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Anti-apoptosis protein inhibitor and application thereof

A technology of apoptosis inhibitory protein and medicinal salt, which is applied in the field of medicine and chemical industry, and can solve the problems of compound efficacy, stability or toxicity limitations

Inactive Publication Date: 2015-04-29
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, although a series of IAPs inhibitors have been developed, there are no marketed drugs yet, and many compounds also involve limitations in potency, stability, or toxicity.

Method used

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  • Anti-apoptosis protein inhibitor and application thereof
  • Anti-apoptosis protein inhibitor and application thereof
  • Anti-apoptosis protein inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1 Synthesis

[0128] Dissolve intermediate A-10 (0.5mmol) in as little ethyl acetate as possible, and add 3mol·L -1 Hydrogen chloride / ethyl acetate solution 3mL, react at low temperature for 0.5h, continue stirring at room temperature for 3h. A white solid was precipitated, filtered, washed with ether, and dried to obtain 221 mg of a white solid, namely Monovalent Example 1 (hydrochloride salt form), with a yield of 83.2%. 1 H-NMR (400MHz, DMSO-d 6 ), δ(ppm):0.85-0.93(m,5H),1.32-1.34(d,3H,J=7.2Hz),1.36-1.52(m,7H),2.00-2.10(m,2H),2.29- 2.34(m,2H),2.46-2.49(m,3H), 3.80-3.95(m,3H),4.20(s,3H),4.46-4.48(t,1H,J=8.0Hz),5.23-5.26( m,1H),7.45-7.48(m,3H),8.32-8.35(m,2H),8.66-8.69(d,1H,J=8.0Hz),8.86(br s,1H),9.36(br s, 1H),12.89(s,1H),MS m / e:520.3([M+1] + ).

Embodiment 23

[0129] Example 23 Synthesis

[0130] Add intermediate A-10 (80mg, 0.138mmol), 1,6-dibromohexane (100mg, 0.415mmol) and catalytic amount of potassium iodide to the 10mL closed reaction tube dedicated to the fully automatic combined microwave synthesis instrument (product of CEM company) and 3 mL of acetone, and set the reaction conditions at 120° C. / 20 minutes. The reaction system was evaporated to dryness under reduced pressure, and then separated by column chromatography. The elution solvent was dichloromethane / methanol (20:1), and 62 mg of oil was obtained with a yield of 72.5%.

[0131] Dissolve this oil in as little ethyl acetate as possible, and add 3mol·L -1 Hydrogen chloride / ethyl acetate solution 3mL, react at low temperature for 0.5h, continue stirring at room temperature for 1h. A white solid precipitated, was filtered, and the solid was washed with ether. After drying, 46 mg of white solid was obtained, that is, the divalent compound Example 23 (dihydrochlor...

Embodiment 7

[0141] Example 7 Synthesis

[0142] Dissolve intermediate B-7 (1mmol, 536mg) in as little ethyl acetate as possible, and add 3mol·L -1 Hydrogen chloride / ethyl acetate solution 3mL, react at low temperature for 0.5h, continue stirring at room temperature for 3h. A white solid was precipitated, filtered, washed with ether, and dried to obtain 402 mg of a white solid, that is, Monovalent Example 7 (hydrochloride salt form), with a yield of 80.2%. 1 H-NMR (400MHz, DMSO-d 6 ), δ(ppm):0.80-0.91(d,6H,J=6.6Hz),1.33-1.35(d,3H,J=6.8Hz),2.15-2.21(m,2H),2.45(s,3H) ,2.50-2.57(m,1H),3.60(brs,1H),3.72(brs,1H),3.83-3.91(m,3H),4.47-4.50(m,2H),5.35-5.37(m,1H ),7.56-8.73(m,8H),8.94(brs,1H),9.58(br s,1H); MS m / e:464.4([M+1] + ).

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Abstract

The invention belongs to the field of medicine and chemical engineering, and relates to an anti-apoptosis protein inhibitor and an application thereof, in particular to a heterocyclic alkane derivative and an application of the derivative taken as the anti-apoptosis protein inhibitor or used for preparing antitumor drugs. More specifically, the invention relates to a compound represented as a general formula I, and an isomer of the compound or the compound can be used as pharmaceutical salt. The compound can effectively inhibit activity of IAPs, and has potential of prevention and treatment of diseases such as tumors and the like.

Description

field of invention [0001] The invention belongs to the field of medicine and chemical industry, and relates to an inhibitor of apoptosis inhibiting protein and its application. Specifically, the present invention relates to a heterocycloalkane derivative and its use as an inhibitor of apoptosis inhibitory protein or in the preparation of antitumor drugs. Background technique [0002] Apoptosis (programmed cell death), normally occurs during the development and maintenance of healthy tissues in multicellular organisms. The apoptotic pathway is known to play an important role in embryonic development, viral pathogenesis, cancer, autoimmune and neurodegenerative diseases, among other events. Alterations in the apoptotic response have been found to be associated with the development of cancer, autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis and with viral infections including those associated with herpesviruses, poxviruses and adenoviruses. [0...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K5/083A61K38/05A61K38/06A61P35/00A61P35/02A61P37/02A61P19/04A61P25/00
Inventor 聂爱华顾为王鑫苏瑞斌李玉蕾李斐
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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