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N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof

A technology of propionamide and compound, applied in the field of medicinal chemistry, can solve problems such as liver toxicity, gastrointestinal discomfort, blurred vision, etc.

Inactive Publication Date: 2008-08-27
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many problems to be solved in the anti-androgen drugs currently on the market: First, patients will experience various side effects after taking them, such as gastrointestinal discomfort, nausea, vomiting, insomnia, fatigue, headache, anxiety, blurred vision, loss of libido and Liver toxicity, etc.; secondly, patients with benign prostatic hyperplasia / prostate cancer will experience "anti-androgen hypofunction syndrome" after taking a single anti-androgen drug, which is manifested as a rapid increase in the originally suppressed prostate-specific antigen level , Tumor volume increases, can only stop taking the drug or switch to other anti-androgen drugs

Method used

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  • N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof
  • N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof
  • N-aryl-beta-aryl amidine-propionamide compounds, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of embodiment 1N-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-propionamide

[0028]

[0029] Add 1.9 g (5 mmol) of 3-phenyl-3-(4-chloroanilino)-1-(4-nitrophenyl)-1-propanone and 20 ml of ethanol into the reaction flask, stir well, then add hydrochloric acid in sequence 0.56 grams (8 mmol) of hydroxylamine, 1.1 grams (8 mmol) of potassium carbonate and 10 ml of deionized water were heated to reflux and stirred for 5 hours. After the reaction was completed, stand at room temperature, filter the precipitated solid, and recrystallize with ethanol / water to obtain 1- (4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone oxime yellow crystal 1.41 g, yield 70.91%; 1 H-NMR (400MHz, CDCl 3 )δ: 8.19(d, 2H, J=9.2Hz), 7.66(d, 2H, J=9.2Hz), 7.36~7.21(m, 5H), 7.00(d, 2H, J=8.8Hz), 6.39( d, 2H, J=8.8Hz), 4.67(t, 1H, J=5.2Hz), 3.67~3.58(m, 1H), 3.08(dd, 1H, J 1 =13.2Hz,J 2 =5.2Hz); ESI-MS m / z: 418.8 (M + +Na).

[0030] In a dry round-bottomed flask, add 4.5 mmo...

Embodiment 2

[0031] The preparation of embodiment 2N-(4-methylphenyl)-3-(2-thienyl)-3-(4-chloroanilino)-propionamide

[0032]

[0033] The operation process is the same as in Example 1, except that 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone is used with 1-(4-methylphenyl)- 3-(2-thienyl)-3-(4-chloroanilino)-1-propanone was substituted to obtain a light yellow powder solid with a yield of 42.6%; mp161~163°C; 1 H-NMR (400MHz, CDCl 3 )δ: 7.41(s, 1H), 7.25(d, 4H, J=8.8Hz), 7.09(d, 2H, J=8.8Hz), 7.20~6.92(m, 3H), 6.62(d, 2H, J =8.8Hz), 5.13(t, 1H, J=6Hz), 2.94(d, 2H, J=6Hz), 2.30(s, 3H); IR (KBr tablet): v NH 3406.51,v NH 3356.05,v ＝CH 3069.80, v C-H 2918.47, v. C＝O 1661.17, beta NH 1597.01, v. C＝C 1503.03, delta CH2 1437.70, # C＝C 896.43-680.00; ESI-MS m / z: 371 (M + +H), 393(M + +Na).

Embodiment 3

[0034] The preparation of embodiment 3N-(4-methylphenyl) 3-phenyl-3-(4-chloroanilino)-propionamide

[0035]

[0036] The operation process is the same as in Example 1, except that 1-(4-nitrophenyl)-3-phenyl-3-(4-chloroanilino)-1-acetone is used with 1-(4-methylphenyl)- Substituted by 3-phenyl-3-(4-chloroanilino)-1-propanone, a white powder solid was obtained with a yield of 21.2%; mp176~178°C; 1 H-NMR (400MHz, CDCl 3 )δ: 7.37~7.25(m, 5H), 7.19(d, 2H, J=8.0Hz), 7.08(d, 2H, J=8.4Hz), 7.04(d, 2H, J=9.2Hz), 6.53( d, 2H, J=8.8Hz), 4.81(t, 2H, J=5.2Hz), 2.86(m, 2H), 2.29(s, 3H); IR (KBr tablet): v NH 3409.49, v NH 3247.84, v ＝CH 3062.83, v C-H 2922.36, v C＝O 1655.34, beta NH 1599.75, v. C＝C 1498.86, delta CH2 1453.34, # C＝C 813.88-676.65; ESI-MS m / z: 365 (M + +H), 388(M + +Na).

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Abstract

The invention relates to a non-steroidal androgen receptor modulator containing N-aryl-beta-aromatic amine-propionamide compound (I) and a relative preparation method. The invention also relates to a drug compound containing the N-aryl-beta-aromatic amine-propionamide compound (I). The N-aryl-beta-aromatic amine-propionamide compound (I) has androgen receptor antagonistic activity, therefore, the compound can be used to prepare the non-steroidal drug for preventing or / treating prostatic hyperplasia, prostate cancer, hirsutism, serious androgen dependence alopecia and acne or the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to N-aryl-β-arylamino-propionamide compounds (I) and preparation thereof [0002] Preparation method, pharmaceutical composition and in the preparation of prevention or / and treatment of benign prostatic hyperplasia, prostate cancer, women's hirsutism, [0003] Use in medicine for symptoms or diseases such as severe androgen-dependent alopecia or acne. [0004] [0005] (where R 1 ,R 2 ,R 3 ,R 4 Indicates H, halogen, C 1 ~C 12 Alkyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 12 Aryl, C 1 ~C 12 Alkoxy, C 6 ~C 12 Aryloxy, C 1 ~C 12 Alkylthio, C 6 ~C 12 Arylthio, nitro, cyano, carboxyl, hydroxyl, CF 3 、NR 5 R 6 ; 5 ,R 6 means H, C 1 ~C 12 Alkyl, C 6 ~C 12 Aryl; R 1 ,R 2 ,R 3 ,R 4 Can be in any possible position of the benzene ring; R 1 ,R 2 ,R 3 ,R 4 Can be the same or different; Ar represents phenyl, substituted phenyl, furyl, substituted furyl, thienyl, substitut...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07D333/24C07D307/54A61K31/167A61K31/341A61K31/381A61P13/08A61P35/00A61P17/00
Inventor 邓勇向玲沈怡周黎丽
Owner SICHUAN UNIV
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