Chemoselective enrichment for compound isolation

Chemoselective isolation of hydroxyl group-containing and carboxyl group-containing compounds is accomplished via formation of polymeric silyl ethers and polymeric siloxyl esters, respectively. Preparation of chemoselective polymeric reagents for capture of hydroxyl group containing compounds and carboxyl group containing compounds is described.

Method for producing silylenol ethers

The invention relates to a method for producing silyl enol ether compound (3) by reacting ketone or aldehyde compound (1) with allylsilane compound (2) in the presence of a base and 0.00001 to 0.5 equivalents of an acid catalyst relative to ketone or aldehyde compound (1).

Compounds and methods for treating neoplasia

The invention features compounds, pharmaceutical compositions and methods useful for the treatment of neoplasia. In particular embodiments, the compounds of the invention are useful for the treatment of multidrug resistant neoplasia.

INHIBITORS OF 17Beta-HSD1, 17Beta-HSD3 AND 17Beta-HSD10

The present application discloses 17β hydroxy steroid dehydrogenase (17β HSD) type 1, 3, 10 inhibitors and use thereof (alone and in combination) in the treatment of cancer and other afflictions. 17β HSD1 inhibitors include estradiol derivatives with a nieta-carbamoylbenzyl substituent at C 16. 17β HSD3/HSD10 inhibitors include androsterone derivatives substituted at the C3 position with a sulfonamide piperazine. Also disclosed are compounds that are inhibitors of both 17β HSD1 and 17β HSD3 that have a spiro-morpholine substituent at C20.

FLUORINATED AND ALKYLATED BILE ACIDS

The present invention relates to fluorinated and alkylated bile acids. 3. The compound according to wherein X claim 2 , X claim 2 , Xand Xare all —F.4. The compound according to wherein any three of X claim 2 , X claim 2 , Xand Xare —F.5. The compound according to wherein any two of X claim 2 , X claim 2 , Xand Xare —F.6. The compound according to wherein one of X claim 2 , X claim 2 , Xand Xis —F.10. The compound according to claim 9 , wherein Xand Xare all alkylated.11. The compounds according to claim 9 , wherein any one of Xand Xare alkylated.13. A method of treating or preventing a disease that is selected from the group consisting of neurological disease claims 1 , diabetes claims 1 , ocular disorders claims 1 , spinal cord injury claims 1 , kidney injury or metabolic syndrome in a subject claims 1 , said method comprising administering to said subject a therapeutically effective amount of a compound according to claims 1 ,14. The method according to claim 13 , wherein the disease is a neurological disease selected from the group consisting of Alzheimer's claim 13 , Parkinson's claim 13 , Huntington's claim 13 , and amyotrophic lateral sclerosis (ALS).15. The method according to claim 13 , wherein the disease is type 2 diabetes.16. The method according to claim 13 , wherein the disease is acute kidney injury.17. The method according to claim 13 , wherein the disease is an ocular disorder selected from macular degeneration (MD) and diabetic retinopathy. This application is a divisional of U.S. patent application Ser. No. 15/556768, filed Sep. 8, 2017, which is a U.S. National Stage Application filed under 35 U.S.C. § 371 from International Application Serial No. PCT/US2016/021809, filed on Mar. 10, 2016, and published as WO 2016/145216 on Sep. 15, 2016, which claims the benefit of priority to U.S. Provisional Application Ser. No. 62/130,931, filed on Mar. 10, 2015 and U.S. Provisional Application Ser. No. 62/141,506, filed on Apr. 1, 2015, which applications ...

BUFALIN PHOSPHATE PRODRUGS AND METHODS OF USE THEREOF

Bufalin phosphate prodrugs are provided herein, as well as methods for their use as small molecule inhibitors of steroid receptor coactivator (SRC) family proteins. Methods for using bufalin phosphate prodrugs in treating or preventing cancer are also provided herein. 5. The compound of claim 4 , wherein the cation is a metal cation.6. The compound of claim 5 , wherein the metal cation is an alkali metal cation or an alkaline earth metal cation.7. The compound of claim 4 , wherein X is selected from the group consisting of Na claim 4 , K claim 4 , Li claim 4 , and NH.10. A composition comprising a compound of and a pharmaceutically acceptable carrier.11. (canceled)12. A method of treating or preventing a steroid receptor coactivator-related disease in a subject claim 1 , comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'administering to the subject an effective amount of a compound of .'}13. The method of claim 12 , wherein the steroid receptor coactivator-related disease is cancer claim 12 , obesity claim 12 , or human immunodeficiency virus.14. The method of claim 13 , wherein the steroid receptor coactivator-related disease is cancer and the cancer is a poor prognosis or invasive cancer claim 13 , breast cancer claim 13 , pancreatic cancer claim 13 , glioblastoma claim 13 , liver cancer claim 13 , lung cancer claim 13 , pancreatic cancer claim 13 , or prostate cancer.15. (canceled)16. The method of claim 14 , wherein the cancer is breast cancer and the breast cancer is triple negative breast cancer.17. (canceled)18. (canceled)19. The method of claim 14 , wherein the cancer is glioblastoma and the glioblastoma is a glioblastoma multiforme tumor.20. The method of claim 19 , wherein the glioblastoma multiforme tumor is a pediatric glioblastoma multiforme tumor.21. (canceled)22. (canceled)23. (canceled)24. (canceled)25. The method of claim 12 , further comprising administering a second compound or composition.26. The method of claim 25 , wherein the ...

PROCESS FOR ALKYNYLATING 16-SUBSTITUTED-17-KETO STEROIDS

A process ethynylates 16-methylene-17-keto steroids to the corresponding 16-methylene-17α-ethynyl-17β-hydroxy steroids by treatment with silyl-protected lithium acetylides followed by further desilylation. The resulting products are useful intermediates in the preparation of several pharmaceutically active agents, such as e.g. Nestorone® or melengestrol acetate. 4. Process according to claim 2 , wherein{'sup': 3', '1', '1, 'sub': 1', '3, 'Ris selected from O or —OR, wherein Ris a C-Calkyl;'}{'sup': '6', 'Ris selected from H, F, methyl and methylene;'}{'sup': '9', 'Ris selected from H and F;'}{'sup': 11', '9', '11, 'sub': 9', '11, 'Ris selected from H and OH, or there is a double bond between Cand Cand Rand Rare absent;'}{'sup': '18', 'Ris selected from methyl and ethyl;'}{'sup': '19', 'Ris selected from H and methyl.'}6. Process according to claim 1 , wherein each R is independently selected from C-Calkyl and phenyl.7. Process according to claim 1 , wherein the compound of formula (I) is lithium trimethylsilylacetylene.8. Process according to claim 1 , wherein desilylation step (b) is performed by treatment with potassium carbonate.9. Process according to claim 1 , wherein the ethynylated product is further converted to a compound selected from the group formed by Nestorone® claim 1 , nestorone alcohol and melengestrol acetate.15. Process for the preparation of a compound selected from the group formed by Nestorone® claim 12 , nestorone alcohol and melengestrol acetate claim 12 , said process comprising the use of a compound as defined in .16. Process according to claim 2 , comprising one of the following conditions (a) to (d):{'sub': 1', '3, '(a) wherein each R is independently selected from C-Calkyl and phenyl;'}(b) wherein the compound of formula (I) is lithium trimethylsilylacetylene;(c) wherein desilylation step (b) is performed by treatment with potassium carbonate;(d) wherein the ethynylated product is further converted to a compound selected from the group ...

Commands and method of treating cancer via RHO pathway

Lanosterol derivatives useful as anti-cancer agent, which can inhibit the growth of lung cancer cells, liver cancer cells, mammary cancer cells, brain cancer cells and pancreatic cancer cells, possibly by acting on the RHO pathway. These lanosterol derivatives are represented by compound LD030:

TANDEM FACIAL AMPHIPHILES

The invention provides tandem facial amphiphiles for biochemical manipulations and characterization of membrane proteins, such as intrinsic membrane proteins. Members of this new family display favorable behavior with several membrane proteins. These amphiphiles can form relatively small micelles, and small changes in amphiphile chemical structures can result in large changes in their physical properties. The tandem facial amphiphiles can be used to aid the solubilization, isolation, purification, stabilization, crystallization, and/or structural determination of membrane proteins. 2. The compound of wherein each Ris (C-C)alkyl.3. The compound of wherein Y is a direct bond.4. The compound of wherein at least two of R claim 1 , Rand Rare O-Sac and each Sac is a disaccharide.15. The compound of wherein a plurality of the compounds form a micelle in water comprising about 6 to about 15 molecules of the compound.1620-. (canceled) This application is a continuation of U.S. patent application Ser. No. 13/669,198, filed Nov. 5, 2012, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61/556,625, filed Nov. 7, 2011, all of which are incorporated herein by reference.This invention was made with government support under GM075913 awarded by the National Institutes of Health. The government has certain rights in the invention.Membrane proteins (MPs) play crucial roles in biology, but these proteins are difficult to handle and analyze because of their physical properties. The native conformations of MPs display extensive nonpolar surfaces. The display of these nonpolar surfaces is necessary for residence in a lipid bilayer but leads to denaturation and/or aggregation in an aqueous medium. Detergents such as dodecyl-β--maltoside (DDM) are typically employed to render MPs soluble by coating the nonpolar protein surfaces. However, only some MPs can be maintained in native-like conformations when solubilized with conventional detergents (Serrano ...

Protected Linker Compounds

The invention features protected linker compounds which comprise at one terminus a protected amino group and at another other terminus a phosphorous activating group, such as a phosphoramidite group. These protected linker compounds are introduced chemically at the 5′-end of oligonucleotides for the purpose of preparing 5′-amino modified oligonucleotides. After deprotection, the thereby introduced amino group then allows further modification (e.g. attachment of dyes) or immobilization (on surfaces or beads) of the oligonucleotide. Specifically, the presented amino protecting group is designed to provide such protected linker compounds in a solid form, which facilitates efficient purification by precipitation or crystallization and aliquoting for distribution and storage.

GANAXOLONE DERIVATIVES FOR TREATMENT OF CENTRAL NERVOUS SYSTEMS DISORDERS

The present invention is directed to Ganaxolone prodrugs with increased aqueous solubility and oral bioavailability relative to Ganaxolone and that enable development of stable extended release formulations which offer a significant therapeutic advantage and improved patience compliance by enabling treatments with lower doses over prolonged periods of time. 223-. (canceled)25. A compound according to claim 24 , wherein Xis selected from the group consisting of:{'sup': 2', '1', '2', '1', '2', '−', '+', '2', '2', '1', '2', '2', '2, 'sub': 2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2, '(C═O)—OC(R)O(C═O)R, (C═O)—OC(R)O(C═O)OR, (C═O)—OC(R)O(P═O)—(OM), (C═O)—OC(R)O(P═O)—(OC(R)O(C═O)YR), (C═O)—OC(R)O(C═O)(CHR)N(R), (C═O)—OC(R)O(C═O)N(R), and (C═O)—OC(R)O(C═O)N(CHCOR).'}26. A compound according to claim 24 , wherein Xis selected from the group consisting of:{'sup': 1', '−', '+', '−', '+', '4', '+', '−', '1', '−', '+', '2', '1, 'sub': 2', 'n', '2', '2', 'n', '2', '2', 'm', '2', 'n', '2', '2', '2', 'n', '2', '2', 'n', '2', '2', 'p', '2', '2', '3', '2', '2', '2', '2', '2', '2, '(C═O)R, (C═O)—(CH)COM, (C═O)—(CH)COR, (C═O)—(CH)O(C═O)R, (C═O)—(CH)OR, (C═O)—CH═CH—COR, (C═O)—CH═CH—COM, (C═O)—(CH)N(R), (C═O)—(CH)(C═O)N(R), (C═O)—(CH)N(C═O)R, (C═O)—(CHR)N(R), (C═O)—(CH)NRA, (C═O)OR, (P═O)—(OM), (P═O)—(OC(R)O(C═O)YR), and (C═O)—N(CHCOR).'}27. A compound according to claim 24 , wherein Xis selected from the group consisting of:{'sup': 2', '1', '2', '1', '2', '−', '+', '2', '2', '1', '2', '2', '2, 'sub': 2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2', '2, 'C(R)O(C═O)R, C(R)O(C═O)OR, C(R)O(P═O)—(OM), C(R)O(P═O)—(OC(R)O(C═O)YR), C(R)O(C═O)(CHR)N(R), C(R)O(C═O)N(R), and C(R)O(C═O)N(CHCOR).'}28. A compound according to wherein R is hydrogen.29. A compound according to wherein R is methyl.30. (canceled)31. A compound according to wherein Ris alkyl.32. (canceled)33. (canceled)34. (canceled)35. A compound according to wherein Ris hydrogen36. A ...

HYDROXYSTEROID COMPOUNDS, THEIR INTERMEDIATES, PROCESS OF PREPARATION, COMPOSITION AND USES THEREOF

The present invention relates to novel steroidal compounds of formula (I), process for preparation of the same and composition comprising these compounds. 4. (canceled)5. The compound of claim 3 , wherein the compound is selected from the group consisting of:xiii. (10R,11S,13S,17S)-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid;xiv. (10R,11S,13S,17S)-11-hydroxy-N,N,10,13-tetramethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxamide;xv. (10R,11S,13S,17S)-17-acetyl-1-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;xvi. (10R,11S,13S,17S)-11-hydroxy-17-((R)-1-hydroxyethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;xxxiii. (10R,11S,13S,17S)-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;xxxiv. (10R,11S,13S)-11-hydroxy-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione;xli. (10R,11S,13S,17S)-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxamide;xlii. (10R,11S,13S,17S)-11-hydroxy-17-(hydroxymethyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;xliii. (10R,11S,13S,17S)-17-((dimethylamino)methyl)-11-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;lvi. (8S,9S,10R,11S,13S,14S,Z)-11-hydroxy-17-(hydroxyimino)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;lvii. (8S,9S,10R,11S,13S,14S)-17-amino-11-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one;lviii. (8S,9S,10R,11S,13S,14S)-11-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; andlix. (8S,9S, ...

Process and intermediates for the production of 17(20)-ene b-seco steroids

The invention pertains to a process for producing a compound of formula (11) wherein R7 and R8 are each independently selected from H, halogen, alkyl, aryl, or alkylaryl, R42 is H or a protective group, R43 is H or R3, wherein R3 is a protective group, by contacting a compound of formula (10) with an olefmation reagent, wherein compound of formula (10) comprises a counter acid X1 when R42═H and R43═H.

Radiolabeled cationic steroid antimicrobials and diagnostic methods

The disclosure provides compounds, methods, and kits for diagnosis, detection, screening, and imaging of a disease condition (e.g., infection, cancer, tumor, neoplasia), in vitro, ex vivo, and/or in vivo. Certain embodiments include administering a cationic steroid antimicrobial “CSA” or “ceragenin”), the CSA including a steroidal backbone and a heterocyclic ring separated from the steroidal backbone by at least 4 atoms (and up to 24 atoms or more), to a subject having or at risk of having a disease condition in an amount effective to diagnose, detect, screen for or image the disease condition in the subject.

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described. 2. At least one chemical entity of wherein Z is OR.3. At least one chemical entity of wherein Ris chosen from optionally substituted alkyl claim 2 , optionally substituted cycloalkyl claim 2 , and optionally substituted heterocycloalkyl.4. At least one chemical entity of wherein Z is NRR.5. At least one chemical entity of wherein Ris chosen from hydrogen claim 4 , optionally substituted alkyl claim 4 , optionally substituted cycloalkyl claim 4 , and optionally substituted heterocycloalkyl claim 4 , and Ris chosen from optionally substituted alkyl claim 4 , optionally substituted cycloalkyl claim 4 , and optionally substituted heterocycloalkyl.6. At least one chemical entity of wherein Ris hydrogen and Ris chosen from optionally substituted alkyl.7. At least one chemical entity of wherein Rand Rare joined together to form a 5- to 7-membered heterocycloalkyl ring.8. At least one chemical entity chosen from compounds I-a-I-f and pharmaceutically acceptable salts thereof.10. At least one chemical entity of wherein Rand Rare each independently chosen from hydrogen and optionally substituted lower alkyl.11. At least one chemical entity of wherein Rand Rare both hydrogen.12. At least one chemical entity of wherein Rand Rare joined together to form a 5- to 7-membered heterocycloalkyl ring.13. At least one chemical entity of any one of to wherein Rand Rare each independently chosen from hydrogen and optionally substituted lower alkyl.14. At least one chemical entity of any one of to wherein n is chosen from 1 claim 9 , 2 claim 9 , and 3.15. At least one chemical entity of wherein n is 1 claim 9 , and Rand Rare joined together to form a 5- to 7-membered heterocycloalkyl ring.16. At least one chemical entity chosen from compounds II-a-II-h and pharmaceutically acceptable salts thereof.18. At least one chemical entity of wherein Ris chosen from hydrogen ...

Synthesis of a substituted indene derivative

This invention is directed to methods of preparing AQX-1125 having the formula: This invention is also directed to intermediates utilized in the methods of preparing AQX-1125.

Polyethylene Glycol-Conjugated Glucocorticoid Prodrugs and Compositions and Methods Thereof

Polyethylene glycol (PEG)-conjugated glucocorticoid prodrugs, methods of preparation, and use for the treatment of diseases and disorders are disclosed. In particular, PEG-conjugated dexamethasone compounds and methods of using them for treating inflammatory and autoimmune diseases, including but not limited to lupus, are disclosed. 2. The pharmaceutical composition of claim 1 , wherein E is a linker comprising a branched structure capable of covalently bonding to two or more Rgroups claim 1 , said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O claim 1 , S claim 1 , and N.3. The pharmaceutical composition of claim 1 , wherein Z is a linker comprising a branched structure capable of covalently bonding to two or more dexamethasone moieties claim 1 , said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O claim 1 , S claim 1 , and N.17. The pharmaceutical composition of claim 1 , wherein n is 40 to 50.18. The pharmaceutical composition of claim 1 , wherein the composition is in oral claim 1 , nasal claim 1 , topical claim 1 , buccal claim 1 , sublingual claim 1 , rectal claim 1 , vaginal claim 1 , intravenous claim 1 , intramuscular claim 1 , intraperitoneal claim 1 , or other parenteral form.19. The pharmaceutical composition of in vaporization-ready claim 1 , nebulization-ready claim 1 , nanoparticle formulation claim 1 , or liposomal formulation.20. The pharmaceutical composition of claim 1 , further comprising a second therapeutic agent selected from the group consisting of a NSAID (e.g. Aspirin claim 1 , Naproxen claim 1 , Celebrex) claim 1 , a Glucocorticoid (e.g. Dexamethasone claim 1 , Prednisone claim 1 , Betamethasone) claim 1 , and a DMARD (e.g. Methotrexate claim 1 , Leflunomide claim 1 , Sulfasalazine claim 1 , Hydroxychoroquine) claim 1 , and a biologic drug.21. A method of treating an autoimmune disease and/or inflammatory disorder claim 1 ...

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described. 131.-. (canceled)32. A compound selected from the group consisting of:(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-aminopropanoate;(S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-aminopropanoate;(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-amino-3-methylbutanoate;(S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-amino-3-methylbutanoate;(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-amino-4-methylpentanoate;(S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-amino-4-methylpentanoate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate;4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- ...

Progesterone Phosphate Analogs and Uses Related Thereto

This disclosure relates to progesterone phophate derivatives and uses related thereto. In certain embodiments, the disclosure relates to compounds disclosed herein and uses for managing inflammation such as those resulting from traumatic brain injury or stroke. 2. The method of claim 1 , wherein X is N—OCRROPZ(OR)and Y is O.3. The method of claim 1 , wherein Y is N—OCRROPZ(OR)and X is O.4. The method of claim 1 , wherein Rand Rare hydrogen or alkyl.5. The method of claim 1 , wherein Rand Rform a cyclopropyl ring.6. The method of claim 1 , wherein Ris phosphate ion claim 1 , hydrogen claim 1 , alkanoyl claim 1 , or alkyl.9. A method of treating or preventing inflammation or CNS injury comprising administering an effective amount of a pharmaceutical composition comprising (E)-(((1-(10 claim 1 ,13-dimethyl-3-oxo-2 claim 1 ,3 claim 1 ,6 claim 1 ,7 claim 1 ,8 claim 1 ,9 claim 1 ,10 claim 1 ,11 claim 1 ,12 claim 1 ,13 claim 1 ,14 claim 1 ,15 claim 1 ,16 claim 1 ,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethylidene)amino)oxy)methyl dihydrogen phosphate or salts thereof claim 1 , to a subject in need thereof.10. The method of claim 1 , wherein the pharmaceutical composition is administered to a subject that incurred trauma to the head or other organ or tissue.11. The method of claim 1 , wherein the pharmaceutical composition is administered after a medical procedure.12. The method of claim 1 , wherein the pharmaceutical composition is administered in combination with a second anti-inflammatory agent.13. A method of treating stroke or traumatic brain injury comprising administering an effective amount of a pharmaceutical composition of to a subject in need thereof.14. A method of treating a neurodegenerative disease or condition comprising administering an effective amount of a pharmaceutical composition of to a subject in need thereof.15. The method of claim 14 , wherein the neurodegenerative disease or condition is selected from Alzheimer's disease claim 14 , ...

Process and new intermediates for the preparation of 11-methylene steroids

The invention relates to a process for the preparation of 11-methylene steroids through selective olefination of the ketone at position 11. The resulting products are useful intermediates in the preparation of several pharmaceutically active agents, such as Etonogestrel and Desogestrel.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 1. (canceled)3. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Rand Rare not both hydrogen.45.-. (canceled)6. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein each of Rand Ris independently hydrogen claim 2 , —P(O)(R) claim 2 , —S(O)R claim 2 , —C(O)R claim 2 , —C(O)OR claim 2 , —C(O)N(R) claim 2 , —(CH)C(O)N(R) claim 2 , —(CH)OP(O)(R) claim 2 , —(CH)OS(O)R claim 2 , —(CH)OC(O)R claim 2 , or —(CH)C(O)OR;{'sup': a', 'b', 'd, 'each of Rand Ris independently selected from —ORor substituted or unsubstituted alkyl;'}{'sup': 'c', 'each Ris independently substituted or unsubstituted alkyl;'}{'sup': 'd', 'each Ris independently hydrogen or substituted or unsubstituted alkyl;'}each x is independently 1 or 2; andeach of n, m, p is independently 1, 2, 3, or 4.7. (canceled)8. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris substituted or unsubstituted Calkyl.9. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris hydrogen.1011.-. (canceled)12. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein each of Rand Ris independently hydrogen claim 2 , methyl claim 2 , —CF claim 2 , ethyl claim 2 , isopropyl claim 2 , cyclopropyl claim 2 , or butyl.13. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris a moiety cleavable under biological conditions and Ris hydrogen.14. The compound or pharmaceutically acceptable salt thereof claim 2 , of claim 2 , wherein Ris hydrogen and Ris a moiety cleavable under biological conditions.15. The compound or ...

Compounds and methods for managing cancer through immune system

The present disclosure relates to methods of managing cancer by modulating/inhibiting cap methyltransferase enzyme. The modulation/inhibition is carried out by pharmacological or biological inhibitors, including but not limited to compounds of formula (VIII) or Compound A or A-1. Thus, the present disclosure relates to such inhibitors including compounds of formula (VIII) and their use for management of cancer. In some aspects, the compound of formula (VIII) is Compound 1. The present disclosure also relates to methods of activating B cells or T cells via modulation of cap methyltransferases. The present disclosure also relates to methods of managing cancer with a molecule or biologic that generates unmethylated RNA. The generation of unmethylated RNA activates B cells and presents the RNA to B-cell receptor (BCR). The present disclosure therefore also relates to management of cancer by activating B cells and then adoptively transferring the B cells to exert an anticancer effect.

COMPOUNDS AND METHODS FOR TRANS-MEMBRANE DELIVERY OF MOLECULES

A novel delivery system for drugs, and especially macromolecules such as proteins or oligonucleotides through biological membranes is provided, and specifically delivery of siRNA The delivery system comprises conjugation of the macromolecule drug to a moiety that enables effective passage through the membranes. Respectively, novel compounds and pharmaceutical compositions are provided, utilizing said delivery system. In one aspect of the invention, the compounds may be utilized in medical practice, for example, in delivery of siRNA or antisense oligonucleotides across biological membranes for the treatment of medical disorders. 4. (canceled)610.-. (canceled)11. The Conjugate according to claim 5 , as set forth in Formula (XIV) claim 5 , wherein s is 2 or 4.12. (canceled)13. (canceled)14. The Conjugate according to claim 5 , as set forth in Formula (XVI) claim 5 , wherein t is 2 or 4.15. A Conjugate as claimed in claim 3 , according to general Formula (I) claim 3 , where E claim 3 , E′ or E″ has the structure as set forth in any of Formulae II claim 3 , VII claim 3 , VIII or VIIIa claim 3 , attached to a drug.16. The Conjugate according to claim 15 , wherein the drug is a macromolecule claim 15 , selected from the group consisting of siRNA claim 15 , ASO and a therapeutic protein.17. The Conjugate according to claim 16 , wherein the therapeutic protein comprises a CRISPR protein.18. The Conjugate according to claim 17 , wherein the CRISPR protein is Cas9 protein.19. The pharmaceutical composition claim 15 , comprising a Conjugate according to and a pharmaceutically-acceptable salt or carrier.20. A method for delivery of a drug into biological cells claim 15 , wherein said cells are in culture claim 15 , or in a living animal or a human subject; the method comprising contacting the cells with a Conjugate according to .21. A method for treatment of a medical disorder claim 19 , said method comprising administration to a patient in need claim 19 , therapeutically ...

Compositions for the prevention and treatment of parkinson's disease

Methods of preventing or retarding or reversing or abolishing the onset of Parkinson's and other neurodegenerative diseases are discussed.

Compounds and methods for trans-membrane delivery of molecules

A novel delivery system for drugs, and especially macromolecules such as proteins or oligonucleotides through biological membranes is provided, and specifically delivery of siRNA. The delivery system comprises conjugation of the macromolecule drug to a moiety that enables effective passage through the membranes. Respectively, novel compounds and pharmaceutical compositions are provided, utilizing said delivery system. In one aspect of the invention, the compounds may be utilized in medical practice, for example, in delivery of siRNA or antisense oligonucleotides across biological membranes for the treatment of medical disorders.

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-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. 153-. (canceled)55. The compound of claim 54 , wherein the Rgroup is selected from the group consisting of H claim 54 , methyl claim 54 , and trifluoromethyl.56. The compound of claim 54 , wherein Ris selected from the group consisting of H claim 54 , methoxy claim 54 , ethoxy claim 54 , and an optionally substituted morpholinyl ring.57. The compound of claim 54 , wherein Ris H.58. The compound of claim 54 , wherein each instance of - - - between C-Cand C-Cis absent and C—H is in the alpha position.59. The compound of claim 54 , wherein each instance of - - - between C-Cand C-Cis absent and C—H is in the beta position.60. The compound of claim 54 , wherein each instance of - - - between C-Cis absent and Ris in the beta position.61. The compound of claim 54 , wherein Ris ═O claim 54 , methoxy or H.62. The compound of claim 54 , wherein Ris methyl.63. The compound of claim 54 , wherein Ris beta-methoxy.64. The compound of claim 54 , wherein Ris beta-spirooxirane.65. The compound of claim 54 , wherein Ris beta-cyano.66. The compound of claim 54 , wherein Ris ═O.67. The compound of claim 54 , wherein Ris beta-nitro.68. The compound of claim 54 , wherein Ris beta-CHC(O)—.69. The compound of claim 54 , wherein Ris beta-HOCHC(O)—.73. The method of claim 72 , wherein the disorder is selected from the group consisting of insomnia claim 72 , mood disorders claim 72 , convulsive disorders claim 72 , anxiety claim 72 , or symptoms of ethanol withdrawal. This application is a continuation application and claims priority to U.S. patent application Ser. No. 15/459,492, filed on Mar. 15, 2017, which claims ...

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described. 131.-. (canceled)33. The method of claim 32 , wherein the subject is a human.34. The method of claim 32 , wherein the compound or the pharmaceutically acceptable salt is administered orally claim 32 , subcutaneously claim 32 , intravenously claim 32 , intranasally claim 32 , transdermally claim 32 , intraperitoneally claim 32 , intramuscularly claim 32 , intrapulmonary claim 32 , vaginally claim 32 , rectally claim 32 , or intraocularly.35. The method of claim 32 , wherein the compound or the pharmaceutically acceptable salt is administered intravenously.36. The method of claim 32 , wherein the compound or the pharmaceutically acceptable salt is administered orally.37. The method of claim 32 , further comprising administering to the subject an additional anti-cancer and/or cytotoxic agent.38. The method of claim 37 , wherein the additional anti-cancer and/or cytotoxic agent is administered simultaneously with the compound or the pharmaceutically acceptable salt.39. The method of claim 32 , wherein the amount of the compound or the pharmaceutically acceptable salt administered is in the range of 0.01 mg to 100 mg per kilogram body weight of the subject.40. The method of claim 32 , wherein amount of the compound of Formula I administered is in the range of about 0.01 mg to 1000 mg.41. The method of claim 32 , wherein Rand Rare each independently chosen from hydrogen and optionally substituted lower alkyl.42. The method of claim 32 , wherein Rand Rare both hydrogen.43. The method of claim 32 , wherein Rand Rare joined together to form a 5- to 7-membered heterocycloalkyl ring.44. The method of claim 32 , wherein each Rand Ris independently chosen from hydrogen and optionally substituted lower alkyl.45. The method of claim 32 , wherein n is chosen from 1 claim 32 , 2 claim 32 , and 3.46. The method of claim 32 , wherein n is 1 claim 32 , and Rand ...

METATHESIS CATALYSTS AND METHODS THEREOF

The present application provides, among other things, compounds and methods for metathesis reactions. In some embodiments, the present disclosure provides methods for preparing alkenyl halide with regioselectivity and/or stereoselectivity. In some embodiments, the present disclosure provides methods for preparing alkenyl halide with regioselectivity and Z-selectivity. In some embodiments, the present disclosure provides methods for preparing alkenyl halide with regioselectivity and E-selectivity. In some embodiments, provided technologies are particularly useful for preparing alkenyl fluorides. In some embodiments, a provided compound useful for metathesis reactions has the structure of formula II-a. In some embodiments, a provided compound useful for metathesis reactions has the structure of formula II-b. 120-. (canceled)22. The compound of claim 21 , wherein M is Mo. This application is a divisional application of U.S. patent application Ser. No. 14/933,741, filed Nov. 5, 2015, which claims priority to U.S. Provisional Application No. 62/075,315, filed Nov. 5, 2014, the entirety of each of which is incorporated herein by reference.This invention was made with government support under Grant No. GM59426 awarded by the National Institute of Health and Grant No. CHE-1362763 awarded by the National Science Foundation. The U.S. government has certain rights in the invention.The present invention generally relates to metathesis reactions.Catalytic metathesis has transformed chemical synthesis and offers exceptionally efficient pathways for the synthesis of many commercially important chemicals including biologically active molecules, oleochemicals, renewables, fine chemicals, and polymeric materials. There remains an unmet need for improved methods and catalysts for metathesis reactions, for example, in terms of better catalyst stability and/or activity, efficiency and stereoselectivity.Among other things, the present disclosure recognizes that it is particularly ...

Boron-based prodrug strategy for increased bioavailability and lower-dosage requirements for drug molecules containing at least one phenol (or aromatic hydroxyl) group

Boron-based prodrugs of phenol- or aromatic hydroxyl group-containing therapeutic molecules (“original drugs”), uses thereof, and methods of making the same, are provided for achieving, for example, improved bioavailability, prolonged retention (e.g., in a circulatory system) and, in particular, significantly lowered therapeutically effective dosage in order to reduce adverse effects while maintaining the desired therapeutic effects of the original drugs.

Compound for treating metabolic diseases and preparation method and use thereof

Provided are a compound for treating metabolic diseases having the structure as shown in formula (I) or formula (II), or a racemate, stereoisomer, geometric isomer, tautomer, solvate, hydrate, metabolite, pharmaceutically acceptable salt or prodrug thereof. The compound is an activator of FXR and/or a TGR5 receptor, and thus has the activity of activating FXR and/or a TGR5 receptor, and can be used in the preparation of drugs for treating chronic liver diseases, metabolic diseases or portal hypertension.

Cholic acid derivative, and preparation method and medical use thereof

The present invention relates to a cholic acid derivative, and a preparation method and a medical use thereof. In particular, the present invention relates to a cholic acid derivative of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof. The series of compounds can be used to treat FXR mediated diseases, including cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia and chronic hepatitis diseases, chronic liver diseases, gastrointestinal diseases, nephrosis, heart vascular diseases, metabolic diseases, cancer (for example colorectal cancer) or neurological diseases, such as strokes and other diseases, with a wide range of medical applications, and are expected to develop into a new generation of FXR agonists.

Intermediates for the Synthesis of Bile Acid Derivatives, in Particular of Obeticholic Acid

The present invention relates to compounds which are intermediates in the synthesis of bile acid derivatives with pharmacological activity. The invention relates to compounds of general formula (I): wherein: , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids which are useful in the treatment of conditions such as liver disease. In addition, the invention relates to a method of synthesizing these intermediates and a method of preparing obeticholic acid and obeticholic acid analogues from the compounds of the invention.

Compounds and methods involving sterols

Compounds and methods of synthesizing oxysterols are provided. The compounds and methods provided allow the oxysterol to be safely produced at a high yield. The compounds and methods provided can produce the oxysterol in a stereoselective manner.

PROGESTERONE ANTAGONISTS

Described herein are compounds which either act as pure antiprogestins or as antiprogestins with partial agonistic activity and methods of treating cancer using such compounds. 19-. (canceled)11. (canceled)12. The method of claim 10 , wherein:{'sup': '7', 'sub': 3', '2', '2', '2', '2, 'Ris —CH═CH—CF, —CH—CF═CF, or —CF—CH═CH.'}1314-. (canceled)16. (canceled)18. (canceled) The present application is a divisional of U.S. patent application Ser. No. 13/193,426, filed Jul. 28, 2011, which is incorporated herein by reference.The present invention relates to the identification of a class of compounds that behave either as pure antiprogestins or as antiprogestins with partial agonistic activity, also called mesoprogestins. Pure antiprogestins has been known to suppress the growth of cancer and other proliferative diseases, whereas mesoprogestins has been shown to be useful in the treatment of fibroids and endometriosis etc. The present invention also relates to processes of preparation and the use in therapy of such novel compounds.In the past, progesterone antagonists have been postulated to be of potential benefit in the treatment of breast cancer where the primary lesion contains both estrogen and progesterone receptors. In a recent study of an in vivo rat model of progesterone receptor positive breast cancer, it was shown that the administration of a new antiprogestin (Proellex, CDB-4124) resulted in a regression of tumor size as well as a decrease in the development of new tumors. shows a series of selected progesterone receptor modulators that have been shown to be effective in vitro and in vivo. The prototype antagonist, Mifepristone (see ), is characterized by the 19-nor-4,9-diene steroid nucleus, the 17α-propynyl-17β-hydroxy functionality, and the 11β-(4-dimethylamino)phenyl functional group which is believed to be responsible for its antagonistic activity. While Mifepristone is a potent progesterone antagonist, its long-term clinical use is limited due to its ...

Preparation and Uses of Obeticholic Acid

The present invention relates to obeticholic acid: or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. Obeticholic acid is useful for the treatment or prevention of a FXR mediated disease or condition, cardiovascular disease or cholestatic liver disease, and for reducing HDL cholesterol, for lowering triglycerides in a mammal, or for inhibition of fibrosis. The present invention also relates to processes for the synthesis of obeticholic acid.

NEUROACTIVE STEROIDS AND COMPOSITIONS AND METHODS THEREOF

The invention provides novel neuroactive steroids and pharmaceutical compositions thereof, as well as methods of their preparation and use, in therapy of various diseases and conditions, for example, various neurological or brain diseases. 2. The compound of claim 1 , wherein at least one of Rand Ris a halogen.3. (canceled)4. The compound of claim 2 , wherein the halogen is F.5. The compound of claim 1 , wherein each of Rand Ris H6. The compound of claim 1 , wherein Ris CH.7. The compound of claim 1 , wherein Ris H.8. The compound of claim 1 , wherein Ris an unsubstituted C-Calkyl.9. The compound of claim 8 , wherein Ris an unsubstituted methyl.10. The compound of claim 8 , wherein Ris a substituted C-Calkyl.11. The compound of claim 10 , wherein Ris a substituted methyl which is substituted with a heterocyclic or heterobicyclic group.12. (canceled)14. The compound of claim 13 , wherein X is CH.15. The compound of claim 13 , wherein X is N.16. The compound of claim 13 , wherein each of X claim 13 , X claim 13 , Xand Xis CH.17. The compound of claim 13 , wherein Ris CN claim 13 , F claim 13 , is C═O(NH claim 13 , O(CHCHO)CHor CHO(CHCHO)CH.1821-. (canceled)24. A pharmaceutical composition comprising a compound according to claim 1 , effective to treat or reduce one or more diseases or disorders claim 1 , in a mammal claim 1 , including a human claim 1 , and a pharmaceutically acceptable excipient claim 1 , carrier claim 1 , or diluent.2531-. (canceled)32. A unit dosage form comprising a pharmaceutical composition of .33. (canceled)3548-. (canceled) This application claims the benefit of priority to U.S. Provisional Application No. 62/944,006, filed Dec. 5, 2019, the entire content of which is incorporated herein by reference for all purposes.The invention generally relates to pharmaceuticals and therapeutic methods. More particularly, the invention provides novel neuroactive steroids and pharmaceutical compositions thereof, as well as methods of their preparation and ...

Preparation comprising hexose-6-phosphate-modified cholesterol derivative

Provided is a compound represented by the general formula (1) (where: G represents a hexose-6-phosphate residue; and L represents a divalent linker group).

SELECTIVE METAL-MEDIATED ARYLATION OF DICHALCOGENIDES IN BIOMOLECULES

Disclosed are methods of selective cysteine and selenocysteine modification on peptide/protein molecules under physiologically relevant conditions. The methods feature several advantages over existing methods of peptide modification, such as specificity towards thiols and selenols over other nucleophiles (e.g., amines, hydroxyls), excellent functional group tolerance, and mild reaction conditions, including completely aqueous reaction conditions. Also disclosed are methods of preparing palladium complexes in the presence of oxygen. 2. The method of claim 1 , wherein the biopolymer is a peptide claim 1 , an oligopeptide claim 1 , a polypeptide claim 1 , a protein claim 1 , an antibody claim 1 , an antibody fragment claim 1 , an oligonucleotide claim 1 , a polynucleotide claim 1 , an oligosaccharide claim 1 , or a polysaccharide.3. (canceled)5. (canceled)713-. (canceled)1520-. (canceled)21. The method of claim 4 , wherein the solvent comprises an aqueous buffer.23. (canceled)24. The method of claim 22 , wherein the compound containing a thiol moiety or a selenol moiety is a biomolecule selected from the group consisting of a natural or unnatural amino acid claim 22 , a plurality of natural or unnatural amino acids claim 22 , a peptide claim 22 , an oligopeptide claim 22 , a polypeptide claim 22 , and a protein.2544-. (canceled)4647-. (canceled)4960-. (canceled)61. The method of claim 45 , wherein Aris (C-C)carbocyclic aryl claim 45 , (C-C)heteroaryl claim 45 , (C-C)polycyclic aryl claim 45 , or alkenyl; and Aris optionally substituted by one or more substituents independently selected from the group consisting of halide claim 45 , acyl claim 45 , azide claim 45 , isothiocyanate claim 45 , alkyl claim 45 , aralkyl claim 45 , alkenyl claim 45 , alkynyl or protected alkynyl claim 45 , alkoxyl claim 45 , arylcarbonyl claim 45 , cycloalkyl claim 45 , formyl claim 45 , haloalkyl claim 45 , hydroxyl claim 45 , amino claim 45 , nitro claim 45 , sulfhydryl claim 45 , amido ...

COMPOUNDS AND METHODS OF MAKING STEROLS USING DIOLS

Compounds and methods of synthesizing oxysterols are provided. The compounds and methods provided allow the oxysterol to be safely produced at a high yield. The compounds and methods provided can produce the oxysterol in a stereoselective manner. 2. A method of claim 1 , wherein the borane compound is BHand is reacted with a peroxide.3. A method of claim 2 , wherein the peroxide is hydrogen peroxide.4. A method of claim 3 , wherein the BHand the hydrogen peroxide are reacted in the presence of tetrahydrofuran to form the oxysterol.5. (canceled)6. A method of claim 4 , wherein (i) the oxysterol is hydrated claim 4 , (ii) the borane is reacted with the diol at a temperature of less than 5° C. claim 4 , (iii) the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C. claim 4 , or (iv) the oxysterol is solidified and separated by filtration.8. A method of claim 1 , wherein the oxysterol is purified by dissolving the oxysterol in an organic solvent.9. A method of claim 8 , wherein the oxysterol is purified by dissolving the oxysterol in an acetone and water to recover purified oxysterol crystals.10. A method of claim 8 , wherein the oxysterol is purified by reflux and recrystallization by dissolving the oxysterol in an acetone and water to recover purified oxysterol crystals.11. A method of claim 1 , wherein the oxysterol is anhydrous.12. A method of claim 10 , wherein the purified oxysterol is hydrated after crystallization.13. A method of claim 10 , wherein the purified crystallized oxysterol is a monohydrate.14. A method of claim 1 , wherein the borane compound is reacted with the diol at a temperature of less than 5° C.15. A method of claim 4 , wherein the hydrogen peroxide is reacted with the diol after the borane is reacted and the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C.16. A method of claim 1 , wherein the reaction is carried out in a single container to yield the oxysterol.18. (canceled)19. ( ...

COMPOUNDS AND METHODS OF MAKING STEROLS USING DIOLS

Compounds and methods of synthesizing oxysterols are provided. The compounds and methods provided allow the oxysterol to be safely produced at a high yield. The compounds and methods provided can produce the oxysterol in a stereoselective manner. 2. A method of claim 1 , wherein the borane compound is BHand is reacted with a peroxide.3. A method of claim 2 , wherein the peroxide is hydrogen peroxide.4. A method of claim 3 , wherein the BHand the hydrogen peroxide are reacted in the presence of tetrahydrofuran to form the oxysterol.5. A method of claim 1 , wherein the R1 and R2 comprise a hexyl group and the diol comprises (3S claim 1 ,8S claim 1 ,9S claim 1 ,10R claim 1 ,13R claim 1 ,14S claim 1 ,17R)-10 claim 1 ,13-dimethyl-17-[(S)-2-hydroxyoctan-yl]-2 claim 1 ,3 claim 1 ,4 claim 1 ,7 claim 1 ,8 claim 1 ,9 claim 1 ,11 claim 1 ,12 claim 1 ,14 claim 1 ,15 claim 1 ,16 claim 1 ,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol and the hydrate is a monohydrate.6. A method of claim 4 , wherein (i) the oxysterol is hydrated claim 4 , (ii) the borane is reacted with the diol at a temperature of less than 5° C. claim 4 , (iii) the hydrogen peroxide is reacted with the diol at a temperature of less than 15° C. claim 4 , or (iv) the oxysterol is solidified and separated by filtration.8. A method of claim 1 , wherein the oxysterol is purified by dissolving the oxysterol in an organic solvent.9. A method of claim 8 , wherein the oxysterol is purified by dissolving the oxysterol in an acetone and water to recover purified oxysterol crystals.10. A method of claim 8 , wherein the oxysterol is purified by reflux and recrystallization by dissolving the oxysterol in an acetone and water to recover purified oxysterol crystals.11. (canceled)12. A method of claim 10 , wherein the purified oxysterol is hydrated after crystallization.13. (canceled)14. A method of claim 1 , wherein the borane compound is reacted with the diol at a temperature of less than 5° C.15. A method of claim 4 , ...

Synthesis of a substituted indene derivative

This invention is directed to methods of preparing AQX-1125 having the formula: This invention is also directed to intermediates utilized in the methods of preparing AQX-1125.

OXYSTEROLS AND METHODS OF USE THEREOF

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R, R, R, R, R, and Rare as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. 3. The compound of claim 1 , wherein Rand Rare not both hydrogen.4. (canceled)5. (canceled)6. The compound of claim 1 , wherein each of Rand Ris independently hydrogen claim 1 , —P(O)(R) claim 1 , —S(O)R claim 1 , —C(O)R claim 1 , —C(O)OR claim 1 , —C(O)N(R) claim 1 , —(CH)C(O)N(R) claim 1 , —(CH)OP(O)(R) claim 1 , —(CH)OS(O)R claim 1 , —(CH)OC(O)R claim 1 , or —(CH)C(O)OR;{'sup': a', 'b', 'd, 'each of Rand Ris independently selected from —ORor alkyl;'}{'sup': 'c', 'sub': 2', '2', '2', '2', '2', '3', '2', '2', '2', '2', '3', '2, 'each Ris independently alkyl (e.g., —CHNH, —CHCHCOH, —CH(CH(CH))NH, —CHCHC(O)OH, or —CH(CH)NH);'}{'sup': 'd', 'each Ris independently hydrogen or alkyl;'}each x is independently 1 or 2; andeach of n, m, p is independently 1, 2, 3, or 4.7. (canceled)8. The compound of claim 1 , wherein Ris Calkyl (e.g. claim 1 , substituted or unsubstituted Calkyl).9. (canceled)10. The compound of claim 8 , wherein Ris hydrogen claim 8 , methyl (e.g. claim 8 , —CH claim 8 , —CFor —CHOCH) claim 8 , ethyl claim 8 , or isopropyl.11. (canceled)12. The compound of claim 1 , wherein each of Rand Ris independently hydrogen claim 1 , methyl (e.g. claim 1 , —CH claim 1 , —CF) claim 1 , ethyl claim 1 , isopropyl claim 1 , cyclopropyl claim 1 , or butyl.13. The compound of claim 1 , wherein Ris a moiety cleavable under biological conditions and Ris hydrogen.14. The compound of claim 1 , wherein Ris hydrogen and Ris a moiety cleavable under biological conditions.15. The compound of claim 1 , wherein each of Rand Ris a moiety cleavable under biological conditions.16. (canceled)17. The compound of claim 16 , wherein when Ris hydrogen and Ris —S(O)Rand x is 2 claim 16 , ...

NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF

Described herein are neuroactive steroids of the Formula (I): 27-. (canceled)10. The compound of claim 8 , wherein Ror Ris alkyl claim 8 , methoxy claim 8 , substituted ethoxy claim 8 , or C-Calkoxy.11. The compound of claim 10 , wherein Ris alkyl claim 10 , methoxy claim 10 , substituted ethoxy claim 10 , or C-Calkoxy.12. The compound of claim 9 , wherein Ris hydrogen.1526-. (canceled)2839-. (canceled)40. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.41. (canceled)42. A method of inducing sedation and/or anesthesia in a subject claim 14 , comprising administering to the subject an effective amount of a compound of claim 14 ,or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.4344-. (canceled)45. A method for treating disorders related to GABA function in a subject in need thereof claim 14 , the method comprising administering to the subject a therapeutically effective amount of a compound ofor a pharmaceutically acceptable salt or a pharmaceutical composition thereof.46. A method for treating seizure in a subject claim 14 , comprising administering to the subject an effective amount of a compound ofor a pharmaceutically acceptable salt or a pharmaceutical composition thereof.47. A method for treating epilepsy or status or status epilepticus in a subject claim 14 , comprising administering to the subject an effective amount of a compoundor a pharmaceutically acceptable salt or a pharmaceutical composition thereof.48. A method of administering an effective amount of a compound ofor a pharmaceutically acceptable salt or a pharmaceutical composition thereof.4952-. (canceled)53. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.54. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient.55. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable excipient. This application ...

Immune memory induction by platinum based compounds

The present invention pertains to a method of treating cancer or its relapse in mammals by employing platinum based compounds. More particularly, the present invention provides to enhance immunity in a mammal, using a compound of Formula I and/or Formula II, preferably Compound 1 or its derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof. The method of inducing an immune response in a mammal is mediated through immune memory. The present invention also provides for such platinum based compounds and their use in treating cancer, metastasis or cancer relapse.

Polyethylene Glycol-Conjugated Glucocorticoid Prodrugs and Compositions and Methods Thereof

Polyethylene glycol (PEG)-conjugated glucocorticoid prodrugs, methods of preparation, and use for the treatment of diseases and disorders are disclosed. In particular, PEG-conjugated dexamethasone compounds and methods of using them for treating inflammatory and autoimmune diseases, including but not limited to lupus, are disclosed. 5. The method of claim 4 , wherein E is a linker comprising a branched structure capable of covalently bonding to two or more Rgroups claim 4 , said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O claim 4 , S claim 4 , and N; and wherein Z is a linker comprising a branched structure capable of covalently bonding to two or more dexamethasone moieties claim 4 , said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O claim 4 , S claim 4 , and N.18. The method of claim 4 , wherein n is 40 to 50.19. The method of claim 1 , in conjunction with administration to the subject a second therapeutic agent selected from the group consisting of a nonsteroidal anti-inflammatory drug (NSAID) claim 1 , a glucocorticoid claim 1 , a disease-modifying anti-rheumatic drug (DMARD) claim 1 , and a biologic drug.20. The method of claim 19 , wherein the NSAID is selected from the group consisting of aspirin claim 19 , naproxen claim 19 , and celecoxib; the glucocorticoid is selected from the group consisting of dexamethasone claim 19 , prednisone claim 19 , and betamethasone; and the DMARD is selected from the group consisting of methotrexate claim 19 , leflunomide claim 19 , sulfasalazine claim 19 , and hydroxychloroquine.21. The method of claim 1 , wherein the disease or disorder is selected from the group consisting of systemic lupus erythematosus claim 1 , lupus nephritis claim 1 , minimal change disease claim 1 , focal segmental glomerulosclerosis claim 1 , IgA nephropathy claim 1 , transplant rejection claim 1 , rheumatoid arthritis claim 1 , ...

COMPOUNDS AND METHODS INVOLVING STEROLS

Compounds and methods of synthesizing oxysterols are provided. The compounds and methods provided allow the oxysterol to be safely produced at a high yield. The compounds and methods provided can produce the oxysterol in a stereoselective manner. 19-. (canceled)11. A method of claim 10 , wherein Rcomprises a (C-C) alkyl or heteroalkyl claim 10 , a (C-C) aryl or heteroaryl claim 10 , a (C-C) arylalkyl or heteroalkyl and a (C-C) arylalkyl or heteroaryl-heteroalkyl claim 10 , a (C-C) alkyldiyl or heteroalkyldiyl claim 10 , or a (C-C) alkyleno or heteroalkyleno.12. A method of claim 10 , wherein the sterol comprises (3S claim 10 ,8S claim 10 ,9S claim 10 ,10R claim 10 ,13R claim 10 ,14S claim 10 ,17R)-10 claim 10 ,13-dimethyl-17-[(S)-2-hydroxyoctan-yl]-2 claim 10 ,3 claim 10 ,4 claim 10 ,7 claim 10 ,8 claim 10 ,9 claim 10 ,11 claim 10 ,12 claim 10 ,14 claim 10 ,15 claim 10 ,16 claim 10 ,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol and the hydrate is a monohydrate.13. A method of claim 10 , wherein (i) the organometallic compound comprises the formula RMgX claim 10 , where X is a halide and Rcomprises an aliphatic or cyclic substituent having at least one carbon atom or (ii) the organometallic compound comprises the formula RLi claim 10 , where Rcomprises an aliphatic or cyclic substituent having at least one carbon atom.14. A method of claim 10 , wherein (i) pregnenolone acetate is reacted with the organometallic compound and quenched with aqueous ammonium chloride to produce the sterol in the form of a gel claim 10 , or (ii) pregnenolone is reacted with the organometallic compound and quenched with acetic acid to produce the sterol in the form of a gel.15. A method of claim 14 , wherein pregnenolone is reacted with the organometallic compound at a temperature of less than 5° C.16. A method of claim 14 , wherein the sterol is reacted with acetic acid in tetrahydrofuran at a temperature of less than 10° C.18. A method of wherein Rand Rcomprise a hexyl group and the ...

Water-soluble ursodeoxycholic acid prodrugs

Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti-apoptotic activity in both in vitro and in vivo models. Water-soluble prodrugs of UDCA for use in indications where intravenous administration of UDCA may be preferable, such as reducing damage from stroke or acute kidney injury, are disclosed. The disclosed prodrugs showed significant anti-apoptotic activity in a series of in vitro assays.

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described. 131-. (canceled)33. The method of claim 32 , wherein the subject is a human.34. The method of claim 32 , wherein the compound or the pharmaceutically acceptable salt is administered orally claim 32 , subcutaneously claim 32 , intravenously claim 32 , intranasally claim 32 , transdermally claim 32 , intraperitoneally claim 32 , intramuscularly claim 32 , intrapulmonary claim 32 , vaginally claim 32 , rectally claim 32 , or intraocularly.35. The method of claim 32 , wherein the compound or the pharmaceutically acceptable salt is administered intravenously.36. The method of claim 32 , wherein the compound or the pharmaceutically acceptable salt is administered orally.37. The method of claim 32 , further comprising administering to the subject an additional anti-cancer and/or cytotoxic agent.38. The method of claim 37 , wherein the additional anti-cancer and/or cytotoxic agent is administered simultaneously with the compound or the pharmaceutically acceptable salt.39. The method of claim 32 , wherein the amount of the compound or the pharmaceutically acceptable salt administered is in the range of 0.01 mg to 100 mg per kilogram body weight of the subject.40. The method of claim 32 , wherein the amount of the compound of Formula III administered is in the range of about 0.01 mg to 1000 mg.41. The method of claim 32 , wherein Ris hydrogen or an optionally substituted lower alkyl.42. The method of claim 32 , wherein Ris hydrogen or methyl.43. The method of claim 32 , wherein Ris an optionally substituted alkyl.44. The method of claim 32 , wherein Ris an optionally substituted acyl.45. The method of claim 44 , wherein Ris chosen from acetyl claim 44 , propionyl claim 44 , isobutyryl claim 44 , and pivaloyl.46. The method of claim 32 , wherein Ris an optionally substituted alkoxycarbonyl.47. The method of claim 46 , wherein Ris chosen from optionally ...

Benzoic Acid Derivatives of Bile Acid as FXR/TGR5 Agonists and Methods of Use Thereof

The present invention provides compounds of Formula I: pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR and/or TGR5.

Neuroactive enantiomeric 15-, 16- and 17-substituted steroids as modulators for gaba type-a receptors

The present disclosure is generally directed to neuroactive enantiomeric 15-, 16- and 17-substituted steroids with additional optional substituents at carbons 3, 4, 6, 7, 10 and 13, and pharmaceutically acceptable salts thereof, for use as, for example, modulators for GABA type-A receptors. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

Systems and methods for targeted cancer therapies

Systems and methods for producing liposomes, including control liposomes and various targeted liposomes. Systems and methods for treating conditions, such as, but not limited to various cancers, using targeted liposomes produced according to various methods disclosed herein. For example, estrone-conjugated liposomes may be used deliver chemotherapeutic agent(s) to breast cancer tissues for the treatment of breast cancer. Systems and methods for actuating liposomes using ultrasound. For example, systems and methods for actuating estrone-conjugated liposomes accumulated in breast cancer tissues for the treatment of breast cancer.

NEUROACTIVE 19-ALKOXY-17-SUBSTITUTED STEROIDS, PRODRUGS THEREOF, AND METHODS OF TREATMENT USING SAME

The present disclosure is generally directed to neuroactive 19-alkoxy-17-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. 2. The method of claim 1 , wherein the Rgroup is selected from the group consisting of H claim 1 , methyl claim 1 , and trifluoromethyl.3. The method of claim 1 , wherein Ris ═O claim 1 , methoxy or H.4. The method of claim 1 , wherein Ris beta-cyano.6. The method of claim 1 , wherein{'sub': 1', '1', '4', '1', '4', '1', '4, 'Ris selected from (C-Calkyl)-O, spirooxirane, cyano, ═O, (C-Calkyl)C(O), and HO(C-Calkyl)C(O).'}7. The method of claim 1 , wherein the mood disorder is selected from the group consisting of depression claim 1 , dysthymic disorder claim 1 , and bipolar disorder. This application is divisional of U.S. patent application Ser. No. 15/586,853 filed on May 4, 2017, which is a divisional of U.S. patent application Ser. No. 14/652,717 filed on Jun. 16, 2015 (now U.S. Pat. No. 9,676,812), which is a U.S. National Stage Application based on International Patent Application No. PCT/US2013/076214 filed on Dec. 18, 2013, which claims priority benefit of U.S. Provisional Patent Application Ser. No. 61/738,822 filed on Dec. 18, 2012, the entire contents of which are incorporated herein by reference.The invention was made with government support under GM047969, awarded by the National Institutes of Health. The government has certain rights in the invention.The present disclosure is generally directed to novel compounds having utility as an anesthetic and/or in the treatment of disorders relating to GABA function and activity. More specifically, the present disclosure is directed to steroids having a 19-alkoxy-17-substituted tetracyclic structure that are neuroactive and suitable for use ...

Compositions and methods for treating cns disorders

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein , A, R 1 , R 2 , and R 3 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, e.g., for treating a subject suffering from a disease or disorder described herein.

PROCESS FOR PREPARATION OF SULFONYLUREA BILE ACID DERIVATIVES

The present invention relates to processes for preparing a compound of Formula I: 111-. (canceled)1621-. (canceled) This application is a divisional application of U.S. application Ser. No. 15/826,233, filed Nov. 29, 2017, which claims the benefit of U.S. Provisional Application No. 62/427,354 filed on Nov. 29, 2016. The entire teachings of the above applications are incorporated herein by reference.The present invention relates to processes and intermediates useful in the preparation of biologically active molecules useful as FXR or TGR5 modulators, especially relates to bile acid derivatives and methods for their preparation and use.Farnesoid X Receptor (FXR) is an orphan nuclear receptor initially identified from a rat liver cDNA library (BM. Forman, et al., 1995, 81(5), 687-693) that is most closely related to the insect ecdysone receptor. FXR is a member of the nuclear receptor family of ligand-activated transcription factors that includes receptors for the steroid, retinoid, and thyroid hormones (DJ. Mangelsdorf, et al., 1995, 83(6), 841-850). The relevant physiological ligands of FXR are bile acids (D. Parks et al., 1999, 284(5418), 1362-1365). The most potent one is chenodeoxycholic acid (CDCA), which regulates the expression of several genes that participate in bile acid homeostasis. Farnesol and derivatives, together called farnesoids, are originally described to activate the rat orthologue at high concentration but they do not activate the human or mouse receptor. FXR is expressed in the liver, throughout the entire gastrointestinal tract including the esophagus, stomach, duodenum, small intestine, colon, ovary, adrenal gland and kidney. Beyond controlling intracellular gene expression, FXR seems to be also involved in paracrine and endocrine signaling by upregulating the expression of the cytokine Fibroblast Growth Factor (J. Holt et al., 2003, 17(13), 1581-1591; T. Inagaki et al., 2005, 2(4), 217-225).Small molecule compounds which act as FXR modulators ...

NI(0) CATALYSTS

Provided herein are nickel(O) catalysts that are stable when exposed to air and can be used to catalyze the formation of a C—C, C—O, or C—N bond. 2. The catalyst of claim 1 , wherein the dashed line represents a double bond.3. The catalyst of or claim 1 , wherein each Ris the same.4. The catalyst of any one of to claim 1 , wherein Ris selected from the group consisting of methyl claim 1 , ethyl claim 1 , propyl claim 1 , isopropyl claim 1 , butyl claim 1 , sec-butyl claim 1 , isobutyl claim 1 , t-butyl claim 1 , pentyl claim 1 , 3-pentyl claim 1 , and diphenylmethyl.5. The catalyst of any one of to claim 1 , wherein Ris H.6. The catalyst of any one of to claim 1 , wherein each Ris the same.7. The catalyst of any one of to claim 1 , wherein each Ris selected from H claim 1 , chloro claim 1 , and methyl.8. The catalyst of any one of to claim 1 , wherein both Rtogether with the carbons to which they are attached form a 6-membered ring.9. The catalyst of any one of to claim 1 , wherein Ris aryl.10. The catalyst of claim 9 , wherein Ris phenyl.11. The catalyst of any one of to claim 9 , wherein Ris Calkyl.12. The catalyst of claim 11 , wherein Ris methyl or ethyl.13. The catalyst of any one of to claim 11 , wherein Ris H.14. The catalyst of any one of to claim 11 , wherein Ris Calkylene-aryl.15. The catalyst of claim 14 , wherein Ris Calkylene-aryl.16. The catalyst of or claim 14 , wherein the aryl of Rcomprises phenyl or naphthyl.17. The catalyst of claim 16 , wherein Ris toluyl claim 16 , methoxyphenyl claim 16 , tri(alkyl)phenyl (e.g. claim 16 , trimethylphenyl or triisopropylphenyl) claim 16 , MeCO-phenyl claim 16 , or phenyl.18. The catalyst of any one of to claim 16 , wherein Ris Calkylene-Calkene.19. The catalyst of claim 18 , wherein Ris Calkylene-Calkene.20. The catalyst of claim 18 , wherein Ris Calkylene-Calkene.21. The catalyst of any one of to claim 18 , wherein the Calkene is Calkene.22. The catalyst of any one of to claim 18 , wherein Ris Calkyl.23. The ...

Prodrugs of 17.beta.-hsd1-inhibitors

The present invention accordingly provides novel compounds of formula (I) wherein R1, R2, R3 and R4 are as defined in the claims. The invention further relates to their in treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of the 17β-HSD1 enzyme and/or requiring the lowering of the endogenous estradiol concentration.

METAL-FREE DIRECT ARYLATION OF DIALKYL PHOSPHONATES FOR THE SYNTHESIS OF MIXED ALKYL ARYL PHOSPHONATES

Provided herein are phosphates, thiophosphates, phosphonates, and phosphinates, methods of making same, and methods of using these compounds and methods for the generation of pharmaceutically relevant phosphate, phosphonate, and phosphinate analogs. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention. 79-. (canceled)10. The method of claim 1 , wherein the activating agent is triflic anhydride.11. The method of claim 1 , wherein the base is pyridine.1517-. (canceled)18. The method of claim 12 , wherein the activating agent is triflic anhydride.19. The method of claim 12 , wherein the base is pyridine.21. (canceled)22. The compound of claim 20 , wherein n is 1.23. The compound of claim 20 , wherein A is selected from O and S.2428-. (canceled)3059-. (canceled) This application claims the benefit of U.S. Provisional Application No. 62/540,773, filed on Aug. 3, 2017 and U.S. Provisional Application No. 62/610,825, filed on Dec. 27, 2017, which are incorporated herein fully by reference in their entireties.Organophosphonate compounds are ubiquitous structural motifs widely present in pharmaceuticals (Horsman and Zechel (2017) 117: 5704; Mucha et al. (2011) 54: 5955; McGrath et al. (2013) 11: 412), agrochemicals (Nowack (2003) 37: 2533; Duke and Powles (2008) 64: 319), and ligand scaffolds (Martin and Buchwald (2008) 41: 1461), highlighting the significance of these structures. Among them, mixed alkyl aryl phosphonates have attracted significant attention in nucleoside phosphonate prodrugs (Pradere et al. (2014) 114: 9154; Thornton et al. (2016) 59: 10400; Okon et al. (2017) 60: 8131) and in coordination chemistry for the study of biological system A (; Park et al. (2016) 6: 7458; Wieczorek et al. (2012) Organometallics 31: 2810; Galbiati et al. (2015) 26: 680; Boersma et al. (2008) 9: 1110). Mixed phosphonates show a wide range of biological activities such as phosphonate ...

Progesterone phosphate analogs and uses related thereto

This disclosure relates to progesterone phophate derivatives and uses related thereto. In certain embodiments, the disclosure relates to compounds disclosed herein and uses for managing inflammation such as those resulting from traumatic brain injury or stroke.

OXYSTEROL-STATIN COMPOUNDS FOR BONE GROWTH

Oxysterol-statin compounds and methods of synthesizing the same are provided for use in promoting osteogenesis, osteoinduction and/or osteoconduction. Methods of synthesizing in a single container OXY133-statin compounds having high yields and improved process safety are also provided. Methods for synthesizing OXY133-statin compounds that are stereoselective are also provided. 2. (canceled)3. The method of claim 1 , wherein (i) the organometallic compound comprises the formula RMgX claim 1 , where X is a halide and Ris a hexyl group; or (ii) the organometallic compound comprises the formula RLi claim 1 , where Ris a hexyl group; or (iii) Ris methyl claim 1 , ethyl claim 1 , tert-butyl claim 1 , allyl claim 1 , carbamate or silyl group; or (iv) Ris methyl claim 1 , ethyl claim 1 , tert-butyl claim 1 , allyl claim 1 , carbamate claim 1 , triisopropylsilyl claim 1 , or tert-butyldimethylsilyl group.8. (canceled)11. The method of claim 10 , wherein the iodine source is trimethylsilyl iodide claim 10 , the fluoride source is tetra-n-butylammonium fluoride or HF pyridine complex.12. The method of claim 11 , wherein the reactions are carried out in a single container to yield an oxysterol-statin compound or a pharmaceutically acceptable salt claim 11 , hydrate or solvate thereof.13. The method of claim 10 , wherein the reactions are carried out in a single container to yield an oxysterol-statin compound containing the linker L or a pharmaceutically acceptable salt claim 10 , hydrate or solvate thereof.16. The method of claim 15 , wherein the bone disorder comprises a bone fracture claim 15 , osteoporosis or osteopenia.18. The compound of claim 17 , wherein Ris a methyl claim 17 , ethyl claim 17 , silyl or carbamate group with the proviso that Ris not tert-butyl dimethyl silyl when Ris (C-C) alkyl.21. The method of claim 1 , wherein the oxysterol-statin compound comprises (3S claim 1 ,5S claim 1 ,6S claim 1 ,8R claim 1 ,9S claim 1 , 10R claim 1 ,13S claim 1 ,14S claim 1 , ...

OXYSTEROL-THERAPEUTIC AGENT DERIVATIVE FOR BONE HEALING

Oxysterol-therapeutic agent derivatives or OXY133-therapeutic agent derivative compounds and methods of synthesizing the same are provided for use in promoting osteogenesis, osteoinduction and/or osteoconduction. Methods of synthesizing in a single container OXY133-therapeutic agent derivatives having high yields and improved process safety are also provided. Methods for synthesizing OXY133-therapeutic agent derivatives that are stereoselective are also provided. 2. The method of claim 1 , wherein the organometallic compound corresponds to the formula RMgX or RLi where X is a halide and Ris an aliphatic or cyclic substituent having at least one carbon.4. The method of claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , silyl or carbamate group and Ris (C-C) alkyl or heteroalkyl claim 1 , a (C-C) aryl or heteroaryl claim 1 , a (C-C) arylalkyl or heteroalkyl or a (C-C) arylalkyl or heteroaryl-heteroalkyl claim 1 , a (C-C) alkyldiyl or heteroalkyldiyl claim 1 , a (C-C) alkyleno or heteroalkyleno or carbamate.5. The method of claim 1 , wherein the pregnenolone derivative of formula II is prepared by reacting pregnenolone with RX in a base claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , silyl or carbamate claim 1 , X is a halide claim 1 , wherein the base is NaOH claim 1 , KOH or Ca(OH).9. The method of claim 6 , wherein the pregnenolone derivative of formula IIa is prepared by reacting pregnenolone with RX in a base claim 6 , wherein Ris methyl claim 6 , ethyl claim 6 , silyl or carbamate claim 6 , X is a halide claim 6 , and the base is NaOH claim 6 , KOH or Ca(OH).12. The method of claim 10 , wherein the iodine source is trimethylsilyl iodide or the fluoride source is tetra-n-butylammonium fluoride or HF pyridine complex.15. The method of claim 14 , wherein the iodine source is trimethylsilyl iodide claim 14 , the fluoride source is tetra-n-butylammonium fluoride or HF pyridine complex.17. The method of claim 1 , wherein Ris a kanamycin moiety.18. The method ...

PREPARATION AND USES OF OBETICHOLIC ACID

The present invention relates to obeticholic acid: 120.-. (canceled)21. A tablet comprising non-crystalline obeticholic acid in the amount of about 1 mg to about 25 mg wherein the non-crystalline obeticholic acid comprises less than 1% of chenodeoxycholic acid.22. The tablet of claim 21 , wherein the non-crystalline obeticholic acid further comprises not more than 0.15% of 6β-ethylchenodeoxycholic acid.23. The tablet of claim 21 , wherein the non-crystalline obeticholic acid comprises less than about 0.5% of chenodeoxycholic acid.24. The tablet of claim 23 , wherein the non-crystalline obeticholic acid comprises less than about 0.3% of chenodeoxycholic acid.25. The tablet of claim 24 , wherein the non-crystalline obeticholic acid comprises less than about 0.2% of chenodeoxycholic acid.26. The tablet of claim 21 , wherein the non-crystalline obeticholic acid further comprises not more than 0.15% of 3α(3α claim 21 ,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.27. The tablet of claim 21 , wherein the non-crystalline obeticholic acid further comprises not more than 0.15% of 6β-ethylchenodeoxycholic acid and not more than 0.15% of 3α(3α claim 21 ,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.28. The tablet of claim 27 , wherein the non-crystalline obeticholic acid comprises less than about 0.5% of chenodeoxycholic acid.29. The tablet of claim 28 , wherein the non-crystalline obeticholic acid comprises less than about 0.3% of chenodeoxycholic acid.30. The tablet of claim 29 , wherein the non-crystalline obeticholic acid comprises less than about 0.2% of chenodeoxycholic acid.31. The tablet of claim 21 , wherein the non-crystalline obeticholic acid comprises less than about 0.05% of 6β-ethylchenodeoxycholic acid claim 21 , and less than about 0.05% of 3α(3α claim 21 ,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.32. The tablet of claim 31 , wherein the non- ...

A PROCESS FOR THE PRODUCTION OF 19-NORPREGN-4-EN-3,20-DIONE-17ALPHA-OL(GESTONORONE) AND INTERMEDIATES THEREFOR

The present invention relates to a new stereoselective process for the synthesis of 17(α)-17-acetyl-17-hydroxy-estr-4-en-3-one of formula (I), as well as to the new intermediates of the process. The 17(α)-17-acetyl-17-hydroxy-estr-4-en-3-one (gestonorone) is an important intermediate in the synthesis of the active ingredients having progestogen activity—such as gestonorone capronate and nomegestroi acetate. Formulas (I), (II) and (III). 3. The process according to claim 2 , characterized by carrying out the reaction in step i) in ethanol.4. The process according to claim 2 , characterized by using potassium cyanide or sodium cyanide as reagent in step i).5. The process according to claim 2 , characterized by using 2-4 mol excess of cyanide reagent in step i).6. The process according to claim 2 , characterized by using acetic acid as mild organic acid in step i).7. The process according to claim 2 , characterized by using 1.5-3 mol excess of acetic acid in step i).8. The process according to claim 2 , characterized by carrying out the reaction in step ii) at a temperature between 0 and +10° C.9. The process according to claim 2 , characterized by carrying out the reaction in step ii) in methyl tert-butyl ether or tetrahydrofuran.10. The process according to claim 2 , characterized by using 2.5-4 mol excess of reagent in step ii).11. The process according to claim 1 , characterized by using 2.5-5 mol excess of methyl lithium.12. The process according to claim 1 , characterized by using N claim 1 ,N claim 1 ,N′ claim 1 ,N′-tetramethylethylendiamine as substituted 1 claim 1 ,2-diamino-ethane.13. The process according to claim 1 , characterized by carrying out the reaction at a temperature between −40 and −20° C.14. The process according to claim 1 , characterized by using hydrochloric acid in the transformation of the protected imine obtained as intermediate into the compound of formula (I).15. The process according to claim 1 , characterized by carrying out the ...

Thionyl tetrafluoride modified compounds and uses

Thionyl tetrafluoride gas reacts efficiently with primary amines to form reactive iminosulfur oxydifluoride compounds. These dual S VI —F loaded iminosulfur oxydifluoride compounds, in turn, readily react with secondary amines or aryloxy silyl ethers (ArO—SiR 3 ), yielding the corresponding fused heteroatom-linked substrates. Iminosulfur oxyfluoride polymers also are provided by disclosed methods.

Intermediates for the Synthesis of Bile Acid Derivatives, in Particular of Obeticholic Acid

The invention relates to compounds of general formula (I): wherein: , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids which are useful in the treatment of conditions such as liver disease.

Combinations Of Lanosterol Or 25-Hydroxycholesterol Including Derivatives Thereof Useful In The Treatment Of Lens Disorders

Novel lanosterol derivatives and novel 25-hydroxycholesterol derivatives including their pharmaceutically acceptable salts as well as methods of treatment and pharmaceutical compositions and formulations of lanosterol and derivatives thereof and 25-hydroxycholesterol and derivatives thereof useful in treating ophthalmic disorders including cataracts and presbyopia. 142-. (canceled)47. A method of treating an eye cataract in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of .48. A method of treating an eye presbyopia in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of .53. A method of treating an eye cataract in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of .54. A method of treating an eye presbyopia in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of .55. A method of treating an eye cataract in a mammal in need of such treatment comprising administering an effective amount of lanosterol or a derivative thereof and an oxidative protective agent claim 43 , wherein the lanosterol derivative is a compound of and with lanosterol the oxidative protective agent is N-acetylcarnosine claim 43 , N-acetylcysteine or N-acetylcysteine amide.56. A method of treating an eye cataract in a mammal in need of such treatment comprising administering an effective amount of 25-hyroxycholesterol or a derivative thereof and an oxidative protective agent claim 49 , wherein the 25-hyroxycholesterol derivative is a compound of and with 25-hyroxycholesterol claim 49 , the oxidative protective agent is N-acetylcysteine claim 49 , N-acetylcarnosine or N-acetylcysteine amide.57. A method of treating an eye presbyopia in a mammal in need of such treatment comprising administering an ...

Endosomolytic Agents for Gene Therapy

Compounds of formula (I), wherein Ar is an aryl group optionally further substituted with one or more groups R; A is a lipophilic, hydrophobic moiety; Ris a phosphodiester, phosphotriester, thioether or amide group; X is an unsubstituted or substituted Cto Calkylene or alkenylene group, which is optionally interrupted by one or more —NR—, —O— or —S— linkages, Ris —YC(R)(R)COR; and pharmaceutically acceptable salts or solvates thereof are useful as endosomolytic agents particularly for the delivery of nucleic acids useful in gene therapy. 2. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein either A is —RCH(OR)RCH—(OR)Z claim 1 , wherein Rand Rare the same or different and each is a Cto Calkyl or alkenyl group claim 1 , Rand Rare the same or different and each is a covalent bond or a —(CH)— group wherein s is 1 claim 1 , 2 or 3 claim 1 , Z is a hydrogen atom or a Cto Calkyl group; or A is an unsubstituted or substituted Cto Cgroup comprising the fused ring system of a steroid.3. A compound of formula (I) as depicted in a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein A is (R)-2 claim 1 ,3-di(octadecyloxy)propyl or cholesteryl.4. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof wherein the aryl group Ar is a phenyl group.5. A compound of formula (I) as depicted in claim 1 , or a pharmaceutically acceptable salt or solvate thereof claim 1 , which comprises at least one Rgroup which is of the formula —YC(R)(R)CORand is the same or different to the group R.7. A compound of formula (I) as depicted in or a pharmaceutically acceptable salt or solvate thereof claim 1 , wherein Ris a phosphodiester or phosphotriester group.8. A compound of formula (I) as depicted in or a pharmaceutically acceptable salt or solvate thereof wherein Y is —CH—.9. A compound of formula (I) as depicted in or a pharmaceutically acceptable salt ...

Preparation and Uses of Obeticholic Acid

The present invention relates to obeticholic acid: 113-. (canceled)14. A crystalline form of obeticholic acid , wherein the crystalline form is selected from the group consisting of D , F , G , and I.15. The crystalline form of claim 14 , wherein the crystalline form is Form D and characterized by an X-ray diffraction pattern including peaks at about 4.4 claim 14 , 5.2 and 7.5 degrees 2-Theta.16. The crystalline form of claim 15 , wherein the crystalline form is characterized by an X-ray diffraction pattern including peaks at about 9.5 claim 15 , 12.3 claim 15 , 14.5 claim 15 , 15.9 claim 15 , and 16.8 degrees 2-Theta.17. The crystalline form of claim 14 , wherein the crystalline form is Form F and characterized by an X-ray diffraction pattern including peaks at about 8.0 claim 14 , 13.2 claim 14 , and 13.8 degrees 2-Theta.18. The crystalline form of claim 17 , wherein the crystalline form is characterized by an X-ray diffraction pattern including peaks at about 9.9 claim 17 , 10.5 claim 17 , 15.7 claim 17 , 16.0 and 17.5 degrees 2-Theta.19. The crystalline form of claim 14 , wherein the crystalline form is Form G and characterized by an X-ray diffraction pattern including peaks at about 12.9 and 13.4 degrees 2-Theta.20. The crystalline form of wherein the crystalline form is characterized by an X-ray diffraction pattern including peaks at about 7.9 claim 19 , 12.3 claim 19 , 14.5 claim 19 , 16.9 and 23.1 degrees 2-Theta.21. The crystalline form of claim 14 , wherein the crystalline form is Form I and characterized by an X-ray diffraction pattern including a peak at about 7.2 degrees 2-Theta.22. The crystalline form of wherein the crystalline form is characterized by an X-ray diffraction pattern including peaks at about 13.9 claim 21 , 14.5 claim 21 , 17.4 claim 21 , 19.2 and 22.8 degrees 2-Theta.23. The crystalline form of claim 15 , wherein the crystalline form is obtained from the recrystallization of obeticholic acid from methyl isobutyl ketone.24. The ...

PROCESS FOR THE PRODUCTION OF 21-METHOXY-11-BETA-PHENYL-19-NOR-PREGNA-4,9-DIENE-3,20-DIONE DERIVATIVES

The present invention relates to a process for the synthesis of compounds of formula (I), 2. The process according to claim 1 , characterized by synthesizing the methoxymethyl lithium reagent the following way:a) an isolated or a condensed ring aromatic hydrocarbon is dissolved in an ether type solvent,b) lithium metal is added to the so obtained solution under inert atmosphere,c) the mixture is stirred at 0-20° C. until lithium is dissolved,d) the mixture is cooled to (−78)-(−40)° C. and methoxymethyl chloride is added.3. The process according to claim 2 , characterized by using naphthalene or biphenyl as an isolated or a condensed ring aromatic hydrocarbon.4. The process according to claim 2 , characterized by using tetrahydrofuran as an ether type solvent.5. The process according to claim 2 , characterized by carrying out the reaction of step c) of at a temperature between 5-10° C.6. The process according to claim 2 , characterized by carrying out the reaction of step d) of at a temperature of −55° C.7. The process according to characterized by removing the protective groups by acid hydrolysis and dehydration.8. The process according to claim 1 , characterized by synthesizing the methoxymethyl lithium reagent in situ. The present invention relates to a new process for the synthesis of 21-methoxy-pregnane derivatives of formula (I),wherein the meaning of R is dimethylamino or acetyl group, using methoxymethyl lithium reagent, as well as to the intermediate of formula (III), wherein the meaning of R′ is 2-methyl-1,3-dioxan-2-yl group.21-Alkoxy-pregnane compounds possessing significant antiprogestogen activity were first described in the patent applications No. WO97041145 and WO01074840. Telapristone acetate (CDB-4124) is this type of compound, which is currently under clinical development in Phase III studies. According to the results published so far it is exceptionally promising for the treatment of uterine fibroma (a benign tumor of connective tissue).The ...

Compositions and methods for treating cns disorders

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein , A, R 1 , R 2 , and R 3 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, e.g., for treating a subject suffering from a disease or disorder described herein.

PROCESS FOR PREPARATION OF SULFONYL CARBAMATE BILE ACID DERIVATIVES

The present invention relates to processes for preparing compounds of Formula (I) and Formula (II): 118-. (canceled)22. The process of claim 19 , wherein Ris imidazol-1-yl claim 19 , MeO— claim 19 , EtO— or PhO—.24. The process of claim 23 , wherein the compound of Formula 15E is compound 15C wherein Ris phenyl.26. The process of claim 25 , wherein the compound of Formula 15E is compound 15C wherein Ris phenyl.27. The process of claim 19 , wherein PG is tert-butyl dimethylsilyl.28. The process of claim 19 , wherein step (1) is carried out in an aprotic solvent.29. The process of claim 28 , wherein the aprotic solvent is tetrahydrofuran claim 28 , dichloromethane or toluene.30. The process of claim 19 , wherein the base is trimethylamine or diisopropylethylamine. This application is a continuation application of U.S. application Ser. No. 15/948,370, filed on Apr. 9, 2018, which claims the benefit of U.S. Provisional Application No. 62/483,044, filed on Apr. 7, 2017. The entire teachings of the above applications are incorporated herein by reference.The present invention relates to processes and intermediates useful in the preparation of biologically active molecules useful as FXR or TGR5 modulators, especially relates to bile acid derivatives and methods for their preparation and use.Farnesoid X Receptor (FXR) is an orphan nuclear receptor initially identified from a rat liver cDNA library (BM. Forman, et al., 1995, 81(5), 687-693) that is most closely related to the insect ecdysone receptor. FXR is a member of the nuclear receptor family of ligand-activated transcription factors that includes receptors for the steroid, retinoid, and thyroid hormones (DJ. Mangelsdorf, et al., 1995, 83(6), 841-850). The relevant physiological ligands of FXR are bile acids (D. Parks et al., 1999, 284(5418), 1362-1365). The most potent one is chenodeoxycholic acid (CDCA), which regulates the expression of several genes that participate in bile acid homeostasis. Farnesol and derivatives, ...

PROCESS

An efficient and commercial phosphorylation process of a complex alcohol, such as secondary and tertiary alcohols, with POat high temperatures, and a product obtained by the process.

Conjugated Neuroactive Steroid Compositions And Methods Of Use

The present disclosure provides modified neuroactive steroids. The modified neuroactive steroids may comprise, consist of or consist essentially of a therapeutic agent and/or a modifying moiety. The modified neuroactive steroid can have modified characteristics as compared to native neuroactive steroids that do not include a modifying moiety and/or therapeutic agent. The modified neuroactive steroid may be, for example, modified pregnenolone, pregnenolone metabolites, allopregnanolone, and/or allopregnanolone metabolites. The modified neuroactive steroids can be used to treat, prevent and/or ameliorating a phenotypic state of interest in a subject.

PRO-DRUG FORMING COMPOUNDS

Various prodrug compounds having the general structure: Active agent-(acid)-(linker)-SONRRare described herein. Compounds having this general structure were shown to be more orally active than the unmodified parent molecule. 140-. (canceled)43. The compound of claim 41 , wherein the active agent is testosterone.44. The compound of claim 41 , wherein the active agent is 7α claim 41 , 11β-dimethyl-estra-4 claim 41 , 9-dien-17β-ol.45. The compound of claim 41 , wherein the active agent is estradiol.46. The compound of claim 41 , wherein the active agent is estriol.47. The compound of claim 41 , wherein the active ingredient is trimesgestone.48. The compound of claim 41 , wherein Ris alkyl.49. The compound of claim 41 , wherein Ris H; Y and X are H; and Rand Rare H.50. The compound of claim 41 , wherein Ris isopropyl.51. The compound of claim 41 , wherein Ris methyl.52. The compound of claim 41 , wherein hAr is thiophene claim 41 , pyridine claim 41 , isoxazole claim 41 , phthalimide claim 41 , pyrazole claim 41 , indole claim 41 , or furan.53. The compound of claim 41 , wherein hAr is pyridine or furan.55. A pharmaceutical composition comprising a compound as described in and one or more pharmaceutically acceptable carriers.58. The compound of claim 56 , wherein Ar is naphthyl claim 56 , biphenyl claim 56 , diphenylmethyl claim 56 , or 2 claim 56 ,2-diphenyl-1-ethyl. The present application is a continuation of U.S. patent application Ser. No. 14/329,322, filed Jul. 11, 2014, which claims priority to U.S. Provisional Application Ser. No. 61/844,985 entitled “Pro-Drug Forming Compounds” filed Jul. 11, 2013, both of which are incorporated herein by reference in its entirety.The invention generally relates to derivatives of biologically active molecules which show a higher oral bioavailability and therefore higher biological activity than the original biologically active drug.Many endogenic substances, natural products and synthetic substances with therapeutically useful ...

Prodrugs of 17.BETA.-HSD1-inhibitors

The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof wherein R1 to R4 are as defined in the claims. The invention further relates to their use as inhibitors of 17β-HSD1 and in treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of the 17β-HSD1 enzyme and/or requiring the lowering of the endogenous estradiol concentration. The present invention also relates to the preparation of the aforementioned compounds and to pharmaceutical compositions comprising as an active ingredient(s) one or more of the aforementioned compounds or pharmaceutically acceptable salts thereof.

Iodine(III)-Mediated Radiofluorination

A process for fluorination of aromatic compounds employing iodonium ylides and applicable to radiofluorination using 18 F is described. Processes, intermediates, reagents and radiolabelled compounds are described.

Method for preparing cholic acid compound

The present application belongs to the field of pharmaceutical chemistry, and relates to a method for preparing a cholic acid compound. Specifically, the present application provides a process for preparing a compound as shown in formula I, comprising subjecting a compound of formula 2 to an oxidization reaction to obtain a compound of formula 3; attaching a trimethylsilyl group to the compound of formula 3 to obtain a compound of formula 4; reacting the compound of formula 4 with acetaldehyde to obtain a compound of formula 5; subjecting the compound of formula 5 to a catalytic hydrogenation reaction to obtain a compound of formula 6; and converting a cyano group of the compound of formula 6 to a carboxyl group to give the compound of formula I. The preparation method has high yield, requires less purification operations, and is suitable for industrial application.

Neuroactive steroids and compositions thereof

Provided herein is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7a , R 11a , R 11b , R 12a , R 12b , R 16a , R 16b , R 19 , R 11a , R 22 , R X , R Y and n are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

17-Aryl and 17-heterocyclyl-14beta-5alpha-androstane, androstene and androstadiene derivatives active on the cardiovascular system, processes for their preparation and pharmaceutical compositions containing same

17B-Aryl and 17B-heterocyclyl-5-beta,14-beta-andostane derivatives active on the cardiovascular system, processes for their preparation and pharmaceutical compositions containing same

Cyclic hydrocarbons with an aminoalkyl sidechain

Provided are cyclic hydrocarbons of Formula I ##STR1## with an aminoalkyl sidechain that are useful for treating phospholipase A2 mediated conditions, diabetes, and obesity.

Cyclic hydrocarbons with an aminoalkyl sidechain

Les hydrocarbures cycliques de Formule (I) avec chaîne latérale aminoalkyle sont utiles pour le traitement d'états induits par la phospholipase A2, du diabète et de l'obésité. Cyclic hydrocarbons of Formula (I) with an aminoalkyl side chain are useful for the treatment of phospholipase A2 mediated conditions, diabetes and obesity.

Pseudonucleosides and pseudonucleotides and their polymers

STEROL ANALOGS AND USES THEREOF

The invention relates to compositions and methods for the preparation, manufacture, and therapeutic use of compositions comprising mRNA and a lipid nanoparticle comprising a compound of the invention and an ionizable lipid. 6. The compound of any one of to , wherein Lis absent.9. The compound of any one of to , wherein Lis absent.11. The compound of claim 10 , wherein m is 1 or 2.14. The compound of any one of to claim 10 , wherein Lis absent.17. The compound of any one of to claim 10 , wherein Ris optionally substituted C-Caryl.18. The compound of claim 17 , wherein Ris optionally substituted C-Caryl.19. The compound of claim 18 , wherein Ris optionally substituted C-Caryl.22. The compound of claim 21 , wherein n1 is 0 claim 21 , 1 claim 21 , or 2.24. The compound of any one of to claim 21 , wherein Ris optionally substituted C-Ccycloalkyl.26. The compound of claim 25 , wherein Ris claim 25 , whereinn0 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and{'sup': '8', 'sub': 1', '6, 'each Ris, independently, halo or optionally substituted C-Calkyl.'}28. The compound of claim 27 , wherein n0 is 0 claim 27 , 1 claim 27 , 2 claim 27 , 3 claim 27 , 4 claim 27 , 5 claim 27 , or 6.30. The compound of to claim 27 , wherein Ris optionally substituted C-Ccycloalkyl.31. The compound of claim 30 , wherein Ris optionally substituted C-Cmonocycloalkyl.34. The compound of claim 33 , wherein n2 is 0 or 1.36. The compound of claim 33 , wherein n3 is 0 or 1.38. The compound of claim 33 , wherein n4 is 0 claim 33 , 1 claim 33 , or 2.40. The compound of claim 33 , wherein n5 is 0 claim 33 , 1 claim 33 , 2 claim 33 , or 3.42. The compound of claim 33 , wherein n6 is 0 claim 33 , 1 claim 33 , 2 claim 33 , 3 claim 33 , or 4.44. The compound of claim 30 , wherein Ris optionally substituted C-Cpolycycloalkyl.46. The compound of any one of to claim 30 , wherein Ris optionally substituted C-Ccycloalkenyl.47. The compound of claim 46 , wherein Ris ...

BILE ACID DERIVATIVES AS FXR/TGR5 AGONISTS AND METHODS OF USE THEREOF

The present invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or combination thereof, 27.-. (canceled)9. A method for treating or preventing an FXR-mediated disease or condition in a subject in need thereof claim 1 , comprising administering to the subject a therapeutically effective amount of a compound according to .10. The method according to claim 9 , wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease claim 9 , gastrointestinal disease claim 9 , renal disease claim 9 , cardiovascular disease claim 9 , and metabolic disease.11. The method according to claim 10 , wherein the FXR-mediated disease or condition is a chronic liver disease selected from the group consisting of primary biliary cirrhosis (PBC) claim 10 , cerebrotendinous xanthomatosis (CTX) claim 10 , primary sclerosing cholangitis (PSC) claim 10 , drug induced cholestasis claim 10 , intrahepatic cholestasis of pregnancy claim 10 , parenteral nutrition associated cholestasis (PNAC) claim 10 , bacterial overgrowth or sepsis associated cholestasis claim 10 , autoimmune hepatitis claim 10 , chronic viral hepatitis claim 10 , alcoholic liver disease claim 10 , nonalcoholic fatty liver disease (NAFLD) claim 10 , nonalcoholic steatohepatitis (NASH) claim 10 , liver transplant associated graft versus host disease claim 10 , living donor transplant liver regeneration claim 10 , congenital hepatic fibrosis claim 10 , choledocholithiasis claim 10 , granulomatous liver disease claim 10 , intra- or extrahepatic malignancy claim 10 , Sjogren's syndrome claim 10 , Sarcoidosis claim 10 , Wilson's disease claim 10 , Gaucher's disease claim 10 , hemochromatosis claim 10 , and alpha 1-antitrypsin deficiency.12. The method according to claim 10 , wherein the FXR-mediated disease or condition is a renal disease selected from the group consisting of diabetic nephropathy claim 10 , focal ...

Preparation process for nucleoside derivative

Nucleoside derivative (I) having function of anti-bacteria and anti- cancer agent was prepared by condensation reaction of conpound (IV), which was produced by masking of functional groups in compound (III), and compound (V) and 2,4,6-triiso-propylbenzene sulfonylchloride (TPS) under anhydrous condition and then followed by removal of masking agent.

Новые производные бетулина, получение указанных соединений и их применение

1. Соединение формулы Iили его фармацевтически приемлемая соль или пролекарство, в которойRозначает С-Салканоил, карбоксиалканоил, карбоксиалкеноил, алкоксикарбонилалканоил, алкенилоксикарбонилалканоил, цианоалканоил, гидроксиалканоил, аминокарбонилалканоил, гидроксиаминокарбонилалканоил, моноалкиламинокарбонилалканоил, диалкиламинокарбонилалканоил, гетероарилалканоил, гетероциклилалканоил, гетероциклилкарбонилалканоил, гетероариламинокарбонилалканоил, гетероциклиламинокарбонилалканоил, цианоаминокарбонилалканоил, алкилсульфониламинокарбонилалканоил, арилсульфониламинокарбонилалканоил, сульфоаминокарбонилалканоил, фосфоноаминокарбонилалканоил, фосфоно, сульфо, фосфоноалканоил, сульфоалканоил, алкилсульфонилалканоил или алкилфосфоноалканоил;Rозначает формил, карбоксиалкенил, гетероциклил, гетероарил, -CHSR, -CHSOR, -CHSOR,,,,,,или;Rозначает водород, гидроксил, изопропенил, изопропил, 1'-гидроксиизопропил, 1'-галогенизопропил, 1'-тиоизопропил, 1'-трифторметилизопропил, 2'-гидроксиизопропил, 2'-галогенизопропил, 2'-тиоизопропил, 2'-трифторметилизопропил, 1'-гидроксиэтил, 1'-(алкокси)этил, 1'-(алкоксиалкокси)этил, 1'-(арилалкокси)этил, 1'-(арилкарбонилокси)этил, ацетил, 1'-(гидроксил)-1'-(гидроксиалкил)этил, (2'-оксо)тетрагидрооксазолил, 1',2'-эпоксиизопропил, 2'-галогенизопропенил, 2'-гидроксиизопропенил, 2'-аминоизопропенил, 2'-тиоизопропенил, 3'-галогенизопропенил, 3'-гидроксиизопропенил, 3'-аминоизопропенил, 3'-тиоизопропенил, 1'-алкоксиэтил, 1'-гидроксииминоэтил, 1'-алкоксиимино или;где Y означает -SRили -NRR;Rозначает водород или гидрокси;Rи Rнезависимо означают водород, алкил, алканоил, арилалкил, гетероарилалкил, арилсульфо ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß (19) RU (11) 2007 121 729 (13) A (51) ÌÏÊ C07J 3/00 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÇÀßÂÊÀ ÍÀ ÈÇÎÁÐÅÒÅÍÈÅ (21), (22) Çà âêà: 2007121729/04, 14. ...

一种间位取代联芳基型叔膦配体的制备方法

本发明公开一种间位取代联芳基型叔膦的制备方法，属于有机合成技术领域。采用的技术方案为：在钌催化剂、配体和碱存在下，将联芳基叔膦1与卤代物2有机溶剂中反应得到间位取代联芳基型叔膦配体3。本发明使用商业易得的钌催化剂、叔膦原料和卤代烷烃一步即可实现系列间位修饰联芳基叔膦化合物的合成，为该类化合物合成提供了简洁有效的途径。

신규한 수용성 베툴린 유도체, 이의 제조방법 및 이를 포함하는 주름 개선용 화장료 조성물

본 발명은 신규한 수용성 베툴린 유도체, 이의 제조방법 및 이를 포함하는 주름 개선용 화장료 조성물에 관한 것이다. 본 발명에 따른 수용성 베툴린 유도체는 화학적 안정성 및 용해도가 증가하여, 피부에 자극 없이 콜라겐 합성을 증가시켜 피부재생 및 주름 감소, 피부탄력 증대, 엘라스틴 분해 억제 등 피부노화 억제에 유용하게 사용될 수 있다. 베툴린, 폴리에틸렌글리콜, 유도체, 콜라겐, 주름

METHOD OF OBTAINING 3-CYCLOPENTYLOXY-7a-METHYL-3, 16a, 17cc - TRIOXYSTRAEN

17-aryl and 17-heterocyclyl-5α, 14β-androstane, androsten and androstadiene derivatives effective for cardiovascular diseases, methods for their preparation, and pharmaceutical compositions containing the same

본 발명은 심장병 및 고혈압과 같은 심장혈관계 질환 치료에 유효한 다음 일반식(Ⅰ)로 표시되는 17-아릴 및 17-헤테로사이클일-5α,14β-안드로스탄, 안드로스텐 및 안드로스타디엔 유도체와 이들의 제조방법 및 이를 합유하는 약제학적 조성물에 관한 것이다. 상기 식에서, 는 17번 위치 치환기의 α또는 β 배치를 나타내고, 는 단일 또는 이중결합을 나타내며, 4 또는 5번위치에 이중결합이 존재하지 않을때 5번위치의 수소는 α배치를, 3번위치의 가 이중결합을 나타낼때 Y는 산소원자 또는 구아니디노이미노기를, 그리고 3번위치의 가 단일결합을 나타낼때 Y는 하이드록시, OR 2 또는 SR 2 를 각각 나타내고 이 기는 α또는 β배치를 가질 수 있으며, R이 아릴고리이거나 포화 또는 불포화된 모노 또는 디헤테로고리를 나타내며 헤테로고리는 산소, 황, 질소원자중에서 선택된 하나 또는 그 이상의 헤테로원자를 포함하고 할로겐, 하이드록시, 하이드록시메틸, 알콕시, 옥소, 아미노, 알킬아미노, 디알킬아미노, 시아노, 니트로, 술폰아미도, C 1 -C 6 저급알킬기 또는 COR 3 중에서 하나 또는 그 이상의 치환체로 치환되거나 치환되지 않는 경우를 나타내고, R 1 은 수소원자, 메틸, 하이드록시 또는 NR 4 R 5 에 의해 치환된 에틸 또는 n-프로필기이고, R 2 는 수소원자, 메틸, 4급암모늄기이거나 OR 6 , NR 7 R 8 , CHO, C(NH)NH 2 , 구아니디노이미노 및 하이드록시기를 갖는 NR 7 R 8 중에서 하나 또는 그 이상이 선택되어 치환되지 않은 C 2 -C 6 알킬, C 3 -C 6 알케닐 또는 C 2 -C 6 아실기이고, R3는 수소원자, 하이드록시, C 1 -C 4 알콕시 또는 C 1 -C 4 알킬기이고, R 4 와 R 5 는 각각 수소원자, 메틸, NR 9 R 10 에 의해 치환되거나 치환되지 않은 C 2 -C 6 알킬기, 또는 R 4 와 R 5 는 질소원자를 갖고 있는 기로서 또다른 헤테로원자 즉, 산소, 황 또는 질소원자를 선택적으로 포함하는 치환되거나 치환되지 않은 또는 포화되거나 불포화된 5각형 또는 6각형의 헤테로고리를 이루고, R 6 은 수소원자, 메틸, NR 9 R 10 또는 하이드록시기를 갖는 NR 9 R 10 중에서 하나 또는 그 이상 치환되거나 치환되지 않은 C 2 -C 4 알킬기이고, R 7 과 R 8 은 각각 수소원자, 메틸, NR 9 N 10 또는 하이드록시기를 갖는 NR 9 N 10 중에서 하나 또는 그 이상 치환되거나 치환되지 않은 C 2 -C 6 알킬 또는 C 3 -C 6 알케닐기, 또는 R 7 과 R 8 은 질소원자를 갖고 있는 기로서 또다른 헤테로원자 즉, 산소, 황 또는 질소원자를 선택적으로 포함하는 치환되거나 치환되지 않은 또는 포화되거나 불포화된 5각형 또는 6각형의 헤테로고리, 또는 R 7 은 수소원자이고, R 8 은 C(NH)NH 2 이며, R 9 와 R 10 은 각각 수소원자, C 1 -C 6 알킬기 또는 R 9 와 R 10 은 질소원자를 갖고 있는 기로서 포화되거나 불포화된 5각형 또는 6각형 헤테로고리를 형성한다.

Chelating compounds, their complexes with paramagnetic metals

Compounds able to chelate bi- and trivalent paramagnetic metal ions, their chelated complexes with these metal ions and physiologically compatible salts thereof and therein magnetic resonance imaging.

Neuroactive steroids, compositions and their use

FIELD: pharmaceutics.SUBSTANCE: invention relates to a compound of Formula (II), in which R2ais methyl, ethyl, methoxy, trifluoromethoxy, cyclopropyloxy, C3-C6alkoxy, ethoxy, –OCH2CH2OCH3, –OCH2CH2OH, –CH(CH3)2, –OCH2CH(CH3)2or –OCH2CF3; and R2bis hydrogen. The invention also relates to individual compounds, to a pharmaceutical composition, to a method for inducing a sedative effect and/or anesthesia, to a method for treating disorders associated with gamma-aminobutyric acid (hereinafter – GABA) function, to a method for treating a convulsive seizure, to a method for treating epilepsy or an epileptic condition, to a method for treating depression.EFFECT: new compounds of Formula (II) are obtained, which have the properties of GABA modulators.Formula (II)11 cl, 12 dwg, 4 tbl, 36 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 754 534 C2 (51) МПК C07J 3/00 (2006.01) C07J 41/00 (2006.01) A61K 31/56 (2006.01) A61P 23/00 (2006.01) A61P 25/08 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК C07J 3/00 (2013.01); C07J 41/0094 (2013.01); A61K 31/56 (2013.01) (21)(22) Заявка: 2016105436, 18.07.2014 (24) Дата начала отсчета срока действия патента: Дата регистрации: 03.09.2021 (73) Патентообладатель(и): СЕЙДЖ ТЕРАПЬЮТИКС, ИНК. (US) 19.07.2013 US 61/856,592 (43) Дата публикации заявки: 24.08.2017 Бюл. № 24 (45) Опубликовано: 03.09.2021 Бюл. № 25 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 19.02.2016 US 2014/047246 (18.07.2014) C 2 C 2 (86) Заявка PCT: (56) Список документов, цитированных в отчете о поиске: DE 2330342 А1, 17.01.1974. US 3943124 A, 09.03.1976. DE 2700267 A1, 14.07.1977. G. H. Phillipps et al. "Water-soluble steroidal anaesthetics" Journal of Steroid Biochemistry, vol.11, 1979, 79-86, соед. 71, 74 табл. 2. A. K. Bandyopadhyaya et al. "Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of (см. прод.) (87) Публикация заявки PCT: WO 2015/010054 (22.01.2015) 2 ...

Neuroactive 19-alkoxy-17-substituted steroids and methods of treatment using same

FIELD: chemistry.SUBSTANCE: invention relates to a compound of formula (I-g) or a pharmaceutically acceptable salt thereof, where Rchosen from (C-Calkyl)-O, spirooxirane, cyano, =O, nitro, (C-Calkyl)C(O) and HO(C-Calkyl)C(O); Ris H; Ris H; Ris methyl; Ris H; - - - is an optional additional C-C bond providing a C=C bond between C-C, provided that, if present, Ris not =O or spirooxirane. Invention also relates to individual compounds, a method for inducing anesthesia, to a method for treating disorders associated with the GABA function..EFFECT: technical result: obtaining novel compounds of formula (I-g), which can be useful in the treatment of disorders associated with the GABA function.11 cl, 5 tbl РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (51) МПК C07J 1/00 (2006.01) C07J 5/00 (2006.01) C07J 7/00 (2006.01) C07J 9/00 (2006.01) C07J 13/00 (2006.01) C07J 21/00 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА C07J 41/00 (2006.01) ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ A61K 31/56 (2006.01) A61K 31/566 (2006.01) A61K 31/57 (2006.01) (12) (13) 2 663 665 C2 A61K 31/575 (2006.01) A61K 31/58 (2006.01) A61P 23/00 (2006.01) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК (21)(22) Заявка: 2015129546, 18.12.2013 (24) Дата начала отсчета срока действия патента: (73) Патентообладатель(и): ВАШИНГТОН ЮНИВЕРСИТИ (US), СЕЙДЖ ТЕРАПЬЮТИКС, ИНК. (US) Дата регистрации: 08.08.2018 Приоритет(ы): (30) Конвенционный приоритет: (56) Список документов, цитированных в отчете о поиске: Jan-Ake Gustafsson et al. "Steroid 18.12.2012 US 61/738,822 (45) Опубликовано: 08.08.2018 Бюл. № 22 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 20.07.2015 R U 2 6 6 3 6 6 5 (86) Заявка PCT: US 2013/076214 (18.12.2013) (87) Публикация заявки PCT: WO 2014/100228 (26.06.2014) Адрес для переписки: 129090, Москва, ул. Б. Спасская, 25, стр. 3, ООО "Юридическая фирма Городисский и Партнеры" (54) НЕЙРОАКТИВНЫЕ 19-АЛКОКСИ-17-ЗАМЕЩЕННЫЕ СТЕРОИДЫ И СПОСОБЫ ЛЕЧЕНИЯ С ИХ ПРИМЕНЕНИЕМ (57) Реферат: Изобретение относится к соединению H; - - - означает ...

Corticosteroid-beta-agonist-muscarinic antagonist compounds for use in therapy

The instant invention relates to new chemical entities which comprise corticosteroids, phosphorylated β-agonists and muscarinic (M3) antagonists for use in therapy and compositions comprising and processes for preparing the same.

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

본 개시내용은 일반적으로, 예를 들어 마취제로서 및/또는 GABA 기능 및 활성과 관련된 장애의 치료에서 사용하기 위한 본원에 언급된 바와 같은 신경활성 19-알콕시-17-치환된 스테로이드 및 그의 제약상 허용되는 염에 관한 것이다. 본 개시내용은 추가로 이러한 화합물을 포함하는 제약 조성물에 관한 것이다. The present disclosure generally relates to neuroactive 19-alkoxy-17-substituted steroids and pharmaceutically acceptable thereof as mentioned herein, for example, for use as an anesthetic and / or for the treatment of disorders associated with GABA function and activity. It is about salt becoming. The present disclosure further relates to pharmaceutical compositions comprising such compounds.

METHOD FOR PREPARING 7α-METHYLSTEROIDS, COMPOUND

FIELD: organic chemistry, steroids, chemical technology. SUBSTANCE: invention relates to an improved method for synthesis of 7α-methylsteroids of the general formula (I) wherein R1 means hydrogen atom (-H), -CH 3 or -C≡CH; R2 means -(CH 2 ) n OH wherein n = 0, 1 or 2. Method involves using copper (Cu(II) acetate or chloride preferably), 1,6-coupled addition of Grignard reagent of the formula CH 3 MgX wherein X means halogen atom to 4,6-unsaturated 3-ketosteroid of the formula (II) wherein r1 and R2 have above given values and wherein hydroxy-group of steroid of the formula (II) is protected by trialkylsilyl group followed by its treatment with Grignard reagent and removal of a protective group. Method enhances stereoselectivity by the yield of 7α-isomer. EFFECT: improved method of synthesis. 18 cl, 3 ex ÐÎÑÑÈÉÑÊÀß ÔÅÄÅÐÀÖÈß RU (19) (11) 2 305 105 (13) C2 (51) ÌÏÊ C07J 51/00 (2006.01) C07J 1/00 (2006.01) C07J 5/00 (2006.01) ÔÅÄÅÐÀËÜÍÀß ÑËÓÆÁÀ ÏÎ ÈÍÒÅËËÅÊÒÓÀËÜÍÎÉ ÑÎÁÑÒÂÅÍÍÎÑÒÈ, ÏÀÒÅÍÒÀÌ È ÒÎÂÀÐÍÛÌ ÇÍÀÊÀÌ (12) ÎÏÈÑÀÍÈÅ ÈÇÎÁÐÅÒÅÍÈß Ê ÏÀÒÅÍÒÓ (21), (22) Çà âêà: 2004125580/04, 14.01.2003 (30) Êîíâåíöèîííûé ïðèîðèòåò: 21.01.2002 (ïï.1-18) EP 02075230.9 (73) Ïàòåíòîîáëàäàòåëü(è): Í.Â.ÎÐÃÀÍÎÍ (NL) (43) Äàòà ïóáëèêàöèè çà âêè: 27.01.2006 R U (24) Äàòà íà÷àëà îòñ÷åòà ñðîêà äåéñòâè ïàòåíòà: 14.01.2003 (72) Àâòîð(û): ÑÒÓËÂÈÍÄÅÐ É. (NL), ÎÑÒÅÍÄÎÐÔ Ì. (NL), ÁÞÃÅÍÞÌ Âàí Ï.À.Ì. (NL) (45) Îïóáëèêîâàíî: 27.08.2007 Áþë. ¹ 24 2 3 0 5 1 0 5 (56) Ñïèñîê äîêóìåíòîâ, öèòèðîâàííûõ â îò÷åòå î ïîèñêå: US 3341557 À, 12.09.1967. WO 0105806 À, 25.01.2001. (85) Äàòà ïåðåâîäà çà âêè PCT íà íàöèîíàëüíóþ ôàçó: 23.08.2004 2 3 0 5 1 0 5 R U (87) Ïóáëèêàöè PCT: WO 03/059931 (24.07.2003) C 2 C 2 (86) Çà âêà PCT: EP 03/00339 (14.01.2003) Àäðåñ äë ïåðåïèñêè: 129010, Ìîñêâà, óë. Á.Ñïàññêà , 25, ñòð.3, ÎÎÎ "Þðèäè÷åñêà ôèðìà Ãîðîäèññêèé è Ïàðòíåðû", ïàò.ïîâ. Å.Å.Íàçèíîé, ðåã. ¹ 517 (54) ÑÏÎÑÎÁ ÏÎËÓ×ÅÍÈß 7α-ÌÅÒÈËÑÒÅÐÎÈÄÎÂ, ÑÎÅÄÈÍÅÍÈÅ (57) Ðåôåðàò: Èçîáðåòåíèå îòíîñèòñ ê óëó÷øåííîìó ñïîñîáó ïîëó÷åíè 7 ...

The method of obtaining 3-cyclopentyloxy-methyl-3,16, 17-trioxyestratriene

Steroid derivatives

A steroid derivative of the formula: ST--A--X--R.sup.1 wherein ST is a 7α-linked steroid nucleus of the general formula: ##STR1## wherein the double bond(s) between carbon atoms 6 and 7 and/or carbon atoms 8 and 9 are optional; wherein the aromatic ring A may optionally bear one or two halogen or alkyl substituents; wherein R 3 is hydrogen, alkyl, or acyl; wherein R 16 is hydrogen, alkyl or hydroxy; wherein either R 17 is hydroxy or acyloxy and R 27 is hydrogen, alkyl, alkenyl or alkynyl, or R 17 and R 27 together form oxo (═O); wherein R 18 is alkyl; wherein A is alkylene, alkenylene or alkynylene optionally fluorinated and optionally interrupted by --O--, --S--, --SO--, --SO 2 --, --CO--, --NR--, --NRCO--, --CONR--, --COO--, --OCO-- or phenylene, wherein R is hydrogen or alkyl; wherein R 1 is hydrogen, alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, or dialkylaminoalkyl, or R 1 is joined to R 2 as defined below; and wherein X is --CONR 2 --, --CSNR 2 --, --NR 12 CO--, --NR 12 CS--, --NR 12 CONR 2 --, ##STR2## --SO 2 NR 2 -- or --CO--; or, when R 1 is not hydrogen, is --O--, --NR 2 --, --(NO)R 2 --, --(PO)R 2 --, --NR 12 COO--; --NR 12 SO 2 --, --S--, --SO-- or --SO 2 --; wherein R 2 is hydrogen or alkyl or R 1 and R 2 together form alkylene or halogenoalkylene; wherein R 12 is hydrogen or alkyl and wherein R 22 is hydrogen, cyano or nitro; or a salt thereof when appropriate.

Steroid derivatives

Compounds for trans-membrane delivery of molecules

FIELD: medicine. SUBSTANCE: invention relates to biochemistry and medicine. Disclosed is a compound for use in transmembrane drug delivery, having structure (VI), (VII), (VIIa), (VIII), (IX) or (IXa), as given in formula. Molecule structure creates a vector system which promotes movement of the molecule within the phospholipid membrane from the membrane/water interface to the membrane core. EFFECT: compounds can be used in medical practice, for example in delivery of natural or modified RNA or DNA, low interfering RNA (siRNA), antisense oligonucleotide (ASO) or therapeutic protein, CRISPR protein, daiser substrate containing a double stranded RNA of 25–30 nucleotides, which includes a sequence of the targeting gene for side hair, or any combination thereof through biological membranes for treating diseases. 3 cl, 5 dwg, 7 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 703 416 C2 (51) МПК A61K 31/567 (2006.01) A61K 48/00 (2006.01) A61K 47/54 (2017.01) C07J 31/00 (2006.01) C07J 41/00 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК A61K 31/567 (2019.05); A61K 47/554 (2019.05); C07J 31/006 (2019.05); C07J 41/0094 (2019.05); C07J 51/00 (2019.05) (21)(22) Заявка: 2016142510, 29.03.2015 29.03.2015 (73) Патентообладатель(и): ЭПОСЕНС ЛТД. (IL) Дата регистрации: 16.10.2019 28.03.2014 US 61/971,548; 13.04.2014 US 61/978,903; 25.05.2014 US 62/002,870; 06.06.2014 US 62/008,509; 14.12.2014 US 62/091,551 (43) Дата публикации заявки: 03.05.2018 Бюл. № 13 2 7 0 3 4 1 6 Приоритет(ы): (30) Конвенционный приоритет: (56) Список документов, цитированных в отчете о поиске: US 2006167223 A1, 27.07.2006. YUE XUYI et al. "Synthesis and characterization of fluorinated conjugates of albumin", JOURNAL OF FLUORINE CHEMISTRY, 2013, v.152, p.173181, DOI: 10.1016/J.JFLUCHEM.2013.01.026. WO 98/50041 A1, 12.11.1998. US 6028066 A, 22.02.2000. WO 2005/077968 A2, 25.08.2005. US 2011123457 A1, 26.05.2011. BELLUCCI M.C. et al. (см. прод.) R U (24) ...