Benzoxadiazatetradecene derivatives and uses thereof

A technology of benzoxadiazatetradecene and its derivatives, which is applied in the field of benzoxadiazatetradecene derivatives, can solve the problems of easy drug resistance, large drug dosage, and toxicity Side effects and other problems, to achieve the effect of prolonging the drug's large metabolic half-life, excellent pharmacodynamic performance, and good inhibitory activity

Active Publication Date: 2021-09-07
南京雷正医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the metabolic stability of the drug is not good, the half-life is short, and the dosage of the drug is large, which is prone to drug resistance and side effects.

Method used

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  • Benzoxadiazatetradecene derivatives and uses thereof
  • Benzoxadiazatetradecene derivatives and uses thereof
  • Benzoxadiazatetradecene derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1: (10R)-7-Hydroxymethylamino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4 -(Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepinetetradecane-3-carbonitrile (Compound 1)

[0146]

[0147] Intermediate 18 (100 mg, 0.245 mmol) was suspended in water (1 mL), dichloromethane (1 mL), methanol (1 mL), and aqueous formalin (37%, 0.4 mL) and tetrabutylammonium fluoride (1 M were added) , 0.08mL). After overnight at room temperature, the reaction solution was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column to obtain 80 mg of solid with a yield of 74.7%.

[0148] ESI-MS m / z: 437.2[M+H] + .

[0149] l HNMR (400MHz, DMSO-d 6 )δ: 9.29(s, 1H), 7.61-7.58(m, 2H), 7.48-7.45(m, 1H), 7.20-7.16(m, 1H), 6.81(s, 1H), 6.39(d, J= 4.0Hz, 2H), 5.61(q, J=8.0Hz, 1H), 4.44(d, J=16.0Hz, 1H), 4.20(d, J=12.0Hz, 1H), 4.04(s, 3H), 2.99 (s,3H),1.68(d,J=8.0Hz,3H...

Embodiment 2

[0150]Example 2: (10R)-7-ethylcarbamate-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4 -(Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepinetetradecane-3-carbonitrile (compound 2)

[0151]

[0152] Intermediate 18 (100 mg, 0.245 mmol) was dissolved in THF, DIPEA (38 mg, 0.294 mmol) was added, and ethyl chloroformate (26.5 mg, 0.245 mmol) was slowly added at 0 °C, and then stirred at room temperature overnight. Washed with water, extracted with ethyl acetate, the organic phase was dried and spin-dried, and purified by column to obtain 35 mg, yield: 29.7%.

[0153] ESI-MS m / z: 479.2[M+H] + .

[0154] l HNMR (400MHz, DMSO-d 6 )δ: 9.51(s, 1H), 7.98(s, 1H), 7.83-7.80(m, 1H), 7.49-7.47(m, 1H), 7.21-7.16(m, 2H), 5.66(q, J= 8.0Hz, 1H), 4.48(d, J=16.0Hz, 1H), 4.25(d, J=12.0Hz, 1H), 4.18(q, J=8.0Hz, 2H), 4.08(s, 3H), 3.00 (s,3H),1.68(d,J=8.0Hz,3H),1.28(t,J=8.0Hz,3H).

Embodiment 3

[0155] Example 3: (10R)-7-Aminocarboxy-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4- (Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepinetetradecane-3-carbonitrile (compound 3)

[0156]

[0157] Under ice bath conditions, intermediate 18 (100 mg, 0.245 mmol) was slowly added to formic acid (113 mg, 2.45 mmol), acetic anhydride (37 mg, 0.367 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried, concentrated, and subjected to column chromatography to obtain 42 mg of solid, yield: 39.2%.

[0158] ESI-MS m / z: 435.2[M+H] + .

[0159] l HNMR (400MHz, DMSO-d 6 )δ: 10.42(d, J=12.0Hz, 1H), 9.23(s, 1H), 7.89(s, 1H), 7.81(d, J=8.0Hz, 1H), 7.50-7.46(m, 1H), 7.21-7.17(m, 2H), 5.73(q, J=8.0Hz, 1H), 4.48(d, J=16.0Hz, 1H), 4.23(d, J=12.0Hz, 1H), 4.08(s, 3H ),3.01(s,3H),1.72(d,J=8.0Hz,3H).

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Abstract

The invention discloses benzoxadiazatetradecene derivatives and applications thereof, belonging to the field of medicine. A class of benzoxadiazatetradecene derivatives with a structure represented by the general formula (I) provided by the present invention has excellent anaplastic lymphoma enzyme (ALK) inhibitory activity and excellent pharmacodynamic properties, It can significantly prolong the half-life of drug metabolism; it can be safely and effectively used in the treatment of anaplastic lymphoma kinase positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC), etc. Vascular and neurological diseases provide new means.

Description

technical field [0001] The invention relates to benzoxadiazetatetradecene derivatives and uses thereof, and belongs to the field of medicine. Background technique [0002] As we all know, lung cancer is one of the malignant tumors that threaten the most human beings, with the morbidity and mortality ranking the first among men and the second morbidity and mortality among women. Among the lung cancers, the most common is non-small cell lung cancer (NSCLC), accounting for about 85% of lung cancers; the positive incidence of anaplastic lymphoma enzyme (ALK) accounts for 3% to 5% of non-small cell lung cancers (NSCLC). [0003] ALK is a member of the receptor tyrosine kinase superfamily and is most closely related at the amino acid sequence level to members such as Ros-1, leukocyte tyrosine kinase, insulin receptor and cMet (liver growth factor receptor), as this gene All members of the family, which have an extracellular ligand binding domain, a transmembrane sequence, and an ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/18C07F9/6561A61K31/439A61K31/675A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D498/18C07F9/65616
Inventor 范文华唐春雷范为正吴露婷张晴张永杰
Owner 南京雷正医药科技有限公司
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