphatides and 25 mg of glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), Liposyn® III emulsion 2 % (a 2% fat emulsion solution containing 100 mg of safflower oil, 100 mg of soybean oil, 12 mg of egg phosphatides and 25 mg of glycerin per ml of solution; Abbott Laboratories, Chicago, IL), derivatives of natural or synthetic glycerol containing the docosahexaenoyl group at levels between 25% and 100% by weight, based on the total fatty acid content (Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro® (from Daito Enterprises, Los Angeles, Calif.), Soyacal® and Travemulsion®.
[0100] Additional minor components can be included in the disclosure compositions for a variety of purposes well known in the pharmaceutical industry. Most of these components will confer properties that increase the retention of the compound at the site of administration, protect the stability of the composition, control the pH, facilitate the processing of the compound in pharmaceutical and similar formulations. Preferably, each of these components is individually present in less than about 15% by weight of the total composition, more preferably less than about 5% by weight, and more preferably less than about 0.5% by weight , of the total composition. Some components, such as fillers or thinners, can make up over 90%, by weight, of the total composition, as is well known in the formulation technique. Such additives include cryoprotective agents to prevent reprecipitation, surface active agents, humectants or emulsifiers (for example, lecithin, polysorbate-80, Tween® 80, Pluronic 60, polyoxyethylene stearate), preservatives (for example, ethyl-p-hydroxybenzoate ), microbial preservatives (eg benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), pH adjusting agents or buffering agents (eg acids, bases, sodium acetate, sodium monolaurate) sorbitan), osmolarity adjusting agents (eg glycerin), thickeners (eg aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, triestearin, wax cetyl esters, polyethylene glycol ), dyes, pigments, flow aids, non-volatile silicones (for example, cyclomethicone), clays (for example, bentonites), adhesives, bulking, flavoring, sweetening agents, adsorbents, fillers (for example, sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), thinners (for example, water, saline, electrolyte solutions), binders (for example, starches such as corn starch , wheat starch, rice starch, or potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (for example, starches such as corn starch , wheat starch, rice starch, potato starch or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (for example, silica, talc , stearic acid or salts thereof, such as magnesium stearate, or polyethylene glycol), coating agents (for example, concentrated sugar solutions including arabic gum, talc, polyvinyl pyrrolidone, carbopol gel , polyethylene glycol, or titanium dioxide), and antioxidants (for example, sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols and thiophenols).
[0101] The dosage of administration through these routes can be continuous or intermittent, depending, for example, on the patient's physiological condition, whether the purpose of administration is therapeutic or prophylactic and other factors known and evaluable by a competent professional.
[0102] Elements skilled in the art for administering anesthetics can easily determine the dosage and regimens for administering the pharmaceutical compositions of the disclosure or titration of an effective dosage for use in the treatment of insomnia, mood disorders, seizure disorders, anxiety or symptoms of abstinence from ethanol. It is understood that the dosage of the compounds will be dependent on the age, sex, health and weight of the recipient, type of simultaneous treatment, if any, frequency of treatment, and the nature of the desired effect. For any mode of administration, the actual amount of compound administered, as well as the dosing schedule required to obtain the beneficial effects described in this document, will also depend, in part, on such factors as the bioavailability of the compound, the disorder that will be treated, the desired therapeutic dose, and other factors that will become evident to those skilled in the art. The dose administered to an animal, particularly a human, in the context of the present disclosure should be sufficient to affect the desired therapeutic response in the animal for a reasonable period of time. Preferably, an effective amount of the compound, whether orally administered or otherwise, is any amount that could result in a desired therapeutic response when administered by that route. The dosage may vary depending on the dosing schedule, which can be adjusted as necessary to obtain the desired therapeutic effect. The most preferred dosage will be adjusted to the individual individual, as understood and determined by an element skilled in the art without undue experimentation.
[0103] In one embodiment, solutions for oral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent capable of dissolving a compound (for example, ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier that is a solution, such as beta-hydroxypropyl-cyclodextrin, is added to the solution during agitation to form a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount, or to be free of ethanol, which is known in the art to cause adverse physiological effects when administered in certain concentrations in oral formulations.
[0104] In another embodiment, powders or tablets for oral administration are prepared by dissolving a compound in any pharmaceutically acceptable solvent capable of dissolving the compound (for example, ethanol or methylene chloride) to form a solution. The solvent may optionally be able to evaporate when the solution is dried under vacuum. An additional carrier can be added to the solution before drying, such as beta-hydroxypropyl-cyclodextrin. The resulting solution is dried under vacuum to form a glass. The glass is then mixed with a binder to form a powder. The powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral administration to a patient. The powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration.
[0105] Emulsions for parenteral administration can be prepared by dissolving a compound in any pharmaceutically acceptable solvent capable of dissolving the compound (for example, ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier that is an emulsion, such as Liposyn® II or Liposyn® III emulsions, is added to the solution during agitation to form a pharmaceutically acceptable emulsion for parenteral administration to a patient.
[0106] Solutions for parenteral administration can be prepared by dissolving a compound in any pharmaceutically acceptable solvent capable of dissolving the compound (for example, ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier that is a solution, such as beta-hydroxypropyl-cyclodextrin, is added to the solution during agitation to form a pharmaceutically acceptable solution for parenteral administration to a patient.
[0107] If desired, the emulsions or solutions described above for oral or parenteral administration can be packed in IV bags, conceptacles or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable concentration before use as is known in the art.
[0108] Still further covered by the invention are kits (for example, pharmaceutical packaging). The kits provided may comprise a compound as described in this document and a container (for example, a conceptacle, ampoule, bottle, syringe and / or dispenser packaging or other suitable container). In some embodiments, the kits provided may optionally also include a second container comprising a pharmaceutical carrier for diluting or suspending the pharmaceutical composition or compound. In some embodiments, the pharmaceutical composition or compound supplied in the container and the second container are combined to form a unit dosage form.
[0109] Optionally, instructions for use are additionally provided in such kits of the invention. Such instructions can generally provide, for example, instructions for dosing and administration. In other embodiments, the instructions may also provide additional details regarding specialized instructions for containers and / or particular systems for administration. In addition, the instructions may provide specialized instructions for use together and / or in combination with an additional therapeutic agent. DEFINITIONS
[0110] The term "steroid" as used in this document describes an organic compound that contains the cyclopenta [a] phenanthrene ring system in its chemical core.
[0111] As used herein, the term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and smaller animals without undue toxicity, irritation, response allergic and the like, and are commensurable with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, glycosulfonate, glycoside, glycate, fumarate, formate salts hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, phalate, palmitate, phalate, palate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 salts. Representative alkali metal or alkaline earth salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
[0112] The term “prodrug” as used in this document describes a pharmacological substance that is administered in a less active or inactive form. After administration, a prodrug is metabolized in vivo, for example, through hydrolysis, oxidation or reaction under biological conditions (in vitro or in vivo), to provide an active metabolite. See, for example, Wu, Pharmaceuticals (2009) 2: 77-81. In certain embodiments, a prodrug has improved physical and / or delivery properties over the original compound. Prodrugs are typically designed to enhance the pharmaceutical and / or pharmacokinetic-based properties associated with the parent compound. The advantage of a prodrug can be found in its physical properties, such as increased water solubility for parenteral administration at physiological pH compared to the original compound, or it increases the absorption of the digestive tract or the skin, or it can increase the stability of the drug during long-term storage.
[0113] As used herein, an "individual" for whom administration is contemplated includes, but is not limited to, mammals, for example, humans (i.e., a male or female of any age group, for example , a pediatric individual (e.g., child, teenager) or adult individual (e.g., young adult, middle-aged adult or elderly)), other primates (e.g., cynomolgus monkeys, rhesus monkeys) and commercially related mammals such as livestock , pigs, horses, sheep, goats, cats and / or dogs. In any aspect and / or embodiment of the invention, the individual is a human.
[0114] As used herein, a "therapeutically effective amount", "a sufficient amount" or "sufficient amount" of a compound means the level, amount or concentration of the compound required for a desired biological response, for example, analgesia.
[0115] The term "saturated" as used in this document describes the state in which all available valence bonds of an atom (especially carbon) are linked to other atoms.
[0116] The term "unsaturated" as used in this document describes the state in which not all valence bonds available along the alkyl chain are satisfied; in such compounds the additional bonds form double or triple bonds (mainly with carbon).
[0117] When a range of values is listed, it is intended to cover each value and sub-range within the range. For example, "C1-4 alkyl" is intended to cover alkyl, C1, C2, C3, C4, C1-3, C1-2, C2-4, C2-3 and C3-4, while "C1-22 alkyl" is intended to cover , for example, Ci, C2, C3, C4, etc., as well as C1-21, C1-20, C1-15, C1-10, C2-20, C2-15, C2-10, C3-15, alkyl, C3-10, etc.
[0118] As used herein, "alkyl" refers to a radical of a straight or branched chain saturated hydrocarbon group that has from, in some embodiments, 1 to 4 carbon atoms ("C1-4 alkyl" ), and in other embodiments 1 to 22 carbon atoms (“C1-22 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 4 carbon atoms ("C2-4 alkyl"). In still other embodiments, an alkyl group has 1 to 21 carbon atoms ("C1-21 alkyl"), 1 to 20 carbon atoms ("C1-20 alkyl"), 1 to 15 carbon atoms ("C1- alkyl) 15 ”), 1 to 10 carbon atoms (“ C1-10 alkyl ”), etc. Examples of such alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso -butyl (C4), pentyl (C5), and the like.
[0119] As used herein, “alkenyl” or “alkene” refers to a radical of a straight or branched chain hydrocarbon group that has from, in some embodiments, 2 to 4 carbon atoms (“C2 alkenyl -4 ”), and in other embodiments 2 to 22 carbon atoms (“ C2-22 alkenyl ”), and one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). In still other embodiments, an alkenyl group has 2 to 21 carbon atoms (“C2-21 alkenyl”), 2 to 20 carbon atoms (“C2-20 alkenyl”), 2 to 15 carbon atoms (“C2- alkenyl) 15 ”), 2 to 10 carbon atoms (“ C2-10 alkyl ”), etc. The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). Examples of such alkenyl groups include ethylene (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), 1-pentenyl (C5) , 2-pentenyl (C5), and the like.
[0120] As used herein, "alkynyl" or "alkaline" refers to a radical of a straight or branched chain hydrocarbon group that has from 2 to 4 carbon atoms and one or more carbon-carbon triple bonds ("C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds may be internal (as in 2-butynyl) or terminal (as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
[0121] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic aromatic ring system (for example, bicyclic or tricyclic) 4n + 2 (for example, it has 6, 10, or 14 electrons shared in a cyclic arrangement) that has 6 to 14 carbon atoms in the ring and zero heteroatom provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 carbon atoms in the ring ("C6 aryl"; for example, phenyl). In some embodiments, an aryl group has 10 carbon atoms in the ring ("C10 aryl"; for example, naphthyl as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 carbon atoms in the ring ("C14 aryl"; for example, anthracyl).
[0122] As used herein, "alkoxy" refers to an alkyl, alkenyl or alkynyl group, as defined herein, attached to an oxygen radical.
[0123] The alkyl, alkenyl, alkynyl and aryl groups, as defined in this document, are substituted or unsubstituted, also referred to in this document as "optionally substituted". In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present in a group (for example, a carbon or nitrogen atom) is replaced by a permissible substituent, for example, a substituent that upon substitution results in a stable compound, for example, a compound that is not spontaneously subjected to transformation as by rearrangement, cyclization, elimination or other reaction. Except where otherwise indicated, a "substituted" group has a substituent in one or more replaceable positions in the group, and when more than one position in any given structure is replaced, the substituent is the same or different in each position. The term "substituted" is contemplated to include substitution by all permissible substituents on organic compounds, any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all of these combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein that satisfies the valences of the hetero atoms and results in the formation of a stable moiety.
[0124] Exemplary substituents include groups that contain a heteroatom (such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom), halogen (such as chlorine, bromine, fluorine or iodine), a heterocycle, alkoxy, alkenoxy, alkoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, starch, nitro, cyano, thiol, ketals, acetals, esters and ethers. TREATMENT METHODS
[0125] Previous studies (see, for example, Gee et al., European Journal of Pharmacology, 136: 419-423 (1987)) have shown that certain 3α-hydroxylated steroids have more powerful orders of magnitude as modulators of the GABA receptor complex (GRC) than others reported (see, for example, Majewska et al., Science 232: 10041007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241: 346-353 (1987)). Majewska et al. and Harrison et al. have taught that 3β-hydroxylated-5-reduced steroids are only capable of much lower levels of effectiveness. Experimental data in vitro and in vivo has now demonstrated that the high potency of these steroids allows them to be therapeutically useful in modulating brain excitability through GRC (see, for example, Gee et al., European Journal of Pharmacology, 136: 419 -423 (1987); Wieland et al., Psychopharmacology 118 (1): 65-71 (1995)).
[0126] Several synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Patent 5,232,917, which describes neuroactive steroid compounds useful for treating stress, anxiety, insomnia, seizures, and mood disorders, which favor active GRC agents, such as depression, in a therapeutically beneficial way. In addition, these steroids have previously been shown to interact at a single site in the GRC that is different from other known interaction sites (eg, barbiturates, benzodiazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizures were previously obtained (see, for example, Gee, KW and Yamamura, HI, “Benzodiazepines and Barbiturates: Drugs for the treatment of Anxiety, Insomnia and Seizure Disorders,” in Central Nervous System Desorders, Horvell, ed., Marcel -Dekker, New York (1985), pp. 123-147; Lloyd, KG and Morselli, PL, “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology: The Third Generation of Progress, HY Meltzer, ed., Raven Press, NY ( 1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136: 419-423 (1987). These compounds are desired for their duration, potency, and oral activity (along with other forms of administration) .
[0127] The compounds of the present invention, as described herein, are generally designed to modulate GABA function and therefore to act as neuroactive steroids for the treatment and prevention of CNS-related conditions in an individual. Modulation, as used in this document, refers to the inhibition or enhancement of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics to prevent and / or treat CNS conditions in mammals that include both human and non-human mammals. Thus, and as previously determined, the present invention includes within its scope, and extends to the aforementioned treatment methods, as well as the compounds for such methods and the use of such compounds for the preparation of medicaments useful for such methods.
[0128] In one embodiment, methods of treating a condition related to GABAA receptor modulation by administering to an individual an effective amount of a compound described herein are described in the present document. Exemplary conditions related to GABAA receptor modulation include, but are not limited to: (a) Neurological disorders that include sleep disorders [eg, insomnia and REM sleep behavioral disorders], epilepsy [eg, status epilepticus, monogenic forms epilepsy (for example, Dravet's syndrome), Lennox-Gastaut syndrome, infantile spasms, juvenile myoclonic epilepsy, recurrent epilepsy, febrile seizure], movement disorders [e.g. Huntington's disease, Parkinson's disease, cerebellar ataxia , Friedrich ataxia, Stiff-Person syndrome, dystonia, Tourette's syndrome, essential tremor], traumatic brain injury, pain disorders [e.g., neuropathic pain, chronic injury-related pain, acute pain, migraine, migrainosus status], vascular disorders [eg, stroke, ischemia, sequelae of vascular malformations], neurodegenerative disorders [eg, Alzheimer's disease, dementia with Lewy bodies, fronto-temporal dementia, multiple system atrophy, dementia due to multiple infarctions] and tinnitus; (b) Psychiatric disorders including schizophrenia and schizoaffective disorder, mood disorders [eg, depression, dysthymic disorder, bipolar disorder, anxiety disorders (eg generalized anxiety disorder, social anxiety disorder, phobia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder), stress], cognitive disorders [eg, hyperactivity disorder and attention deficit], personality disorders [eg, antisocial personality disorder, obsessive compulsive personality disorder], disorders autism spectrum [eg idiopathic autism, monogenic causes of autism (eg Rett syndrome, tuberous sclerosis complex, fragile X syndrome, Angleman syndrome)] and substance abuse disorders [eg, opiate addiction , addiction to stimulants (eg, cocaine addiction), alcohol addiction]; (c) Women’s health disorders including postpartum depression, postpartum dysphoric disorder, polycystic ovary syndrome, catamenial epilepsy, preterm labor, preeclampsia, eclampsia, premenstrual and menstrual migraine; (d) Inflammatory disorders including multiple sclerosis, asthma and rheumatoid arthritis; (e) Anesthesiology indications that comprise the full sedation spectrum that includes mild sedation / anxiolysis, moderate / procedural sedation, monitored anesthetic care, deep sedation, general anesthesia.
[0129] In another aspect, a method is provided for treating or preventing cerebral excitability in a subject susceptible or afflicted with a condition associated with cerebral excitability, which comprises administering to the individual an effective amount of a compound of the present invention to the individual.
[0130] In yet another aspect, a method is provided for treating or preventing stress or anxiety in an individual, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
[0131] In yet another aspect, a method for relieving or preventing seizure activity in an individual is provided, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention.
[0132] In yet another aspect, a method is provided to relieve or prevent insomnia in an individual, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
[0133] In yet another aspect, a method is provided to induce sleep and substantially maintain the level of REM sleep that is found in normal sleep, in which substantial rebound insomnia is not induced, which comprises administering an effective amount of a compound of the present invention.
[0134] In yet another aspect, a method is provided for relieving or preventing PMS or PND in an individual, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention.
[0135] In yet another aspect, a method is provided for treating or preventing mood disorders in an individual, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.
[0136] In yet another aspect, a method of inducing anesthesia in an individual is provided, which comprises administering to the individual an effective amount of a compound of the present invention.
[0137] In yet another aspect, a method of increasing cognition or treating memory disorder is provided by administering to the individual a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett's syndrome.
[0138] In yet another aspect, a method of treating attention disorders is provided by administering to the individual a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.
[0139] In yet another aspect, a combination of a compound of the present invention and another pharmacologically active agent is provided. The compounds provided in this document can be administered as the only active agent or they can be administered in combination with other agents. Combined administration can proceed by any technique evident to those skilled in the art including, for example, separate, sequential, simultaneous and alternate administration.
[0140] In certain embodiments, the compound is administered to the individual chronically. In certain embodiments, the compound is administered to the individual orally, subcutaneously, intramuscularly or intravenously. ANESTHESIA / SEDATION
[0141] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. These effects can be obtained from a single drug that individually provides the correct combination of effects, or occasionally with a combination of drugs (for example, hypnotics, sedatives, paralytics, analgesics) to obtain very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the anguish and pain they might otherwise experience.
[0142] Sedation is the reduction of irritability or agitation through the administration of a pharmacological agent, usually to facilitate a medical procedure or diagnostic procedure.
[0143] Sedation and analgesia include continuous states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.
[0144] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient normally responds to verbal commands. Cognitive function and coordination can be compromised. Ventilatory and cardiovascular functions are not affected.
[0145] Moderate sedation / analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient intentionally responds to a verbal command, both individually and accompanied by tactile light stimulation. No intervention is necessary to keep the airways clear. Spontaneous ventilation is adequate. Cardiovascular function is generally maintained.
[0146] Deep sedation / analgesia is a drug-induced depression of consciousness during which the patient cannot be easily stimulated, but responds intentionally (not a reflex withdrawal of a painful stimulus) after repeated or painful stimulation. Independent ventilatory function can be compromised. The patient may require assistance to keep the airway clear. Spontaneous ventilation may be inadequate. Cardiovascular function is generally maintained.
[0147] General anesthesia is a drug-induced loss of consciousness during which the patient is not stimulable, even for painful stimuli. The ability to maintain independent ventilatory function is generally impaired. Assistance is usually required to keep the airways clear. Positive pressure ventilation may be required due to spontaneous ventilation depression or drug-induced neuromuscular function depression. Cardiovascular function can be compromised.
[0148] Sedation in the intensive care unit (ICU) allows the depression of consciousness of patients in the environment and reduction of their response to external stimulation. It plays an important role in the treatment of the seriously ill patient and includes a broad spectrum of symptom control that will vary between patients and between individuals during their illness. Heavy sedation in critical treatment was used to facilitate endotracheal tube tolerance and ventilator synchronization, usually with neuromuscular blocking agents.
[0149] In some embodiments, sedation (for example, long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (for example, 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedating agents can have a long-lasting action. Sedating agents in the ICU may have a short elimination half-life.
[0150] Procedural sedation and analgesia, also referred to as conscious sedation, is a technique for administering sedatives or dissociative agents with or without analgesics to induce a condition that allows an individual to tolerate unpleasant procedures while maintaining cardiorespiratory function. ANXIETY DISORDERS
[0151] Anxiety disorder is a general term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders.
[0152] Generalized anxiety disorder is a common chronic disorder characterized by lasting anxiety that does not focus on any object or situation. Those who suffer from generalized anxiety experience nonspecific fear and persistent worry and become overly concerned with everyday issues. Generalized anxiety disorder is the most common anxiety disorder because it affects the elderly.
[0153] In a panic disorder, a person suffers from brief attacks of intense terror and apprehension, usually marked by tremor, agitation, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that suddenly appears and reaches its maximum in less than ten minutes, can last for several hours and can be triggered by stress, fear or even exercise; although the specific cause is not always evident. In addition to unexpected recurring panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: concern about the potential implications of the attacks, persistent fear of future attacks, or significant changes in behavior related to the attacks. Consequently, those who suffer from panic disorder experience symptoms even outside of specific panic episodes. Normally, normal changes in heartbeat are observed by a person suffering from panic, leading them to think that something is wrong with their heart or they are about to have another panic attack. In some cases, an increased awareness (hypervigilance) of the body's functioning occurs during panic attacks, in which any perceived physiological change is interpreted as a possible life-threatening disease (ie, extreme hypochondria).
[0154] Obsessive compulsive disorder is a type of anxiety disorder mainly characterized by repetitive obsessions (distressing, persistent and intrusive thoughts or images) and compulsions (wishes to perform specific actions or rituals). The OCD thought pattern can be compared to superstitions in that it involves a belief in a causative relationship where, in reality, a person does not exist. Usually, the process is completely illogical; for example, the compulsion to walk in a certain pattern can be employed to alleviate the obsession with imminent harm. And in many cases, the compulsion is totally inexplicable, simply a desire to complete a ritual triggered by nervousness. In the minority of cases, people suffering from OCD can only experience obsessions, without obvious compulsions; far fewer sufferers experience only compulsions.
[0155] The only major category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences of finding the object of their fear, which can be anything from an animal to a location to a bodily fluid.
[0156] Post-traumatic stress disorder or PTSD is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even a serious accident. The same can also result from long-term (chronic) exposure to a severe stressor, for example, soldiers who face individual battles, but cannot handle continuous combat. Common symptoms include flashbacks, avoidance behaviors and depression. NEURODEGENERATIVE DISEASES AND DISORDERS
[0157] The term "neurodegenerative disease" includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including symptoms associated with mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and seizure (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia that includes McLeod's neuroacanthocytosis syndrome (MLS); closed head trauma; with the; contusion injuries (for example, spinal cord injury and head injury); dementia including dementia due to multiple heart attacks and senile dementia; disturbances of consciousness; Down's syndrome; drug-induced or drug-induced parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing loss and impairment; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, cortical-basal degeneration, multiple system atrophy, ALS parkinsonism-dementia complex, Parkinson's disease, post-encephalitic parkinsonism and progressively supranuclear paralysis); muscle spasms and disorders associated with muscle spasticity or weakness that includes chorea (such as benign hereditary chorea, drug-induced chorea, hemibalism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including complex tics, simple tics and symptomatic tics), myoclonus (including generalized and focal myoclonus), tremor (such as resting tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic cramp of the clerk, hemiplegic dystonia, paroxysmal dystonia and focal dystonia as blepharospasm , oromandibular dystonia and spasmodic dysphonia and torticollis); neuronal damage that includes eye damage, retinopathy or macular degeneration of the eye; neurotoxic injury that accompanies stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure; status epilepticus; stroke; buzz; tubular sclerosis and neurodegeneration induced by viral infection (for example, caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury that accompanies stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing the loss of neuronal function characteristic of a neurodegenerative disorder. EPILEPSY
[0158] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, for example, childhood absence epilepsy, juvenile nioclonic epilepsy, epilepsy with major arousal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy , for example, temporal lobe epilepsy, frontal lobe epilepsy, benign childhood focal epilepsy. STATUS EPILEPTICUS (SE)
[0159] Status epilepticus (SE) may include, for example, seizure status epilepticus, eg initial status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, eg generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Seizure status epilepticus is characterized by the presence of seizure status epileptic seizures, and may include initial epilepticus status, established epilepticus status, refractory epilepticus status, and super-refractory epilepticus status. The initial status epilepticus is treated with first-line therapy. The status epilepticus established is characterized by epileptic seizures that persist despite treatment with first-line therapy and second-line therapy is administered. Refractory epilepticus status is characterized by epileptic seizures that persist despite treatment with first-line and second-line therapy and a general anesthetic is generally administered. Super-refractory status epilepticus is characterized by epileptic seizures that persist despite treatment with first-line therapy, second-line therapy and general anesthetic for 24 hours or more.
[0160] Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, for example, complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, for example, late-onset absence-type epilepticus status, atypical absence-type non-convulsive status epilepticus or typical absence-type non-convulsive status epilepticus.
[0161] The compositions described in this document can also be administered as a prophylactic to an individual who has a CNS disorder, for example, a traumatic brain injury, status epilepticus, for example, status epilepticus convulsive, for example, initial epilepticus status, status epilepticus established, status epilepticus refractory, status epilepticus super-refractory; non-convulsive status epilepticus, eg generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; before the onset of a seizure. CONVULSIVE CRISES
[0162] A seizure consists of physical discoveries or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term "seizure crisis" is generally used interchangeably with "seizure". Seizures are when a person's body shakes quickly and uncontrollably. During seizures, the person's muscles contract and relax repeatedly.
[0163] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.
[0164] Generalized seizures are produced by electrical impulses from the entire brain, while partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that generates seizures is sometimes called the focus.
[0165] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized seizure, also called the seizure crisis of great evil. In this type of seizure, the patient loses consciousness and usually passes out. Loss of consciousness is followed by generalized body stiffness (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent chorea (the "clonic" phase) for 30 to 60 seconds, after which the patient enters in a deep sleep (the "post-seizure" phase or after the seizure). During seizures of great evil, injuries and accidents can occur, such as tongue biting and urinary incontinence.
[0166] Absence-type seizures cause a small loss of consciousness (just a few seconds) with little or no symptoms. The patient, more generally a child, typically interrupts an activity and stares. These seizures begin and end abruptly and can occur several times a day. Patients are generally unaware that they are having a seizure, except that they may be aware of "wasting time".
[0167] Myoclonic seizures consist of sporadic chorea, usually on both sides of the body. Patients sometimes describe chorea as brief electrical shocks. When violent, these crises can result in dropping or throwing objects involuntarily.
[0168] Clonic seizures are repetitive, rhythmic chorea that involve both sides of the body at the same time.
[0169] Tonic crises are characterized by stiffening of the muscles. Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which usually results in a fall. AUTISM
[0170] Autism is a neurobehavioral development syndrome that arises in early childhood and is comprised of a combination of social deficits, limited verbal and / or non-verbal communication and restricted, repetitive and stereotyped patterns of behavior, interests or activities. The autism spectrum disorder as defined by the American Psychiatric Association (DSMV) diagnostic and statistical manual for mental disorders (DSMV) incorporates autism, Asperger's syndrome, childhood disintegrative disorder, and invasive developmental disorder not otherwise specified (PDD-NOS ).
[0171] Autism begins before three years of age. This implies that there is a period of normal development after which there is a period of regression.
[0172] Asperger's syndrome is comprised of social deficits and restricted, repetitive and stereotyped interests without a delay in language development or cognitive delay.
[0173] Childhood disintegrative disorder is a milder form of autistic regression n with an onset after 3 years of age.
[0174] PDD-NOS is characterized by milder symptoms than autism in only one domain (for example, social deficits).
[0175] Autism spectrum disorder can be idiopathic. However, there are many genetic causes of autism that include single gene mutations with a high degree of penetrance [eg, Rett's syndrome, tuberous sclerosis complex, fragile X's syndrome, Angleman's syndrome]. In some cases, the individual genetic mutation is used to refer to the disease [for example, 22q13.3 deletion syndrome]. EXAMPLES
[0176] The following Examples describe or illustrate various achievements of the present disclosure. Other achievements within the scope of the appended claims will become evident to an element skilled in the art considering the disclosure report or practice of the disclosure as described in this document. It is intended that the descriptive report, together with the Examples, be considered as exemplary only, with the scope and spirit of the disclosure being indicated by the claims, which follow the Example. A. COMPOUND CHEMISTRY
[0177] According to the following methods and Examples, the following compounds have been prepared for purposes of illustration: SCHEME 1

[0178] According to Scheme 1, the following compounds were prepared, using methods generally known in the art and as described below.

[0179] 19 - [[(1,1-Dimethyl) dimethylsilyl] oxy] -androst-4-ene-3,17-dione (1). A mixture of 19-hydroxyandrostenedione (1 g, 3.31 mmol), tert-butyldimethylsilyl chloride (602 mg, 4 mmol), imidazole (315 mg, 4.63 mmol), DMF (5 ml) and methylene chloride ( Known 5mL) was stirred at room temperature for 15 h. Water (100 ml) was added to the reaction mixture and extracted with methylene chloride (50 ml x 3). The combined organic extracts were washed with brine, dried and concentrated to generate a white solid. The solid was purified by flash column chromatography (silica gel eluted with 10 to 20% EtOAc in hexanes) to generate a white solid (1.3 g, 94%): mp 154-156 ° C; IR 2856, 2930, 1739, 1670, 1472, 1359, 1255, 1228 cm -1; 1H NMR (CDCI3) δ 5.85 (s, 1H), 3.87 (dd, J = 12.9, 10.0 Hz, 2H), 2.65-0.95 (m), 0.89 ( s, 3H), 0.83 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3) δ 220.0, 199.6, 167.2, 126.0, 65.8, 54.0, 51.3, 47.5, 43.5, 35.9, 35.6, 34.6, 33.5, 33.2, 31.7, 30.7, 25.7 (3 x C), 21.6, 20.9, 18.0, 13.8, -5.76, -5.83.

[0180] (5a) -19 - [[(Dimethylethyl) dimethylsilyl] oxy] -androstane-3,17-dione (2). A lithium wire in small pieces (140 mg, 20 mmoI) was added to a cold stirred solution (-78 ° C) of freshly condensed liquid ammonia (250 mI) and the mixture was stirred for 15 min. Steroid 1 (1.25 g, 3 mmoI) in THF (75 mI) was added to the resulting blue-dark solution and stirring continued at -78 ° C for 2 h. Solid ammonium chloride (5 g) was added and the ammonia was allowed to evaporate. Water (200 mI) was added and the reaction mixture was extracted with EtOAc (100 mI x 3). The combined EtOAc extracts were washed with brine, dried and concentrated to generate an oil. The oil was dissolved in agitated acetone (50 mI) and cooled in a ice bath. Jones' reagent was added to the stirred cold solution until an orange color persisted for 1 h. The excess of Jones' reagent was reduced by adding a few drops of isopropyl alcohol. The acetone was removed under reduced pressure and the resulting solution was diluted with water (200 ml) and extracted with EtOAc (80 ml x 3). The combined EtOAc extracts were dried and removed to generate a white solid which was purified by chromatography (silica gel) to yield steroid 2 (830 mg, 63%): mp 130-132 ° C; IR 3339, 2922, 2857, 1445, 1360 cm -1; 1H NMR (CDCl3) δ 3.87 (dd, J = 21.2, 10.0 Hz, 2H), 2.60-0.70 (m), 0.87 (s, 9H), 0.07 ( s, 3H), 0.06 (s, 3H); 13C NMRD (CDCb) □□ 220.6, 211.8, 60.9, 54.3, 51.6, 47.7, 46.1, 44.8, 39.4, 38.5, 35.7 , 35.4, 33.9, 31.9, 30.5, 28.3, 25.7 (3 x C), 21.7, 18.0, 13.8, -5.7, -5, 9.

[0181] (5a) -19 - [[(Dimethylethyl) dimethylsilyl] oxy] -androstane-3,17-dione, 1,2-etandiyl acetal 3-cyclic (3). A solution of steroid 2 (4.6 g, 11.0 mmol) in benzene (~ 100 ml) containing ethylene glycol (5 ml) and PPTS (500 mg) was heated under reflux with Dean-Stark apparatus for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel eluted with 20% EtOAc in hexanes) to generate 3.17-biscetal (3.5 g) and steroid 3 as a solidified foam (1.25 g): 1H NMR (CDCl3) δ 3.85-3.90 (m, 4H), 3.81 (d, J = 10.6 Hz, 1H), 3.65 (d, J = 10.6 Hz, 1H), 2.36-0.76 (m), 0.83 (s, 9H), 0.10 (d, J = 3.9 Hz, 6H); 13C NMR (CDCl3) δ 221.2, 109.1, 64.1, 60.3, 59.9, 54.5, 51.8, 47.8, 43.6, 39.2, 38.3, 35.7, 35.4, 32.0, 31.3, 30.7, 30.6, 27.8, 25.7, 21.7, 20.9, 17.0, 14.1, -5 , 7, -5.9; Anal. Calcd for C27H46O4Si: C, 70.08; H, 10.02, Found: C, 69.89; H, 10.0.

[0182] (5α) -19-Hydroxyandrostane-3,17-dione, 1,2-etandiyl acetal 3-cyclic (4). To a solution of steroid 3 (1.0 g, 2.4 mmol) in THF (10 ml) was added TBAF (6.0 mmol, 1.0 M in THF, 6.0 ml) at room temperature. The reaction mixture was refluxed for 16 h and the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel eluted with 30% EtOAc in hexanes) to generate steroid 4 as an oil (638 mg , 84%): IR vmax 3487, 1738 cm -1; 1H NMR (CDCI3) δ 3.90-3.85 (m, 4H), 3.86 (d, J = 11.4 Hz, 1H), 3.78 (d, J = 11.4 Hz, 1H) , 2.42-0.76 (m), 0.86 (s, 3H); 13C NMR (CDCls) δ 221.4, 108.9, 64.1, 64.0, 60.0, 54.4, 51.6, 47.8, 43.7, 39.2, 38.2, 35.7, 35.4, 31.9, 31.4, 30.6, 30.1, 27.7, 21.9, 21.7, 13.9.

[0183] (5α, 17β) -17,17-Diidroxiandrostan-3-one, cyclic 1,2-etandiyl acetal (5). To a solution of steroid 4 (635 mg, 1.8 mmol) in ethanol (40 ml) was added sodium borohydride (152 mg, 4 mmol) at room temperature. After 3 h, the mixture was cooled by aqueous NH4Cl. The mixture was extracted with EtOAc (50 ml x 3), the organic layers were combined and dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 35% EtOAc in hexanes) to generate steroid 5 as an oil (638 mg, 100%): 1H NMR (CDCl3) δ 3.92-3.90 (m, 5H), 3.90 (d, J = 12.4 Hz, 1H), 3.61 (t, J = 8.6 Hz, 1H), 2.22-0.73 (m), 0 , 76 (s, 3H); 13C NMR (CDGls) δ 109.1, 81.8, 64.2, 64.1, 60.2, 54.4, 51.3, 43.8, 43.1, 39.3, 38.3, 37.2, 36.0, 31.6, 31.3, 30.4, 30.1, 27.9, 23.4, 22.5, 11.4.

[0184] (5α, 17β) -17,19-Dimetoxiandrostan-3-one, 1,2-etandiiI cyclic acetic (6). To a solution of steroid 5 (635 mg, 1.8 mmoI) in THF (30 mI) was added sodium hydride (400 mg, 60% in mineral oil, 6.0 mmoI). After the addition, the mixture was refluxed for 1 h, iodomethane was added and refluxed for an additional 3 h. After cooling to room temperature, the mixture was cooled by water and extracted with EtOAc (100 mI x 3). The organic extracts were combined and dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel with 20% EtOAc in hexanes) to generate steroid 6 (623 mg, 92%): mp 102-104 ° C; IR vmax 2922, 1448 cm -1; 1H NMR (CDCI3) δ 3.84 (m, 4H), 3.43 (d, J = 9.4 Hz, 1H), 3.36 (d, J = 9.4 Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H), 3.12 (t, J = 7.8 Hz, 1H), 2.10-0.63 (m), 0.68 (3H); 13C NMR (CDCI3) δ 109.1, 90.6, 70.9, 64.0 (2 x C), 58.9, 57.6, 54.2, 51.3, 43.7, 42.9 , 38.8, 38.3, 38.2, 35.6, 31.4, 31.3, 30.9, 28.0, 27.5, 23.2, 21.9, 11.5.

[0185] (5α, 17β) -17,19-Dimetoxiandrostan-3-one (7, MQ-88). The mixture of steroid 6 (625 mg, 1.65 mmoI), PTSA (100 mg), acetone (30 mI) and water (3 mI) was stirred at room temperature for 16 h. The solvents were removed under reduced pressure, aqueous NaHCO3 was added and the product extracted in EtOAc (100 ml x 3). The organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 20% EtOAc in hexanes) to generate steroid 7 (408 mg, 74%): mp 91-93 ° C; [OJD20 = 18.4 (c = 0.37, CHCl3); vmax 2922, 1714 cm -1; 1H NMR (CDClβ) δ 3.60 (d, J = 10.2 Hz, 1H), 3.55 (d, J = 9.7 Hz, 1H), 3.24 (s, 6H), 3.12 (t, J = 8.2 Hz, 1H), 2.45-0.64 (m), 0.70 (s, 3H); 13C NMR (CDCl3) δ 212.1, 90.4, 71.8, 59.0, 57.6, 54.0, 51.2, 46.3, 44.8, 42.8, 38.8, 38.7, 38.0, 35.5, 34.3, 31.0, 28.3, 27.5, 23.1, 21.8, 11.5, Anal. Calcd for C21H34O3: C, 75.41; H, 10.25. Found: C, 75.37; H, 10.13. SCHEME 2

[0186] (5α, 17β) -17,19-Dimetoxiandrostan-3-ol (8, MQ-89). To a solution of steroid 7 (200 mg, 0.60 mmol) in THF (10 ml) was added K-selectride ® (1.0 mmol, 1.0 M in THF, 1.0 ml) at -78 ° Ç. After 2 h, 3 N NaOH (10 ml) and H2O2 (5 ml) were added at -78 ° C and the reaction was allowed to warm up to room temperature for 1 h. The product was extracted into EtOAc (100 ml x 2) and washed with brine. The organic layers were combined and dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 20% EtOAc in hexanes) to generate steroid 8 (172 mg, 86%): mp 62-64 ° C; [O.] D20 = 1.1 (c = 0.26, CHCl3); vmax 3382, 1447 cm -1; 1H NMR (CDCl3) δ 4.10-4.05 (m, 1H), 3.50 (d, J = 10.2 Hz, 1H), 3.42 (d, J = 9.8 Hz, 1H) , 3.33 (s, 3H), 3.29 (s, 3H), 3.23 (t, J = 8.2, 1H), 2.01-0.80 (m), 0.76 (s , 3H); 13C NMR (CDClβ) δ 90.9, 71.1, 66.4, 59.1, 57.8, 54.7, 51.6, 43.0, 39.6, 39.3, 38.5, 36.2, 35.8, 31.5, 29.5, 28.1, 27.7, 27.0, 23.3, 21.7, 11.7, Anal. Calcd for C21H36O3: C, 74.95; H, 10.78. Found: C, 75.19; H, 10.79. SCHEME 3

[0187] (5α) -19-Methoxyandrostane-3,17-dione, bis- (1,2-ethanediyl acetal cyclic) (9). A mixture of cyclic (5α) -19-hydroxyandrostane-3,17-dione, bis- (1,2-ethanediyl) acetal (430 mg, 1.1 mmol), NaH (200 mg, 5 mmol) and THF (10 ml) was heated to reflux for 2 h under N2. The reaction mixture was cooled to room temperature, and methyl iodide (2 ml, 32 mmol) was added and the mixture was stirred at room temperature for 13 h. The reaction mixture was cooled to 0 ° C and the excess NaH was carefully cooled by adding MeOH (2 ml). Water (100 ml) was added and the product was extracted into EtOAc (80 ml x 3). The combined organic extracts were washed with brine, dried and concentrated to generate a colorless liquid. The crude product was purified by flash column chromatography (silica gel eluted with 15 to 20% EtOAc in hexanes) to generate the product as a colorless liquid (440 mg, 99%): IR Umax 2923, 1457, 1378, 1306 , 1210 cm-1; 1H NMR δ 3.89 (s, 4H), 3.87-3.82 (m, 4H), 3.47 (d, J = 10.0 Hz, 1H), 3.39 (d, J = 9 , 9 Hz, 1H), 3.25 (s, 3H), 2.20-0.85 (m), 0.82 (s, 3H); 13C NMR δ 119.3, 109.2, 71.0, 65.0, 64.5, 64.0, 59.0, 54.0, 50.4, 46.0, 43.8, 38.9 , 38.4, 36.2, 34.1, 31.5, 31.1, 31.0 (2 x C), 29.6, 28.1, 22.6, 21.7, 14.4. Anal. Calcd for: C24H38O5: C, 70.90%; H 9.42%. Found: C, 71.17%; H, 9.53%.

[0188] (5α) -19-Methoxyandrostane-3,17-dione (10). A mixture of steroid 9 (400 mg, 0.98 mmol), PTSA (100 mg), acetone (8 ml) and water (0.5 ml) was stirred at room temperature for 14 h. the reaction was neutralized with aqueous NaHCO3 and the acetone was removed under reduced pressure. Water (80 ml) was added and the product was extracted into EtOAc (60 ml x 3). The combined EtOAc extracts were dried and concentrated to generate a white solid which was purified by flash column chromatography (silica gel eluted with 20 to 30% EtOAc in hexanes) to yield product 10 (230 mg, 73%): mp 94-96 ° C; IR Umax 2918, 1738, 1712, 1452, 1407, 1373, 1270, 1248, 1220, 1202, cm-1; 1H NMR δ 3.60 (d, J = 11.0 Hz, 1H), 3.57 (d, J = 11.0 Hz, 1H), 3.26 (s, 3H), 2.50-0, 74 (m), 0.82 (s, 3H); 13C NMR δ 220.5, 211.7, 71.7, 59.0, 53.9, 51.3, 47.6, 46.1, 44.7, 38.9, 38.5, 35.6 , 35.3, 34.2, 31.5, 30.3, 28.1, 21.5, 21.3, 13.7, HRMS Calcd for C20H30O3: 318.2195. Found: 318.2180.

[0189] (3a, 5a) -3-Hydroxy-19-methoxyandrostan-17-one (11, KK-125). A 1 M solution of K-Selectride ® in THF (2 ml, 2 mmol, 3 eq) was added to a cold solution (-78 ° C) of steroid 10 (210 mg, 0.66 mmol) in THF (5 ml) and the reaction was stirred at -78 ° C for 1.5 h. The reaction was cooled by adding a few drops of acetone and then allowed to warm to room temperature. 3 N aqueous NaOH (10 ml) followed by 30% aqueous H2O2 (10 ml) was added and the reaction was stirred at room temperature for 1.5 h. The product was extracted into EtOAc (3 x 60 ml) and the combined EtOAc extracts were washed with brine, dried and concentrated to generate an off-white solid which was purified by flash column chromatography (silica gel eluted with 20 to 40 ml). % EtOAc in hexanes). Product 11 (142 mg, 67%) had: mp 172-174 ° C; IR Umax 3436, 2921, 1738, 1453, 1406, 1372, 1248, 1203 cm -1; 1H NMR δ 4.05 (bs, 1H), 3.48 (d, J = 9.9 Hz, 1H), 3.38 (d, J = 10.2 Hz, 1H), 3.25 (s, 3H), 2.39 (dd, J = 19.3, 8.8 Hz, 1H), 2,2,10-0,70 (m), 0.84 (s, 3H); 13C NMR δ 221.5, 71.1, 66.1, 59.0, 54.6, 51.7, 47.8, 39.6, 39.2, 36.0, 35.7, 35.5 , 31.8, 30.7, 29.2, 27.9, 27.1, 21.6, 21.1, 13.8, Anal. Calcd for C20H32O3: C, 74.96%; H, 10.06%. Found: C, 74.91%; H, 9.86%.

[0190] (3α, 5α, 17β) -19-Methoxyspiro [androstano-17,2'-oxiran] -3-ol (12, MQ-90). To a solution of steroid 11 (100 mg, 0.3 mmol) in DMF (10 ml) was added trimethylsulfonium iodide (306 mg, 1.5 mmol) and potassium tert-butoxide (168 mg, 1.5 mmol ) at room temperature. The reaction was cooled by aqueous NH4Cl after 2 h. the mixture was extracted with dichloromethane (100 ml x 2) and washed with brine. The organic layers were combined and dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 25% EtOAc in hexanes) to generate steroid 12 (76 mg, 75%): mp 168-170 ° C; [O.] D20 = -3.1 (c = 0.16, CHCl3); vmax 3420, 1445 cm -1; 1H NMR (CDClβ) δ 4.10-4.05 (m, 1H), 3.51 (d, J = 10.2 Hz, 1H), 3.42 (d, J = 10.2 Hz, 1H) , 3.29 (s, 3H), 2.90 (d, J = 5.1 Hz, 1H), 2.60 (d, J = 5.0 Hz, 1H), 2.00-0.77 ( m), 0.89 (s, 3H); 13C NMR (CDCl3) δ 71.0, 70.6, 66.4, 59.1, 54.6, 53.6, 53.1, 40.2, 39.6, 39.3, 36.2, 36.1, 34.3, 31.4, 29.4, 29.0, 28.1, 27.1, 23.5, 21.4, 14.4. Anal. Calcd for C21H34O3: C, 75.41; H, 10, .25. Found: C, 75.44; H, 9.98. SCHEME 4

[0191] (3a, 5a) -19-Methoxy-3- (methoxymethoxy) -androstan-17-one (13): To a solution of steroid 11 (800 mg, 2.5 mmol) in DCM (20 ml) added - chloromethyl methyl ether (302 mg, 3.75 mmol) and N, N-diisopropylethylamine (774 mg, 6 mmol) at room temperature. The mixture was cooled with water after 16 h and extracted with EtOAc (100 ml x 2) and washed with brine. The organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 25% EtOAc in hexanes) to generate product 13 as an oil (900 mg, 100%): IR vmax 2921, 1740 cm-1; 1H NMR (CDClβ) δ 4.65 (q, J = 6.6, 10.9, 1H), 3.86-3.84 (m, 1H), 3.52 (d, J = 10.2 Hz , 1H), 3.43 (d, J = 9.8 Hz, 1H), 3.35 (s, 3H), 3.28 (s, 3H), 2.44-0.83 (m), 0 , 86 (s, 3H); 13C NMR (CDCl3) δ 221.4, 94.5, 71.3, 71.2, 59.1, 55.1, 54.6, 51.7, 47.9, 39.9, 39.4, 35.8, 35.5, 34.0, 31.9, 30.8, 28.0, 27.7, 26.5, 21.7, 21.2, 13.9.

[0192] (3a, 5a) -19-Methoxy-3- (methoxymethoxy) -androst-16-ene-17-carbonitrile (14): To a solution of steroid 13 (800 mg, 2.5 mmol) in THF ( 20 ml) potassium bis (trimethylsilyl) amide (3.0 mmol, 0.5 M in toluene, 6.0 ml) was added at -78 ° C. After 30 min., N-phenyltrifluoromethanesulfonimide (1.07 g, 3.0 mmol) in 5 ml of THF was added at -78 ° C. After 2 h at -78 ° C, the mixture was cooled with water and extracted with EtOAc (50 ml x 3). The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel) to provide the enol triflate intermediate (1.21 g containing an inseparable impurity). To the enol triflate (1.21 g) in a 50 ml round flask was added sodium cyanide (300 mg, 6.0 mmol), copper (I) iodide (120 mg, 0.6 mmol) and Pd ( PPh3) 4 (60 mg) at room temperature. Acetonitrile (25 ml) was added and the mixture was refluxed for 3 h. the mixture was cooled by aqueous NH4Cl and extracted with EtOAc (50 ml x 3). The combined organic layers were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to provide product 14 as an oil (886 mg containing an inseparable impurity): 1H NMR (CDCls) δ 6.54-6 , 53 (m, 1H), 4.62 (q, J = 7.0, 9.8 Hz, 2H), 3.80-3.70 (m, 1H), 3.47 (d, J = 9 , 8 Hz, 1H), 3.39 (d, J = 10.2 Hz, 1H), 3.30 (s, 3H), 3.23 (s, 3H), 2.29-0.82 (m ), 0.85 (s, 3H); 13C NMR (CDCl3) δ 147.7, 127.3, 116.0, 94.4, 71.5, 71.3, 59.1, 56.2, 55.0, 54.8, 48.4, 39.9, 39.5, 34.3, 34.2, 33.8, 32.8, 31.6, 27.9, 27.4, 26.4, 21.5, 16.3.

[0193] (3a, 5a) -3-Hydroxy-19-methoxyandrost-16-ene-17-carbonitrile (15, MQ-91): To steroid 14 containing an inseparable impurity (886 mg) in methanol (20 ml) were 6 N HCl (15 ml) was added at room temperature. After 14 h, the mixture was extracted with dichloromethane (50 ml x 2). The organic layers were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to provide product 15 (480 mg, 58% steroid yield 13): mp 167-169 ° C; [a] D20 = 11.1 (c = 0.18, CHCla); IR vmax 3337, 2212 cm -1; 1H NMR (CDCl3) δ 6.59-6.55 (m, 1H), 4.08-4.05 (m, 1H), 3.53 (d, J = 10.1 Hz, 1H), 3, 43 (d, J = 10.1 Hz, 1H), 3.28 (s, 3H), 2.37-0.89 (m), 0.91 (s, 3H); 13C NMR (CDCl3) δ 147.2, 127.5, 115.9, 71.1, 66.1, 59.1, 56.2, 54.8, 48.3, 39.7, 39.3, 36.0, 34.4, 34.3, 32.8, 31.6, 29.3, 28.0, 26.9, 21.5, 16.3. Anal. Calcd for C21H31NO2: C, 76.55; H, 9.48, N, 4.5. Found: C, 76.59; H, 9.32; N, 4.06.

[0194] (3α, 5α, 17β) -3-Hydroxy-19-methoxyandrostane-17-carbonitrile (16, MQ-92): To a solution of steroid 15 (430 mg, 1.3 mmol) in EtOAc (30 ml ) Pd / C (10%, 100 mg) was added. Hydrogenation was carried out under 7 atm of H2 at room temperature for 3 h. The mixture was filtered through Celite and washed with EtOAc (100 ml). The solvents were removed and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to provide product 16 (415 mg, 96%): mp 146-148 ° C; [α] D20 = 42.1 (c = 0.29, CHCl3); vmax 3412, 2235 cm -1; 1H NMR (CDCle) δ 4.08-4.05 (m, 1H), 3.49 (d, J = 9.8 Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H) , 3.29 (s, 3H), 2.25 (t, J = 8.8 Hz, 1H), 2.10-0.79 (m), 0.92 (s, 3H); 13C NMR (CDCI3) δ 121.4, 70.9, 66.3, 59.1, 54.7, 54.3, 44.5, 40.2, 39.5, 39.2, 37.5, 36.4, 36.1, 31.9, 29.4, 28.0, 27.1, 26.5, 24.5, 21.6, 14.4. AnaI. CaIcd for C21H33NO2: C, 76.09; H, 10.03, N, 4.23. Found: C, 76.16; H, 9.90; N, 4.05.

[0195] (3a, 5a) -3-Hydroxy-19-methoxypregnan-20-one (17, MQ-93): To a solution of steroid 16 (360 mg, 1.09 mmoI) in THF (20 mI) added magnesium methyl bromide (3.0 M, 2 mI, 6.0 mmoI) at room temperature. The mixture was then refluxed for 16 h and subsequently allowed to cool to room temperature and cooled by 6 N addition of HCI. The product was extracted in dichloromethane (50 ml x 3). The organic layers were dried, filtered and concentrated. The 1H NMR of the crude product (300 mg, 79%) showed 17β (steroid 17) and 17α diastereomer in the ratio of 8 to 1, respectively. The crude product was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to provide pure product 17 (135 mg) pure: mp 160-162 ° C; [α] D20 = 41.7 (c = 0.31, CHCl3); IR vmax 3407, 1703 cm-1; 1H NMR (CDClβ) δ 4.07-4.05 (m, 1H), 3.47 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 10.2 Hz, 1H) , 3.26 (s, 3H), 2.50 (t, J = 9.4 Hz, 1H), 2.17-0.78 (m), 2.08 (s, 3H), 0.59 ( s, 3H); 13C NMR (CDCI3) δ 209.8, 70.9, 66.3, 63.8, 59.0, 56.9, 54.4, 44.3, 39.5, 39.4, 39.2, 36.1, 35.9, 31.8, 31.4, 29.3, 28.1, 26.9, 24.3, 22.6, 22.0, 13.5. AnaI. CaIcd for C22H36O3: C, 75.82; H, 10.41; found: C, 75.71; H, 10.29. SCHEME 5

[0196] (3a, 5a) -3- (Acetyloxy) -19-methoxypregnan-20-one (18): To a solution of steroid 17 (100 mg, 0.29 mmoI) in pyridine (5 mI) anhydride was added acetic (51 mg, 0.5 mmoI) and DMAP (5 mg) at room temperature. The reaction mixture was cooled with water after 2 h and extracted with EtOAc (50 mI x 2). The organic layers were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel eluted with 20% EtOAc in hexanes) to generate product 18 as an oil (112 mg, 100%): 1H NMR (CDCl3) δ 5.01-4.98 (m, 1H), 3.46 (d, J = 9.8 Hz, 1H), 3.37 (d, J = 9.8 Hz, 1H), 3.23 (s, 3H), 2.47 (t, J = 9.0 Hz, 1H), 2,220.79 (m), 2.06 (s, 3H), 2.00 (s, 3H), 0.57 (s, 3H); 13C NMR (CDCl3) δ 209.4, 170.5, 70.9, 69.9, 63.7, 59.0, 56.8, 54.2, 44.2, 40.1, 39.3, 39.1, 35.8, 33.1, 31.7, 31.4, 27.8, 27.7, 26.3, 24.2, 22.6, 21.9, 21.4, 13, 4.

[0197] (3α, 5α) -3,21-bis (Acetyloxy) -19-methoxypregnan-20-one (19): To a solution of steroid 18 (112 mg, 0.29 mmol) in benzene (10 ml) and methanol (0.5 ml), lead tetraacetate (513 mg, 1.15 mmol) and ether complex and boron trifluoride (1 ml) were added at room temperature. After 3 h, water was added and the product extracted in EtOAc (50 ml x 2). The organic layers were dried over with MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to generate product 19 as a foam (82 mg, 63%): 1H NMR (CDCl3) δ 5.03-5.01 (m, 1H), 4.70 (d, J = 16.8 Hz, 1H), 4.53 (d, J = 16.8 Hz, 1H), 3.47 (d, J = 10.2 Hz , 1H), 3.34 (d, J = 10.2 Hz, 1H), 3.25 (s, 3H), 2.47 (t, J = 9.0 Hz, 1H), 2.20-0 , 80 (m), 2.14 (s, 3H), 2.03 (s, 3H), 0.65 (s, 3H); 13C NMR (CDCl3) δ 203.8, 170.6, 170.2, 70.9, 69.9, 69.1, 59.4, 59.0, 57.1, 54.2, 45.0, 40.1, 39.2, 39.1, 35.9, 33.2, 31.8, 27.9, 27.8, 26.4, 24.4, 22.7, 22.0, 21, 5, 20.4, 13.3.

[0198] (3α, 5α) -3,21-Dihydr0xi-19-methoxypregnan-20-one (20, MQ-98): To a solution of steroid 19 (82 mg, 0.18 mmol) in methanol was added potassium bicarbonate (280 mg, 2.0 mmol) at room temperature. The mixture was refluxed for 5 h. Water was added and the product was extracted into EtOAc (50 ml x 2). The organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to generate product 20 (22 mg, 37%): mp 88-90 ° C; [α] D20 = 50.0 (c = 0.13, CHCl3); IR vmax 3415, 1708 cm -1; 1H NMR (CDClβ) δ 4.20-4.10 (m, 3H), 3.49 (d, J = 9.8 Hz, 1H), 3.42 (d, J = 9.8 Hz, 1H) , 3.28 (d, J = 1.9 Hz, 3H), 2.47 (t, J = 8.6 Hz, 1H), 2.22-0.80 (m), 0.65 (J = 1.2 Hz, 3H); 13C NMR (CDCI3) δ 210.4, 70.9, 69.4, 66.4, 59.4, 59.1, 57.1, 54.3, 45.1, 39.5, 39.2, 39.1, 36.1, 36.0, 31.9, 29.4, 28.1, 27.0, 24.5, 22.9, 22.0, 13.6. AnaI. CaIcd for C22H36O4: C, 72.49; H, 9.95; found: C, 72.77; H, 10.10. SCHEME6

[0199] 19-Hydroxyandrost-5-ene-3,17-dione, 1,2-etandiyl acetal 3-cyclic (21): To a solution of 19-hydroxyandrost-4-ene-3,17-dione (1, 0 g, 3.3 mmol) known in benzene (100 ml) was added ethylene glycol (267 mg, 4.3 mmol) and PPTS (100 mg). The mixture was refluxed in a flask equipped with a Dean-Stark distillation trap. After 4 h, the mixture was cooled below room temperature and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel eluted with 15% EtOAc in hexanes) to provide the known 19-hydroxyandrost-5-eno-3,17-dione, 3,17-bis (1,2- cyclic etandiyl acetal) (260 mg, 20%) and product 21 (450 mg, 39%): mp 190-192 ° C; IR vmax 3468, 1735 cm -1; 1H NMR (CDCI3) δ 5.67-5.65 (m, 1H), 3.93-3.3.77 (m, 5H), 3.58-3.55 (m, 1H), 2,480.96 (m), 0.87 (s, 3H); 13C NMR (CDClβ) δ 221.2, 135.4, 126.4, 109.0, 64.4, 64.2, 62.5, 52.4, 50.0, 47.8, 41.8, 41.6, 35.7, 32.8, 32.4, 31.6, 31.3, 30.0, 21.7, 20.9, 13.9.

[0200] (17β) -17,19-Diidroxiandrost-5-en-3-one, 1,2-etandiiI acetaI 3-cyclic (22): To a solution of steroid 21 (450 mg, 1.29 mmoI) in ethaneI (50 mI) sodium borohydride (152 mg, 4 mmoI) was added at room temperature. After 3 h, aqueous NH4 Cl yarn is added and the product is extracted into EtOAc (50 mI x 3). The organic layers were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel with 35% EtOAc in hexanes) to generate product 22 (374 mg, 83%): mp 208-210 ° C; IR vmax 3440 cm-1; 1H NMR (CDCI3) δ 5.74-5.70 (m, 1H), 4.00-3.92 (m, 4H), 3.85 (d, J = 11.4 Hz, 1H), 3, 70-3.62 (m, 2H), 2.22-0.84 (m), 0.82 (s, 3H); 13C NMR (CDCI3) δ 135.1, 127.3, 109.1, 81.8, 64.5, 64.3, 62.6, 52.1, 50.0, 42.9, 41.9, 41.8, 36.8, 33.4, 32.4, 31.4, 30.6, 30.5, 23.3, 21.3, 11.3.

[0201] (17β) -17,19-Dimetoxiandrost-5-en-3-one, 1,2-ethandiiI 3-cyclic acetic (23): To a solution of steroid 22 (374 mg, 0.72 mmoI) in THF (30 mI) sodium hydride (400 mg, 60% in mineral oil, 6.0 mmoI) was added. After the addition, the mixture was refluxed for 1 h, iodomethane (2.13 g, 15 mmoI) was added and the reflux continued for 3 h. After allowing to cool to room temperature, water was added and the product was extracted in EtOAc (100 mI x 3). The organic layers were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel with 20% EtOAc in hexanes) to generate product 22 (402 mg, 100%): mp 97-99 ° C; IR vmax 2918, 1450, 1105 cm -1; 1H NMR (CDCl3) δ 5.52-5.50 (m, 1H), 3.95-3.83 (m, 4H), 3.51 (d, J = 9.8 Hz, 1H), 3, 27 (s, 3H), 3.27 (d, J = 11.4 Hz, 1H), 3.24 (s, 3H), 3.15 (t, J = 7.8 Hz, 1H), 2, 56-0.78 (m), 0.73 (s, 3H); 13C NMR (CDCI3) δ 136.1, 124.8, 109.1, 90.6, 73.6, 64.2, 64.0, 58.8, 57.6, 51.9, 49.9, 42.6, 42.0, 40.6, 38.0, 32.6, 32.5, 31.3, 30.8, 27.5, 23.1, 21.2, 11.3.

[0202] (17β) -17,19-Dimethoxyandrost-4-en-3-one (24, MQ-99): To a solution of steroid 23 (402 mg, 1.07 mmoI) in THF (20 mI) fpra , 3 N HCl (10 ml at room temperature were added. The mixture was stirred for 2 h and the product extracted in dichloromethane (50 ml x 2). The organic layers were dried with MgSO4, filtered and concentrated. The residue was purified by chromatography on flash column (silica gel eluted with 25% EtOAc in hexanes) to generate product 24 (355 mg, 100%): IR vmax 1671 cm-1; mp 93-95 ° C; [a] D20 = 124.7 (c = 0.32, CHCh); 1H NMR (CDCls) δ 5.80 (d, J = 0.7 Hz, 1H), 3.68 (d, J = 9.3 Hz, 1H), 3, 51 (d, J = 9.4 Hz, 1H), 3.28 (s, 3H), 3.25 (s, 3H), 3.18 (t, J = 8.2 Hz, 1H), 2, 27-0.90 (m), 0.74 (s, 3H); 13C NMR (CDCl3) δ 199.9, 167.5, 125.5, 90.2, 76.0, 59.2, 57, 7, 54.1, 50.9, 42.8, 42.7, 37.8, 35.9, 34.8, 33.6, 33.4, 31.6, 27.4, 23.0, 21.2, 11.5 Calcd Anal for C21H32NO3: C, 75.86, H, 9.70 Found: C, 76.00, H, 9.98 SCHEME 7

[0203] (3α, 17β) -17,19-Dimetoxiandrost-5-en-3-ol (25, MQ-101) and (3β, 17β) -17,19-Dimetoxiandrost-5-en-3-ol ( 26, MQ-100). To a solution of steroid 24 (355 mg, 1.07 mmol) in acetic anhydride (10 ml) was added sodium iodide (600 mg, 4 mmol) and TMSCl (435 mg, 4 mmol) at 0 ° C. After the addition, the mixture was allowed to warm up to room temperature for 1 h. Thin layer chromatography showed no remaining starting material. Aqueous NaHCO3 was added and the product was extracted into EtOAc (50 ml x 3). The organic layers were dried over MgSO4, filtered and concentrated. The residue was dissolved in ethanol (20 ml) and NaBH4 (200 mg) was added. After 16 h, aqueous NH4Cl was added and the product extracted into EtOAc (50 ml x 3). The organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to generate product 25 (30 mg, 8%), and product 26 (248 mg, 69%).
[0204] Product 25 had: mp 132-134 ° C; [a] D20 = -64.0 (c = 0.10, CHCl3); IR vmax 3337, 1446 cm -1; 1H NMR (CDCls) δ 5.67-5.65 (m, 1H), 4.05-4.00 (m, 1H), 3.60 (d, J = 9.8 Hz, 1H), 3, 35 (s, 3H), 3.31 (s, 3H), 3.28 (d, J = 9.8 Hz, 1H), 3.25 (t, J = 8.2 Hz, 1H), 2, 64-2.60 (m, 1H), 2.17-0.85 (m), 0.80 (s, 3H); 13C NMR (CDCl3) δ 134.8, 126.9, 90.8, 73.7, 66.9, 59.1, 57.9, 52.1, 50.8, 42.8, 41.5, 40.0, 38.2, 32.9, 31.1, 30.2, 29.3, 27.7, 23.3, 21.1, 11.5. Anal. Calcd for C21H34O3: C, 75.41, H, 10.25. Found: C, 75.31, H, 10.41.
[0205] Product 26 had: mp 160-162 ° C; [a] D20 = -76.7 (c = 0.45, CHCl3); IR vmax 3408 cm-1; 1H NMR (CDCl3) δ 5.53-5.50 (m, 1H), 3.54 (d, J = 9.7 Hz, 1H), 3.51-3.44 (m, 1H), 3, 28 (s, 3H), 3.24 (s, 3H), 3.22 (d, J = 9.7 Hz, 1H), 3.18 (t, J = 8.2 Hz, 1H), 2, 65 (s, br, 1H), 2.32-0.76 (m), 0.73 (s, 3H); 13C NMR (CDCl3) δ 136.9, 124.4, 90.7, 73.8, 71.1, 58.8, 57.7, 51.9, 50.4, 42.6, 42.2, 40.5, 38.0, 33.6, 32.6, 31.6, 30.7, 27.5, 23.1, 21.2, 11.3. Anal. Calcd for C21H34O3: C, 75.41, H, 10.25. Found: C, 75.51, H, 10.30. SCHEME 8

[0206] (3α, 5α) -3 - [[(Dimethylethyl) dimethylsilyl] 0xi] -19-methoxyandrostan-17on (27). To a solution of steroid 11 (150 mg, 0.47 mmol) in DMF (5 ml) was added tert-butyldimethylsilyl chloride (150 mg, 1.0 mmol) and imidazole (132 mg, 2.0 mmol) at temperature environment. After 16 h, water was added and the product extracted in EtOAc (50 ml x 2). The organic layers were dried over MgSO4, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to provide product 27 as an oil (198 mg, 99%): 1H NMR (CDGls) δ 4.00-3.95 ( m, 1H), 3.51 (d, J = 9.7Hz, 1H), 3.40 (d, J = 9.7Hz, 1H), 3.27 (s, 3H), 2.44-0, 80 (m), 0.89 (s, 3H), 0.87 (s, 9H), 0.00 (d, J = 1.6 Hz, 6H); 13C NMR (CDCI3) δ 221.6, 71.3, 66.6, 59.1, 54.7, 51.7, 47.9, 39.6, 39.2, 37.0, 35.8, 35.5, 31.8, 30.9, 29.9, 28.1, 27.2, 25.8 (3 x C), 25.6, 21.7, 21.2, 13.9, - 4.90, -4.92.

[0207] (3α, 5α) -3 - [[(Dimethylethyl) dimethylsilyl] 0xi] -19-methoxyandrostan- 17-one, oxime (28): To a solution of steroid 27 (195 mg, 0.45 mmol) in pyridine (10 ml) hydroxyamine hydrochloride (140 mg, 2.0 mmol) was added at room temperature. After 14 h, water was added and the product extracted in EtOAc (50 ml x 2). The organic layers were dried over MgSO4, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to provide product 28 as an oil (202 mg, 100%): 1H NMR (CDClβ) δ 9.05 (s, br, 1H), 4.00-3.95 (m, 1H), 3.50 (d, J = 9.8 Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H), 3.27 (s, 3H), 2.500.82 (m), 0.91 (s, 3H), 0.88 (s, 9H), 0.11 (d, J = 1.9 Hz, 6H); 13C NMR (CDCl3) δ 171.1, 71.4, 66.7, 59.1, 54.7, 54.1, 44.2, 39.6, 39.2, 37.1, 35.2, 34.3, 31.5, 30.0, 28.2, 27.1, 25.8 (3 x C), 25.0, 23.1, 21.5, 18.1, 17.2, - 4.85, -4.89.

[0208] (3a, 5a, 17e) -19-methoxy-17-nitroandrostan-3-ol (29, MQ-97): To a solution of NBS (231 mg, 1.3 mmol) in dioxane (4 ml) aqueous KHCO3 (260 mg, 2.6 mmol, 4 ml) was added at room temperature. The mixture was stirred for 30 min. at room temperature, then oxime (202 mg, 0.45 mmol) in dioxane (10 ml) was added. The reaction was stirred in an open flask for 14 h at room temperature. NaBH4 (200 mg) was added in 5 portions and the reaction was stirred for 3 h at room temperature. 6 N HCl (10 ml) was added slowly and stirring at room temperature continued for 1 h. The product was extracted into dichloromethane (50 ml x 2). The organic layers were dried over MgSO4, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to provide product 29 (79 mg, 50%): mp 52-54 ° C; [α] D20 = 25.8 (c = 0.21, CHCl3); IR vmax 3307, 1541, 1370 cm -1; 1H NMR (CDCI3) δ 4.38 (t, J = 8.6 Hz, 1H), 4.10-4.05 (m, 1H), 3.49 (d, J = 9.8 Hz, 1H) , 3.41 (d, J = 9.8 Hz, 1H), 3.27 (s, 3H), 2.55-0.79 (m), 0.74 (s, 3H); 13C NMR (CDCI3) δ 94.5, 71.0, 66.3, 59.1, 54.2, 53.4, 46.0, 39.5, 39.1, 37.6, 36.0, 31.5, 29.3, 28.0, 27.1, 24.7, 23.6, 21.7, 12.2. AnaI. CaIcd for C20H33NO4: C, 68.34, H, 9.46. Found: C, 68.40, H, 9.45. SCHEME9

[0209] (3a, 5e) -3-Hydroxy-19-methoxyandrostan-17-one (30, MQ-94). To a solution of steroid 10 (295 mg, 0.93 mmoI) in THF (20 mI) was added lithium tri-tert-butoxide hydride and aluminum (2.0 mmoI, 1.0 M in THF, 2, 0 mI) at -40 ° C. After 2 h, the mixture was cooled by 3 N HCl at -40 ° C, the reaction was allowed to warm up to room temperature for 1 h. The product was extracted into dichloromethane (100 ml x 2) and washed with brine. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to generate product 30 (239 mg, 81%): mp 208-210 ° C; IR vmax 3428, 1737, 1642 cm -1; [α] D20 = 81.3 (c = 0.31, CHCl3); 1H NMR (CDCI3) δ 3.65-3.58 (m, 1H), 3.52 (d, J = 9.8 Hz, 1H), 3.43 (d, J = 9.8 Hz, 1H) , 3.27 (s, 3H), 2.44-0.65 (m), 0.85 (s, 3H); 13C NMR (CDCI3) δ 221.4, 71.5, 70.8, 59.1, 54.6, 51.6, 47.9, 44.9, 39.0, 38.3, 35.8, 35.5, 32.0, 31.8, 31.6, 30.8, 28.0, 21.7, 21.6, 13.8. AnaI. CaIcd for C20H32O3: C, 74.96; H, 10.06. Found: C, 75.10; H, 9.95. SCHEME10

[0210] (3β, 5α, 17β) -17.19-Dimetoxiandrostan-3-oI (31, MQ-96). To a solution of steroid 7 (65 mg, 0.20 mmoI) in THF (10 mI) was added lithium tri-tert-butoxide hydride and aluminum (1.0 mmoI, 1.0 M in THF, 1, 0 mI) at -40 ° C. After 2 h, the mixture was cooled with 3 N HCl at -40 ° C and the reaction allowed to warm up to room temperature for 1 h. The product was extracted into dichloromethane (50 ml x 2) and washed with brine. The organic layers were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel with 25% EtOAc in hexanes) to generate product 31 (55 mg, 85%): mp 164-166 ° C; IR vmax 3370 cm-1; [a] D20 = 1.0 (c = 0.10, CHCla); 1H NMR (CDClβ) δ 3.65-3.57 (m, 1H), 3.51 (d, J = 10.2 Hz, 1H), 3.43 (d, J = 10.2 Hz, 1H) , 3.33 (s, 3H), 3.29 (s, 3H), 3.22 (t, J = 8.2 Hz, 1H), 2.24-0.60 (m), 0.76 ( s, 3H); 13C NMR (CDCl3) δ 90.8, 71.5, 71.0, 59.1, 57.8, 54.7, 51.5, 45.0, 43.0, 38.9, 38.5, 38.4, 35.8, 32.0, 31.8, 31.6, 28.2, 27.7, 23.2, 22.2, 11.7. Anal. Calcd for C21H36O3: C, 74.95; H, 10.78. Found: C, 74.91; H, 10.82. B. [35S] - DISPLACEMENT OF TBPS
[0211] IC50 values for non-competitive [35S] -TBPS shifters from the picrotoxin binding site on GABAA receptors are reported in Table 1. TABLE 1: [35S] -TBPS BINDING INHIBITION BY EXAMPLE COMPOUNDS
a The results presented are from duplicate experiments carried out in triplicate. The error limits are calculated as standard error of the mean. The methods used are known in the art (see, Jiang, X., et al., Neurosteroid analogues. 9. Conformationally constrained pregnanes: structure-activity studies of 13,24-cyclo-18,21-dinorcholane analogues of the GABA modulatory e anesthetic steroids (3α, 5α) - and (3α, 5α) -3-hydroxypregnan- 20-one. J. Med. Chem., 46: 5334-48 (2003) - whose contents are hereby incorporated by reference in your totality). C. ELECTROPHYSIOLOGY RESULTS
[0212] The compounds of the present disclosure were evaluated for their ability to potentiate chloride currents mediated by 2 μM GABA in rat αABβ2Y2L GABAA receptors expressed in Xenopus laevis oocytes and the results are shown in Table 2. TABLE 2: MODULATION GABAAαiβ2Y2L RAT RECEPTOR FUNCTION BY EXAMPLE COMPOUNDS

a The GABA concentration used for the control response was 2 μM. Each compound was evaluated in at least four different oocytes at the indicated concentrations and the reported results are the current ratio measured in the presence / absence of added compound. Gating represents the closed direct current per 10 μM of compound in the absence of GABA, and this current is reported as the current ratio of compound only / 2 μM of GABA current. The error limits are calculated as standard error of the mean (N> 4). The methods used are known in the art (see Jiang, X., et al.). D. LOSS OF STRAIGHTENING AND SWIMMING IN SWIRLS
[0213] Table 3 describes the anesthetic effects of the compounds of the present disclosure. In particular, the anesthetic effect of the compounds of the present disclosure on Loss of Straightening Reflex (LRR) and Loss of Swimming Reflex (LSR). TABLE 3: EFFECTS OF EXAMPLES ON SWIMMING AND SWIMMING REFLECTIONS


[0214] The methods used are known in the art (see Jiang, X., et al.). The error limits are calculated as standard error of the mean (N = 10 or more animals in each of the five or more different concentrations). E. LOSS OF RIGHT REFLECTION IN RATS
[0215] Plasma pharmacokinetics and a qualitative assessment of sedation were obtained in male Sprague Dawley rats according to the following procedure. The rats were dosed by intravenous bolus dose (60 seconds) through the dorsal vein of the paw in doses ranging from 5 to 15 mg / kg in an appropriate vehicle. To assess sedation, the rats were gently restrained by the hands to a lateral position for dose administration. If reduced muscle tone is observed during dose administration, the limitation has been gradually reduced. If the animal is unable to return to an upright position, time was recorded as the onset of loss of straightening reflex (LRR). In the event that LRR did not occur during dosing, the animals were evaluated at 5-minute intervals and then placed in a dorsal recumbency. Slow or incomplete straightening twice consecutively within a 30 second interval qualifies a loss of straightening reflex. After the start of LRR, the animals were evaluated every 5 minutes in the same way. Straightening reflex recovery is defined as the ability of a rat to straighten up completely within 20 seconds of being placed on a dorsal recumbency. The LRR duration is defined as the time interval between LRR and the straightening reflex return. TABLE 4: LOSS OF RIGHTINGO OF RIGHTING (LRR) IN RATS
A <10min; B 10-20 min; C> 20 min F. LOSS OF SIDE RECUMBENCE IN DOGS
[0216] Plasma pharmacokinetics and a qualitative assessment of sedation were obtained in male beagle dogs according to the following procedure. The dogs were dosed by bolus intravenous dose (60 seconds) through the cephalic vein at 5 mg / kg dose in an appropriate vehicle. To assess sedation, dogs were gently restricted to dose administration. If reduced muscle tone, limb weakness or a headache is observed during dose administration, the onset of lateral recumbency was recorded. In the case where the lateral recumbency does not occur during dosing, the animals were evaluated at 5-minute intervals, then being placed in a lateral recumbency. Slow or incomplete straightening to the sternal position qualifies as lateral recumbency. After the onset of lateral recumbency, the animals were evaluated every 5 minutes in the same way. The duration of lateral recumbency was recorded as the time interval between the beginning of lateral recumbency and the return to the sternal position. TABLE 5: DURATION OF SIDE RECUMBENCE IN DOGS
At <10 min; B 10-20 min; C> 20 min GENERAL METHODS
[0217] The compounds discussed in the present disclosure were produced as discussed elsewhere throughout that disclosure and by the following methods.
[0218] The solvents were used as purchased or dried and purified by standard methodology. The extraction solvents were dried with anhydrous Na2SO4 and after filtration, removed on a rotary evaporator. Flash chromatography was performed using silica gel (32 to 63 μm) purchased from Scientific Adsorbents (Atlanta, GA). The melting points were determined in a Kofler micro hot stage and are not corrected. FT-IR spectra were recorded as films on a NaCl plate. NMR spectra were recorded on CDCl3 at room temperature in 300 MHz (1H) or 74 MHz (13C). Purity was determined by TLC on 250 µm Uniplates ™ from Analtech (Newark, DE). All pure compounds (purity> 95%) generated a single spot on TLC. Elementary analyzes were performed by M-H-W Laboratories (Phoenix, AZ). EQUIVALENTS AND SCOPE
[0219] In view of the foregoing, it will be noted that several advantages of the disclosure are obtained and other advantageous results obtained. As several changes can be made to the above processes and composites without abandoning the scope of the disclosure, it is intended that the whole subject contained in the description above and shown in the attached drawings should be interpreted as illustrative and not in a limiting sense.
[0220] When introducing the elements of this disclosure or the various versions, realization (s) or aspects of it, the articles “one”, “one”, “o” and “said” are intended to mean that there is one or more elements. It will also be noted that the terms "comprising", "including", "having" or "containing" are intended to be unlimited and allow for the inclusion of additional elements or steps.

权利要求:
Claims (20)
[0001]
1. COMPOUND, characterized by being of formula (Ig):
[0002]
2. COMPOUND, according to claim 1, characterized in that the group R3 is selected from the group consisting of H, methyl and trifluoromethyl.
[0003]
COMPOSITE according to claim 1, characterized in that R2 is = O, methoxy or H.
[0004]
COMPOSITE according to claim 1, characterized in that R1 is beta-cyano.
[0005]
5. COMPOUND, according to claim 1, characterized by being selected from the group consisting of:
[0006]
6. COMPOUND according to claim 1, characterized in that R1 is selected from (C1-C4 alkyl) -O, spiro-oxirane, cyano, = O, (C1-C4 alkyl) C (O) and HO (C1 alkyl) -C4) C (O).
[0007]
7. COMPOUND, according to claim 1, characterized in that it has the formula:
[0008]
8. COMPOUND, according to claim 1, characterized in that it has the formula:
[0009]
9. COMPOUND, according to claim 1, characterized in that it has the formula:
[0010]
10. COMPOUND, according to claim 1, characterized in that it has the formula:
[0011]
11. COMPOUND, according to claim 1, characterized in that it has the formula:
[0012]
12. COMPOUND, according to claim 1, characterized in that it has the formula:
[0013]
13. PHARMACEUTICAL COMPOSITION, characterized in that it comprises a compound, as defined in any one of claims 7 to 12, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
[0014]
14. USE OF A COMPOUND, as defined in any one of claims 1 to 12, of a pharmaceutically acceptable salt thereof or of a pharmaceutical composition, as defined in claim 13, characterized in that it is for the manufacture of a medicament for inducing anesthesia in a guy who needs it.
[0015]
15. USE, according to claim 14, characterized in that the compound is of the formula:
[0016]
16. USE, according to claim 14, characterized in that the compound is of the formula:
[0017]
17. USE, according to claim 14, characterized in that the compound is of the formula:
[0018]
18. USE, according to claim 14, characterized in that the compound is of the formula:
[0019]
19. USE, according to claim 14, characterized in that the compound is of the formula:
[0020]
20. USE, according to claim 14, characterized in that the compound is of the formula: or a pharmaceutically acceptable salt thereof.

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KR101993899B1|2019-09-24|

---

AU2020202016A1|2020-04-09|

---

US20170152282A9|2017-06-01|

---

MX2019006739A|2019-08-22|

---

MX365644B|2019-06-10|

---

US9630986B2|2017-04-25|

---

SG10201706063UA|2017-09-28|

---

ES2680582T3|2018-09-10|

---

IL239501A|2020-11-30|

---

US20170232006A1|2017-08-17|

---

CN105026415A|2015-11-04|

---

CY1121150T1|2020-05-29|

---

MX2015007900A|2016-02-05|

---

EP2935307A4|2016-08-03|

---

US20150315230A1|2015-11-05|

---

AU2020202016B2|2021-09-23|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB820779A|1954-12-08|1959-09-23|Syntex Sa|Cyclopentanophenanthrene derivatives|

---

US2856415A|1957-11-13|1958-10-14|Searle & Co|3,19-dihydroxy-5-androstene derivatives|

---

BE632431A|1962-05-16|

---

US3206459A|1962-10-19|1965-09-14|Syntex Corp|10alpha-pregnan-19-ol derivatives|

---

US4071625A|1974-05-13|1978-01-31|Richardson-Merrell Inc.|19-Oxygenated-5α-androstanes for the enhancement of libido|

---

US4139617A|1974-05-13|1979-02-13|Richardson-Merrell Inc.|19-Oxygenated-androst-5-enes for the enhancement of libido|

---

DE2632677C2|1976-07-16|1988-06-16|Schering Ag, 1000 Berlin Und 4709 Bergkamen, De|

---

MA18433A1|1978-05-26|1979-12-31|Ciba Geigy Ag|PROCESS FOR THE SYNTHESIS OF THE HYDROXYACETYL SIDE CHAIN OF PREGNAGNE-TYPE STEROIDS, NEW 21-HYDROXY-20-OXO-17 ALPHA-PREGNAGNES AND PHARMACEUTICAL PRODUCTS CONTAINING|

---

US4389345A|1981-10-09|1983-06-21|G.D. Searle & Co.|3-Oxoestra-17-acetonitrile and unsaturated analogs|

---

US4495102A|1982-09-03|1985-01-22|G. D. Searle & Co.|Aminoalkyl steroids|

---

US5232917A|1987-08-25|1993-08-03|University Of Southern California|Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series|

---

EP0656365B1|1993-12-02|1997-04-09|Akzo Nobel N.V.|Substituted 2beta-morpholinoandrostane derivatives|

---

US5661141A|1995-03-27|1997-08-26|Petrow; Vladimir|19-oxygenated steroids as therapeutic agents|

---

BR9608592A|1995-06-06|1999-06-29|Cocensys Inc|Neuroactive steroids of the androstane and pregnane series|

---

US20020091112A1|2000-09-04|2002-07-11|Bernd Menzenbach|17-methylene steroids, process for their production and pharmaceutical compositions that contain these compounds|

---

US6844456B2|2000-11-03|2005-01-18|Washington University|Modified, hydroxy-substituted aromatic structures having cytoprotective activity|

---

GR1003861B|2000-12-29|2002-04-11|Θεοδωρα Καλογεροπουλου|Novel gabaa modulating neurosteroids|

---

AT454395T|2003-03-24|2010-01-15|Sterix Ltd|OESTROGEN DERIVATIVES AS STEROID SULPHATASE INHIBITORS|

---

CN1281561C|2003-04-23|2006-10-25|中国科学院上海有机化学研究所|Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof|

---

EP1626980A4|2003-05-29|2007-07-04|Univ Washington|Neuroactive 13,24-cyclo-18,21-dinorcholanes and structurally-related pentacyclic steroids|

---

WO2005051972A1|2003-11-24|2005-06-09|Merck & Co., Inc.|Estrogen receptor modulators|

---

DE102007027636A1|2007-06-12|2008-12-18|Bayer Schering Pharma Aktiengesellschaft|17β-Cyano-18α-homo-19-nor-androst-4-ene derivative, its use and the derivative-containing drug|

---

US8575375B2|2007-06-15|2013-11-05|Research Triangle Institute|Androstane and pregnane steroids with potent allosteric GABA receptor chloride ionophore modulating properties|

---

GB0711948D0|2007-06-20|2007-08-01|Bionature E A Ltd|Neurosteriod compounds|

---

AU2011284606A1|2010-07-30|2013-03-14|Pharmacellion Ltd|Compounds and methods for treating neoplasia|

---

CN103347525A|2010-12-15|2013-10-09|哈博生物科学公司|Methods and compounds for preparing 3alpha-oxygen substituted steroids|

---

WO2012116290A2|2011-02-25|2012-08-30|Washington University|Neuroactive 17-z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same|

---

ES2657986T3|2011-03-23|2018-03-07|Etsuro Ito|Method and kit for measuring very high sensitivity of protein and nucleic acid and a novel enzyme substrate|

---

WO2013188792A2|2012-06-15|2013-12-19|Sage Therapeutics, Inc.|Neuroactive steroids, compositions, and uses thereof|

---

US9765110B2|2012-10-08|2017-09-19|Washington University|Neuroactive 19-alkoxy-17-Z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same|

---

SI2935307T1|2012-12-18|2018-08-31|Washington University|Neuroactive 19-alkoxy-17-substituted steroids, useful in methods of treatment|

---

US9562026B2|2013-03-14|2017-02-07|Washington University|Neuroactive substituted cyclopent[a]anthracenes as modulators for GABA type-A receptors|

---

PT3035940T|2013-08-23|2019-01-28|Sage Therapeutics Inc|Neuroactive steroids, compositions, and uses thereof|NZ568700A|2005-11-28|2012-03-30|Marinus Pharmaceuticals|Solid stabilized particulate formulations comprising ganaxolone|

---

CN103958540B|2011-09-08|2017-12-05|萨奇治疗股份有限公司|Neuroactive steroids, composition, and application thereof|

---

CN108976272B|2011-10-14|2021-05-25|萨奇治疗股份有限公司|3, 3-disubstituted 19-norpregnane compounds, compositions, and uses thereof|

---

HUE046800T2|2012-01-23|2020-03-30|Sage Therapeutics Inc|Neuroactive steroid formulations comprising a complex of allopregnanolone and sulfobutyl ether beta-cyclodextrin|

---

SI2935307T1|2012-12-18|2018-08-31|Washington University|Neuroactive 19-alkoxy-17-substituted steroids, useful in methods of treatment|

---

CA2905359C|2013-03-13|2021-05-25|Sage Therapeutics, Inc.|Neuroactive steroids and methods of use thereof|

---

WO2014169836A1|2013-04-17|2014-10-23|Sage Therapeutics, Inc.|19-nor neuroactive steroids and methods of use thereof|

---

LT3498725T|2013-04-17|2021-09-27|Sage Therapeutics, Inc.|19-nor c3,3-disubstituted c21-n-pyrazolyl steroid for use in therapy|

---

WO2014169831A1|2013-04-17|2014-10-23|Sage Therapeutics, Inc.|19-nor c3,3-disubstituted c21-c-bound heteroaryl steroids and methods of use thereof|

---

RU2019126333A|2013-04-17|2019-10-08|Сейдж Терапьютикс, Инк.|19-NOR NEUROACTIVE STEROIDS AND WAYS OF THEIR APPLICATION|

---

AU2014290400B2|2013-07-19|2019-12-05|Sage Therapeutics, Inc.|Neuroactive steroids, compositions, and uses thereof|

---

PT3035940T|2013-08-23|2019-01-28|Sage Therapeutics Inc|Neuroactive steroids, compositions, and uses thereof|

---

WO2015195967A1|2014-06-18|2015-12-23|Sage Therapeutics, Inc.|Oxysterols and methods of use thereof|

---

WO2015195962A1|2014-06-18|2015-12-23|Sage Therapeutics, Inc.|Neuroactive steroids, compositions, and uses thereof|

---

JOP20200195A1|2014-09-08|2017-06-16|Sage Therapeutics Inc|Neuroactive steroids, compositions, and uses thereof|

---

EP3753927A1|2014-10-16|2020-12-23|Sage Therapeutics, Inc.|Compositions and methods for treating cns disorders|

---

RU2733756C2|2014-10-16|2020-10-06|Сейдж Терапьютикс, Инк.|Compositions and methods for treating cns disorders|

---

PT3224269T|2014-11-27|2020-06-01|Sage Therapeutics Inc|Compositions and methods for treating cns disorders|

---

RS61530B1|2015-01-26|2021-04-29|Sage Therapeutics Inc|Compositions and methods for treating cns disorders|

---

EP3258939A4|2015-02-20|2018-08-29|Sage Therapeutics, Inc.|Neuroactive steroids, compositions, and uses thereof|

---

MA45276A|2015-06-18|2018-04-25|Sage Therapeutics Inc|NEUROACTIVE STEROID SOLUTIONS AND THEIR METHODS OF USE|

---

DK3319612T3|2015-07-06|2021-08-23|Sage Therapeutics Inc|OXYSTEROLS AND METHODS FOR USE THEREOF|

---

CA2991311A1|2015-07-06|2017-01-12|Sage Therapeutics, Inc.|Oxysterols and methods of use thereof|

---

ES2865258T3|2015-07-06|2021-10-15|Sage Therapeutics Inc|Oxysterols and procedures for their use|

---

EP3362042A1|2015-10-16|2018-08-22|Marinus Pharmaceuticals, Inc.|Injectable neurosteroid formulations containing nanoparticles|

---

WO2017087864A1|2015-11-20|2017-05-26|Sage Therapeutics, Inc.|Compounds and methods of their use|

---

CN113616661A|2016-03-08|2021-11-09|萨奇治疗股份有限公司|Neuroactive steroids, compositions and uses thereof|

---

US10752653B2|2016-05-06|2020-08-25|Sage Therapeutics, Inc.|Oxysterols and methods of use thereof|

---

LT3481846T|2016-07-07|2021-08-25|Sage Therapeutics, Inc.|11-substituted 24-hydroxysterols for use in the treatment of nmda related conditions|

---

JP2019524853A|2016-08-23|2019-09-05|セージ セラピューティクス， インコーポレイテッド|Crystalline 19-nor C3,3-disubstituted C21-N-pyrazolyl steroid|

---

US10391105B2|2016-09-09|2019-08-27|Marinus Pharmaceuticals Inc.|Methods of treating certain depressive disorders and delirium tremens|

---

EP3519422A1|2016-09-30|2019-08-07|Sage Therapeutics, Inc.|C7 substituted oxysterols and methods as nmda modulators|

---

TW201827057A|2016-10-18|2018-08-01|美商賽吉醫療公司|OXYSTEROL and methods of use thereof|

---

RU2019115113A3|2016-10-18|2020-12-21|

---

CN109988210A|2017-12-30|2019-07-09|天津药业研究院有限公司|A kind of preparation method of progesterone and progesterone intermediate|

---

CN109289095B|2018-11-23|2021-03-26|淮海工学院|Enteroscope gel containing lidocaine hydrochloride and preparation method thereof|

---

US11266662B2|2018-12-07|2022-03-08|Marinus Pharmaceuticals, Inc.|Ganaxolone for use in prophylaxis and treatment of postpartum depression|

---

US10857163B1|2019-09-30|2020-12-08|Athenen Therapeutics, Inc.|Compositions that preferentially potentiate subtypes of GABAA receptors and methods of use thereof|

---

WO2021195297A1|2020-03-25|2021-09-30|Sage Therapeutics, Inc.|Use of agents for treatment of respiratory conditions|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-10-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2019-11-12| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-06-30| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-02| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/12/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261738822P| true| 2012-12-18|2012-12-18|

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US61/738,822|2012-12-18|

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PCT/US2013/076214|WO2014100228A1|2012-12-18|2013-12-18|Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using same|

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