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Quinoline compound, preparation method and application thereof

A compound, unsubstituted technology, applied in the fields of pharmacy, medicinal chemistry and pharmacology, which can solve problems such as unclear specific reasons, low bioavailability, safety risks, etc.

Pending Publication Date: 2021-03-30
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, like most other anti-tuberculosis drugs, bedaquiline also has obvious shortcomings, such as prolonging the QTc interval in the electrocardiogram, which may cause serious cardiac safety risks
It is also worth noting that the clinical trial C208 phase 2 trial found that the mortality rate of bedaquiline group (12.7%) was higher than that of the placebo group (2.5%), but the specific reason is not clear
Patients currently using bedaquiline still need to monitor their cardiac electrophysiological status and drug safety response frequently during the treatment cycle of 18-20 months. In addition, low bioavailability and obvious liver toxicity And side effects such as phospholipid disease caused by drugs have limited the application of this new mechanism drug in tuberculosis patients to a certain extent

Method used

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  • Quinoline compound, preparation method and application thereof
  • Quinoline compound, preparation method and application thereof
  • Quinoline compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210] Embodiment 1: the preparation of compound 1

[0211]

[0212] Using intermediate IV-1 and 2-cyclopropyl ethyl methanesulfonate as starting materials, compound 1 was prepared according to the following reaction scheme

[0213]

[0214] Preparation of Compound 1-1

[0215] Intermediate IV-1 (834mg, 2.00mmol), 2-cyclopropyl ethyl methanesulfonate (966mg, 5.46mmol), K 2 CO 3 (829mg, 6.00mmol), KI (33mg, 0.20mmol) were added to acetone (10mL), protected by Ar gas, and reacted overnight at 50°C. TLC detected a small amount of remaining raw material, cooled to room temperature and directly mixed the sample through the column (petroleum ether: ethyl acetate = 40:1-30:1) to obtain a light yellow solid: 644 mg, yield 66%. LC-MS(ESI):485.1[M+H] +

[0216] Preparation of compound 1-2

[0217] CuBr·Me 2 S (27mg, 0.1mmol) was added to a 25mL three-neck flask, under the protection of Ar gas, a solution of newly prepared allyl zinc bromide in tetrahydrofuran (4mL, 3.98mmol...

Embodiment 2

[0234] Embodiment 2: the preparation of compound 2

[0235]

[0236] Using intermediate IV-1 and 2-(1-methylcyclopropyl)ethyl p-toluenesulfonate as starting materials, using the same reaction process as the preparation of compound 1, compounds 2A (104 mg) and 2B (85 mg ).

[0237] 2A (104mg), resolved by chiral HPLC to obtain 2A-1 (45mg) and 2A-2 (39mg)

[0238] LC-MS(ESI):572.2[M+H] +

[0239] 1 H NMR (400MHz, CDCl 3 )δ:8.17(s,1H),7.87(d,J=2.2Hz,1H),7.68(s,1H),7.64(d,J=2.2Hz,1H),6.57(s,2H),4.08( s,3H),3.96(s,6H),2.03(s,1H),1.96(s,6H),1.88(s,2H),1.86–1.76(m,2H),1.52–1.34(m,4H) ,1.26–1.22(m,3H),0.74(s,4H).

[0240] 2B (85mg), resolved by chiral HPLC to obtain 2B-1 (36mg) and 2B-2 (29mg)

[0241] LC-MS(ESI):572.3[M+H] +

[0242] 1 H NMR (400MHz, CDCl 3 )δ:8.03(s,1H),7.73(d,J=2.2Hz,1H),7.54(s,1H),7.50(d,J=2.2Hz,1H),6.43(s,2H),3.94( s,3H),3.82(s,6H),1.89(s,1H),1.82(s,6H),1.74(s,2H),1.72–1.62(m,2H),1.38–1.20(m,4H) ,1.12–1.08(m,3H),0.60(s,4H).

Embodiment 3

[0243] Embodiment 3: the preparation of compound 3

[0244]

[0245] Using intermediate IV-1 and 3-cyclopropylpropyl p-toluenesulfonate as starting materials, using the same reaction process as the preparation of compound 1, compounds 3A (69 mg) and 3B (87 mg) were obtained

[0246] 3A (69mg) was resolved by chiral HPLC to obtain 3A-1 (22mg) and 3A-2 (20mg)

[0247] LC-MS(ESI):572.2[M+H] +

[0248] 1 H NMR (400MHz, CDCl 3 )δ: 8.23(s, 1H), 7.90(d, J=2.2Hz, 1H), 7.72(d, J=8.8Hz, 1H), 7.65(dd, J=8.9, 2.2Hz, 1H), 6.56( s,2H),4.11(s,3H),3.97(s,6H),3.60(dd,J=12.0,3.0Hz,1H),2.21(ddd,J=26.4,9.4,5.4Hz,1H),1.94 (s,9H),1.51–1.40(m,2H),1.25(s,2H),0.96(t,J=5.5Hz,2H),0.43–0.31(m,1H),0.20(d,J=7.8 Hz,2H),0.14–0.28(m,2H).

[0249] 3B (87mg) was resolved by chiral HPLC to obtain 3B-1 (27mg) and 3B-2 (32mg)

[0250] LC-MS(ESI):572.2[M+H] +

[0251] 1 H NMR (400MHz, CDCl 3 )δ: 8.18(s, 1H), 7.85(d, J=2.2Hz, 1H), 7.67(d, J=8.8Hz, 1H), 7.60(dd, J=8.9, 2.2Hz, 1H), 6.51( s,2H),4.06(s,3...

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PUM

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Abstract

The invention relates to quinoline compounds, a preparation method and application thereof, and specifically provides a class of novel quinoline compounds, a pharmaceutically acceptable salt and a preparation method thereof, and application in preparation of medicines for treating tubercle bacillus infectious diseases, particularly infectious diseases caused by drug-resistant tubercle bacillus. The quinoline compound or the pharmaceutically acceptable salt thereof provided by the invention has good anti-tubercle bacillus activity, and especially has strong activity on drug-resistant tubercle bacillus.

Description

technical field [0001] The invention belongs to the fields of pharmacology, medicinal chemistry and pharmacology, and more specifically, relates to a class of novel quinoline compounds and a preparation method thereof, and the use of the compounds for treating tuberculosis, especially drug-resistant tuberculosis infection. related diseases. Background technique [0002] Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) infection and is one of the oldest human diseases. According to the World Health Organization (WHO) estimate in 2017, about 23% of the world's people (about 1.7 billion) have latent tuberculosis infection, and 5-10% of them will develop into active tuberculosis in their lifetime . At present, tens of millions of new people have symptoms of active tuberculosis every year, and the annual death toll caused by tuberculosis has surpassed that of AIDS, becoming the world's number one killer of infectious diseases. [0003] At present, the first-line trea...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D401/14C07D215/227C07D471/04C07D409/06A61K31/4709A61K31/47A61P31/06
CPCC07D401/06C07D401/14C07D215/227C07D471/04C07D409/06A61P31/06A61K31/47A61K31/4709
Inventor 赵传生胡杰陶志刚宋海峰
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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