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Steroid compound with 5-alpha reductase active and preparation process thereof

A technology of steroidal compounds and inhibitory activity, which is applied in the field of medicinal chemistry and can solve the problems of reproductive system toxic side effects and slow onset of action

Inactive Publication Date: 2007-12-19
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs are all slow in action and have toxic side effects on the reproductive system, so a new 5α-reductase inhibitor is still the direction people are looking for

Method used

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  • Steroid compound with 5-alpha reductase active and preparation process thereof
  • Steroid compound with 5-alpha reductase active and preparation process thereof
  • Steroid compound with 5-alpha reductase active and preparation process thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: 3-carbonyl-4-ethyl-4-aza-5-androstene-17-oxime N-O-ethyl ether

[0025] Step 1: Preparation of 5,17-carbonyl-A-anorca-3,5-cleavage-androstane-3-carboxylic acid:

[0026] Dissolve androst-4-ene-3,17-dione (10.0g, 35.0mmol) in tert-butanol (350mL), add anhydrous sodium carbonate solution (23g, 20%) to it under stirring, and raise the temperature To 90°C, slowly add a solution of sodium periodate (41.2g, 0.2mol) and potassium permanganate (0.33g, 2.1mmol) dissolved in water (250mL) dropwise, and the dropwise is completed within about 1.5h. After the dropwise addition, reflux for 5h. Cool to room temperature, filter, wash the filter cake with water (50mL×4), distill off most of the tert-butanol from the filtrate under reduced pressure, adjust the pH to ≈1.5 with dilute hydrochloric acid, extract with dichloromethane (100mL×3), and dry over anhydrous sodium sulfate , filtered, and concentrated under reduced pressure to obtain a light yellow paste. Column chroma...

Embodiment 2

[0033] Example 2: Preparation of 3-carbonyl-4-benzyl-4-aza-5-androstene-17-oxime N-O-benzyl ether:

[0034] Step 1, step 2, and step 3 of this embodiment are the same as in embodiment 1.

[0035] Step 4: Preparation of 3-carbonyl-4-benzyl-4-aza-5-androstene-17-oxime N-O-benzyl ether:

[0036] 3-Carbonyl-4-aza-5-androstene-17-oxime (0.5g, 1.66mmol) and potassium hydroxide (0.38g, 6.64mmol) were added to N,N-dimethylformamide (60mL ), stirred and dissolved, added dropwise benzyl chloride (1.2mL, 9.93mmol), and reacted at 70°C for 12h. The reaction solution was cooled to room temperature, added with water (100 mL), and extracted with dichloromethane (50 mL×3). The organic phase was washed with distilled water (50 mL×10), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (methanol / dichloromethane=1 / 99) to obtain 0.46 g of a white solid. 1 H NMR (400MHz, CDCl 3 )δ: 0.93(s, 3H, 18-C H 3 ), 1.08(s, 3H, 19-...

Embodiment 3

[0037] Example 3: Preparation of 3-carbonyl-4-isobutyl-4-aza-5-androstene-17-oxime N-O-isobutyl ether:

[0038] Step 1, step 2, and step 3 of this embodiment are the same as in embodiment 1.

[0039] Step 4: Preparation of 3-carbonyl-4-isobutyl-4-aza-5-androstene-17-oxime N-O-isobutyl ether:

[0040] 3-Carbonyl-4-aza-5-androstene-17-oxime (0.5g, 1.66mmol) and potassium hydroxide (0.23g, 4.1mmol) were added to N,N-dimethylformamide (50mL ), stirred and dissolved, added isoiodobutane (1.52mL, 9.93mmol) dropwise, and reacted at 30°C for 20h. The reaction solution was cooled to room temperature, added with water (100 mL), and extracted with dichloromethane (50 mL×3). The organic phase was washed with distilled water (50 mL×10), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (methanol / dichloromethane=1 / 99) to obtain 0.04 g of a white solid. 1 H NMR (400MHz, CDCl 3 )δ: 0.88(s, 3H, 18-C H 3 ), 0.90(s, 3...

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Abstract

The invention discloses a structure of steroid class compound that has 5alpha-reductase to restrain activity that belongs to medicine chemical field. R1 is hydrogen, alkyl and benzyl of C1-C5; R2 is alkyl of C1-C8, alkanoyl of C1-C8, one from benzyl, substituted benzyl, benzoyl, and phenylacetyl and substituted benzoyl. It uses androstenedione as raw material, oxidizing open loop to form 5, 17-carbonyl-A-decarbonization-3, 5-cracking-androstane-3-carboxylic acid and taking reaction with oximation to form intermediate that would react with halogenated hydrocarbon or acyl chloride to gain the product. The advantages of the invention are that it uses common raw material, simple technology, has the activity restraining function to 5alpha-reductase.

Description

technical field [0001] The invention relates to a structure of a steroid compound with 5α-reductase inhibitory activity and a preparation method thereof, and the technology belongs to the field of medicinal chemistry. Background technique [0002] Steroid 5α reductase is a membrane protein located on target cell microsomes, which relies on reducing coenzyme II (NADPH) as a hydrogen donor to catalyze the reduction of a series of steroid substrates such as testosterone, 17α-hydroxyprogesterone, androstenedione, etc. . 5α-reductase plays a key role in the process of catalyzing the reduction of the androgen testosterone [Testosterone(T)] into the more active androgen dihydrotestosterone [dihydrotestos-terone(DHT)]. It can reduce the 4,5-position unsaturated double bond of testosterone, and keep the hydrogen on the C-5 position in α configuration. [0003] T and its reduced metabolite DHT are essential male hormones that maintain male dominant characteristics and sexual maturit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00C07J75/00
Inventor 刘东志杨雄文周雪琴李爱军
Owner TIANJIN UNIV
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