Aryl [a] indole [2,3-g] quinolizine compound as well as preparation method, pharmaceutical composition and application thereof

A compound, 3-g technology, applied in the field of medicinal chemistry and chemotherapy, can solve problems such as poor effect, inability to significantly reduce prostate volume, and lack of subtype selectivity

Active Publication Date: 2014-03-26
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Application Information

AI Technical Summary

Problems solved by technology

where α 1 -Adrenoceptor antagonists can provide rapid relief of symptoms, but cannot significantly reduce the size of the prostate and early development of these drugs often have serious adverse reactions
5α-reductase inhibitors can reduce the size of the prostate gland and fundamentally relieve symptoms, but they are less effective and slo

Method used

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  • Aryl [a] indole [2,3-g] quinolizine compound as well as preparation method, pharmaceutical composition and application thereof
  • Aryl [a] indole [2,3-g] quinolizine compound as well as preparation method, pharmaceutical composition and application thereof
  • Aryl [a] indole [2,3-g] quinolizine compound as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1: (S)-2,3-methylenedioxy-5,8,14,14a-tetrahydro-6H-benzo[a]indole[2,3-g]quinoquinazine (A001) (prepared by reaction scheme 1)

[0134] 1.1 Preparation of N-3,4-methylenedioxyphenethylindole-3-acetamide

[0135] 1.5 grams of 3,4-methylenedioxyphenethylamine, 1.5 grams of indole-3-acetic acid and 2.8 grams of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (all purchased in Shaoyuan Chemical Technology Co., Ltd.) was dissolved in 30 mL of dichloromethane, and 2.0 mL of triethylamine was added thereto, and reacted at room temperature for 12 hours, and the disappearance of the raw material was monitored by TLC. Extract with dichloromethane, wash with water, dry and evaporate the organic layer to dryness. Purified by column chromatography to obtain 2.1 g of a yellow solid product with a yield of 76%.

[0136] 1 H NMR (CDCl 3 ,300MHz):δ8.63(br,1H),7.51-7.48(m,1H),7.42-7.39(m,1H),7.26-7.22(m,1H),7.17-7.12(m,1H),7.06 -7.05(m,1H),6.53-6.51(m,1H),6.43-6.42(m,1H),6.27...

Embodiment 2

[0146] Example 2: (R)-2,3-methylenedioxy-5,8,14,14a-tetrahydro-6H-benzo[a]indole[2,3-g]quinoquinazine (A002) (prepared by reaction scheme 1)

[0147] According to the preparation method in Example 1, the catalyst (R, R)-Noyori in Example 1.3 was replaced by the catalyst (S, S)-Noyori.

[0148] 1 H NMR (CD 3 OD,300MHz):δ7.42-7.40(m,1H),7.20-7.17(m,1H),7.13-7.10(m,1H),7.08-7.03(m,1H),6.89-6.85(m,1H ),6.67(s,1H),5.88(s,2H),5.44(s,1H),3.89-4.80(m,2H),3.78-3.70(m,2H),3.40-3.28(m,2H), 3.00-2.86(m,2H).ESI-MS m / z:319[M+H] + .

Embodiment 3

[0149] Example 3: (S)-2,3-methylenedioxy-12-methoxy-5,8,14,14a-tetrahydro-6H-benzene[a]indole[2,3-g] Quinazine (A003) (prepared by reaction scheme 1)

[0150] According to the preparation method of Example 1, except that 5-methoxyindole-3-acetic acid was used as the initial raw material instead of indole-3-acetic acid. .

[0151] 1 H NMR (CDCl 3 ,400MHz):δ7.27-7.24(m,1H),6.88-6.87(m,1H),6.80-6.78(m,2H),6.60(s,1H),5.93(s,2H),5.38(s ,1H),3.83(s,3H),3.70-3.63(m,2H),3.23-3.08(m,2H),2.72-2.61(m,4H).ESI-MS m / z:349[M+H ] + .

[0152] Wherein the preparation of 5-methoxyindole-3-acetic acid is carried out according to the following steps (prepared by reaction scheme four):

[0153] 3.1 Preparation of 5-methoxyindole-3-oxoacetic acid

[0154] Dissolve 1.5 g of 5-methoxyindole (purchased from Bailingwei Technology Co., Ltd.) in 30 mL of anhydrous tetrahydrofuran, slowly inject 1.2 ml of oxalyl chloride under nitrogen protection at 0°C, and react at 0°C for half an hour. Then sl...

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Abstract

The invention relates to an aryl [a] indole [2,3-g] quinolizine compound as well as a preparation method, a pharmaceutical composition and application thereof, and particularly relates to a aryl [a] indole [2,3-g] quinolizine compound with a novel structure as shown in a general formula (I) and a derivative, a preparation method and a pharmaceutical composition thereof and application of the aryl [a] indole [2,3-g] quinolizine compound in preparation of a drug for treating diseases related to alpha 1-adrenoreceptor and urinary system diseases, such as benign prostatic hyperplasia, uroschesis and bladder outlet obstruction, especially.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and chemotherapeutics. Specifically, the present invention relates to a class of aryl[a]indole[2,3-g]quinoquinazine compounds and their derivatives represented by general formula (I) with novel structure, their preparation method and pharmaceutical composition and its preparation in treatment with alpha 1 - Adrenergic receptor-related diseases, especially the application of drugs for urinary system diseases such as benign prostatic hyperplasia, urinary retention, and bladder outlet obstruction. Background technique [0002] Benign prostatic hyperplasia (BPH) is a common physiological disease in middle-aged and elderly men. One of the most common geriatric diseases. Data show that the incidence of benign prostatic hyperplasia is very low before the age of 40, and about half of men over the age of 50 suffer from benign prostatic hyperplasia, and nearly 90% of men over the age of 80 suf...

Claims

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Application Information

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IPC IPC(8): C07D491/22C07D459/00C07D495/22C07D471/22A61K31/4375A61P13/08A61P7/10A61P13/10
CPCC07D471/14C07D471/22C07D491/22C07D495/22
Inventor 柳红谢欣郭涤亮李静张逸陈颖孙海丰栗增蒋华良陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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