The invention a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp.sup.3 carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

A process is provided for the making of estetrol starting from a 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, wherein A is an C.sub.1-C.sub.5 alkyl group, preferably a methyl group, or a C.sub.7-C.sub.12 benzylic group, preferably a benzyl group. This process is particularly suitable to industry.

A process is provided for the making of estetrol starting from a 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, wherein A is an C.sub.1-C.sub.5 alkyl group, preferably a methyl group, or a C.sub.7-C.sub.12 benzylic group, preferably a benzyl group. This process is particularly suitable to industry.

Methods for modulating (inhibiting or stimulating) retinoid-related orphan receptor (ROR) activity. This modulation has numerous effects, including inhibition of T.sub.H-17 cell function and/or T.sub.H-17 cell activity, and inhibition of re-stimulation of T.sub.H-17 cells, which are beneficial to treatment of inflammation and autoimmune disorders. Stimulation of ROR results in stimulation of T.sub.H-17 cell function and/or activity which is beneficial for immune-enhancing compositions (e.g., vaccines).

Methods for modulating (inhibiting or stimulating) retinoid-related orphan receptor (ROR) activity. This modulation has numerous effects, including inhibition of T.sub.H-17 cell function and/or T.sub.H-17 cell activity, and inhibition of re-stimulation of T.sub.H-17 cells, which are beneficial to treatment of inflammation and autoimmune disorders. Stimulation of ROR results in stimulation of T.sub.H-17 cell function and/or activity which is beneficial for immune-enhancing compositions (e.g., vaccines).

The automated synthesis of clinically relevant amounts of 16-.sup.18F-fluoro-5-dihydrotestosterone (.sup.18F-FDHT) using a commercially available radiosynthesizer. Synthesis was performed in 90 minutes with a decay-corrected radiochemical yield of 295%. The specific activity was 4.6 Ci/mol (170 GBq/mol) at end of formulation with a starting activity of 1.0 Ci (37 GBq). The formulated .sup.18F-FDHT yielded sufficient activity for multiple patient doses and passed all quality control tests required for routine clinical use.

This invention provides novel compounds comprising the following anti-inflammatory pharmacore:

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wherein X, R.sub.1 and R.sub.2 are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds and compositions.

The present disclosure is generally directed to neuroactive 19-alkoxy-17(20)-Z-vinylcyano-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): ##STR00001##
and pharmaceutical compositions thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, tinnitus, status epilepticus.

Provided herein are 19-nor C3, 3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined herein, and A is a heteroaryl ring system comprising 3 or 4 nitrogens as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

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