COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Abstract

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein, R.sup.1, R.sup.2a, R.sup.2b, R.sup.3 and A are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

##STR00001##

Claims

1. A compound of the Formula (I): ##STR00051## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

2. The compound of claim 1, wherein R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., haloalkyl).

3. The compound of any one of the preceding claims, wherein R.sup.1 is methyl or CF.sub.3.

4. The compound of any one of the preceding claims, wherein R.sup.2a is methyl.

5. The compound of any one of the preceding claims, wherein R.sup.2b is hydrogen.

6. The compound of any one of the preceding claims, wherein R.sup.2a is methyl and R.sup.2b is hydrogen.

7. The compound of any one of the preceding claims, wherein represents a single bond.

8. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (II) or Formula (III): ##STR00052## or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, R.sup.2a, and R.sup.ab are defined as for Formula (I).

9. The compound of any one of the preceding claims, wherein the compound of Formula (II) is a compound of Formula (II-a) or Formula (II-b): ##STR00053## or a pharmaceutically acceptable salt thereof, wherein A and R.sup.1 are defined as for Formula (I).

10. The compound of any one of the preceding claims, wherein the compound of Formula (III) is a compound of Formula (III-a) or Formula (III-b): ##STR00054## or a pharmaceutically acceptable salt thereof, wherein A and R.sup.1 are defined as for Formula (I).

11. The compound of any one of the preceding claims, wherein A is heterocyclyl or heteroaryl (e.g., nitrogen-containing heterocyclyl or a nitrogen-containing heteroaryl).

12. The compound of any one of the preceding claims, wherein A is monocyclic or bicyclic.

13. The compound of any one of the preceding claims, wherein A is substituted with at least one R.sup.A, wherein R.sup.A is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, C.sub.1-6 haloalkyl, halogen, cyano, —OR.sup.A6, —C(═O)OR.sup.A6, —SR.sup.B6, —S(═O)R.sup.B6, or S(═O).sub.2R.sup.B6, wherein R.sup.A6 is hydrogen or C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, or C.sub.1-6 haloalkyl, and R.sup.B6 is C.sub.1-6 alkyl or C.sub.3-6 carbocylyl.

14. The compound of claim 13, wherein R.sup.A is C.sub.1-6 alkyl, halogen, or cyano.

15. The compound of any one of claims 13-14, wherein A is substituted with 1-3 instances of R.sup.A.

16. A compound of the Formula (IV): ##STR00055## or a pharmaceutically acceptable salt thereof wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; R.sup.A is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, C.sub.1-6 haloalkyl, halogen, cyano, —OR.sup.A6, —C(═O)OR.sup.A6, —SR.sup.B6, —S(═O)R.sup.B6, or S(═O).sub.2R.sup.B6, wherein R.sup.A6 is hydrogen or C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, or C.sub.1-6haloalkyl, and R.sup.B6 is C.sub.1-6 alkyl or C.sub.3-6 carbocylyl; n is 0, 1, 2 or 3; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

17. The compound of claim 16, wherein R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., haloalkyl).

18. The compound of any one of claims 16-17, wherein R.sup.1 is methyl or CF.sub.3.

19. The compound of any one of claims 16-18, wherein R.sup.2a is methyl.

20. The compound of any one of claims 16-19, wherein R.sup.2b is hydrogen.

21. The compound of any one of claims 16-20, wherein R.sup.2a is methyl and R.sup.2b is hydrogen.

22. The compound of any one of claims 16-21, wherein represents a single bond.

23. The compound of claims 16-22, wherein the compound of Formula (IV) is a compound of Formula (V) or Formula (VI): ##STR00056## or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, R.sup.2a, R.sup.2b, R.sup.A, and n are defined as for Formula (IV).

24. The compound of any one of claims 16-23, wherein the compound of Formula (V) is a compound of Formula (V-a) or Formula (V-b): ##STR00057## or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, R.sup.2a, R.sup.2b, R.sup.A, and n are defined as for Formula (IV).

25. The compound of any one of claims 16-24, wherein the compound of Formula (VI) is a compound of Formula (VI-a) or Formula (VI-b): ##STR00058## or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, are defined as for Formula (I).

26. The compound of any one of the preceding claims, wherein A is selected from: ##STR00059##

27. The compound of any one of the preceding claims, wherein A is selected from: ##STR00060##

28. The compound of any one of the preceding claims, wherein the compound is selected from: ##STR00061## ##STR00062## ##STR00063## or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.

30. A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the Formula (I): ##STR00064## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

31. A method of administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of any one of the preceding claims to a subject in need thereof, wherein the subject experiences sedation and/or anesthesia within two hours of administration.

32. The method of claim 31, wherein the subject experiences sedation and/or anesthesia within one hour of administration.

33. The method of claim 31, wherein the subject experiences sedation and/or anesthesia instantaneously.

34. The method of claim 31, wherein the compound is administered by intravenous administration.

35. The method of claim 31 wherein the compound is administered chronically.

36. The method of claim 31, wherein the subject is a mammal.

37. The method of claim 36, wherein the subject is a human.

38. The method of claim 31, wherein the compound is administered in combination with another therapeutic agent.

39. A method for treating seizure in a subject, comprising administering to the subject an effective amount of a compound of the Formula (I): ##STR00065## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); form a ring (e.g., R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

40. A method for treating epilepsy or status or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of the Formula (I): ##STR00066## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

41. A method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition comprising a compound of Formula (I): ##STR00067## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

42. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount a compound of Formula (I): ##STR00068## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

43. The method of claim 42, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

44. The method of claim 42, wherein the compound is administered orally.

45. The method of claim 42, wherein the compound is administered intramuscularly.

46. The method of claim 42, wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

47. The method of claim 42, wherein the CNS-related disorder is a sleep disorder, an eating disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

48. The method of claim 42, wherein the CNS-related disorder is depression (e.g., post partum depression).

49. The method of claim 42, wherein the CNS-related disorder is tremor (e.g., essential tremor).

50. The method of claim 42, wherein the CNS-related disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge-eating disorder, cachexia).

51. A kit comprising a solid composition comprising a compound of Formula (I): ##STR00069## or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent; and a sterile diluent.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0145] As generally described herein, the present invention provides C21-substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder.

[0146] Compounds

[0147] In one aspect, provided is a compound of Formula (I):

##STR00025##

or a pharmaceutically acceptable salt thereof, wherein: A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; and represents a single or double bond, wherein when one of is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

[0148] In some embodiments, R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., haloalkyl). In some embodiments, R.sup.1 is methyl or CF.sub.3.

[0149] In some embodiments, R.sup.2a is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2b is hydrogen. In some embodiments, R.sup.2b is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is methyl and R.sup.2b is hydrogen.

[0150] In some embodiments, R.sup.3 is absent. In some embodiments, R.sup.3 is hydrogen.

[0151] In some embodiments, represents a single bond. In some embodiments, one of represents a double bond and the other represents a single bond.

[0152] In some embodiments, the compound of Formula (I) is a compound of Formula (II) or Formula (III):

##STR00026##

or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, R.sup.2a, and R.sup.2b are defined as for Formula (I).

[0153] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a) or Formula (II-b):

##STR00027##

or a pharmaceutically acceptable salt thereof, wherein A and R.sup.1 are defined as for Formula (I).

[0154] In some embodiments, the compound of Formula (III) is a compound of Formula (III-a) or Formula (III-b):

##STR00028##

or a pharmaceutically acceptable salt thereof, wherein A and R.sup.1 are defined as for Formula (I).

[0155] In some embodiments, A is heterocyclyl or heteroaryl (e.g., nitrogen-containing heterocyclyl or a nitrogen-containing heteroaryl). In some embodiments, A is monocyclic or bicyclic. In some embodiments, A is substituted with at least one R.sup.A, wherein R.sup.A is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, C.sub.1-6 haloalkyl, halogen, cyano, —OR.sup.A6, —C(═O)OR.sup.A6, —SR.sup.B6, S(═O)R.sup.B6, or S(═O).sub.2R.sup.B6, wherein R.sup.A6 is hydrogen or C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, or C.sub.1-6 haloalkyl, and R.sup.B6 is C.sub.1-6 alkyl or C.sub.3-6 carbocylyl. In some embodiments, R.sup.A is C.sub.1-6 alkyl, halogen, or cyano. In some embodiments, A is substituted with 1-3 instances of R.sup.A.

[0156] In another aspect, provided is a compound of the Formula (IV):

##STR00029##

or a pharmaceutically acceptable salt thereof wherein A is aryl, heterocyclyl or heteroaryl; R.sup.1 is C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl; R.sup.2b is hydrogen or C.sub.1-6 alkyl; or R.sup.2a and R.sup.2b are joined to form an oxo (═O) group; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring)); R.sup.3 is absent or hydrogen; R.sup.A is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, C.sub.1-6 haloalkyl, halogen, cyano, —OR.sup.A6, —C(═O)OR.sup.A6, —SR.sup.B6, —S(═O)R.sup.B6, or S(═O).sub.2R.sup.B6, wherein R.sup.A6 is hydrogen or C.sub.1_6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 carbocylyl, or C.sub.1-6 haloalkyl, and R.sup.B6 is C.sub.1-6 alkyl or C.sub.3-6 carbocylyl; n is 0, 1, 2 or 3; and represents a single or double bond, wherein when one is a double bond, the other is a single bond; and when one of the is a double bond, R.sup.3 is absent.

[0157] In some embodiments, R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., haloalkyl). In some embodiments, R.sup.1 is methyl or CF.sub.3.

[0158] In some embodiments, R.sup.2a is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2b is hydrogen. In some embodiments, R.sup.2b is substituted or unsubstituted C.sub.1-6 alkyl. In some embodiments, R.sup.2a is methyl. In some embodiments, R.sup.2a is methyl and R.sup.2b is hydrogen.

[0159] In some embodiments, R.sup.3 is absent. In some embodiments, R.sup.3 is hydrogen.

[0160] In some embodiments, represents a single bond. In some embodiments, one of represents a double bond and the other represents a single bond.

[0161] In some embodiments, the compound of Formula (IV) is a compound of Formula (V) or Formula (VI):

##STR00030##

or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, R.sup.2a, R.sup.2b, R.sup.A, and n are defined as for Formula (IV).

[0162] In some embodiments, the compound of Formula (V) is a compound of Formula (V-a) or Formula (V-b):

##STR00031##

or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, R.sup.2a, R.sup.2b, R.sup.A, and n are defined as for Formula (IV).

[0163] In some embodiments, the compound of Formula (VI) is a compound of Formula (VI-a) or Formula (VI-b):

##STR00032##

or a pharmaceutically acceptable salt thereof, wherein A, R.sup.1, are defined as for Formula (I).

[0164] In some embodiments, A is selected from:

##STR00033##

[0165] In some embodiments, A is:

##STR00034##

[0166] In some embodiments, the compound is selected from:

##STR00035## ##STR00036## ##STR00037##

or a pharmaceutically acceptable salt thereof.

[0167] In one aspect, provided is a method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of one of a compound as described herein, e.g., a compound of the Formula (I), Formula (II) (e.g., (II-a), (II-b)), Formula (III) (e.g., (III-a), (III-b)), Formula (IV), Formula (V) (e.g., (V-a), (V-b)), or Formula (VI) (e.g., (VI-a) or (VI-b)).

[0168] In one aspect, provided is a method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound as described herein, e.g., a compound of the Formula (I), Formula (II) (e.g., (II-a), (II-b)), Formula (III) (e.g., (III-a), (III-b)), Formula (IV), Formula (V) (e.g., (V-a), (V-b)), or Formula (VI) (e.g., (VI-a) or (VI-b)), or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus. In some embodiments, the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

[0169] In one aspect, provided is a kit comprising a solid composition comprising a compound as described herein, e.g., a compound of the Formula (I), Formula (II) (e.g., (II-a), (II-b)), Formula (III) (e.g., (III-a), (III-b)), Formula (IV), Formula (V) (e.g., (V-a), (V-b)), or Formula (VI) (e.g., (VI-a) or (VI-b)), and a sterile diluent.

[0170] Pharmaceutical Compositions

[0171] In one aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0172] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0173] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0174] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0175] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0176] The pharmaceutical compostions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.

[0177] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0178] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

[0179] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0180] Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.

[0181] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0182] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

[0183] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0184] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0185] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0186] The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0187] The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0188] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.

[0189] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21.sup.st Edition (Lippincott Williams & Wilkins, 2005).

[0190] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be employed include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0191] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0192] The injectable composition can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0193] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.

[0194] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0195] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0196] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21.sup.st ed., Lippincott Williams & Wilkins, 2005.

[0197] Methods of Use and Treatment

[0198] As generally described herein, the present invention is directed to C21-substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

[0199] Thus, in one aspect, the present invention provides a method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof. In certain embodiments, the compound is administered by intravenous administration.

[0200] Earlier studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) demonstrated that certain 3α-hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than others had 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. taught that 3α-hydroxylated-5-reduced steroids are only capable of much lower levels of effectiveness. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0201] Various synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders such as depression, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. Furthermore, it has been previously demonstrated that these steroids interact at a unique site on the GRC which is distinct from other known sites of interaction (e.g., barbiturates, benzodiazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e.g., Gee, K. W. and Yamamura, H. I., “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, K. G. and Morselli, P. L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology: The Third Generation of Progress, H. Y. Meltzer, ed., Raven Press, N.Y. (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency, and oral activity (along with other forms of administration).

[0202] Compounds of the present invention, as described herein, are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.

[0203] Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

[0204] In yet another aspect, provided is a combination of a compound of the present invention and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

[0205] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present invention to the subject.

[0206] In yet another aspect, provided is a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0207] In yet another aspect, provided is a method of alleviating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0208] In yet another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0209] In yet another aspect, provided is a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present invention.

[0210] In yet another aspect, provided is a method of alleviating or preventing PMS or PND in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0211] In yet another aspect, provided is a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments the mood disorder is depression.

[0212] 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 present invention.

[0213] In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0214] In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.

[0215] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[0216] Anesthesia/Sedation

[0217] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.

[0218] Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.

[0219] Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0220] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.

[0221] Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.

[0222] Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

[0223] 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 and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0224] Sedation in the intensive care unit (ICU) allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.

[0225] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action. Sedation agents in the ICU may have short elimination half-life.

[0226] Procedural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

[0227] Anxiety Disorders

[0228] Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0229] Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0230] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0231] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

[0232] The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

[0233] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.

[0234] Neurodegenerative Diseases and Disorders

[0235] The term “neurodegenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.

[0236] Epilepsy

[0237] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

[0238] Status Epilepticus (SE)

[0239] Status epilepticus (SE) can include, 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 lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0240] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0241] Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a 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 lateralized epileptiform discharges; prior to the onset of a seizure.

[0242] Seizure

[0243] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly.

[0244] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0245] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0246] There are six types of generalized seizures. The most common and dramatic, and therefore the most well known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the “tonic” phase of the seizure) for 30 to 60 seconds, then by violent jerking (the “clonic” phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the “postictal” or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0247] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of “losing time.”

[0248] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0249] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0250] Tonic seizures are characterized by stiffening of the muscles.

[0251] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0252] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

EQUIVALENTS AND SCOPE

[0253] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0254] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0255] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0256] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

EXAMPLES

[0257] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope.

[0258] Materials and Methods

[0259] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0260] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0261] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative heteroaryls and heterocyclyls that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB—H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0262] The stereochemistry assigned herein (e.g., the assignment of “R” or “S” to the C21 position of the steroid) may be tentatively (e.g., randomly) assigned. For example, a C21 position may be drawn in the “R” configuration when the C21 position is in the “S” configuration.

[0263] .sup.1H-NMR reported herein (e.g., for intermediates) may be a partial representation of the full NMR spectrum of a compound, e.g., a compound described herein. For example, the reported .sup.1H NMR may exclude the region between δ (ppm) of about 1 to about 2.5 ppm.

[0264] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 □m C18, 19*250 mm. Mobile phase: aectonitrile, water (NH.sub.4HCO.sub.3) (30 L water, 24 g NH.sub.4HCO.sub.3, 30 mL NH.sub.3.Math.H.sub.2O). Flow rate: 25 mL/min

[0265] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH.sub.4HCO.sub.3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 C.

Synthetic Methods

Example 1. Synthesis of 1 and 2

[0266] ##STR00038##

[0267] To a solution of A1 (500 mg. 1.29 mmol) in THE (4 mL) was added KOH (144 mg, 2.58 mmol) and MeI (200 mg, 1.41 mmol) at 25° C. The mixture was stirred at 25° C. for 211, After TLC showed the starting material was consumed, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuum. The residue was purified by prep-HPLC to afford (R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)propan-1-one (79.5 mg, 15.4%) and (S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-: 1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)propan-1-one (93.1 mg, 18%) as white solid.

[0268] .sup.1H NMR (1) (400 MHz, CDCl3) δ 7.67 (s, 2H), 5.27-5.22 (m, 1H), 2.25-2.23 (m, 1H), 2.11-2.05 (m, 1H), 1.87-1.66 (m, 9H), 1.41-1.02 (m, 19H), 0.65 (s, 3H). LCMS Rt=0.945 min in 1.5 min chromatography, 5-95AB, purity 100%, MS ESI calcd. for C.sub.24H.sub.38N.sub.3O.sub.2 [M+H].sup.+ 400, found 382 [M+H−18].

[0269] .sup.1H NMR (2) (400 MHz, CDCl3) δ 7.66 (s, 2H), 5.42-5.37 (m, 1H), 2.66-2.64 (m, 1H), 2.14-2.11 (m, 2H), 1.83-1.65 (m, 10H), 1.41-1.07 (m, 17H), 0.68 (s, 3H). LCMS Rt=0.922 min in 1.5 min chromatography, 5-95AB, purity 100%, MS ESI calcd. for C.sub.24H.sub.38N.sub.3O.sub.2 [M+H].sup.+ 400, found 382 [M+H−18].

Example 2. Synthesis of 3 and 4

[0270] ##STR00039##

To a solution of A2 (400 mg, 0.976 mmol) in THF (3 mL) was added KOH (109 trig, 1.95 mmol) and MeI (1.58 g, 11.1 mmol) at 25° C. The mixture was stirs-red at 25° C. for 2 h. After TLC showed the starting material was consumed, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL×2), The organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE/EtOAc=5/1 to EtOAc) to afford 1-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopropan-2-yl)-1H-pyrazole-4-carbonitrile (100 mg, 24.2%) and 1-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopropan-2-yl)-1H-pyrazole-4-carbonitrile (139 mg, 33.6%) as a white solid.

[0271] .sup.1H NMR (3) (400 MHz, CDCl.sub.3) δ 7.99 (s, 1H), 7.77 (s, 1H), 5.27-5.25 (m, 1H), 2.73-2.71 (m, 1H), 2.18-2.13 (m, 2H), 1.81-1.58 (m, 10H), 1.48-1.07 (m, 17H), 0.56 (s, 3H). LCMS Rt=0.934 min in 1.5 min chromatography, 5-95AB, purity 100%, MS ESI calcd. for C.sub.26H.sub.38N.sub.3O.sub.2 [M+H].sup.+ 424, found 406 [M+H-18].

[0272] .sup.1H NMR (4) (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.81 (s, 1H), 5.06-5.01 (m, 1H), 2.48 (t, J=8.8 Hz, 1H), 2.09-2.00 (m, 1H), 1.79-1.59 (m, 12H), 1.50-1.07 (m, 16H), 0.66 (s, 3H). LCMS Rt=0.946 min in 1.5 min chromatography, 5-95AB, purity 100%, MS ESI calcd. for C.sub.26H.sub.38N.sub.3O.sub.2 [M+H].sup.+ 424, found 406 [M+H-18].

Example 3. Synthesis of 5

[0273] ##STR00040## ##STR00041##

[0274] Step 1. Synthesis of A4. To a solution of 2,6-di-tert-butyl-4-methylphenol (A3, 24 g, 109 mmol) in toluene (100 mL) was added AlMe.sub.3 (2 M in toluene, 27.3 mL, 54.6 mmol) dropwise at 10° C. The mixture was then stirred at 25° C.; for 1 hour. To the mixture was added a solution of compound (5R,8R,9R,10S,13S,14S)-13-methyldodecahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione (5 g, 18.2 mmol) in toluene (50 mL) dropwise at −70° C.; dropwise under N.sub.2. The mixture was stirred at −70° C.; for 1 hour. MeMgBr (3 M in ether, 18.2 mL, 54.6 mmol) was added dropwise at −70° C. The mixture was stirred at −70° C.; for another 3 hours. TLC showed the reaction was completed. The mixture was poured into citric acid (150 mL, 20% aq.). The mixture was extracted with EtOAc (100 mL*2). The combined organic layer was concentrated under vacuum, purified by column chromatography on silica gel (petroleum ether:EtOAc=50:1 to 1:1) to give (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-17(2H)-one (4.8 g, 90%) as a white solid.

[0275] .sup.1H NMR (A4) (400 MHz, CDCl.sub.3) δ 2.50-2.35 (m, 1H), 2.14-2.01 (m, 1H), 1.96-1.00 (m, 25H), 0.85 (s, 3H).

[0276] Step 2. Synthesis of A5. To a suspension of PPh.sub.3PrBr (19 g, 49.5 mmol) in THF (100 mL) was added t-BuOK (5.5 g, 49.5 mmol) at 25° C. The color of the suspension was turned to dark red. After stirring at 60° C.; for 1 h, (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-17(2H)-one (4.8 g, 16.5 mmol) was added at 60° C. The reaction mixture was stirred at 60° C.; for 16 h. TLC showed the reaction was completed. To the reaction mixture was added water (50 mL) and EtOAc (100 mL). The color of the mixture was turned to light yellow. The organic layer was separated. The aqueous phase was extracted with EtOAc (100 mL). The combined organic layer was concentrated in vacuum, purified by column chromatography on silica gel (PE:EtOAc=100:1 to 20:1) to give (3R,5R,8R,9R,10S,13S,14S,Z)-3,13-dimethyl-17-propylidenehexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.6 g, 30%) as colorless oil.

[0277] .sup.1H NMR (A5) (400 MHz, CDCl.sub.3) δ 5.06-4.95 (m, 1H), 2.42-2.32 (m, 1H), 2.26-2.00 (m, 4H), 1.90-1.05 (m, 21H), 1.00-0.85 (m, 9H).

[0278] Step 3. Synthesis of A6. To a solution of (3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-17-propylidenehexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.6 g, 5.05 mmol) in THF (5 mL) was added BH.sub.3-Me.sub.2S (2.5 mL, 25 mmol) at 0° C.; dropwise. The solution was stirred at 25° C. for 16 h. TLC (PE/EtOAc=5/1) showed the reaction was completed. After cooling to 0° C., NaOH (10%, 10 mL, aq.) was added very slowly. After the addition was complete, H.sub.2O.sub.2 (30%, 10 mL, aq.) was added slowly and the inner temperature was maintained below 10° C. The resulting solution was stirred at 25° C.; for 1 h. The mixture was extracted with EtOAc (50*2 mL). The combined organic layer was separated, washed with Na.sub.2S.sub.2O.sub.3 (500 mL, 20%, aq.), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give (3R,5R,8R,9R,10S,13S,14S,17S)-17-(1-hydroxypropyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.6 g, 95%) as light yellow solid.

[0279] .sup.1H NMR (A6) (400 MHz, CDCl.sub.3) δ 3.55-3.45 (m, 1H), 1.95-0.60 (m, 37H).

[0280] Step 4. Synthesis of A7. To a solution of (3R,5R,8R,9R,10S,13S,14S,17S)-17-(1-hydroxypropyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.6 g, 4.8 mmol) in DCM (20 mL), was added silica gel (4 g) and PCC (2 g, 9.6 mmol). The mixture was stirred at 25° C.; for 3 h. TLC showed the reaction was completed. The mixture was filtered and the filter cake was washed with DCM (20 mL). The combined filtrate was concentrated in vacuum, purified by column chromatography on silica gel column eluted with PE/EtOAc=10/1 to 8/1 to give 1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (0.5 g, 31%) as light yellow solid.

[0281] .sup.1H NMR (A7) (400 MHz, CDCl.sub.3) δ 2.58-2.50 (m, 1H), 2.44-2.30 (m, 2H), 2.25-2.11 (m, 1H), 2.00-1.91 (m, 1H), 1.88-1.57 (m, 8H), 1.50-0.99 (m, 20H), 0.59 (s, 3H). LCMS (A7) Rt=1.315 min in 2 min chromatography, 10-80AB, purity 100%, MS ESI calcd. for C22H37O2 [M+H].sup.+333, found 315 ([M+H-18].sup.+).

[0282] Step 5. Synthesis of A8. To a solution of 1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (0.5 g, 1.5 mmol) in McOH (5 mL) was added HBr (0.01 mL, 48% in water). Br.sub.2 (149 uL, 3 mmol) was added at 25° C. The reaction mixture was stirred at 25° C.; for 16 h. LCMS showed the reaction was completed. To the mixture was added Na.sub.2SO.sub.3 (10%, 10 mL, aq.) and extracted with EtOAc (50 mL*2). The combined organic layer was dried over Na.sub.2SO.sub.4, concentrated under vacuum to give 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (0.6 g, 97%) as a colorless oil.

[0283] .sup.1H NMR (A8) (400 MHz, CDCl.sub.3) δ 4.48-4.35 (m, 1H), 3.12-2.70 (m, 1H), 2.40-1.00 (m, 30H), 0.75-0.60 (m, 3H).

[0284] Step 6. Synthesis of 5. To a solution of 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (200 mg, 0.49 mmol) in acetone (2 mL) was added morpholine (200 mg, 2.29 mmol). After stirring at 25° C.; for 16 h, LCMS showed the reaction was completed. The reaction mixture was in vacuum to give the crude product which was purified by prep-HPLC to give 1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-morpholinopropan-1-one, HCl salt (8.7 mg, 4.3%) as a light yellow solid.

[0285] .sup.1H NMR (5) (400 MHz, methanol-d4) δ 4.45-4.20 (m, 1H), 4.15-4.00 (m, 2H), 3.95-3.80 (m, 2H), 3.55-3.45 (m, 1H), 3.30-3.20 (m, 2H), 3.02-2.65 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.75 (m, 8H), 1.75-1.25 (m, 17H), 1.25-1.10 (m, 3H), 0.90-0.70 (m, 3H). LCMS (5) Rt=1.972 min in 3 min chromatography, 10-80CD, purity 100%, MS ESI calcd. for C.sub.26H.sub.44NO.sub.3 [M+H].sup.+ 418, found 418.

Example 4. Synthesis of 6 and 7

[0286] ##STR00042##

[0287] Step 1. To a solution of A9 (500 mg, 1.25 mmol) in acetone (3 mL) was added 2H-benzo[d][1,2,3]triazole (222 mg, 1.87 mmol) at 25° C. and stirred at this temperature for 12 h. After TLC showed the starting material was consumed completely, the mixture was filtrated and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE/EtOAc=3/1 to 1/1) to afford 410 (200 mg, purity=60%) and A11 (400 mg, purity=70%) as white solid.

[0288] .sup.1H NMR (A10): (400 MHz, CDCl3) δ 7.87 (dd, J.sub.1=2.8 Hz, J.sub.2=6.4 Hz, 2H), 7.39 (dd, J.sub.1=2.8 Hz, J.sub.2=6.4 Hz, 2H), 5.56-5.51 (m, 2H), 2.69-2.65 (m, 1H), 2.23-2.16 (m, 2H), 1.87-1.60 (m, 11H), 1.45-1.01 (m, 66H), 0.87-075 (m, 25H)

[0289] .sup.1H NMR (A11): (400 MHz, CDCl.sub.3) δ 8.06 (d, J=8 Hz, 1H), 7.50-7.46 (m, 1H), 1.82-1.63 (m, 7H), 1.45-1.11 (m, 33H), 0.87-0.82 (m, 6H), 0.72 (s, 3H)

[0290] Step 2. To a solution of A10 (200 mg, 0.459 mmol) in THF (3 mL) was added KOH (51.3 mg, 0.918 mmol) and MeI (1.14 g, 8.03 mmol) at 25° C. The mixture was stirred at 25° C. for 211, After TLC showed the starting material was consumed, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuum. The residue was purified by prep-HPLC to afford (S)-2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,1:3-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (9.3 mg, 4.51%) and (R)-2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (6.1 mg, 2.96%) as white solid.

[0291] .sup.1H NMR (6): (400 MHz, CDCl.sub.3) δ 7.90 (dd, J.sub.1=3.2 Hz, J.sub.2=6.4 Hz, 2H), 7.41 (dd, J.sub.1=2.8 Hz, J.sub.2=6.4 Hz, 2H), 5.52-5.50 (m, 1H), 2.28-2.25 (m, 2H), 1.82-1.58 (m, 10H), 1.40-1.21 (m, 15H), 1.03-0.86 (m, 3H), 0.68 (s, 3H). LCMS Rt=1.014 min in 1.5 min chromatography, 5-95AB, purity 95%, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.2 [M+H].sup.+ 450, found 432 [M+H-18].

[0292] .sup.1H NMR (7): (400 MHz, CDCl3) δ 7.88 (dd, J.sub.1=3.2 Hz, J.sub.2=6.4 Hz, 2H), 7.38 (dd, J.sub.1=3.2 Hz, J.sub.2=6.4 Hz, 2H), 5.69-5.68 (m, 1H), 2.72-2.70 (m, 1H), 2.20-1.63 (m, 13H), 1.44-1.08 (m, 16H), 072 (s, 3H). LCMS Rt=0.991 min in 1.5 min chromatography, 5-95AB, purity 95%, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.2 [M+H].sup.+ 450, found 432 [M+H−18].

Example 5. Synthesis of 8 and 9

[0293] ##STR00043##

[0294] Step 1. Synthesis of A12-A. To a solution of compound A3 (274 mg. 1 mmol) in methanol (1 mL) was added iodine (25.4 mg, 0.1 mmol), After stirring at 60° C. for 12 h, TLC showed no compound 2 remained and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20 mL) and washed with saturated NaHCO.sub.3 (15 mL), brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on basic alumina (petroleum ether/EtOAc=9:1) to give compound A12-A (280 mg, 88%) as a white solid.

[0295] .sup.1H NMR (A11): (400 MHz, CDCl.sub.3), δ (ppm), 3.19 (s, 3H), 3.13 (s, 3H), 3.18-3.13 (dd, 1H, J=19.2, 8.8 Hz), 0.83 (s, 3H).

[0296] Step 2. Synthesis of A12. A solution of CH.sub.3CH.sub.2CH.sub.2PPh.sub.3I (20.2 g, 47 mmol) and KOtBu (4.9 g, 43.6 mmol) in THE (40 mL) was heated to reflux for 1 h. Then compound A11 (5 g, 15.6 mmol) was added. The resulting solution was refluxed overnight, then TLC showed the reaction was complete. The reaction was cooled to room temperature and quenched with NaHCO.sub.3 (60 mL), the resulting solution was extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give crude compound A12 (30 g, crude) which was used in the next step without further purification.

[0297] Step 3. Synthesis of A13. To a solution of compound A12 (30 g, crude) in TI-IF (40 mL) was added aqueous HCl (12 M. 5 mL) and stirred at room temperature for 30 min, then TLC showed the reaction was complete. The solution was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/PE=1:10) to give compound A13 (3.7 g, 80%, two steps yield) as a white solid.

[0298] .sup.1H NMR: (500 MHz, CDCl.sub.3), δ (ppm), 5.06 (t, 1H, J=7.5 Hz), 2.63 (t, 1H, J=14 Hz), 0.96 (t, 3H, J=7.5 Hz), 0.93 (s, 3H).

[0299] Step 4. Synthesis of A14. To a solution of compound A13 (1.5 g, 5 mmol) in THE (15 mL) was added TMSCF.sub.3 (850 mg, 6 mmol) and MAE (130 tug, 0.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. Then TBAF (1M in THF, 10 mL) was added and stirred at room temperature for 30 min, TLC showed the reaction was complete. The reaction solution was concentrated and the residue was diluted with EtOAc (40 mL). The resulting solution was washed with brine (20 mL×2), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/PE=1:10) to give A14 (1.3 g. 70%) as a white solid.

[0300] .sup.1H NMR (A14): (500 MHz, CDCl.sub.3), δ (ppm), 5.05-5.02 (m, 1H), 0.96 (t, 3H, J=7.5 Hz), 0.90 (s, 3H).

[0301] Step 5. Synthesis of A15. To a solution of compound A14 (200 mg, 0.54 mmol) in anhydrous THF (5 MI-) was added borane-tetrahydrofuran complex (1.0 M solution in THF, 2 mL, 2 mmol). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed 30% aqueous solution of H.sub.2O.sub.2 (1.2 mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried over MgSO.sub.4, filtered and concentrated to afford 7 (260 mg, crude) as white solid which was used in the next step without further purification.

[0302] Step 6. Synthesis of A16. To a solution of compound A15 (300 mg, crude) was dissolved in 10 mL DCM was added Dess-Martin periodinate (980 mg, 2.31 mmol) and stirred at room temperature overnight. Then TLC showed the reaction was complete. The reaction was then filtered through a plug of celite and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, EtOAc/PE=1:6) to give compound A16 (210 mg, 70%) as a white solid.

[0303] .sup.1H NMR: (500 MHz, CDCl.sub.3), δ (ppm), 2.56 (t, 3H, J=9 Hz), 1.06 (t, 3H, J=7.3 Hz), 0.63 (s, 3H).

[0304] Step 7. Synthesis of A17 and A18. To a solution of compound A16 (500 mg, 1.29 mmol) in MeOH (10 mL) was added 5 drops of HBr (48%) followed by bromine (1029 mg, 6.45 mmol). After stirring at room temperature for 2 h, the reaction mixture was poured into ice-water (20 mL) then the resulting mixture was extracted with EtOAc (15 mL×3), The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated, the residue was purified by column chromatography (silica gel, EtOAc/PE=1:8) to give A17 (210 mg, 35%) and A18 (250 mg, 41%) as a white solid.

[0305] .sup.1H NMR: (A17): (500 MHz, CDCl.sub.3), δ (ppm) 4.46-4.42 (q, 1H, J=7 Hz), 2.79 (t, 1H, J=9.5 Hz), 1.73 (d, 3H, J=7 Hz), 0.76 (s, 3H).

[0306] .sup.1H NMR: (A18): (500 MHz, CDCl.sub.3), δ (ppm), 4.42-4.38 (q, 1H, J=6.5 Hz), 3.11 (t, 1H, J=9 Hz), 1.72 (d, 3H, J=6.5 Hz), 0.63 (s, 3H).

[0307] Step 8. Synthesis of 8. To a solution of compound A17 (50 mg, 0.11 mmol) and Cs.sub.2CO.sub.3 (720 mg, 2.20 mmol) in THE (3 mL) was added 1H-pyrazole (150 mg, 2.2 mmol). The reaction mixture was heated at 30° C. and stirred overnight. LCMS showed the reaction was complete and the reaction mixture was diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by Prep-HPLC to give compound 8 as a white solid.

[0308] .sup.1H NMR (8): (500 MHz, CDCl.sub.3), δ (ppm), 7.58 (d, 1H, J=2 Hz), 7.54 (d, 1H, J=1.5 Hz), 6.35 (t, 1H, J=4.5 Hz), 5.23 (q, 1H, J=7.5 Hz), 2.69 (t, 1H, J=9 Hz), 1.67 (d, 3H, J=7 Hz), 0.63 (s, 3H).

Example 6. Synthesis of 10 and 11

[0309] ##STR00044##

[0310] To a solution of A11 (400 mg, 0.918 mmol) in THF (5 mL) was added KOH (102 mg, 1.83 mmol) and MeI (156 mg, 1.10 mmol) at 25° C. The mixture was stirred at 25° C. for 2 h. After TLC showed the starting material was consumed, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuum. The residue was purified by prep-HPLC to afford compound 10 (63.3 mg, 15%) and compound 11 (33.4 mg, 8%) as off white solids.

[0311] .sup.1H NMR (10): (400 MHz, CDCl.sub.3) δ 8.09 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 1H), 7.39-7.37 (m, 2H), 5.62-5.60 (m, 1H), 2.34 (t, J=9.2 Hz 1H), 2.15-2.00 (m, 1H), 1.79-1.60 (m, 11H), 1.39-1.21 (m, 14H), 1.02-0.99 (m, 3H), 0.67 (s, 3H). LCMS Rt=0.972 min in 1.5 min chromatography, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.2 [M+H].sup.+ 450, found 450.

[0312] .sup.1H NMR (11): (400 MHz, CDCl.sub.3) δ 8.07 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.38-7.36 (m, 1H), 5.79-5.77 (m, 1H), 2.70-2.69 (m, 1H), 2.03-1.91 (m, 2H), 1.89-1.66 (m, 9H), 1.39-1.20 (m, 15H), 1.07-0.99 (m, 3H), 0.62 (s, 3H). LCMS Rt=0.954 min in 1.5 min chromatography, MS ESI calcd. for C.sub.28H.sub.40N.sub.3O.sub.2 [M+H].sup.+ 450, found 450.

Example 7. Synthesis of 12 and 13

[0313] ##STR00045## ##STR00046##

[0314] Step 1. Synthesis of A20. To a suspension of EtPPh.sub.3Br (17.8 g, 48.2 mmol) in THF (60 mL) was added t-BuOK (5.40 g, 48.2 mmol). After stirring at 60° C.; for 1 h, A19 (2.8 g, 9.64 mmol) was added in portions at 60° C. The reaction mixture was stirred at the same temperature for 8 h. TLC (PE/EtOAc=3/1) showed the reaction was complete, and a main product was found with lower polarity. The reaction mixture was quenched with aq.Math.NH.sub.4Cl (50 mL) and extracted with EtOAc (50 mL×3) for three times. The combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give the crude product. The crude product was purified by column chromatography (PE:EA=10:1-6:1) to give A20 (2.6 g, 89%) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.15-5.10 (m, 1H), 2.42-2.12 (m, 3H), 1.75-0.95 (m, 26H), 0.90 (s, 3H), 0.79-0.62 (m, 2H).

[0315] Step 2. Synthesis of A21. To a solution of A20 (2.6 g, 8.59 mmol) in THF (20 mL) was added dropwise a solution of BH.sub.3-Me.sub.2S (8.59 mL, 10 M) at 0° C. The solution was stirred at 25° C.; for 8 h. TLC (PE:EtOAc=3:1) showed the reaction was almost complete, and a main product was found with higher polarity. After cooling to 0° C., a solution of NaOH (34.3 mL, 3M) was added very slowly. After the addition, H.sub.2O.sub.2 (15.5 mL, 33%) was added slowly and the inner temperature was maintained below 10° C. The resulting solution was stirred at 25° C. for 2 h. The resulting solution was extract with EtOAc (20 mL×3). The combined organic solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (20 mL×2), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give the crude product A21 (3 g, crude) as a solid. The crude product was used for the next step without further purification.

[0316] Step 3. Synthesis of A22. A mixture of A21 (3 g, 9.36 mmol), PCC (3.01 g, 14.0 mmol) and silica gel (3.31 g, w/w=1/1.1) in DCM (50 mL) was stirred at 25° C.; for 2 h, the reaction mixture color became brown. TLC (PE/EtOAc=3/1) showed the reaction was complete, and a main product was found with lower polarity. The solution was filtered and the filter cake was washed with DCM (20 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=15/1 to 6/1 to give A22 (2.3 g, 77%) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.59-2.51 (m, 1H), 2.22-2.12 (m, 4H), 2.06-1.97 (m, 1H), 1.88-0.95 (m, 23H), 0.80-0.62 (m, 5H).

[0317] Step 4. Synthesis of A23. To a solution of A22 (2.3 g, 7.22 mmol) and a catalytic amount of concentrated HBr (28.9 mg, 40% in water) in McOH (20 mL) was added dropwise dibromine (1.27 g, 7.94 mmol) at 0° C. The reaction mixture was stirred at 25° C.; for 2 h. TLC (PE:EtOAc=3:1) showed the reaction was complete. The reaction was quenched by saturated aqueous NaHCO.sub.3 and the pH was adjusted to 7-8. The reaction mixture was extracted with DCM (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated to get the crude product A23 (2.6 g, 91%) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.98-3.90 (m, 2H), 2.89-2.81 (m, 1H), 2.26-2.15 (m, 1H), 1.98-0.95 (m, 24H), 0.81-0.62 (m, 5H).

[0318] Step 5. Synthesis of A24. To a solution of A23 (300 mg, 754 μmol) in acetone (10 mL) was added K.sub.2CO.sub.3 (155 mg, 1.13 mmol) and 1H-pyrazole-4-carbonitrile (84.1 mg, 904 μmol). The mixture was stirred at 25° C. for 4 hours. TLC (PE/EA=3/1) showed the starting material was consumed completely. The solvent was removed by rotary evaporator. To the mixture was added water (10 mL) and ethyl acetate (10 mL). The organic layer was separated. The aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic layers was washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude product A24 (350 mg) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (s, 1H), 7.84 (s, 1H), 5.06-4.90 (m, 2H), 2.68-2.59 (m, 1H), 2.28-1.98 (m, 1H), 1.92-1.01 (m, 24H), 0.82-0.65 (m, 5H).

[0319] Step 5. Synthesis of 12 and 13. To a solution of A24 (400 mg, 976 μmol) in THE (10 mL) was added KOH (81.7 mg, 1.46 mmol) and MeI (207 mg, 1.46 mmol) at 25° C. The mixture was stirred at 25° C. for 2 h. After LCMS showed the starting material was consumed, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated in vacuum. The residue was purified by prep-HPLC to afford both compound 12 (61 mg, 14.7%) and compound 13 (43 mg, 10.4%) as off white solids.

[0320] .sup.1H NMR (12): (400 MHz, CDCl.sub.3) δ 8.01 (s, 1H), 7.79 (s, 1H), 5.32-5.27 (m, 1H), 2.78-2.74 (m, 1H), 2.21-2.15 (m, 2H), 1.92-0.98 (m, 26H), 0.79-0.65 (m, 2H), 0.61 (s, 3H). LCMS Rt=0.960 min in 1.5 min chromatography, MS ESI calcd. for C.sub.26H.sub.37N.sub.3O.sub.2 [M+H].sup.+ 424, found 424.

[0321] .sup.1H NMR (13) (400 MHz, CDCl.sub.3) δ 7.89 (s, 1H), 7.83 (s, 1H), 5.09-5.04 (m, 1H), 2.55-2.49 (m, 1H), 2.16-2.05 (m, 2H), 1.91-0.95 (m, 26H), 0.78-0.60 (m, 5H). LCMS Rt=0.968 min in 1.5 min chromatography, MS ESI calcd. for C.sub.26H.sub.37N.sub.3O.sub.2 [M+H].sup.+ 424, found 406 [M+H-18].sup.+.

Example 8. Synthesis of 14 and 15

[0322] ##STR00047##

[0323] Step 1. Synthesis of A24 and A25. To a solution of A23 (400 mg, 1 mmol, 1.00 eq) in acetone (5.00 mL) was added K.sub.2CO.sub.3 (276 mg, 2 mmol, 2 eq) and 2H-1,2,3-triazole (103 mg, 1.5 mmol, 1.5 eq). The mixture was stirred at 25° C. for 12 hours, until TLC showed the reaction was complete. The reaction was quenched by water (30 mL) and then extracted with EA (30 mL*2). The combined organic phase was washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=3/1 to EA) to afford compound A24 (125 mg, 31% yield) and compound A25 (185 mg, 45% yield) as solids.

[0324] .sup.1H NMR (A24): (CDCl.sub.3, 400 MHz) δ 7.71 (s, 2H), 5.26 (d, J=5.27 Hz, 2H), 2.66-2.56 (m, 1H), 2.30-2.05 (m, 2H), 1.94-1.84 (m, 1H), 1.83-1.64 (m, 6H), 1.50-0.96 (m, 25H), 0.94-0.82 (m, 3H), 0.80-0.67 (m, 6H).

[0325] .sup.1H NMR (A25): (CDCl.sub.3, 400 MHz) δ 7.78 (s, 1H), 7.66 (s, 1H), 5.34-5.09 (m, 2H), 2.76-2.63 (m, 1H), 2.32-2.06 (m, 2H), 1.96-1.65 (m, 7H), 1.57-1.47 (m, 2H), 1.23 (m, 17H), 0.90-0.74 (m, 3H), 0.70 (s, 3H).

[0326] Step 2. Synthesis of 14 and 15. To a solution of A24 (125 mg, 324 umol, 1.00 eq) and KOH (36.3 mg, 648 umol, 2 eq) in THE (3.00 mL) was added CH.sub.3I (55 mg, 388 umol, 1.2 eq). The mixture was stirred at 25° C.; for 16 hrs until TLC analysis showed the reaction was complete. The reaction was quenched with water and extracted with EA (2*30 mL), the combined organic phase was washed with brine and dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (0.05% HCl) to afford compound 14 (27.4 mg, 21% yield) and compound 15 (24.9 mg, 19% yield) as off white solids.

[0327] .sup.1H NMR (14) (CDCl.sub.3 400 MHz) δ 7.67 (s, 2H), 5.30-5.21 (m, 1H), 2.31-2.22 (m, 1H), 2.18-2.05 (m, 1H), 1.90-1.71 (m, 3H), 1.70-1.49 (m, 11H), 1.39-1.22 (m, 3H), 1.20 (s, 3H), 1.12-0.89 (m, 7H), 0.67 (s, 3H), 0.65-0.62 (m, 2H). LCMS Rt=1.168 min in 2 min chromatography, MS ESI calcd. for C.sub.24H.sub.37N.sub.3O.sub.2 [M+H].sup.+ 400, found 382 [M+H-18].

[0328] .sup.1H NMR (15) (CDCl.sub.3, 400 MHz) δ 7.67 (s, 2H), 5.47-5.36 (m, 1H), 2.71-2.61 (m, 1H), 2.18-2.06 (m, 2H), 1.86-1.83 (m, 4H), 1.79-1.72 (m, 1H), 1.69-1.64 (m, 4H), 1.60-1.51 (m, 2H), 1.42-1.28 (m, 4H), 1.25-1.19 (m, 6H), 1.17-0.9 (m, 6H), 0.75-0.66 (m, 5H). LCMS Rt=1.134 min in 2 min chromatography, MS ESI calcd. for C.sub.24H.sub.37N.sub.3O.sub.2 [M+H].sup.+ 400, found 382 [M+H−18].

Example 9. Synthesis of 16 and 17

[0329] ##STR00048##

[0330] To a solution of A25 (185 mg, 479 umol, 1.00 eq) and KOH (53.7 mg, 958 umol, 2 eq) in THF (3.00 mL) was added CH.sub.3I (81.4 mg, 574 umol, 1.2 eq). The mixture was stirred at 25° C.; for 5 hrs until TLC showed the reaction was complete. Then, the reaction was quenched with water and extracted with EA (2*30 mL), the combined organic phase was washed with brine and dried over Na2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (0.05% HCl) to afford compound 16 (18.5 mg, 10% yield) and compound 17 (31.4 mg, 16% yield,) as off white solids.

[0331] .sup.1H NMR (16) (CDCl.sub.3, 400 MHz) δ 7.75 (s, 1H), 7.59 (s, 1H), 5.52-5.42 (m, 1H), 2.60-2.52 (m, 1H), 2.13-2.00 (m, 1H), 1.94-1.81 (m, 2H), 1.77-1.53 (m, 12H), 1.48-1.39 (m, 1H), 1.38-1.23 (m, 3H), 1.21-1.19 (m, 3H), 1.18-1.03 (m, 5H), 1.02-0.89 (m, 2H), 0.73-0.65 (m, 5H). LCMS Rt=1.054 min in 2 min chromatography, MS ESI calcd. for C.sub.24H.sub.37N.sub.3O.sub.2 [M+H].sup.+ 400, found 422 [M+23].sup.+.

[0332] .sup.1H NMR (17) (CDCl.sub.3, 400 MHz) δ7.80 (s, 1H), 7.75 (s, 1H), 5.70-5.62 (m, 1H), 2.83-2.76 (m, 1H), 2.24-2.14 (m, 2H), 1.91-1.82 (m, 1H), 1.78-1.65 (m, 8H), 1.59-1.45 (m, 5H), 1.40-1.30 (m, 2H), 1.28-1.23 (m, 2H), 1.21 (s, 3H), 1.16-0.94 (m, 6H), 0.80-0.61 (m, 2H), 0.54 (s, 3H). LCMS Rt=1.020 min in 2 min chromatography, MS ESI calcd. for C.sub.24H.sub.37N.sub.3O.sub.2 [M+H].sup.+ 400, found 422 [M+23].sup.+.

Example 10. Synthesis of 18 and 19

[0333] ##STR00049##

[0334] Step 1. Synthesis of A26 and A27. To a solution of A23 (600 mg, 1.5 mmol, 1.00 eq) in acetone (10 mL) was added K.sub.2CO.sub.3 (414 mg, 3 mmol, 2 eq) and 2H-benzo[d][1,2,3] triazole (268 mg, 2.25 mmol, 1.5 eq). The mixture was stirred at 25° C.; for 12 hours. The reaction was quenched by water (50 mL) and then extracted with EA (50 mL*2). The combined organic phase was washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether/Ethyl acetate=5/1) to afford A26 (170 mg, 292 umol, 19.4% yield, 75% purity) and A27 (405 mg, 883 umol, 58.8% yield, 95% purity) as off-white solids.

[0335] .sup.1H NMR (A26): (CDCl.sub.3, 400 MHz) δ 7.89-7.88 (m, 2H), 7.42-7.40 (m, 2H), 5.60-5.50 (m, 2H), 2.71-2.67 (m, 1H), 2.23-2.15 (m, 2H), 0.77 (s, 3H).

[0336] .sup.1H NMR (A27): (CDCl.sub.3, 400 MHz) δ 8.10 (d, J=8.4 Hz, 1H), 7.51-7.50 (m, 1H), 7.42-7.35 (m, 2H), 5.49-5.39 (m, 2H), 2.76-2.74 (m, 1H), 2.23-2.16 (m, 2H), 0.76 (s, 3H).

[0337] Step 2. Synthesis of 18 and 19. To a solution A26 (170 mg, 390 umol, 1.00 eq) and KOH (43.7 mg, 780 umol, 2 eq) in THE (3.00 mL) was added CH.sub.3I (66.4 mg, 468 umol, 1.2 eq). The mixture was stirred at 25° C.; for 16 hrs. Then, the reaction was quenched with water and extracted with EA (2*30 mL), the combined organic phase was washed with brine and dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by Prep-HPLC (0.5% HCl) to afford compound 18 (28 mg, 16% yield) and compound 19 (18.5 mg, 10.5% yield,) as off white solids.

[0338] .sup.1H NMR (18) (CDCl.sub.3, 400 MHz) δ 7.96-7.87 (m, 2H), 7.48-7.39 (m, 2H), 5.57-5.52 (m, 1H), 2.33-2.29 (m, 1H), 2.23-2.11 (m, 1H), 1.99-1.91 (m, 1H), 1.86-1.74 (m, 5H), 1.71-1.60 (m, 2H), 1.53-1.52 (m, 3H), 1.39-0.87 (m, 16H), 0.71 (s, 3H), 0.61-0.69 (m, 2H). LCMS Rt=1.285 min in 2 min chromatography, MS ESI calcd. for C.sub.28H.sub.39N.sub.3O.sub.2 [M+H].sup.+ 450, found 432 [M+H−18].

[0339] .sup.1H NMR (19) (CDCl.sub.3, 400 MHz) δ 7.95-7.86 (m, 2H), 7.45-7.37 (m, 2H), 5.76-5.67 (m, 1H), 2.80-2.70 (m, 1H), 2.28-2.09 (m, 2H), 2.00 (d, J=7.28 Hz, 3H), 1.91-1.53 (m, 9H), 1.46-1.30 (m, 4H), 1.27-0.96 (m, 10H), 0.75 (s, 3H), 0.71-0.68 (m, 2H). LCMS Rt=1.248 min in 2 min chromatography, MS ESI calcd. for C.sub.28H.sub.39N.sub.3O.sub.2 [M+H].sup.+ 450, found 432 [M+H−18].sup.+

Example 11. Synthesis of 20 and 21

[0340] ##STR00050##

[0341] To a solution of A27 (405 mg, 929 umol, 1.00 eq) and KOH (103 mg, 1.85 mmol, 2 eq) in THE (6.00 mL) was added CH.sub.3I (157 mg, 1.11 mmol, 1.2 eq). The mixture was stirred at 25° C.; for 5 hrs. Then, the reaction was quenched with water and extracted with EA (2*50 mL), the combined organic phase was washed with brine and dried over Na2SO.sub.4, filtered and concentrated. The residue was purified by Prep-HPLC (0.5% HCl) to afford compound 20 (107 mg, 26% yield) and compound 21 (64 mg, 15% yield) as off white solids.

[0342] .sup.1H NMR (20): (CDCl.sub.3, 400 MHz) δ 8.12 (d, J=8 Hz, 1H), 7.53-7.47 (m, 1H), 7.45-7.38 (m, 2H), 5.70-5.61 (m, 1H), 2.42-2.34 (m, 1H), 2.17-2.06 (m, 1H), 1.94-1.87 (m, 1H), 1.86-1.79 (m, 1H), 1.79-1.75 (m, 3H), 1.74-1.63 (m, 2H), 1.63-1.49 (m, 6H), 1.44-1.23 (m, 5H), 1.21 (s, 3H), 1.16-0.85 (m, 6H), 0.71 (s, 3H), 0.68-0.60 (m, 2H). LCMS SAGE-WZF-010-P2B Rt=1.195 min in 2 min chromatography, MS ESI calcd. for C.sub.28H.sub.39N.sub.3O.sub.2 [M+H].sup.+ 450, found 450.

[0343] .sup.1H NMR (21): (CDCl.sub.3, 400 MHz) δ 8.09 (d, J=12 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.49 (m, t, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 5.85-5.76 (m, 1H), 2.78-2.70 (m, 1H), 2.15-2.00 (m, 2H), 1.93 (d, J=7.28 Hz, 3H), 1.88-1.52 (m, 9H), 1.41-1.29 (m, 4H), 1.26-0.49 (m, 10H), 0.73-0.68 (m, 2H), 0.65 (s, 3H). LCMS Rt=1.178 min in 2 min chromatography, MS ESI calcd. for C.sub.28H.sub.39N.sub.3O.sub.2 [M+H].sup.+ 450, found 450

[0344] Assay Methods

[0345] Compounds provided herein can be evaluated using various assays; examples of which are described below.

[0346] Steroid Inhibition of TBPS Binding

[0347] TBPS binding assays using rat brain cortical membranes in the presence of 51.1M GABA has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol. Pharmacol. 1989, 35, 189-194).

[0348] Briefly, cortices are rapidly removed following decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C. The resultant supernatants are centrifuged at 10,000×g for 20 min at 4° C.; to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for 10 min at 4° C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 μL) of the membrane suspensions are incubated with 3 nM [.sup.35S]-TBPS and 5 μL aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 μM GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 μM unlabeled TBPS and ranged from 15 to 25%. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non-linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism (GraphPad). The data are fit to a partial instead of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC.sub.50) of specific binding and the maximal extent of inhibition (I.sub.max) are determined for the individual experiments with the same model used for the overall data and then the means±SEM.s of the individual experiments are calculated. Picrotoxin serves as the positive control for these studies as it has been demonstrated to robustly inhibit TBPS binding.

[0349] Various compounds are or can be screened to determine their potential as modulators of [.sup.35S]-TBPS binding in vitro. These assays are or can be performed in accordance with the above discussed procedures.

[0350] For Table 1, “A” indicates an IC.sub.50<50 nM, “B” indicates an IC.sub.50 of 50 nM to 100 nM, “C” indicates an IC.sub.50 100 nM to 250 nM, “D” indicates an IC.sub.50 of 250 nM to 500 nM, and “E” indicates IC.sub.50>500 nM.

TABLE-US-00001 TABLE 1 35S-TBPS Radioligand Displacement Compound (IC.sub.50)  1 D  2 B  3 A  4 B  5 D  6 A  7 D  8 D  9 D 10 A 11 D 12 C 13 C 14 E 15 E 16 E 17 E 18 B 19 E 20 E 21 C