256955-84-7

Basic information

• Product Name: 3alpha-Hydroxy-21-(1-imidazolyl)-3-(methoxymethyl)-5alpha-pregnan-20-one
• Synonyms: Co-134444
• CAS NO: 256955-84-7
• Molecular Formula: C₂₆H₄₀N₂O₃
• Molecular Weight: 428.6203
• Mol File: 256955-84-7.mol

Chemical Properties

• CAS DataBase Reference: 3alpha-Hydroxy-21-(1-imidazolyl)-3-(methoxymethyl)-5alpha-pregnan-20-one(CAS DataBase Reference)
• NIST Chemistry Reference: 3alpha-Hydroxy-21-(1-imidazolyl)-3-(methoxymethyl)-5alpha-pregnan-20-one(256955-84-7)
• EPA Substance Registry System: 3alpha-Hydroxy-21-(1-imidazolyl)-3-(methoxymethyl)-5alpha-pregnan-20-one(256955-84-7)

Safety Data

• Hazardous Substances Data: 256955-84-7(Hazardous Substances Data)

Upstream product

• 203786-30-5 2-bromo-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone 
• 288-32-4 1H-imidazole 
• 566-65-4 dihydroprogesterone 
• 145-13-1 Pregnenolone 
• 516-55-2 isopregnanolone 
• 148256-45-5 1-((2’R,8R,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2’-oxiran]-17-yl)ethanone 
• 162882-64-6 3α-hydroxy-3β-methoxymethyl-5α,17β-pregnan-20-one 
• 55986-39-5 lithium salt of imidazole 
• 4439-90-1 lithium pyrrolidide 
• 917-54-4 methyllithium 
• 4442-11-9 lithium piperidide 
• 109-72-8 n-butyllithium 

Relevant articles and documents

Synthesis of 3α-hydroxy-21-(1′-imidazolyl)-3β-methoxyl- methyl-5α-pregnan-20-one via lithium imidazole with 17α- acetylbromopregnanone

The synthesis of biologically active 3α-hydroxyl-21-(1′- imidazolyl)-3β-methoxymethyl-5α-pregnan-20-one (11) was accomplished in six steps. The key steps were the improvement of stereoselectivity for acetyl isomers in C-17 and the introduction of imidazole into the core structure by use of lithium imidazole. This latter key step provided the desired product 11 in 82% yield without the formation of 1,3-disubstituted imidazolium salt as impurity, which is generally observed in traditional method.

Synthesis and antiproliferative activity of 3α-hydroxyl-3β-methoxymethyl-5α-pregnan-20-one with a C-21 hydrophilic substituent

A series of 3α-hydroxyl-3β-methoxymethyl-5α-pregnan-20-ones 7-15 possessing C-21 hydrophilic substituents were synthesized from the corresponding C21-bromo steroid 6 in 24%-89% yields. The hydrophilic groups include amino group from Delépine reaction, hydroxyl group from the hydrolysis by cesium formate in anhydrous MeOH, and amino acids, hydrazinecarboxamide, piperazine, and imidazolyl from nucleophilic substitution. Acylation and O-glycosylation of the resulting C-21 hydroxylsteroid also afforded the corresponding acylated and glycosylated products in excellent yield (77%-89%). Among the compounds, aminosteroid 7 and piperazinyl steroid 14 were most potent against the proliferation of human prostate cancer PC-3 cells with IC50 values of 42 and 82?μmol?L?1, respectively.

The mechanism investigation in substitution of 21-bromo-3α-hydroxyl-3β-methoxymethyl-5α-pregnan-20-one with nucleophiles

A mechanistic study on the nucleophilic substitution of a strictly geometric 21-bromo-3α-hydroxyl-3β-methoxymethyl-5α-pregnan-20-one was described. Reaction of the α-bromoketone with excess lithium imidazole followed by the addition of extra bases including n-butyllithium, methyllithium, lithium piperidine, and lithium pyrrolidine provided unexpected α-nucleophilic carbonyl adducts that derived from strong base. Data from HPLC and proton NMR suggested an epoxide as the intermediate. Two possible reaction pathways were proposed for the nucleophilic substitution reaction. One pathway is the normal SN2 substitution reaction, directly provided the imidazoly product without the formation of the unexpected α-substituted products. The other pathway went through an epoxide intermediate, in which imidazole anion or the strong bases added would attack from the less hindered site of the epoxide to give the substitution product. {A figure is presented}.

ORGANIC COMPOUNDS

The invention relates to particular prodrugs and analogs of (3α,5α)-3-hydroxy-21-(1H-imidazol-1-yl)-3-methoxymethyl)-pregnan-20-one, in free or pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use as sedatives, hypnotics, anxiolytics, and/or anesthetics, and methods for treatment of depression, anxiety, insomnia, epilepsy, and other central nervous system disorders, as well as to combinations with other agents.

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein (II), A, R1, R2, R3a, R4a, R4b, R5, R7a, and R7b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

An efficient and convenient method for synthesis of 1-substituted imidazoles

A convenient method for the synthesis 1-substituted imidazoles was developed by the reaction of α-bromoketone with lithium imidazolide. The reaction gave the desired products in improved yields without the formation of 1,3-disubstituted imidazolium salts. Treatment of bromoacetaldehyde ethylene acetal, 2-(bromomethyl)tetrahydro-2H-pyran, and N-(bromomethyl)phthalimide with lithium imidazolide also gave the corresponding 1-substituted imidazole in good to excellent yields. Direct reaction of α-bromoketone with imidazole as control experiment afforded undesired 1,3-disubstituted imidazolium salts with the desired mono-substituted products.

3Alpha-hydroxy-3beta-methoxymethyl-substituted steroids and the use thereof

This invention relates to compounds having the Formula I: or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R1 is H or methyl; R2 is 5α- or 5β-H; R3 is an optionally substituted N-attached heteroaryl group or a group —X—R4; R4 is an optionally substituted carbon-attached heteroaryl group; and X is O, S or N. The invention also is directed to the use of 3α-hydroxy-3β-methoxymethyl-substituted steroids as sedative/hypnotics and for inducing anesthesia.

Response-rate suppression in operant paradigm as predictor of soporific potency in rats and identification of three novel sedative-hypnotic neuroactive steroids

Novel neuroactive steroids were evaluated for their effects on operant responding, rotorod motor performance, and electroencephalogram recording in rats. Co 134444, Co 177843, and Co 127501 were compared with the prototypical γ-aminobutyric acid(A)-positive allosteric modulators triazolam, zolpidem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produced a dose-related decrease in response rates under a variable-interval 2-min schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant increases in nonrapid eye movement sleep in this experiment or have been previously reported to do so. Co 134444, Co 177843, and Co 127501 increased nonrapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant responding than they were at increasing ataxia. Furthermore, the potency of compounds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identification of the novel orally active neuroactive steroids Co 134444, Co 177843, and Co 127501.