Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using the same

Abstract

To provide: compounds for use as an anesthetic and / or in treatment of disorders relating to the GABA function and activity; and pharmaceutical compositions comprising the compounds.SOLUTION: A pharmaceutical composition comprises a neuroactive 19-alkoxy-17-substituted steroid represented by the formula in the figure, and a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] government support The subject matter herein was developed with government support under NIH Grant #GM47969 awarded by the National Institutes of Health. Accordingly, the government has certain rights in the subject matter herein.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61 / 738,822, filed December 18, 2012, the entire contents of which are incorporated herein by reference.

[0003] 2. Background of the Invention The present invention relates generally to novel compounds having utility as anesthetic agents and / or in the treatment of disorders associated with GABA function and activity. More specifically, the present invention relates to steroids having a 19-alkoxy-17-substituted tetracyclic structure, pharma- ceutically acceptable salts and prodrugs thereof, which are neuroactive and suitable for use as anesthetic agents, and pharmaceutical compositions containing them. [Background technology]

[0004] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA is an ionotropic GABA receptor. A and metabolic GABA B GABA activates two types of receptors. B Activation of the receptors causes hyperpolarization and consequent inhibition of neurotransmitter release. A Receptor subtypes control neuronal excitability and rapid mood swings, e.g. anxiety, panic, and stress responses. GABA A The receptor is a chloride ion channel, so that activation of the receptor induces an increase in inward chloride ion flux, leading to membrane hyperpolarization and neuronal inhibition. GABA receptors, like benzodiazepines and barbiturates, ADrugs that stimulate the receptors have anticonvulsant effects (by reducing neuronal excitability and raising the seizure threshold) as well as anxiolytic and anesthetic effects.

[0005] GABA A The effects of certain steroids on GABA receptors are well established. As a result, researchers continue to seek to discover and synthesize neuroactive steroids that may serve as anesthetic agents and / or provide treatment for disorders related to GABA function. For example, the intravenous anesthetic alphaxalone (Compound A, below) inhibits GABA receptors in the brain. A It is now widely recognized that alphaxalone produces general anesthesia in humans by allosterically increasing chloride currents mediated by GABA acting at receptors. However, the various structural features that enable this compound to function in this manner have not been fully understood to date. For example, compared to alphaxalone, Δ 16 -Alphaxalone (compound B, see below) is a GABA A It has been observed to have greatly reduced allosteric activity at the receptor and is not used as an intravenous general anesthetic agent in humans. [ka]

[0006] The difference in the actions of these two compounds is partly due to the presence of a carbon-carbon double bond in the D ring, which has attracted the attention of many researchers. In fact, it has been recently shown that the effect of this double bond on anesthetic activity depends on the group attached to C-17 on the D ring (Bandyopadhyaya, AK, et al., “Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ 16-alphaxalone and their corresponding 17-carbonitrile analogues.” Bioorg. Med. Chem. Lett., 20: 6680-4 (2010))

[0007] In addition to anesthetic properties, neuroactive steroids may be used to treat disorders related to GABA function. For example, neuroactive steroids such as progesterone can be used as hypnotic sedatives, exerting benzodiazepine-like effects, decreasing sleep latency and increasing non-REM sleep, with only minor changes in slow-wave and REM sleep. Furthermore, drugs that enhance GABA responses are often used to treat anxiety in humans. It is therefore expected that GABA-enhancing steroids will exert anxiolytic effects. Neuroactive steroids may also be used to treat depression, given that patients with major depression have reduced levels of GABAergic neurosteroids and accumulating evidence suggests that certain treatments for depression alter the levels of these steroids. Although GABA is not usually thought to have a significant role in the biology of depression, there is evidence that low GABAergic activity may be a predisposing factor for mood disorders. And NMDA receptor inhibition and GABA A Although receptor potentiation is thought to play an important role in mediating the acute effects of ethanol on the nervous system, related studies suggest that GABAergic neurosteroids are involved in some of the pharmacological actions of ethanol and that neuroactive steroids may be useful in the treatment of ethanol withdrawal. Summary of the Invention [Problem to be solved by the invention]

[0008] From the above, it is clear that there are numerous possibilities in which neurosteroids can be used advantageously. As a result, there remains a need to further synthesize and understand new neuroactive steroids, particularly those that have utility as anesthetic agents and / or in the treatment of disorders associated with GABA function and activity. [Means for solving the problem]

[0009] Summary of the Invention In one aspect, the present invention provides a compound of formula (I): [ka] [During the ceremony, R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) and HO(C1-C4 alkyl)C(O), where R1 is preferably in the β position when other than =O and / or in one or more preferred embodiments C1-C4 alkyl is methyl and R1 is therefore selected from methoxy, spirooxirane, cyano, =O, nitro, CH3C(O)- and OHCH2C(O)-; R2 is =O, H or OR a where R a is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl (provided that when R2 is =O, R8 is absent); 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 a substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl (particularly an alkoxy-substituted methyl or, more particularly, -CH2-OR b where R b is C1-C4 alkyl or, more specifically, -CH2-OCH3; R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, an optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; --- is any additional C-C bond resulting in a C=C bond between C4-C5 or C5-C6 (provided that, when present, the hydrogen of R5-H is absent); and --- is C 16 -C 17 and any additional C-C bond resulting in a C=C bond between (provided that, when present, R1 is other than =O). or a pharma- ceutically acceptable salt thereof.

[0010] The present invention further relates to a pharma- ceutically acceptable salt of said compound, or a prodrug thereof. In one embodiment, the present invention relates to a compound of formula (II): [ka] [During the ceremony, R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) and HO(C1-C4 alkyl)C(O), where R1 is preferably in the β position when other than =O and / or in one or more preferred embodiments C1-C4 alkyl is methyl and R1 is therefore selected from methoxy, spirooxirane, cyano, =O, nitro, CH3C(O)- and OHCH2C(O)-; R2 is =O, H or OR a where R a is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl (provided that when R2 is =O, R8 is absent); R x =O or OR d where R d is H or C(O)R e where R eis optionally substituted C1-C 22 Alkyl or optionally substituted C-C 22 alkenyl, R x When is OH, it is in the β position; R4 is independently selected from H and unsubstituted C1-C4 alkyl; R5 is a substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl (particularly an alkoxy-substituted methyl or, more particularly, -CH2-OR b where R b is C1-C4 alkyl or, more specifically, -CH2-OCH3; R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, an optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; --- is any additional C-C bond resulting in a C=C bond between C4-C5 or C5-C6 (provided that, when present, the hydrogen at C5-H is absent); and --- is C 16 -C 17 and any additional C-C bond resulting in a C=C bond between (provided that, when present, R1 is other than =O). or a pharma- ceutically acceptable salt thereof. However, this compound has the following structure: [ka] or (i) R x is ═O, a C═C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and CH3C(O)—; and / or (ii) Rx is β-OH, a C═C bond is present between C5-C6, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and HOCH2C(O)—.

[0011] The present invention further relates to pharmaceutical compositions comprising one or more of the above steroid compounds or their prodrugs or pharma- ceutically acceptable salts, and optionally a pharma- ceutically acceptable carrier. The present invention also provides kits comprising the steroids, prodrugs, salts or pharmaceutical compositions thereof.

[0012] The present invention further provides a method of inducing anesthesia in a subject in need thereof, the method comprising administering to the subject one or more of the above-mentioned steroids or their prodrugs or pharma- ceutically acceptable salts or a pharmaceutical composition thereof.

[0013] The present invention further provides a method for treating a disorder related to GABA function in a subject in need of such treatment, comprising administering to the subject one or more of the above steroids or their prodrugs or pharma- ceutically acceptable salts or pharmaceutical compositions thereof.In some embodiments, the disorder is selected from the group consisting of insomnia, mood disorders, convulsive disorders, anxiety or symptoms of ethanol withdrawal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present invention has found that compounds having certain embodiments of 17-substituted steroid structures, more particularly certain 19-alkoxy-17-substituted steroid structures, and even more particularly certain embodiments of 19-methoxy-17-substituted steroid structures, are neuroactive and suitable for use as anesthetics and in the treatment of disorders related to GABA function, as well as their pharmacologic acceptable salts and prodrugs.The compounds can be used, for example, as effective continuous infusion sedatives for non-surgical procedures (e.g., colonoscopy).The compounds also provide benefits over anesthetics known in the art, such as low potential for bacterial contamination and improved association with solubilizing agents.

[0015] 1. Steroid Structure Generally speaking, the steroids of the present invention have a hydroxyl substituent in the alpha configuration at the C3 position of the A ring and a hydroxyl substituent in the C 17 The fused ring structure has a tetracyclic ring such as a cyclopenta[a]phenanthrene ring system (described in more detail below) with a substituent bonded at position 14 selected from the group consisting of methoxy, spirooxirane, cyano, =O, nitro, CHC(O)-, and HOCHC(O)- (preferably in the β-position when R is other than =O).

[0016] More specifically, in one embodiment, the present invention relates to a compound of formula (I): [ka] [During the ceremony, R1 is selected from (C1-C4 alkyl)-O (e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) (e.g., CH3C(O), CH3CH2C(O), CH3CH2CH2C(O), CH3CH2CH2CH2C(O)) and HO(C1-C4 alkyl)C(O) (e.g., HOCH2C(O), HOCH2CH2C(O), HOCH2CH2CH2C(O), HOCH2CH2CH2CH2C(O)), where R1 is preferably in the β position when other than =O and / or in one or more preferred embodiments C1-C4 alkyl is methyl, R1 is therefore selected from methoxy, spirooxirane, cyano, =O, nitro, CH3C(O)- and OHCH2C(O)-; R2 is =O, H or OR a where R a is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl (provided that when R2 is =O, R8 is absent); 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 a substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl (particularly an alkoxy-substituted methyl or, more particularly, -CH2-OR b where R b is C1-C4 alkyl or, more specifically, -CH2-OCH3; R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, an optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; --- is any additional C-C bond resulting in a C=C bond between C4-C5 or C5-C6 (provided that, when present, the hydrogen of R5-H is absent); and --- is C 16 -C 17 and any additional C-C bond resulting in a C=C bond between (provided that, when present, R1 is other than =O). or a pharma- ceutically acceptable salt thereof.

[0017] As generally defined above, R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) and HO(C1-C4 alkyl)C(O). In some embodiments, R1 is preferably in the β position (when other than =O or when C=C is C 16 -C 17 (when not present between). In some embodiments, R1 is selected from (C1-C4 alkyl)-O (e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) (e.g., CH3C(O), CH3CH2C(O), CH3CH2CH2C(O), CH3CH2CH2CH2C(O)) and HO(C1-C4 alkyl)C(O) (e.g., HOCH2C(O), HOCH2CH2C(O), HOCH2CH2CH2C(O), HOCH2CH2CH2CH2C(O)). In some embodiments, C1-C4 alkyl is methyl, and thus R1 is selected from methoxy, spirooxirane, cyano, =O, nitro, CH3C(O)-, and OHCH2C(O)-.

[0018] R2 is =O, H or OR as generally defined above. a where R ais selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, except that when R2 is =O, R8 is absent. In some embodiments, R2 is =O and R8 is absent. In some embodiments, R2 is H. In some embodiments, R2 is OR a In some embodiments, R2 is OR a and R a is an optionally substituted C1, C2, C3 or C4 alkyl (e.g., methyl, ethyl), an optionally substituted C1, C2, C3 or C4 alkyl substituted with benzyl or O-aryl such as O-benzyl. In some embodiments, R2 is OR a and R a is optionally substituted aryl. In some embodiments, R2 is OR a and R a is H.

[0019] 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 some embodiments, R3 is H. In some embodiments, R3 is optionally substituted C1, C2, C3 or C4 alkyl (e.g., methyl, ethyl, trifluoromethyl, difluoromethyl). In some embodiments, R3 is methyl. In some embodiments, R3 is trifluoromethyl. In some embodiments, R3 is optionally substituted C2, C3 or C4 alkenyl (e.g., optionally substituted allyl). In some embodiments, R3 is optionally substituted C2, C3 or C4 alkynyl (e.g., optionally substituted acetylene or optionally substituted propargyl). In some embodiments, R3 is optionally substituted aryl (e.g., optionally substituted phenyl, e.g., OH, methyl or COR c phenyl substituted with, where R care, for example, optionally substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 or C 22 Alkyl or C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 or C 22 Optionally substituted C-C alkenyl 22 Alkyl or optionally substituted C-C 22 alkenyl).

[0020] As generally defined above, R4 is H or unsubstituted C1-C4 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is unsubstituted C1, C2, C3 or C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl or n-butyl).

[0021] As generally defined above, R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl. In some embodiments, R5 is substituted C1-C4 alkyl, particularly alkoxy-substituted C1-C4 alkyl. In other embodiments, R5 is substituted methyl, more particularly alkoxy-substituted methyl (or even more particularly -CH2-OR b where R bis C1-C4 alkyl, or more specifically -CH2-OCH3. In other embodiments, R5 is an optionally substituted C2-C4 alkenyl. In other embodiments, R5 is an optionally substituted C2-C4 alkynyl.

[0022] As generally defined above, R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy. In some embodiments, R6 is H. In some embodiments, R6 is optionally substituted C1, C2, C3, or C4 alkyl (e.g., methyl). In some embodiments, R6 is optionally substituted C1, C2, C3, or C4 alkoxy (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In some embodiments, when R6 is a non-hydrogen group, R6 is in the α (down) position. In certain preferred embodiments, however, when R6 is a non-hydrogen group, R6 is in the β (up) position.

[0023] As generally defined above, R7 is H, an optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring. In some embodiments, R7 is H. In some embodiments, R7 is an optionally substituted C1, C2, C3, or C4 alkoxy (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In some embodiments, R7 is an optionally substituted morpholinyl ring. In some embodiments, when R7 is a non-hydrogen group, R7 is in the α (down) position. In certain preferred embodiments, however, when R7 is a non-hydrogen group, R7 is in the β (up) position.

[0024] As generally defined above, R8, when present, is H or an optionally substituted C1-C4 alkyl. In some embodiments, R8 is H. In some embodiments, R8 is an optionally substituted C1, C2, C3 or C4 alkyl (e.g., methyl). In some embodiments, when R8 is an optionally substituted C1-C4 alkyl, R8 is in the α (down) position. In some embodiments, when R8 is an optionally substituted C1-C4 alkyl, R8 is in the β (up) position.

[0025] In some embodiments, R2 and R8 are both H. In some embodiments, R2 is OR a and R8 is H.

[0026] As generally defined above, --- is any additional CC bond resulting in a C=C bond between C4-C5 or C5-C6, but when present, the hydrogen of R5-H is absent. In some embodiments, the additional CC bond is absent and the hydrogen of C5 is in the alpha or beta position. In some embodiments, the additional CC bond is absent and the hydrogen of C5 is in the alpha (down) position. In some embodiments, the additional CC bond is absent and the hydrogen of C5 is in the beta (up) position. In some embodiments, --- is any additional CC bond resulting in a C=C bond between C4-C5. In some embodiments, --- is any additional CC bond resulting in a C=C bond between C5-C6.

[0027] As generally defined above, --- is C 16 -C 17 and any additional CC bond resulting in a C=C bond between, but when present, R1 is other than =O. In some embodiments, the additional CC bond is absent (i.e., not a C=C bond), and therefore R1 can be in the alpha or beta position. In some embodiments, the additional CC bond is absent, and R1 is in the alpha (down) position. In some embodiments, the additional CC bond is absent, and R1 is in the beta (up) position.

[0028] It should be noted that the present invention contemplates and intends to include all of the various combinations and permutations (ie, combinations of substituent options, positions and stereochemical configurations) possible herein.

[0029] For example, in various embodiments, the compounds of the invention include, among others, R2 is =O; or R2 can be H and R8 is H (e.g., thus, C 11 has two hydrogen atoms as substituents attached thereto), may be selected from those encompassed by the structure of formula (I). In some embodiments, R2 is OR a where R a is methyl, optionally substituted benzyl or C1-C4 alkyl substituted with O-aryl such as O-benzyl. In some embodiments, R3 is H, methyl, trifluoromethyl or substituted aryl (e.g., substituted phenyl, which may optionally be further substituted, e.g., with OH, methyl or COR c where R c is C1-C4 alkyl); furthermore, when R3 is anything other than H, R3 is preferably in the β-position. In some embodiments, each of R4 and R6 is independently selected from H and methyl, R5 is in the β-position, and R6 is optionally in the α- or β-position (e.g., when R6 is methyl), with the β-position being preferred. In some embodiments, R7 is selected from H, methoxy, ethoxy, and an optionally substituted morpholinyl ring, furthermore, when R7 is anything other than H, R7 is preferably in the β-position. In some embodiments, R8, when present, is selected from H or optionally substituted C1-C4 alkyl. In some embodiments, R8 is methyl (e.g., methyl in the α-position).

[0030] In some embodiments, C5-H is in the α position and R5 is a substituted methyl group (e.g., alkoxy-substituted methyl or especially methoxy-substituted methyl) in the β position. In some embodiments, C5-H is in the β position and R5 is, for example, a substituted methyl group (e.g., methoxy-substituted methyl) in the β position. In some embodiments, R6 is H. In some embodiments, R4 is methyl. In some embodiments, R2 is =O or methoxy.

[0031] Thus, as stated, the steroids of formula (I) may, in accordance with the present invention, encompass a large number of different structures.

[0032] In some embodiments, the compound of formula (Ia) is represented by the formula (Ia) in which R1 is as defined above, R3 is in the β position, R4 is methyl, and therefore R5 is a substituted methyl in the β position, and R6 is H. [ka] wherein --, R2, R3, R7 and R8 are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the alpha configuration. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the beta configuration. In some embodiments, C 16 -C 17 There is no --- between them, and R1 is in the β position.

[0033] In certain embodiments of formula (I) where R2 is =O and R8 is absent, formula (Ib) [ka] wherein --, R3 and R7 are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the alpha configuration. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the beta configuration. In some embodiments, C 16 -C 17 There is no --- between them, and R1 is in the β position.

[0034] In certain embodiments of formula (I), where R2 and R8 are H, formula (Ic) [ka] wherein --, R2, R3 and R7 are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the alpha configuration. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the beta configuration. In some embodiments, C 16 -C 17 There is no --- between them, and R1 is in the β position.

[0035] R2 is OR a and R8 is H. In certain embodiments of formula (I), formula (Id) [ka] [Wherein, ---, R3, R7 and R a is as defined herein, and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the alpha configuration. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the beta configuration. In some embodiments, C16 -C 17 There is no --- between them, and R1 is in the β position.

[0036] In certain embodiments of formula (I), wherein R7 is H, formula (Ie) [ka] wherein --, R2, R3 and R8 are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the alpha configuration. In some embodiments, the -- between C5-C6 and C6-C7 is absent, and C5-H is in the beta configuration. In some embodiments, C 16 -C 17 There is no --- between them, and R1 is in the β position.

[0037] In certain embodiments of formula (I), where -- between C5-C6 and C6-C7 are both absent and C5-H is in the alpha position, formula (If) [ka] wherein R, R, R and R are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. 16 -C 17 There is no --- between them, and R1 is in the β position.

[0038] In some embodiments of formula (I) where R7 is H, formula (Ig) [ka] wherein R2, R3 and R8 are as defined herein; and R bis an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. 16 -C 17 There is no --- between them, and R1 is in the β position.

[0039] In certain embodiments of formula (I), where R2 is =O, formula (Ih) [ka] wherein R3 and R7 are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. 16 -C 17 There is no --- between them, and R1 is in the β position.

[0040] R2 is OR a In certain embodiments of formula (I), wherein the formula is [ka] [In the formula, R a , R3 and R7 are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. 16 -C 17 There is no --- between them, and R1 is in the β position.

[0041] In certain embodiments of formula (I), - between C5-C6 and C6-C7 is an additional C-C bond resulting in a C=C bond between C4-C5, [ka] wherein R, R, R and R are as defined herein; and R bis an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. 16 -C 17 There is no --- between them, and R1 is in the β position.

[0042] In certain embodiments of formula (I), - between C5-C6 and C6-C7 is an additional C-C bond resulting in a C=C bond between C5-C6, [ka] wherein R, R, R and R are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. 16 -C 17 There is no --- between them, and R1 is in the β position.

[0043] In one or more of the preferred embodiments detailed above, R1 may be selected from, in particular, methoxy, or more generally, lower alkoxy, such as -O-(C1-C4 alkyl), or CH3C(O)- or HOCH2C(O)-, or more generally, substituted or unsubstituted lower alkyl-carbonyl, such as (C1-C4 alkyl)C(O)-, it should be noted that one or more of the carbon atoms may be optionally substituted, for example, with a hydroxyl group. Alternatively, R1 may be selected from nitro or cyano, and any C=C may be C 16 -C 17 In yet another embodiment, C 17 may be a carbonyl carbon (i.e., R1 is =O) or may be part of an oxirane ring fused to the D ring (i.e., R1 is a spirooxirane substituent where C 17 is a carbon atom shared by both rings).

[0044] Examples of compounds of formula (I) are: [ka] and pharma- ceutically acceptable salts thereof, wherein in one preferred embodiment, R b is CH3.

[0045] In some embodiments, the steroid of formula (I) is [ka] and pharma- ceutically acceptable salts thereof, where R is as defined above, and in one particular embodiment is H; and in this and other preferred embodiments, R b is CH3.

[0046] In some embodiments, the steroid of formula (I) is [ka] and pharma- ceutically acceptable salts thereof, where R is as defined above, and in one particular embodiment is H; and in this and other preferred embodiments, R b is CH3.

[0047] In some embodiments, the steroid of formula (I) is [ka] and pharma- ceutically acceptable salts thereof, wherein R and / or R are as defined above, and in one particular embodiment, R is H and R is methoxy, and in these or other preferred embodiments, R b is CH3.

[0048] In some embodiments, the steroid of formula (I) is [ka] and pharma- ceutically acceptable salts thereof, where R is as defined above, and in one particular embodiment is H; and in this and other preferred embodiments, R b is CH3.

[0049] In some embodiments, the steroid of formula (I) is [ka] and pharma- ceutically acceptable salts thereof, where R is as defined above, and in one particular embodiment is H; and in this and other preferred embodiments, R b is CH3.

[0050] In this regard, it should be noted that the structures illustrated above are illustrative of various embodiments, and therefore should not be viewed in a limiting sense.

[0051] 2. Prodrug Structure In another aspect, the present invention generally relates to prodrugs of various steroids as detailed above. Generally speaking, as used herein, "prodrugs" refers to inactive or significantly less active forms of the steroids detailed above (and in particular steroids of formula (I)), which are metabolized in vivo after administration to one or more of the active metabolites of the steroids of formula (I). Prodrugs may be formed using means generally known in the art, and therefore may take essentially any form recognized by those skilled in the art. Prodrugs of the present invention may advantageously provide improved absorption, distribution, metabolism and / or excretion optimization of the steroids detailed above (and in particular steroids of formula (I)), while at the same time providing improved oral bioavailability.

[0052] In another embodiment of the present invention, the prodrug of the steroid disclosed herein has the formula (II): [ka] [During the ceremony, R1 is selected from (C1-C4 alkyl)-O (e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) (e.g., CH3C(O), CH3CH2C(O), CH3CH2CH2C(O), CH3CH2CH2CH2C(O)) and HO(C1-C4 alkyl)C(O) (e.g., HOCH2C(O), HOCH2CH2C(O), HOCH2CH2CH2C(O), HOCH2CH2CH2CH2C(O)), where R1 is preferably in the β position when other than =O and / or in one or more preferred embodiments C1-C4 alkyl is methyl, R1 is therefore selected from methoxy, spirooxirane, cyano, =O, nitro, CH3C(O)- and OHCH2C(O)-; R2 is =O, H or OR a where R a is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl (provided that when R2 is =O, R8 is absent); R x =O or OR d where R d is H or C(O)R e where R e is optionally substituted C1-C 22 Alkyl or optionally substituted C-C 22 alkenyl, R x When is OH, it is in the β position; R4 is independently selected from H and unsubstituted C1-C4 alkyl; R5 is a substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, or an optionally substituted C2-C4 alkynyl (particularly an alkoxy-substituted methyl or, more particularly, -CH2-OR b where R b is C1-C4 alkyl or, more specifically, -CH2-OCH3; R6 is H, optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkoxy; R7 is H, an optionally substituted C1-C4 alkoxy or an optionally substituted morpholinyl ring; R8, when present, is H or optionally substituted C1-C4 alkyl; --- is any additional C-C bond resulting in a C=C bond between C4-C5 or C5-C6 (provided that, when present, the hydrogen of C5-H is absent); and --- is C 16 -C 17 (provided that, when present, R1 is not =O.) or a pharma- ceutically acceptable salt thereof; However, this compound has the following structure: [ka] or (i) R x is ═O, a C═C bond is present between C4-C5, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and CH3C(O)—; or (ii) R x is β-OH, a C═C bond is present between C5-C6, and R5 is CH2OCH3, then R1 is selected from methoxy, spirooxirane, cyano, nitro, and HOCH2C(O)—.

[0053] In this regard, it should be noted that the present invention contemplates and is intended to include all of the various combinations and permutations (ie, combinations of substituent options, positions and stereochemical configurations) possible herein.

[0054] As generally defined above, R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) and HO(C1-C4 alkyl)C(O). In some embodiments, R1 is preferably in the β position (when other than =O or when C=C is C 16 -C 17 (when not present between). In some embodiments, R1 is selected from (C1-C4 alkyl)-O (e.g., methoxy, ethoxy, propoxy, butoxy), spirooxirane, cyano, =O, nitro, (C1-C4 alkyl)C(O) (e.g., CH3C(O), CH3CH2C(O), CH3CH2CH2C(O), CH3CH2CH2CH2C(O)) and HO(C1-C4 alkyl)C(O) (e.g., HOCH2C(O), HOCH2CH2C(O), HOCH2CH2CH2C(O), HOCH2CH2CH2CH2C(O)). In some embodiments, C1-C4 alkyl is methyl, and thus R1 is selected from methoxy, spirooxirane, cyano, =O, nitro, CH3C(O)-, and OHCH2C(O)-.

[0055] As generally defined above, R x =O or OR d where R d is H or C(O)R e where R e is optionally substituted C1-C 22 Alkyl or optionally substituted C-C 22 Alkenyl (e.g., optionally substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 or C 22 Alkyl or C2, C3, C4, C5, C6, C7, C8, C9, C10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 or C 22 alkenyl), with the proviso that R x When R is OH, it is in the β (up) position. x is ═O. In some embodiments, R x is OH in the β (upward) position. x OR d , R d is C(O)R e and R e is optionally substituted C1-C 22 Alkyl or optionally substituted C-C 22 alkenyl, e.g., C(O)CH3, in which case the group R x is provided in either the α or β configuration (the β configuration is preferred). x OR d and R d If is H, then R x is an OH atom in the β (upward) configuration.

[0056] R2 is =O, H or OR as generally defined above. a where R a is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl (with the proviso that when R2 is =O, R8 is absent). In some embodiments, R2 is =O and R8 is absent. In some embodiments, R2 is H. In some embodiments, R2 is OR a In some embodiments, R2 is OR a and R ais an optionally substituted C1, C2, C3 or C4 alkyl (e.g., methyl, ethyl), an optionally substituted C1, C2, C3 or C4 alkyl substituted with benzyl or O-aryl such as O-benzyl. In some embodiments, R2 is OR a and R a is optionally substituted aryl. In some embodiments, R2 is OR a and R a is H.

[0057] As generally defined above, R4 is H or unsubstituted C1-C4 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is unsubstituted C1, C2, C3 or C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl or n-butyl).

[0058] As generally defined above, R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl or optionally substituted C2-C4 alkynyl. In some embodiments, R5 is substituted C1-C4 alkyl, particularly alkoxy-substituted C1-C4 alkyl. In other embodiments, R5 is substituted methyl, more particularly alkoxy-substituted methyl (or even more particularly -CH2-OR b where R b is C1-C4 alkyl, or more specifically -CH2-OCH3). In other embodiments, R5 is an optionally substituted C2-C4 alkenyl. In other embodiments, R5 is an optionally substituted C2-C4 alkynyl.

[0059] As generally defined above, R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy. In some embodiments, R6 is H. In some embodiments, R6 is optionally substituted C1, C2, C3, or C4 alkyl (e.g., methyl). In some embodiments, R6 is optionally substituted C1, C2, C3, or C4 alkoxy (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In some embodiments, when R6 is a non-hydrogen group, R6 is in the α (down) position. In certain preferred embodiments, however, when R6 is a non-hydrogen group, R6 is in the β (up) position.

[0060] As generally defined above, R7 is H, an optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring. In some embodiments, R7 is H. In some embodiments, R7 is an optionally substituted C1, C2, C3, or C4 alkoxy (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, or n-butoxy). In some embodiments, R7 is an optionally substituted morpholinyl ring. In some embodiments, when R7 is a non-hydrogen group, R7 is in the α (down) position. In certain preferred embodiments, however, when R7 is a non-hydrogen group, R7 is in the β (up) position.

[0061] As generally defined above, R8, when present, is H or an optionally substituted C1-C4 alkyl. In some embodiments, R8 is H. In some embodiments, R8 is an optionally substituted C1, C2, C3 or C4 alkyl (e.g., methyl). In some embodiments, when R8 is an optionally substituted C1-C4 alkyl, R8 is in the alpha (down) position. In some embodiments, when R8 is an optionally substituted C1-C4 alkyl, R8 is in the beta (up) position.

[0062] In some embodiments, R2 and R8 are both H. In some embodiments, R2 is OR a and R8 is H.

[0063] As generally defined above, --- is any additional CC bond resulting in a C=C bond between C4-C5 or C5-C6, but when present, the hydrogen of R5-H is absent. In some embodiments, the additional CC bond is absent and the hydrogen of C5 is in the alpha or beta position. In some embodiments, the additional CC bond is absent and the hydrogen of C5 is in the alpha (down) position. In some embodiments, the additional CC bond is absent and the hydrogen of C5 is in the beta (up) position. In some embodiments, --- is any additional CC bond resulting in a C=C bond between C4-C5. In some embodiments, --- is any additional CC bond resulting in a C=C bond between C5-C6.

[0064] As generally defined above, --- is C 16 -C 17 and any additional CC bond resulting in a C=C bond between, but when present, R1 is other than =O. In some embodiments, the additional CC bond is absent (i.e., it is not a C=C bond), and therefore R1 can be in the alpha or beta position. In some embodiments, the additional CC bond is absent, and R1 is in the alpha (down) position. In some embodiments, the additional CC bond is absent, and R1 is in the beta (up) position.

[0065] In some embodiments, the prodrugs of the present invention can be selected from those encompassed by the structure of formula (II) where R2 is =O. In some embodiments, R2 is H and R8 is H, e.g., C 11 Thus, R has two hydrogen atoms attached thereto as substituents. In some embodiments, R is OR a where R a is methyl, optionally substituted benzyl or C1-C4 alkyl substituted with O-aryl such as O-benzyl. x is ═O. In some embodiments, R xis β-hydroxy. In some embodiments, R x OR d where R d is H or C(O)R e where R e is an optionally substituted C1-C4 alkyl (e.g., methyl). In some embodiments, each of R4 and R6 is independently selected from H and methyl. In some embodiments, R6 is an optionally substituted alkyl, e.g., methyl, optionally in the alpha configuration, if there is no carbon-carbon double bond between C5-C6. In some embodiments, R6 is an optionally substituted alkyl, e.g., methyl, optionally in the beta configuration, if there is no carbon-carbon double bond between C5-C6. In some embodiments, R7 is selected from H, methoxy, ethoxy, and an optionally substituted morpholinyl ring. In some embodiments, R7 is a non-hydrogen group, and R7 is in the beta configuration. In some embodiments, a carbon-carbon double bond (or unsaturated bond) may be present between the carbon atoms of C4-C5 or C5-C6. In some embodiments, R8, when present, is selected from H or an optionally substituted C1-C4 alkyl, preferably methyl, more preferably alpha-methyl.

[0066] In one embodiment, R x is OH and is in the beta position. In some embodiments, a carbon-carbon double bond is between the C4-C5 carbon atoms. In some embodiments, a carbon-carbon double bond is between the C5-C6 carbon atoms. In some embodiments, R2 is =O. In some embodiments, R2 is methoxy. In some embodiments, R7 is H. In some embodiments, R7 is beta-methoxy. In some embodiments, R7 is beta-ethoxy.

[0067] In some embodiments, R4 is methyl, such that R5 is a substituted methyl in the β-position, and R6 is H. [ka] [In the formula, R1, ---, Rx , R2, R7 (preferably in the β-position) and R8 (preferably in the β-position) are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the β (up) position. In some embodiments, the -- between C5-C6 and C6-C7 are both absent, and C5-H is in the α position. In some embodiments, the -- between C5-C6 and C6-C7 are both absent, and C5-H is in the β position. In some embodiments, -- represents an additional CC bond resulting in a C=C bond between C4-C5 or C5-C6. In some embodiments, C 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0068] In certain embodiments of formula (II) where R2 is =O and R8 is absent, formula (II-b) [ka] [In the formula, R1, ---, R x and R7 (preferably in the β-position) are as defined herein, and further, R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R xis OH in the β (up) position. In some embodiments, the -- between C5-C6 and C6-C7 are both absent, and C5-H is in the α position. In some embodiments, the -- between C5-C6 and C6-C7 are both absent, and C5-H is in the β position. In some embodiments, -- represents an additional CC bond resulting in a C=C bond between C4-C5 or C5-C6. In some embodiments, C 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0069] In some embodiments of formula (II) where R2 is H and R8 is H, formula (II-c) [ka] [In the formula, R1, ---, R x and R7 (preferably in the β-position) are as defined herein, and further, R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the β (up) position. In some embodiments, the -- between C5-C6 and C6-C7 are both absent, and C5-H is in the α position. In some embodiments, the -- between C5-C6 and C6-C7 are both absent, and C5-H is in the β position. In some embodiments, -- represents an additional CC bond resulting in a C=C bond between C4-C5 or C5-C6. In some embodiments, C 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0070] R2 is OR aand R8 is H. In certain embodiments of formula (II), [ka] [Wherein R1, --, R3, R7 (preferably in the β-position) and R a is as defined herein, and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. In some embodiments, none of --- is present and C5-H is in the alpha position. In some embodiments, none of --- is present and C5-H is in the beta position. In some embodiments, --- represents an additional CC bond resulting in a C=C bond between C4-C5 or C5-C6. In some embodiments, C 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0071] In some embodiments of formula (II) where R7 is H, formula (II-e) [ka] [In the formula, R1, ---, R x , R and R (preferably in the β-position) are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the β (up) position. In some embodiments, none of the -- is present and C5-H is in the α position. In some embodiments, none of the -- is present and C5-H is in the β position. In some embodiments, -- represents an additional CC bond resulting in a C=C bond between C4-C5 or C5-C6. In some embodiments, C 16 -C 17is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0072] In certain embodiments of formula (II), where there is no -- between C5-C6 and C6-C7 and C5-H is in the alpha position, formula (II-f) [ka] [In the formula, R1, R x , R2, R7 (preferably in the β-position) and R8 (preferably in the β-position) are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the beta (up) position. 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0073] In certain embodiments of formula (II), where R7 is H, formula (II-g) [ka] [In the formula, R1, R x , R and R (preferably in the β-position) are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the beta (up) position. 16 -C 17is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0074] In certain embodiments of formula (II), where R2 is =O, formula (II-h) [ka] [In the formula, R1, R x and R7 (preferably in the β-position) are as defined herein, and further, R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the beta (up) position. 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0075] R2 is OR a In certain embodiments of formula (II), the formula (II-i) [ka] [In the formula, R1, R x , R a and R7 (preferably in the β-position) are as defined herein, and further, R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the beta (up) position. 16 -C 17is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between 。

[0076] In some embodiments of formula (II), where --- is an additional C-C bond resulting in a C=C bond between C4-C5, formula (II-j) [ka] [In the formula, R1, R x , R2, R7 (preferably in the β-position) and R8 (preferably in the β-position) are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R x is OH in the beta (up) position. 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between 。

[0077] In some embodiments of formula (II), where --- is an additional C-C bond resulting in a C=C bond between C5-C6, formula (II-k) [ka] [In the formula, R1, R x , R2, R7 (preferably in the β-position) and R8 (preferably in the β-position) are as defined herein; and R b is an optionally substituted C1-C4 alkyl. or a pharma- ceutically acceptable salt thereof. x is ═O. In some embodiments, R xis OH in the beta (up) position. 16 -C 17 is absent and R1 is in the β position. 16 -C 17 represents an additional C=C bond between

[0078] In one or more of the preferred embodiments detailed above, R1 may be selected from methoxy, in particular or more generally lower alkoxy, such as -O-(C1-C4 alkyl), or may be selected from CH3C(O)- or HOCH2C(O)- or more generally substituted or unsubstituted lower alkyl-carbonyl, such as (C1-C4 alkyl)C(O)-, where it should be noted that one or more of the carbon atoms may be optionally substituted, for example with a hydroxyl group. Alternatively, R1 may be selected from nitro or cyano, where any C=C may be C 16 -C 17 In yet another embodiment, C 17 may be a carbonyl carbon (i.e., R1 is =O) or may be part of an oxirane ring fused to the D ring (i.e., R1 is a spirooxirane substituent where C 17 is a carbon atom shared by both rings).

[0079] Examples of compounds of formula (II) are: [ka] and pharma- ceutically acceptable salts thereof, wherein in one preferred embodiment, R b is CH3.

[0080] In this regard, it should be noted that the structures illustrated above are exemplary of various embodiments, and therefore should not be viewed in a limiting sense.

[0081] 3. Manufacturing Methods and Pharmaceutical Compositions It should be noted that the steroid or prodrug of the compound of the present invention can be prepared and used in various embodiments by means generally known in the art.For example, in some embodiments, the steroid or prodrug of the present invention can be prepared and used in pharma-ceutically acceptable salt form, for example, when R7 is an optionally substituted morpholinyl ring.Suitable salt forms include, for example, citrate or hydrochloride forms.

[0082] In various aspects of the present invention, the present invention discloses pharmaceutical compositions that may include steroids represented by the formulas disclosed herein, prodrugs, or combinations of two or more thereof. The compounds of the present invention, steroids (or prodrugs thereof), as well as various salt forms and other pharma- ceutically acceptable forms, such as solvates and / or hydrates of the compounds described herein, and pharmaceutical compositions containing them, may be prepared using methods generally known in the art and / or methods and techniques described in the examples provided herein.

[0083] Without wishing to be bound by any particular theory, it is believed that the steroids which are the compounds of the present invention act as GABA receptor antagonists. A These compounds are useful for potentiating GABA at a receptor and therefore for inducing anesthesia in a subject, e.g., a human subject, or for treating a disorder associated with GABA function (e.g., insomnia, mood disorders, seizure disorders, anxiety disorders, or symptoms associated with ethanol withdrawal), preferably administered in the form of a pharmaceutical composition comprising an effective amount of a compound of the invention and optionally a pharma- ceutically or pharmacologically acceptable carrier.

[0084] In one aspect, there is provided a method of inducing anesthesia in a subject in need thereof, the method comprising administering to the subject one or more of the above-mentioned steroids or prodrugs or pharma- ceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0085] In another aspect, a method for treating a disorder associated with GABA function in a subject in need thereof is provided, the method comprising administering to the subject one or more of the above steroids or their prodrugs or pharma- ceutically acceptable salts or pharmaceutical compositions thereof. In some embodiments, the disorder is selected from the group consisting of insomnia, mood disorders, seizure disorders, anxiety, or symptoms associated with ethanol withdrawal.

[0086] In one embodiment of the present invention, the therapeutically effective amount of the 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 to about 16 mg / kg. In some embodiments, the therapeutically effective amount of the compound is about 8 mg / kg. It should be understood that the dosage ranges described herein provide guidance for administering the pharmaceutical composition provided to an adult. For example, the amount to be administered to a child or minor can be determined by a physician or a person skilled in the art, and may be a lower dose than or the same as the amount administered to an adult.

[0087] The amount of compound required to achieve an effective dose varies from subject to subject, for example, depending on the species, age and general physical condition of the subject, the characteristics of the particular compound, the method of administration, etc. The desired dosage can be delivered three times a day, twice a day, once a day, every other day, every third day, every week, every other week, every third week, or every fourth week. In some embodiments, the desired dosage can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0088] It is also recognized that the compounds or compositions described herein can be administered in combination with one or more additional therapeutically active agents to improve bioavailability, reduce and / or modify metabolism, limit excretion, and / or modify biodistribution.

[0089] The compounds or compositions may be administered simultaneously with, prior to, or subsequent to one or more additional therapeutically active agents. Generally, each agent is administered at a dosage and / or time schedule established for that agent. It is also recognized that the additional therapeutically active agents used in the combination may be administered together in a single composition or individually in different compositions. The particular combination to use in a regimen will take into account the compatibility of the compounds of the invention with the additional therapeutically active agents and / or the desired therapeutic effect to be achieved. In general, it is expected that the additional therapeutically active agents used in combination will be utilized at levels that do not exceed the levels when used individually. In some embodiments, the levels used in combination are lower than the levels used individually. Examples of therapeutically active agents include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration under the provisions of 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, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0090] The pharmaceutical composition may also be combined with at least one pharma- ceutically acceptable carrier. A carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant or diluent, refers to any substance that is pharma- ceutically inert, gives the composition a suitable consistency or form, and does not reduce the therapeutic effect of the compound. A carrier is "pharma- ceutically or pharmacologically acceptable" if it does not produce any untoward, allergic or other adverse reaction when administered to a mammal or human, as appropriate.

[0091] Pharmaceutical compositions containing the steroid compounds of the present invention may be formulated in any conventional manner. Suitable formulations depend on the route of administration selected. The compositions disclosed herein may be formulated for any route of administration, provided that the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intrathecal, intraperitoneal or intrasternal), topical (intranasal, transdermal, intraocular), intravesical, intrathecal, intestinal, pulmonary, intralymphatic, intracavity, vaginal, transurethral, ​​intradermal, auricular, intramammary, buccal, orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual and intestinal administration. In some embodiments, the route of administration is oral. In some embodiments, the route of administration is parenteral. In some embodiments, the route of administration is intravenous.

[0092] The pharmaceutically acceptable carrier for use in the composition of the present invention is well known to those skilled in the art and is selected based on many factors, including, for example, the specific compound used and its concentration, stability and intended bioavailability, the disease, disorder or condition treated with the composition, the subject, its age, body size and general physical condition, and / or administration route.Appropriate carrier can be easily determined by those skilled in the art (for example, see JG Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp.1492-1517).

[0093] The compositions may be formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, liquids, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form that can be administered orally. Techniques and compositions for preparing oral dosage forms useful in the present invention are described, for example, in the following 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 2 (1982); nd Edition (1976).

[0094] The composition of the present invention designed for oral administration comprises an effective amount of the compound of the present invention in a pharma-ceutically acceptable carrier.Suitable carriers for solid dosage forms include sugar, starch and other conventional materials, including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate and stearic acid.Furthermore, such solid dosage forms can be uncoated or coated by known techniques (for example, to delay disintegration and absorption).

[0095] The steroids and prodrugs of the compounds of the present invention may also be formulated for parenteral administration (e.g., prepared for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intrathecal, intraperitoneal or intrasternal routes). The compositions of the present invention for parenteral administration contain an effective amount of the compounds in a pharma- ceutically acceptable carrier. The dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage forms that can be administered parenterally. Methods and compositions for preparing parenteral dosage forms are known in the art. Preparations for parenteral administration are typically sterile or sterilized before administration.

[0096] Suitable carriers for preparing liquid dosage forms for oral or parenteral administration include non-aqueous, pharma- ceutically acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons, and mixtures thereof, as well as water, saline solution, dextrose solution (e.g., DW5), electrolyte solutions, or any other aqueous, pharma- ceutically acceptable liquid.

[0097] Suitable non-aqueous, pharma- ceutically acceptable polar solvents include alcohols (e.g., α-glycerol formal, β-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms, such 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 (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidone; esters (e.g. 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetates such as monoacetin, diacetin and triacetin, aliphatic or aromatic esters such as ethyl caprylate or ethyl octanoate, alkyl oleates, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono-, di- or triglycerides of citric or tartaric acid, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceride esters such as glyceryl monostearate, mono-, di- or triglycerides, fatty acid esters such as isopropyl myristate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated) 30-60 sorbitol poly(oleate) 2-4, poly(oxyethylene) 15-20 monooleate, poly(oxyethylene) 15-20 mono 12-hydroxystearate and poly(oxyethylene) 15-20 mono-ricinoleate, polyoxyethylene sorbitan esters (such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate and ICI Americas, Wilmington,Polysorbate® 20, 40, 60 or 80 from Del.), polyvinylpyrrolidone, alkyleneoxy-modified fatty acid esters (e.g. polyoxyl 40 hydrogenated castor oil, cyclodextrins or modified cyclodextrins (e.g. β-hydroxypropyl-cyclodextrin)), saccharide fatty acid esters (i.e. monosaccharides (e.g. pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetraoses, heptoses and octose), disaccharides (e.g. sucrose, maltose, lactose and trehalose) or oligosaccharides or mixtures thereof with C4-C, 22condensation products of fatty acids (s) (e.g. saturated fatty acids, such as caprylic acid, capric acid, 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 ethers having 2 to 30 carbon atoms (e.g. diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3 to 30 carbon atoms (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms (e.g. benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylene sulfone, tetramethylene sulfoxide, toluene, dimethyl sulfoxide (DMSO) or tetramethylene sulfoxide) ;oils of mineral, vegetable, animal, essential or synthetic origin (e.g. mineral oils, such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic-based hydrocarbons and refined paraffin oils, vegetable oils, such as linseed oil, tung oil, safflower oil, soybean oil, castor oil, cottonseed oil, groundnut oil, rapeseed oil, coconut oil, palm oil, olive oil, corn oil, corn germ oil, sesame oil, apricot kernel oil and peanut oil and glycerides, such as mono-, di- or triglycerides, animal oils, such as fish oil, marine oil, sperm whale oil, liver oil, halibut liver oil, squalene, squalane and shark liver oil, oleic acid oil and polyoxyethylated castor oil; alkyl or aryl halides having 1 to 30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzine; trolamine; omega-3 polyunsaturated fatty acids (e.g. alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid); polyglycol esters of 12-hydroxystearic acid and polyethylene glycols (Solutol® HS-15 from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol;Including, but not limited to, sodium laurate; sodium oleate; or sorbitan monooleate.

[0098] Other pharma- ceutically acceptable solvents for use in the present invention are known to those of skill in the art and may be found in such publications as 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 (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, Pa., 1995), The United States Pharmacopeia 24, The National Formulary 19 (National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, J. of Pharm. Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

[0099] Preferred solvents include cyclodextrin or modified cyclodextrins (eg, β-hydroxypropyl-cyclodextrin) as well as triglyceride rich oils such as safflower oil, soybean oil or mixtures thereof and alkyleneoxy-modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil. Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), and Liposyn® III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.). Ill.), natural or synthetic glycerol derivatives containing 25-100% docosahexaenoyl groups by weight, based on total fatty acid content, including DHA Maguro® (Daito Enterprises, Los Angeles, Calif.), Soyacal®, and Travemulsion®.

[0100] Additional minor components may be added to the compositions disclosed herein for various purposes well known in the pharmaceutical industry. These components are mostly those that impart properties that provide benefits such as prolonging the retention of the compound at the site of administration, protecting the stability of the composition, adjusting pH, and facilitating processing of the compound into pharmaceutical formulations. Preferably, each of these components is individually present in less than about 15 wt% of the total composition, more preferably less than about 5 wt% of the total composition, and most preferably less than about 0.5 wt%. Some components, such as fillers or diluents, may constitute up to 90 wt% of the total composition, as is well known in the formulation art.Such additives include low temperature deposition inhibitors, surfactants, wetting agents or emulsifiers (e.g., lecithin, Polysorbate-80, Tween® 80, Pluronic 60, polyoxyethylene stearate), preservatives (e.g., ethyl p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and parabens), pH adjusters or buffers (e.g., acids, bases, sodium acetate, sorbitan monolaurate), osmotic regulators (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guargonium chloride, glyceryl stearate ... cellulose, methylcellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g., bentonite), adhesives, extenders, flavorings, sweeteners, adsorbents, fillers (e.g., sugars, e.g., lactose, sucrose, mannitol or sorbitol, cellulose or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders (e.g., starches, e.g., mayonnaise, starch, for example maize starch, wheat starch, rice starch or potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sugar, polymer, acacia), disintegrating agents (for example starches, for example maize starch, wheat starch, rice starch, potato starch or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, for example sodium alginate, croscarmellose sodium or crospovidone), lubricants (for example silica, talc, stearic acid or a salt thereof, for example magnesium stearate or polyethylene glycol), coating agents (for example gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol or concentrated sugar solutions containing titanium dioxide) and antioxidants (for example sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenol and thiophenol).

[0101] Administration by these routes can be effected continuously or intermittently, taking into account, for example, the physiological state of the patient, whether the purpose of the administration is therapeutic or prophylactic, and other factors known and assessable by the skilled practitioner.

[0102] Those with ordinary skill in administering anesthetics can easily determine the dosage and administration regimen of the pharmaceutical composition of the present invention, or titrate the effective dosage for use in treating insomnia, mood disorders, convulsive disorders, anxiety, or symptoms of ethanol withdrawal. It is understood that the dosage of the compound will depend on the age, sex, physical condition, and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. For any method of administration, the actual delivery amount of the compound and the administration schedule required to achieve the beneficial effects described herein will depend, in part, on the bioavailability of the compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those skilled in the art. The dosage administered to an animal, particularly a human, in the context of the present invention, should be sufficient to produce the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of a compound, whether administered orally or by other route, is that amount that produces the desired therapeutic response when administered by that route. The dosage may vary with administration schedule, and can be adjusted as necessary to achieve the desired therapeutic effect. The most preferred dosage can be determined for each individual subject without undue experimentation, as one of skill in the art will appreciate.

[0103] In one embodiment, the solution for oral administration is prepared by dissolving the compound in any pharma- ceutically acceptable solvent (e.g., ethanol or methylene chloride) that can dissolve the compound to produce a solution. To the solution, an appropriate volume of a solvent carrier, such as β-hydroxypropyl-cyclodextrin, is added with stirring to prepare a pharma-ceutically acceptable solution for oral administration to a patient. If desired, the formulation can be formulated to contain minimal or no ethanol, which is known to cause adverse physiological effects when administered in oral formulations containing more than a certain concentration.

[0104] In other embodiments, to prepare powders or tablets for oral administration, the compound is dissolved in any pharma- ceutically acceptable solvent (e.g., ethanol or methylene chloride) that can dissolve the compound. The solvent can be optionally evaporated and the solution dried under reduced pressure. An additional carrier, such as β-hydroxypropyl-cyclodextrin, can be added to the solution before drying. The resulting solution is dried under reduced pressure to form a glassy material. The glassy material is then mixed with a binder to form a powder. The powder can be mixed with a filler or other conventional tableting agent and compressed to form a tablet for oral administration to a patient. The powder can also be added to any of the liquid carriers listed above to form solutions, emulsions, suspensions, and the like for oral administration.

[0105] To prepare an emulsion for parenteral administration, the compound is dissolved in any pharma- ceutically acceptable solvent (e.g., ethanol or methylene chloride) that the compound can dissolve in. An appropriate volume of a carrier that is an emulsion, such as Liposyn® II or Liposyn® III emulsion, is added to the solution with stirring to form a pharma- ceutically acceptable emulsion for parenteral administration to a patient.

[0106] Solutions for parenteral administration can be prepared by dissolving the compound in any pharma- ceutically acceptable solvent (e.g., ethanol or methylene chloride) that the compound can be dissolved in. An appropriate volume of a carrier, such as β-hydroxypropyl-cyclodextrin, is added to the solution with stirring to form a pharma- ceutically acceptable solution for parenteral administration to a patient.

[0107] If desired, the emulsions or solutions for oral or parenteral administration described above can be packaged in concentrated form in IV bags, vials or other convenient containers and diluted with any pharma- ceutically acceptable liquid, such as saline, to an acceptable concentration prior to use, as known to those of skill in the art.

[0108] Further included in the present invention is a kit (e.g., pharmaceutical pack). The kit provided may include a compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe and / or a dispenser package or other suitable container). In some embodiments, the kit provided may further include a second container that optionally includes a pharmaceutical carrier for dilution or a suspension of the pharmaceutical composition or compound. In some embodiments, the pharmaceutical composition or compound provided in the container and the second container are combined to form a unit dosage form.

[0109] If desired, such kits of the present invention further include instructions for use. Such instructions generally provide, for example, dosage and instructions for administration. In other embodiments, instructions provide additional information related to specific instructions for specific containers and / or systems for administration. Instructions may also provide specific instructions for use in conjunction and / or in combination with other therapeutic agents.

[0110] 4. Definition As used herein, the term "steroid" refers to organic compounds that contain a cyclopenta[a]phenanthrene ring system in their structural backbone.

[0111] The term "pharmaceutically acceptable salts" as used herein refers to salts that, in the opinion of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and that provide a reasonable benefit / risk 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 the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts refer to salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-phenylpropionate salts, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109, 109, 109, 109, 109, 108 + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include non-toxic ammonium, quaternary ammonium and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.

[0112] The term "prodrug" as used herein refers to a pharmacological agent that is administered in a less active or inactive form. After administration, the prodrug is metabolized in vivo, for example, by hydrolysis, oxidation, or reaction under biological conditions (in vitro or in vivo) to produce an active metabolite. See, e.g., Wu, Pharmaceuticals (2009) 2:77-81. In some embodiments, the prodrug has improved physical and / or delivery properties compared to the parent compound. Prodrugs are typically designed to enhance efficacy and / or pharmacokinetic properties based on the parent compound. The advantages of a prodrug are due to its physical properties, such as increased water solubility at physiological pH for parenteral administration, or enhanced absorption through the digestive tract or skin, or enhanced drug stability for long-term storage, compared to the parent compound.

[0113] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, mammals, e.g., humans (i.e., males and females of any age, e.g., pediatric subjects (e.g., children, minors) or adult subjects (e.g., young adults, middle-aged adults, or geriatrics)), other primates (e.g., cynomolgus monkeys, rhesus monkeys), and mammals of commercial value, such as cows, pigs, horses, sheep, goats, cats, and / or dogs. In any aspect and / or embodiment of the invention, the subject is a human.

[0114] As used herein, a "therapeutically effective amount," a "sufficient amount," or a "sufficient amount" of a compound refers to the level, amount, or concentration of a compound required for a desired biological response, e.g., analgesia.

[0115] As used herein, the term "saturated" refers to a state in which all available valence bonds of an atom (especially carbon) are attached to other atoms.

[0116] As used herein, the term "unsaturated" refers to the condition in which not all available valence bonds along an alkyl chain are filled; in such compounds, the extra bonds usually form double or triple bonds (mainly carbon-carbon).

[0117] When a range of values ​​is recited, it is intended to encompass each value and subrange within that range. For example, "C 1-4 Alkyl" is C1, C2, C3, C4, C 1-3 , C 1-2 , C 2-4 , C 2-3 and C 3-4 Alkyl is intended to be included, and "C 1-22 Alkyl" includes, for example, C1, C2, C3, C4, etc., as well as C 1-21 , C 1-20 , C 1-15 , C 1-10 , C 2-20 , C 2-15 , C 2-10 , C 3-15 , C 3-10 Such alkyl groups are intended to include:

[0118] As used herein, "alkyl" refers, in certain embodiments, to alkyl groups having 1 to 4 carbon atoms ("C 1-4 alkyl") and in other embodiments 1 to 22 carbon atoms ("C 1-22 The term "alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C 1-2 In some embodiments, the alkyl group has one carbon atom (“C alkyl”). In some embodiments, the alkyl group has two to four carbon atoms (“C 2-4In yet other embodiments, the alkyl group has 1 to 21 carbon atoms (“C 1-21 alkyl), 1 to 20 carbon atoms ("C 1-20 alkyl), 1 to 15 carbon atoms ("C 1-15 alkyl), 1 to 10 carbon atoms ("C 1-10 Examples of such alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), pentyl (C5), and the like.

[0119] As used herein, "alkenyl" or "alkene" refers, in certain embodiments, to an alkyl group having 2 to 4 carbon atoms ("C 2-4 alkenyl”) and in other embodiments 2 to 22 carbon atoms (“C 2-22 Alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group is a group having 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms (“C alkenyl”). In yet other embodiments, an alkenyl group has 2 to 21 carbon atoms (“C 2-21 alkenyl), 2 to 20 carbon atoms ("C 2-20 alkenyl), 2 to 15 carbon atoms ("C 2-15 alkenyl), 2 to 10 carbon atoms ("C 2-10 The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of such alkenyl groups include ethenyl (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 "alkyne" refers to an alkynyl group containing 2 to 4 carbon atoms and one or more carbon-carbon triple bonds ("C 2-10Alkynyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has two carbon atoms (“C alkynyl”). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.

[0121] As used herein, "aryl" refers to an aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms in the aromatic ring system ("C6- 14 Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 atoms in the ring). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 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 defined herein may be substituted or unsubstituted, also referred to herein as "optionally substituted". In general, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not naturally undergo mutation, such as by rearrangement, cyclization, elimination or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position of a structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution at any of the acceptable substituents of organic compounds, any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein which satisfy the valence of the heteroatom and result in the formation of a stable group.

[0124] Examples of substituents include groups containing a heteroatom (e.g., nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atom), halogen (e.g., chlorine, bromine, fluorine or iodine), heterocycle, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketal, acetal, ester and ether.

[0125] Treatment Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) have demonstrated that certain 3α-hydroxylated steroids are several orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than have been otherwise reported (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and Harrison et al. teach that 3β-hydroxyl-5-reduced steroids may exhibit much lower levels of efficacy. In vitro and in vivo experimental data now indicate that the high potency of these steroids makes them therapeutically useful in modulating GRC-mediated brain excitability (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(l):65-71 (1995)).

[0126] Various synthetic steroids have also been synthesized as neuroactive steroids, see for example U.S. Patent 5,232,917, which discloses neuroactive steroid compounds useful for treating stress, anxiety, insomnia, seizure disorders and mood disorders that can be treated with GRC activators, such as depression, in a therapeutically beneficial manner. Furthermore, these steroids have previously been shown to have beneficial effects in the treatment of stress, anxiety, sleep, mood disorders and seizure disorders (e.g., Gee, KW and Yamamura, HI, “Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders,” in Central Nervous System Disorders, 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 interact at a unique site on the GRC that is distinct from other known sites of interaction (e.g., barbiturates, benzodiazepines, and GABA). These compounds are preferred because of their duration of action, potency, and oral activity (as well as other forms of administration).

[0127] The compounds of the present invention described herein are generally designed to modulate GABA function and therefore act as neuroactive steroids for the treatment and prevention of conditions related to the CNS in a subject. Modulation as used herein refers to the inhibition or enhancement of GABA receptor function. Thus, the compounds and pharmaceutical compositions provided herein have found use as therapeutic agents for the prevention and / or treatment of CNS conditions in mammals, including human and non-human mammals. Thus, and as described above, the present invention includes within its scope and extends to the listed methods of treatment and the use of such compounds for the manufacture of compounds for such methods and medicaments useful for such methods.

[0128] In some embodiments, disclosed herein is a method for treating GABAergic disorders by administering to a subject an effective amount of a compound described herein. A Methods for treating conditions associated with GABA receptor modulation. AExamples of conditions associated with receptor modulation include (a) sleep disorders [e.g., insomnia and REM sleep behavior disorder], epilepsy [e.g., status epilepticus, monogenic forms of epilepsy (e.g., Dravet syndrome), Lennox-Gastaut syndrome, infantile spasms, juvenile myoclonic epilepsy, acute repetitive seizures, febrile seizures], movement disorders [e.g., Huntington's disease, Parkinson's disease, cerebellar ataxia, Friedreich's ataxia, stiff-body syndrome, dystonia, Tourette's syndrome, essential tremor], and the like. (b) neurological disorders, including traumatic brain injury, pain disorders [e.g., neuropathic pain, chronic pain due to injury, acute pain, migraine, status migraineus], ​​vascular disorders [e.g., stroke, ischemia, sequelae of vascular malformations], neurodegenerative disorders [e.g., Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, multiple system atrophy, multi-infarct dementia] and tinnitus; (b) schizophrenia and schizoaffective disorder, mood disorders [e.g., depression, dysthymic disorder, bipolar disorder, anxiety disorder]. (e.g., generalized anxiety disorder, social anxiety disorder, phobias, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder), stress)], cognitive disorders [e.g., attention deficit hyperactivity disorder], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders [e.g., idiopathic autism, monogenic causes of autism (e.g., Rett syndrome, tuberous sclerosis complex, fragile X syndrome, Angelman syndrome)] and substance abuse disorders [e.g., opiate addiction, stimulant drug addiction (e.g., (c) psychiatric disorders including postpartum depression, postpartum dysphoria disorder, polycystic ovary syndrome, catamenial epilepsy, preterm birth, pre-eclampsia, eclampsia, premenstrual and menstrual migraine; (d) inflammatory disorders including multiple sclerosis, asthma and rheumatoid arthritis; (e) anesthetic indications including full spectrum of sedation including mild sedation / anxiolysis, moderate / procedural sedation, monitored sedation management, deep sedation and general anesthesia.

[0129] In another aspect, provided is a method of treating or preventing brain excitability in a subject predisposed to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention.

[0130] In yet another aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof.

[0131] In yet another aspect, provided is a method of reducing or preventing seizure activity in a subject, comprising administering to said subject in need of such treatment an effective amount of a compound of the invention.

[0132] In yet another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0133] In yet another aspect, provided is a method for inducing sleep and substantially maintaining levels of REM sleep observed in normal sleep without inducing substantial rebound insomnia comprising administering an effective amount of a compound of the invention.

[0134] In yet another aspect, provided is a method of alleviating or preventing PMS or PND in a subject, comprising administering to said subject in need of such treatment an effective amount of a compound of the invention.

[0135] In yet another aspect, provided is a method of treating or preventing a mood disorder in a subject, comprising administering to said subject in need of such treatment an effective amount of a compound of the invention. In some embodiments, the mood disorder is depression.

[0136] In yet another aspect, provided is a method of inducing anesthesia in a subject comprising administering to the subject an effective amount of a compound of the invention.

[0137] In yet another aspect, provided is a method for enhancing cognition or treating memory disorders by administering to a subject a therapeutically effective amount of a compound of the present invention. In some embodiments, the disorder is Alzheimer's disease. In some embodiments, the disorder is Rett syndrome.

[0138] In yet another aspect, provided is a method of treating an attention disorder by administering to a subject a therapeutically effective amount of a compound of the invention. In some embodiments, the attention disorder is ADHD.

[0139] In yet another aspect, provided are combinations of the compounds of the present invention with other pharmacologically active agents. The compounds provided herein may be administered as the sole active agent or in combination with other agents. The administration of the combination may be by any method apparent to one skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration.

[0140] In some embodiments, the compound is administered chronically to the subject. In some embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0141] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state of memory loss, 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 alone provides the right combination of effects, or from a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve a combination of sometimes very specific results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.

[0142] Sedation is the reduction of irritability or agitation, typically through the administration of a drug, to facilitate a medical or diagnostic procedure.

[0143] Sedation and analgesia include a continuum of conscious states 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 may be impaired. Ventilatory and cardiovascular function are unaffected.

[0145] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness during which the patient responds purposefully to verbal commands alone or with light tactile stimulation. No interventions are required to maintain a patent airway. Spontaneous ventilation is sufficient. Cardiovascular function is usually preserved.

[0146] Deep sedation / analgesia is a drug-induced reduced state of consciousness during which the patient is not easily aroused but responds purposefully (not with a reflexive escape from) after repetitive or painful stimulation. Independent ventilatory function may be impaired. The patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0147] General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable even to painful stimuli. The ability to maintain independent ventilatory function is often impaired. Assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to spontaneous ventilation depression or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0148] Sedation in the intensive care unit (ICU) allows the patient to suppress awareness of their environment and reduce their response to external stimuli. It has a central role in the care of critically ill patients and encompasses the management of a wide range of symptoms that vary between patients and individualize with the course of the disease. Heavy sedation in critical care is often used in conjunction with neuromuscular blocking agents to facilitate endotracheal tube tolerance and ventilator synchronization.

[0149] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives can have a long duration of action. Sedatives in the ICU can have a short elimination half-life.

[0150] Procedural sedation and analgesia, also called conscious sedation, is a technique in which a state is induced that allows a subject to tolerate unpleasant procedures while preserving cardiopulmonary function by administering sedative or dissociative drugs, with or without analgesics.

[0151] Anxiety disorders Anxiety disorder is a vague umbrella term that includes 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 long-term anxiety that is not specific to any one object or situation. Those who suffer from generalized anxiety experience unspecific and persistent fear and worry, and begin to worry excessively about everyday, mundane things. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0153] In panic disorder, people who suffer from a brief attack of intense fear and anxiety are often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as a sudden onset of fear or discomfort that peaks within 10 minutes, can last for several hours, and can even be triggered by stress, fear, or movement, but the specific cause is not always clear. In addition to the unexpected recurrence of panic attacks, the diagnosis of panic disorder also requires that the attacks have chronicity, either worry about the potential association of the attack, persistent fear of future attacks, or significant changes in behavior related to the attack. Thus, people who suffer from panic disorder experience symptoms even outside of a specific panic episode. Often, panic sufferers worry about the normal changes in their heartbeat, and begin to think that something is wrong with their heart or are on the verge of having another panic attack. In some cases, during a panic attack, there is heightened awareness of bodily functions (hyperarousal), and any perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., extreme hypochondria).

[0154] Obsessive-compulsive disorder is a type of anxiety disorder that is primarily characterized by recurrent obsessions (obsessive, persistent, and intrusive thoughts or images) and compulsions (urges to perform certain actions or rituals). OCD thought patterns can be likened to superstitions in that they involve the belief in causal relationships that do not exist in reality. Often the process is illogical; for example, a compulsion to walk in a certain pattern can be used to alleviate obsessive thoughts of impending harm. And in many cases the compulsions are quite mysterious, simply an urge to complete a ritual triggered by nervousness. In a few cases, OCD patients may experience only obsessions without obvious compulsions, and in far fewer cases patients experience only compulsions.

[0155] The single largest category of anxiety disorder is phobia, which includes all cases in which fear and anxiety are triggered by a particular stimulus or situation. Sufferers typically anticipate frightening consequences upon encountering the feared object, which can be anything from an animal to a place to a bodily fluid.

[0156] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, rape, hostage situations or even worse accidents. It can also be the result of prolonged exposure to severe stressors, such as a soldier who can withstand individual battles but not continuous battles. Common symptoms include flashbacks, avoidance behaviors and depression.

[0157] Neurodegenerative Diseases and Disorders The term "neurodegenerative disease" refers to diseases and disorders associated with the progressive loss of neuronal structure or function, or death of neurons.Neurodegenerative diseases and disorders include Alzheimer's disease (including conditions involving mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and seizures (including the treatment and prevention of seizures caused by schizoaffective disorder or caused by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusion injuries (e.g. spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impaired consciousness; Down's syndrome. Groups; Drug-induced or drug-induced parkinsonism (e.g. 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 impairment and loss; Huntington's disease; Lennox syndrome; Levodopa-induced dyskinesia; Mental retardation; Akinesia and akinetic (rigid) syndromes (basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia combination, Parkinson's disease, postencephalitic parkinsonism) movement disorders including idiopathic chorea (including idiopathic chorea, idiopathic chorea, progressive supranuclear palsy and progressive supranuclear palsy); chorea (e.g. benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, acanthocytosis, Sydenham chorea and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus), tremor (e.g. rest tremor, postural tremor and intention tremor) and dystonia (axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia and focal dystonia). muscle spasms and disorders associated with muscle spasms or weakness, including, for example, blepharospasm, oromandibular dystonia and spasmodic dysphonia and torticollis; neuronal damage, including ocular damage, retinopathy or macular degeneration; stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, memory loss, hypoxia, anoxia, perinatal anoxia and neurotoxic injury following cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; vascular sclerosis and viral infection-induced neurodegeneration (e.g., due to acquired immune deficiency syndrome (AIDS) and encephalopathy).Neurodegenerative diseases also include stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, memory loss, hypoxia, anoxia, perinatal anoxia, and neurotoxic injury following cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0158] Epilepsy Epilepsy is a brain disorder characterized by repeated seizures over a long period of time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0159] Status epilepticus (SE) Status epilepticus (SE) may include, for example, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus episodes and may include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epilepticus episodes that persist despite treatment with first-line therapy, leading to administration of second-line therapy. Refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy and for which second-line therapy and general anesthetics are typically administered. Super-refractory status epilepticus is characterized by status epilepticus that persists for more than 24 hours despite treatment with first-line therapy, second-line therapy and general anesthetics.

[0160] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, fine non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0161] The compositions described herein may be administered prophylactically to subjects with a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges, prior to the onset of seizures.

[0162] Seizures A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A seizure is when a person's body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0163] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0164] Generalized seizures are caused by electrical impulses from anywhere throughout the brain, while partial seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that produces the seizures is sometimes called the focus.

[0165] There are six types of generalized seizures. The most common, dramatic, and therefore best known are generalized convulsions, also called grand mal. During this type of seizure, the patient loses consciousness and usually collapses. After loss of consciousness, there is 30-60 seconds of generalized stiffening of the body (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent convulsions (the "clonic" phase), after which the patient goes into deep sleep (the "postictal" phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0166] Absence seizures cause a brief loss of consciousness (only a few seconds) with minimal or no symptoms. Affected people, most of whom are children, typically have a cessation of activity and a blank stare. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware that they have had a seizure, except that they may notice "time skipping."

[0167] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes refer to the jerks as brief electric shocks. When severe, these seizures can cause a person to drop or throw things involuntarily.

[0168] Clonic seizures are recurrent, rhythmic convulsions that involve both sides of the body at the same time.

[0169] Tonic seizures are characterized by muscle stiffening. Cataractic seizures consist of a sudden and total loss of muscle tone, especially in the arms and legs, often leading to a fall.

[0170] autism Autism is a neurobehavioral developmental syndrome occurring in early childhood consisting of a combination of social impairment, limited verbal and / or nonverbal communication, and restricted, repetitive and stereotyped patterns of behaviors, interests or activities. Autism spectrum disorders, as defined by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSMV), include autism, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified (PDD-NOS).

[0171] Autism has an onset before age 3, implying a period of normal development followed by a period of regression.

[0172] Asperger syndrome consists of social impairment and restricted, repetitive and stereotypical interests without language or cognitive delay.

[0173] Childhood disintegrative disorder is a milder form of autistic regression that begins after age 3.

[0174] PDD-NOS is characterized by milder symptoms than autism in only one domain (eg, social impairment).

[0175] Autism spectrum disorders can be idiopathic. However, there are many genetic causes of autism, including single gene mutations with high penetrance [e.g., Rett syndrome, tuberous sclerosis complex, fragile X syndrome, Angelman syndrome]. In some cases, only the gene mutation is used to designate the disorder [e.g., 22q13.3 deletion syndrome]. EXAMPLES

[0176] The following examples describe or illustrate various aspects of the present invention. Other aspects within the scope of the appended claims will be apparent to those skilled in the art from consideration of the details or practice of the invention disclosed herein. It is intended that the specification, together with the examples, be considered as exemplary only, with the scope and spirit of the invention being indicated in the claims which follow the examples.

[0177] A. Compound chemistry The following compounds have been prepared for illustrative purposes by the following methods and examples. [ka]

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

[0179] [ka] 19-[[(1,1-dimethyl)dimethylsilyl]oxy]-androst-4-ene-3,17-dione (1) A mixture of known 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 (5 mL) was stirred at room temperature for 15 h. Water (100 mL) was added to the reaction mixture and extracted with methylene chloride (50 mL × 3). The combined organic extracts were washed with brine, dried and concentrated to give a white solid. The solid was purified by flash column chromatography (silica gel eluted with 10-20% EtOAc in hexane) to give a white solid (1.3 g, 94%). mp 154-156 °C; IR 2856, 2930, 1739, 1670, 1472, 1359, 1255, 1228 cm -1 ; 1 H NMR (CDCl3) 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); 13 C 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×C), 21.6, 20.9, 18.0, 13.8, -5.76, -5.83

[0180] [ka] (5α)-19-[[(dimethylethyl)dimethylsilyl]oxy]-androstane-3,17-dione (2) A short cut of lithium wire (140 mg, 20 mmol) was added to stirring freshly condensed liquid ammonia (250 mL) (-78 °C) and the mixture was stirred for 15 min. A solution of steroid 1 (1.25 g, 3 mmol) in THF (75 mL) was added to the resulting deep blue solution and stirring was continued at -78 °C for 2 h. Solid ammonium chloride (5 g) was added and the ammonia was allowed to evaporate. Water (200 mL) was added and the reaction mixture was extracted with EtOAc (100 mL x 3). The combined EtOAc extracts were washed with brine, dried and concentrated to give an oil. The oil was dissolved in stirring acetone (50 mL) and cooled in an ice bath. Jones reagent was added to the stirring cold solution until the orange color persisted for 1 h. Excess Jones reagent was reduced with a few drops of isopropyl alcohol. 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 the solvent removed to give a white solid which was purified by chromatography (silica gel) to give steroid 2 (830 mg, 63%). mp 130-132 °C; IR 3339, 2922, 2857, 1445, 1360 cm -1 ; 1 H 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); 13 C NMR (CDCl3) δ 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×C), 21.7, 18.0, 13.8, -5.7, -5.9

[0181] [ka] (5α)-19-[[(dimethylethyl)dimethylsilyl]oxy]-androstane-3,17-dione, 3-cyclic 1,2-ethanediyl acetal (3) A solution of steroid 2 (4.6 g, 11.0 mmol) in benzene (~100 mL) with ethylene glycol (5 mL) and PPTS (500 mg) was heated under reflux in a 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 give 3,17-bisketal (3.5 g) and steroid 3 as a solidified foam (1.25 g). 1 H 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); 13 C 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;C 27 H 46 Analysis of O4Si Calculated: C, 70.08; H, 10.02. Found: C, 69.89; H, 10.0

[0182] [ka] (5α)-19-Hydroxyandrostane-3,17-dione, 3-cyclic 1,2-ethanediyl acetal (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, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give steroid 4 as an oil (638 mg, 84%). IR ν max 3487, 1738 cm -1- ; 1H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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] [ka] (5α,17β)-17,19-Dihydroxyandrostan-3-one, cyclic 1,2-ethanediyl 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 quenched with aqueous NH4Cl. The mixture was extracted with EtOAc (50 mL x 3) and the organic layers were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 35% EtOAc in hexane) to give steroid 5 as an oil (638 mg, 100%). 1 H 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); 13 C NMR (CDCl3) 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] [ka] (5α,17β)-17,19-Dimethoxyandrostane-3-one, cyclic 1,2-ethanediyl acetal (6) To a solution of steroid 5 (635 mg, 1.8 mmol) in THF (30 mL) was added sodium hydride (400 mg, 60% in mineral oil, 6.0 mmol). After 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 quenched with water and extracted with EtOAc (100 mL x 3). The organic extracts were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel eluted with 20% EtOAc in hexane) to give steroid 6 (623 mg, 92%). mp 102-104 °C; IR ν max 2922, 1448 cm -1- ; 1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) δ 109.1, 90.6, 70.9, 64.0 (2×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] [ka] (5α,17β)-17,19-Dimethoxyandrostane-3-one (7, MQ-88) A mixture of steroid 6 (625 mg, 1.65 mmol), PTSA (100 mg), acetone (30 ml) and water (3 mL) was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, aqueous NaHCO3 was added and the product was extracted with 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 hexane) to give steroid 7 (408 mg, 74%). mp 91-93 °C; [α] D 20 = 18.4 (c = 0.37, CHCl3); ν max 2922, 1714 cm -1 ; 1 H NMR (CDCl3) 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); 13 C 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.C 21 H 34 Analysis of O3 Calculated: C, 75.41; H, 10.25. Found: C, 75.37; H, 10.13

[0186] [ka]

[0187] [ka] (5α,17β)-17,19-Dimethoxyandrostan-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° C. After 2 h, 3N NaOH (10 mL) and H2O2 (5 mL) were added at −78° C. and the reaction was allowed to warm to room temperature in 1 h. The product was extracted with EtOAc (100 mL×2) and washed with brine. 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 hexane) to give steroid 8 (172 mg, 86%). mp 62-64° C.; [α] D 20 = 1.1 (c = 0.26, CHCl3); ν max 3382, 1447 cm -1 ; 1 H 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); 13 C NMR (CDCl3) 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.C 21 H 36 Analysis of O3 Calculated: C, 74.95; H, 10.78. Found: C, 75.19; H, 10.79

[0188] [ka]

[0189] [ka] (5α)-19-Methoxyandrostane-3,17-dione, cyclic bis-(1,2-ethanediyl acetal) (9) A mixture of the known (5α)-19-hydroxyandrostane-3,17-dione, cyclic bis-(1,2-ethanediyl)acetal (430 mg, 1.1 mmol), NaH (200 mg, 5 mmol) and THF (10 mL) was heated to reflux under N2 for 2 h. The reaction mixture was cooled to room temperature, 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 excess NaH was carefully consumed by addition of MeOH (2 mL). Water (100 mL) was added and the product was extracted with EtOAc (80 mL x 3). The combined organic extracts were washed with brine, dried and concentrated to give a colorless liquid. The crude product was purified by flash column chromatography (silica gel eluted with 15-20% EtOAc in hexanes) to give the product as a colorless liquid (440 mg, 99%). IR ν max 2923, 1457, 1378, 1306, 1210cm -1 ; 1 H 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); 13 C 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×C), 29.6, 28.1, 22.6, 21.7, 14.4.C 24 H 38 Calculated analysis of O5: C, 70.90%;H, 9.42%. Found: C, 71.17%;H, 9.53%

[0190] [ka] (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 with EtOAc (60 mL x 3). The combined EtOAc extracts were dried and concentrated to give a white solid which was purified by flash column chromatography (silica gel eluted with 20-30% EtOAc in hexanes) to give product 10 (230 mg, 73%). mp 94-96 °C; IR ν max 2918, 1738, 1712, 1452, 1407, 1373, 1270, 1248, 1220, 1202, cm -1 ; 1 H 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); 13 C 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.C 20 H 30 HRMS calculated for O3: 318.2195. Found: 318.2180

[0191] [ka] (3α,5α)-3-Hydroxy-19-methoxyandrostan-17-one (11, KK-125) A 1M solution of K-Selectride® in THF (2 mL, 2 mmol, 3 equiv.) was added to a cold (−78° C.) solution 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 quenched by the addition of a few drops of acetone and allowed to warm to room temperature. 3N aqueous NaOH (10 mL) was added followed by 30% aqueous H2O2 (10 mL) and the reaction was stirred at room temperature for 1.5 h. The product was extracted with EtOAc (3×60 mL) and the combined EtOAc extracts were washed with brine, dried and concentrated to give an off-white solid which was purified by flash column chromatography (silica gel eluted with 20-40% EtOAc in hexanes). The product 11 (142 mg, 67%) had the following properties: mp 172-174° C.; IR ν max 3436, 2921, 1738, 1453, 1406, 1372, 1248, 1203cm -1 ; 1 H 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); 13 C 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.C 20 H 32 Analysis of O3 Calculated: C, 74.96%; H, 10.06%. Found: C, 74.91%; H, 9.86%

[0192] [ka] (3α,5α,17β)-19-Methoxyspiro[androstan-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. After 2 h, the reaction was quenched with aqueous NH4Cl. The mixture was extracted with dichloromethane (100 mL x 2) and washed with brine. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel eluted with 25% EtOAc in hexane) to give steroid 12 (76 mg, 75%). mp 168-170 °C; [α] D 20 = -3.1 (c = 0.16, CHCl3); ν max 3420, 1445 cm -1 ; 1 H NMR (CDCl3) 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); 13 C 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.C 21 H 34 Analysis of O3 Calculated: C, 75.41; H, 10.25. Found: C, 75.44; H, 9.98

[0193] [ka]

[0194] [ka] (3α,5α)-19-Methoxy-3-(methoxymethoxy)-androstan-17-one (13) To a solution of steroid 11 (800 mg, 2.5 mmol) in DCM (20 mL) was added chloromethyl methyl ether (302 mg, 3.75 mmol) and N,N-diisopropylethylamine (774 mg, 6 mmol) at room temperature. After 16 h, the mixture was quenched with water, extracted with EtOAc (100 mL x 2) and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel eluted with 25% EtOAc in hexane) to give the product 13 as an oil (900 mg, 100%). IR ν max 2921, 1740 cm -1 ; 1 H NMR (CDCl3) 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); 13 C 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

[0195] [ka] (3α,5α)-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) was added potassium bis(trimethylsilyl)amide (3.0 mmol, 0.5 M in toluene, 6.0 mL) at −78° C. After 30 min, a solution of N-phenyltrifluoromethanesulfonimide (1.07 g, 3.0 mmol) in THF (5 mL) was added at −78° C. After 2 h at −78° C., the mixture was quenched with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried, filtered, and concentrated. The residue was purified by flash chromatography (silica gel) to give the intermediate enol triflate (1.21 g with inseparable impurity). To the enol triflate (1.21 g) in a 50 mL round-bottom flask were 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 quenched with 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 hexane) to give the product 14 as an oil (886 mg with inseparable impurities). 1 H NMR (CDCl3) 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); 13 C 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.

[0196] [ka] (3α,5α)-3-Hydroxy-19-methoxyandrost-16-ene-17-carbonitrile (15, MQ-91) To a solution of steroid 14 (886 mg) in methanol (20 mL) containing an inseparable impurity was added 6N HCl (15 ml) at room temperature. After 14 h, the mixture was extracted with dichloromethane (50 mL x 2). The combined organic layers were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexane) to give product 15 (480 mg, 58% yield from steroid 13). mp 167-169 °C; [α] D 20 = 11.1 (c = 0.18, CHCl3); IR ν max 3337, 2212 cm -1 ; 1 H 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); 13 C 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.C 21 H 31 Analysis of NO2 Calculated: C, 76.55; H, 9.48, N, 4.25. Found: C, 76.59; H, 9.32; N, 4.06

[0197] [ka] (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) was added Pd / C (10%, 100 mg). Hydrogenation was carried out at room temperature for 3 h under 7 atm H2 atmosphere. The mixture was filtered through Celite and washed with EtOAc (100 mL). The solvent was removed and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexane) to give product 16 (415 mg, 96%). mp 146-148 °C; [α] D 20 = 42.1 (c = 0.29, CHCl3); ν max 3412, 2235 cm -1 ; 1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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.C 21 H 33 Analysis of NO2 Calculated: C, 76.09; H, 10.03, N, 4.23. Found: C, 76.16; H, 9.90; N, 4.05

[0198] [ka] (3α,5α)-3-Hydroxy-19-methoxypregnan-20-one (17, MQ-93) To a solution of steroid 16 (360 mg, 1.09 mmol) in THF (20 mL) was added methylmagnesium bromide (3.0 M, 2 mL, 6.0 mmol) at room temperature. The mixture was refluxed for 16 h, cooled to room temperature, and quenched by the addition of 6 N HCl. The product was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried, filtered, and concentrated. The crude product (300 mg, 79%) was 1 H NMR showed 17β (steroid 17) and 17α diastereomers in an 8 to 1 ratio, respectively. The crude product was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to give purified 17 (135 mg). mp 160-162 °C; [α] D 20 = 41.7 (c = 0.31, CHCl3); IR ν max 3407, 1703 cm -1 ; 1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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.C 22 H 36 Analysis of O3 calculated: C, 75.82; H, 10.41; Found: C, 75.71; H, 10.29.

[0199] TIFF2025024078000058.tif87107

[0200] [ka] (3α,5α)-3-(acetyloxy)-19-methoxypregnan-20-one (18) To a solution of steroid 17 (100 mg, 0.29 mmol) in pyridine (5 mL) was added acetic anhydride (51 mg, 0.5 mmol) and DMAP (5 mg) at room temperature. After 2 h, the reaction mixture was quenched with water and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to give the product 18 as an oil (112 mg, 100%). 1 H 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), 2.22-0.79 (m), 2.06 (s, 3H), 2.00 (s, 3H), 0.57 (s, 3H); 13 C 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

[0201] [ka] (3α,5α)-3,21-bis(acetyloxy)-19-methoxy-1-pregnan-20-one (19) To a solution of steroid 18 (112 mg, 0.29 mmol) in benzene (10 mL) and methanol (0.5 mL) was added lead tetraacetate (513 mg, 1.15 mmol) and boron trifluoride etherate (1 mL) at room temperature. After 3 h, water was added and the product was extracted with EtOAc (50 mL x 2). The combined 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 give the product 19 as a foam (82 mg, 63%). 1 H 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); 13 C 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

[0202] [ka] (3α,5α)-3,21-dihydroxy-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 with EtOAc (50 mL x 2). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexane) to give product 20 (22 mg, 37%). mp 88-90 °C; [α] D 20 = 50.0 (c = 0.13, CHCl3); IR ν max 3415, 1708 cm -1- ; 1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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.C 22 H 36 Analysis of O4 Calculated: C, 72.49; H, 9.95; Found: C, 72.77; H, 10.10

[0203] [ka]

[0204] [ka] 19-Hydroxyandrost-5-ene-3,17-dione, 3-cyclic 1,2-ethanediyl acetal (21) To a solution of the known 19-hydroxyandrost-4-ene-3,17-dione (1.0 g, 3.3 mmol) in benzene (100 mL) were added ethylene glycol (267 mg, 4.3 mmol) and PPTS (100 mg). The mixture was refluxed in a flask equipped with a Dean-Stark trap. After 4 h, the mixture was cooled to 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 hexane) to give the known 19-hydroxyandrost-5-ene-3,17-dione, 3,17-bis(cyclic 1,2-ethanediyl acetal) (260 mg, 20%) and product 21 (450 mg, 39%). mp 190-192 °C; IR ν max 3468, 1735 cm -1 ; 1 H NMR (CDCl3) δ 5.67-5.65 (m, 1H), 3.93-3.3.77 (m, 5H), 3.58-3.55 (m, 1H), 2.48-0.96 (m), 0.87 (s, 3H); 13 C NMR (CDCl3) 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

[0205] [ka] (17β)-17,19-Dihydroxyandrost-5-en-3-one, 3-cyclic 1,2-ethanediyl acetal (22) To a solution of steroid 21 (450 mg, 1.29 mmol) in ethanol (50 mL) was added sodium borohydride (152 mg, 4 mmol) at room temperature. After 3 h, aqueous NH4Cl was added and the product was eluted with EtOAc (50 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 35% EtOAc in hexane) to give product 22 (374 mg, 83%). mp 208-210 °C; IR ν max 3440 cm -1 ; 1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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

[0206] [ka] (17β)-17,19-Dimethoxyandrost-5-en-3-one, 3-cyclic 1,2-ethanediyl acetal (23) To a solution of steroid 22 (374 mg, 0.72 mmol) in THF (30 mL) was added sodium hydride (400 mg, 60% in mineral oil, 6.0 mmol). After addition, the mixture was refluxed for 1 h, iodomethane (2.13 g, 15 mmol) was added, and reflux was continued for 3 h. After cooling to room temperature, water was added and the product was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexane) to give product 22 (402 mg, 100%). mp 97-99 °C; IR νmax 2918, 1450, 1105 cm -1 ; 1 H 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); 13 C NMR (CDCl3) 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

[0207] [ka] (17β)-17,19-Dimethoxyandrost-4-en-3-one (24, MQ-99) To a solution of steroid 23 (402 mg, 1.07 mmol) in THF (20 mL) was added 3N HCl (10 mL) at room temperature. The mixture was stirred for 2 h and the product was extracted with dichloromethane (50 mL x 2). The combined 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 give product 24 (355 mg, 100%). IR ν max 1671 cm -1 ;mp 93-95℃; [α] D 20 = 124.7 (c = 0.32, CHCl3); 1H NMR (CDCl3) 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); 13 C 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.C 21 H 32 Analysis of NO3 Calculated: C, 75.86, H, 9.70. Found: C, 76.00, H, 9.98

[0208] [ka]

[0209] [ka] (3α,17β)-17,19-dimethoxyandrost-5-en-3-ol (25, MQ-101) and (3β,17β)-17,19-dimethoxyandrost-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 warmed to room temperature for 1 h. Thin layer chromatography showed no remaining starting material. Aqueous NaHCO3 was added and the product was extracted with EtOAc (50 mL x 3). The combined 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 was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexane) to give product 25 (30 mg, 8%) and product 26 (248 mg, 69%).

[0210] Physical properties of product 25: mp 132--134℃; [α] D 20 = -64.0 (c = 0.10, CHCl3); IR ν max 3337, 1446 cm -1 ; 1 H NMR (CDCl3) 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); 13 C 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.C 21 H 34Analysis of O3 Calculated: C, 75.41, H, 10.25. Found: C, 75.31, H, 10.41

[0211] Physical properties of product 26: mp 160-162℃; [α] D 20 = -76.7 (c = 0.45, CHCl3); IR ν max 3408 cm -1 ; 1 H 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); 13 C 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.C 21 H 34 Analysis of O3 Calculated: C, 75.41, H, 10.25. Found: C, 75.51, H, 10.30

[0212] [ka]

[0213] [ka] (3α,5α)-3-[[(dimethylethyl)dimethylsilyl]oxy]-19-methoxyandrostan-17-one (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 room temperature. After 16 h, water was added and the product was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over MgSO4, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexane) to give the product 27 as an oil (198 mg, 99%). 1 H NMR (CDCl3) δ 4.00-3.95 (m, 1H), 3.51 (d, J = 9.7 Hz, 1H), 3.40 (d, J = 9.7 Hz, 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); 13 C NMR (CDCl3) 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×C), 25.6, 21.7, 21.2, 13.9, -4.90, -4.92

[0214] [ka] (3α,5α)-3-[[(dimethylethyl)dimethylsilyl]oxy]-19-methoxyandrostan-17-one, oxime (28) To a solution of steroid 27 (195 mg, 0.45 mmol) in pyridine (10 mL) was added hydroxylamine hydrochloride (140 mg, 2.0 mmol) at room temperature. After 14 h, water was added and the product was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over MgSO4, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexane) to give the product 28 as an oil (202 mg, 100%).1 H NMR (CDCl3) 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), 2.50-0.82 (m), 0.91 (s, 3H), 0.88 (s, 9H), 0.11 (d, J = 1.9 Hz, 6H); 13 C 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×C), 25.0, 23.1, 21.5, 18.1, 17.2, -4.85, -4.89

[0215] [ka] (3α,5α,17β)-19-Methoxy-17-nitroandrostan-3-ol (29, MQ-97) To a solution of NBS (231 mg, 1.3 mmol) in dioxane (4 mL) was added aqueous KHCO3 (260 mg, 2.6 mmol, 4 mL) at room temperature. The mixture was stirred for 30 min at room temperature and a solution of oxime (202 mg, 0.45 mmol) in dioxane (10 ml) was added. The reaction was stirred at room temperature for 14 h in an open flask. NaBH4 (200 mg) was added in 5 portions and the reaction was stirred at room temperature for 3 h. 6N HCl (10 ml) was added slowly and stirring at room temperature was continued for 1 h. The product was extracted with dichloromethane (50 mL x 2). The combined organic layers were dried over MgSO4, filtered and removed. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexane) to give product 29 (79 mg, 50%). mp 52-54 °C; [α] D 20 = 25.8 (c = 0.21, CHCl3); IR ν max 3307, 1541, 1370 cm -1 ;1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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.C 20 H 33 Analysis of NO4 Calculated: C, 68.34, H, 9.46. Found: C, 68.40, H, 9.45

[0216] [ka]

[0217] [ka] (3α,5β)-3-Hydroxy-19-methoxyandrostan-17-one (30, MQ-94) To a solution of steroid 10 (295 mg, 0.93 mmol) in THF (20 mL) was added lithium aluminum hydride tri-tert-butoxide (2.0 mmol, 1.0 M in THF, 2.0 mL) at -40 °C. After 2 h, the mixture was quenched with 3N HCl at -40 °C and the reaction was allowed to warm to room temperature for 1 h. The product was extracted with 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 give product 30 (239 mg, 81%). mp 208-210 °C; IR ν max 3428, 1737, 1642 cm -1 [α] D20 = 81.3 (c = 0.31, CHCl3); 1 H NMR (CDCl3) 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); 13 C NMR (CDCl3) 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.C 20 H 32 Analysis of O3 Calculated: C, 74.96; H, 10.06. Found: C, 75.10; H, 9.95

[0218] [ka]

[0219] [ka] (3β,5α,17β)-17,19-Dimethoxyandrostan-3-ol (31, MQ-96) To a solution of steroid 7 (65 mg, 0.20 mmol) in THF (10 mL) was added lithium aluminum hydride tri-tert-butoxide (1.0 mmol, 1.0 M in THF, 1.0 mL) at -40 °C. After 2 h, the mixture was quenched with 3N HCl at -40 °C and the reaction was allowed to warm to room temperature for 1 h. The product was extracted with dichloromethane (50 mL x 2) and washed with brine. The combined 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 give product 31 (55 mg, 85%). mp 164-166 °C; IR ν max 3370 cm -1- [α] D20 = 1.0 (c = 0.10, CHCl3); 1 H NMR (CDCl3) 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); 13 C 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.C 21 H 36 Analysis of O3 Calculated: C, 74.95; H, 10.78. Found: C, 74.91; H, 10.82

[0220] ￥ B. [ 35 S]-TBPS substitution GABA A from the picrotoxin binding site on the receptor 35 IC of noncompetitive displacers of [S]-TBPS 50 The values ​​are shown in Table 1. [Table 1]

[0221] aThe results shown here are from two of three experiments. Error limits are calculated as the standard error of the mean. The methods used are known from the literature (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 and anesthetic steroids (3α,5α)- and (3α,5α)-3-hydroxypregnan-20-one. J. Med. Chem., 46: 5334-48 (2003) - the contents of which are incorporated herein by reference in their entirety).

[0222] C. Electrophysiology Results The compounds of the present invention were administered to rat α1β2γ expressed in Xenopus oocytes. 2L Type GABA A The receptors were assessed for their ability to potentiate chloride currents mediated by 2 μM GABA, and the results are shown in Table 2. [Table 2]

[0223] a The GABA concentration used to control the response was 2 mM. Each compound was tested at the indicated concentrations in at least four different oocytes and the results shown are the ratio of the currents measured in the presence / absence of added compound. Gating represents the direct current gated by 10 mM compound in the absence of GABA and is expressed as the ratio of compound only current / 2 mM GABA current. Error limits are calculated as the standard error of the mean (N≧4). The method used is known from the literature (see Jiang, X., et al.).

[0224] D. Loss of tadpole righting and swimming Table 3 discloses the anesthetic effects of the compounds of the present invention, particularly with respect to loss of righting reflex (LRR) and loss of swimming reflex (LSR). [Table 3]

[0225] The methods used are known from the literature (see Jiang, X., et al.). Error limits are calculated as the standard error of the mean (N=10 or more animals at each of 5 or more concentrations).

[0226] E. Loss of righting reflex in rats Plasma pharmacokinetics and qualitative assessment of sedation were performed in male Sprague Dawley rats according to the following method. Rats were administered an intravenous bolus (60 s) via the dorsalis pedis vein in the appropriate vehicle at doses ranging from 5 to 15 mg / kg. To assess sedation, rats were gently restrained manually in a lateral decubitus position for dosing. If a decrease in muscle tone was observed during dosing, the restraint was gradually relaxed. If the animal was unable to return to an upright position, the time was recorded as the occurrence of loss of righting reflex (LRR). If no LRR occurred during dosing, the animal was subsequently evaluated at 5 min intervals by placing it in a supine position. Two consecutive slow or incomplete rightings within a 30 s interval were deemed to be loss of righting reflex. After the occurrence of the LRR, the animals were evaluated every 5 min in the same manner. Recovery of the righting reflex is defined as the ability of the rat to completely right itself within 20 s after being placed in a supine position. The duration of the LRR is defined as the time interval between the LRR and recovery of the righting reflex. [Table 4] A <10 minutes; B 10~20 minutes; C >20 minutes

[0227] F. Loss of canine lateral recumbency Plasma pharmacokinetics and qualitative assessment of sedation were obtained in male beagle dogs according to the following method. Dogs were administered an intravenous bolus (60 seconds) at a dose of 5 mg / kg in the appropriate vehicle via the cephalic vein. To assess sedation, dogs were gently restrained for dosing. If hypotonia, limb weakness or head drop was observed during dosing, the occurrence of lateral recumbency was recorded. If lateral recumbency did not ultimately occur during dosing, the animals were subsequently evaluated at 5-minute intervals by placing them in lateral recumbency. Slow or incomplete righting into a prone position was identified as lateral recumbency. After the onset of lateral recumbency, animals were evaluated every 5 minutes in the same manner. The duration of lateral recumbency was recorded as the time interval between lateral recumbency and regaining a prone position. [Table 5] A <10 minutes; B 10~20 minutes; C >20 minutes

[0228] general law The compounds described in this invention were prepared by the methods described elsewhere herein and by the following methods.

[0229] Solvents were used as purchased or dried and purified by standard methods. Extraction solvents were dried over anhydrous Na2SO4, filtered, and removed on a rotary evaporator. Flash chromatography was performed using silica gel (32-63 μm) purchased from Scientific Adsorbents (Atlanta, GA). Melting points were determined on a Kofler micro hot stage and are uncorrected. FT-IR spectra were recorded as films on NaCl plates. NMR spectra were recorded at ambient temperature with a 300 MHz ( 1 H) or 74MHz ( 13 C) in CDCl3. Purity was confirmed using 250 μM thick Uniplates from Analtech (Newark, Del.). TMThe purity was determined by TLC above. All pure compounds (purity >95%) gave a single spot by TLC. Elemental analyses were performed by MHW Laboratories (Phoenix, AZ).

[0230] Equivalence and Scope In view of the above, it can be seen that the several advantages of the invention are achieved and other advantageous results attained. Since the methods and compositions described above may be varied without departing from the scope of the disclosure, it is intended that all matter contained in the above description and shown in the accompanying drawings be interpreted as illustrative and not limiting.

[0231] When introducing elements of the invention or various forms, embodiments or aspects thereof, the singular form "a," "an," or "the" is intended to mean one or more of the element. The terms "comprise," "include," "have," or "contain" are intended to be open-ended and allow for the inclusion of additional elements or steps.

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, R １ (C １ -C ４ alkyl)-O, spirooxirane, cyano, =O, nitro, (C １ -C ４ Alkyl)C(O) and HO(C １ -C ４ alkyl)C(O); R ２ = O, H or OR ａ where R ａ is H, optionally substituted C １ -C ４ alkyl or optionally substituted aryl, where R ２ When =O, R ８ does not exist.) R ３ is H, optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ alkenyl, optionally substituted C ２ -C ４ alkynyl or optionally substituted aryl; R ４ are independently H and unsubstituted C １ -C ４ alkyl; R ５ is a substitution C １ -C ４ Alkyl, optionally substituted C ２ -C ４ alkenyl or optionally substituted C ２ -C ４ alkynyl; R ６ is H, optionally substituted C １ -C ４ Alkyl or optionally substituted C １ -C ４ is alkoxy; R ７ is H, optionally substituted C １ -C ４ an alkoxy or an optionally substituted morpholinyl ring; R ８ When present, is H or optionally substituted C １ -C ４ is alkyl; --- is C ４ -C ５ Or C ５ -C ６ (provided that, if present, C ５ There are no -H hydrogen atoms; and --- is C １６ -C １７ (provided that, when present, R １ is other than =O. or a pharma- ceutically acceptable salt thereof.

2. R ６ Or R ７ 2. The compound of claim 1 , wherein one or both, when present, are other than H and are in the β position.

3. R ３ 3. The compound of claim 1 or 2, wherein the group is selected from the group consisting of H, methyl and trifluoromethyl.

4. R ７ The compound of any of claims 1 to 3, wherein is selected from the group consisting of H, methoxy, ethoxy and an optionally substituted morpholinyl ring.

5. R ７ The compound according to any one of claims 1 to 4, wherein is H.

6. R ５ The compound of any one of claims 1 to 5, wherein is substituted methyl.

7. C ５ The compound according to any one of claims 1 to 6, wherein the hydrogen atom of -H is in the α-position.

8. C ５ The hydrogen atom of —H is in the β-position, and R ５ The compound of any one of claims 1 to 6, wherein the group is in the β position.

9. R ６ The compound according to any one of claims 1 to 8, wherein is H.

10. R ２ The compound of any one of claims 1 to 9, wherein is =O, methoxy or H.

11. R ４ The compound according to any one of claims 1 to 10, wherein is methyl.

12. structure 【Chemistry 2】 [In the formula, R ｂ is optionally substituted C １ -C ４ It is alkyl.

2. The compound of claim 1, having the formula:

13. R ｂ The compound of claim 12, wherein is methyl.

14. R １ The compound of claim 12 or 13, wherein is β-methoxy.

15. R １ The compound according to claim 12 or 13, wherein is a β-spirooxirane.

16. R １ The compound of claim 12 or 13, wherein is β-cyano.

17. R １ The compound of claim 12 or 13, wherein is =O.

18. R １ The compound according to claim 12 or 13, wherein is β-nitro.

19. R １ is β-CH ３ The compound according to claim 12 or 13, which is C(O)-.

20. R １ is β-HOCH ２ The compound according to claim 12 or 13, which is C(O)-.

21. 【Chemical 3】 [In the formula, R ｂ is optionally substituted C １ -C ４ It is alkyl. and pharma- ceutically acceptable salts thereof.

22. R ｂ The compound of claim 21 , wherein is methyl.

23. A pharma- ceutically acceptable salt of a compound according to any one of claims 1 to 22.

24. A prodrug of the compound according to any one of claims 1 to 23.

25. Formula (II) 【Chemistry 4】 [During the ceremony, R １ (C １ -C ４ alkyl)-O, spirooxirane, cyano, =O, nitro, (C １ -C ４ Alkyl)C(O) and HO(C １ -C ４ alkyl)C(O); R ２ = O, H or OR ａ where R ａ is H, optionally substituted C １ -C ４ alkyl or optionally substituted aryl, where R ２ When =O, R ８ does not exist.) R ｘ = O or OR ｄ where R ｄ is H or C(O)R ｅ where R ｅ is optionally substituted C １ -C ２２ Alkyl or optionally substituted C ２ -C ２２ alkenyl (wherein R ｘ When is OH, it is in the β-position (and R ｘ R ｄ and R ｄ is C(O)R ｅ If it is, then it is preferably in the β configuration. R ４ are independently H and unsubstituted C １ -C ４ alkyl; R ５ is a substitution C １ -C ４ Alkyl, optionally substituted C ２ -C ４ alkenyl or optionally substituted C ２ -C ４ alkynyl; R ６ is H, optionally substituted C １ -C ４ Alkyl or optionally substituted C １ -C ４ is alkoxy; R ７ is H, optionally substituted C １ -C ４ an alkoxy or an optionally substituted morpholinyl ring; R ８ When present, is H or optionally substituted C １ -C ４ is alkyl; --- is C ４ -C ５ Or C ５ -C ６ (provided that, if present, C ５ There are no -H hydrogen atoms; and --- is C １６ -C １７ (provided that, when present, R １ is not equal to O. or a pharma- ceutically acceptable salt thereof; However, this compound has the following structure: 【Chemistry 5】 or (i) R ｘ is ═O and the C═C bond is C ４ -C ５ exists between R ５ CH ２ OCH ３ If so, then R １ are methoxy, spirooxirane, cyano, nitro and CH ３ C(O)—; or (ii) R ｘ is β-OH and the C=C bond is C ５ -C ６ exists between R ５ CH ２ OCH ３ If so, then R １ are methoxy, spirooxirane, cyano, nitro and HOCH ２ C(O)—.

26. R ｘ The compound of claim 25 , wherein is OH in the β position.

27. R ｘ 26. The compound of claim 25, wherein: is =O.

28. R ７ The compound of any of claims 25-27, wherein is selected from the group consisting of H, methoxy, ethoxy and an optionally substituted morpholinyl ring.

29. R ７ The compound according to any one of claims 25 to 28, wherein is in the β configuration.

30. R ５ The compound of any one of claims 25 to 29, wherein is substituted methyl.

31. C ５ The hydrogen atom of —H is in the α-position, and R ５ The compound according to any one of claims 25 to 30, wherein is in the β configuration.

32. C ５ The hydrogen atom of —H is in the β-position, and R ５ The compound according to any one of claims 25 to 30, wherein is in the β configuration.

33. R ６ The compound according to any one of claims 25 to 32, wherein is H.

34. R ２ The compound of any of claims 25 to 33, wherein is =O, methoxy or H.

35. R ４ The compound according to any one of claims 25 to 34, wherein is methyl.

36. Carbon-carbon double bond is C ４ Carbon atom and C ５ 26. The compound of claim 25, wherein:

37. Carbon-carbon double bond is C ５ Carbon atom and C ６ 26. The compound of claim 25, wherein:

38. structure 【Chemistry 6】 [In the formula, R ｂ is optionally substituted C １ -C ４ It is alkyl.

26. The compound of claim 25, having the formula:

39. R ｂ The compound of claim 38, wherein is methyl.

40. R １ The compound of claim 38 or 39, wherein is β-methoxy.

41. R １ The compound of claim 38 or 39, wherein is a β-spirooxirane.

42. R １ is β-cyano.

43. R １ 40. The compound of claim 38 or 39, wherein is =O.

44. R １ is β-nitro.

45. R １ is β-CH ３ 40. The compound of claim 38 or 39, which is C(O)-.

46. R １ is β-HOCH ２ 40. The compound of claim 38 or 39, which is C(O)-.

47. 【Chemical 7】 [In the formula, R ｂ is optionally substituted C １ -C ４ It is alkyl. and pharma- ceutically acceptable salts thereof.

48. R ｂ 48. The compound of claim 47, wherein is methyl.

49. A pharma- ceutically acceptable salt of a compound according to any one of claims 25 to 48.

50. 49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, a pharma- ceutically acceptable salt thereof, or a combination of two or more thereof, and a pharma- ceutically acceptable carrier.

51. A method of inducing anesthesia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 48, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 50.

52. A method for treating a disorder associated with GABA function in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 48, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 50.

53. 53. The method of claim 52, wherein the disorder is selected from the group consisting of insomnia, a mood disorder, a seizure disorder, anxiety or symptoms of ethanol withdrawal.

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