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Optimized medicine combination and application thereof for treating cancers and autoimmune diseases

A disease and compound technology, applied in the field of inhibition of Brutonine kinase activity, combined drug optimization and screening, can solve problems such as affecting drug efficacy and side effects, and achieve the effect of reducing drug inactivation

Inactive Publication Date: 2016-11-23
ZHEJIANG DTRM BIOPHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] It is known that BTK inhibitors produce various derivatives in vivo, which will also affect the efficacy and side effects

Method used

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  • Optimized medicine combination and application thereof for treating cancers and autoimmune diseases
  • Optimized medicine combination and application thereof for treating cancers and autoimmune diseases
  • Optimized medicine combination and application thereof for treating cancers and autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 and 2

[0103]

[0104] 1-[(R)-3-[4-amino-3-[2-fluoro-4-(2,3,5,6-trifluorophenoxy)phenyl]-1H-pyrazolo[3, 4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one

[0105]

[0106] 1-[(S)-3-[4-amino-3-[2-fluoro-4-(2,3,5,6-trifluorophenoxy)phenyl]-1H-pyrazolo[3, 4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one

[0107] Step A:

[0108]

[0109] 3-(4-Bromo-3-fluorophenoxy)-1,2,4,5-tetrafluorobenzene

[0110] Steps:

[0111] To a solution of compound 3-fluoro-4-bromophenol (47.0 g, 246.1 mmol, 1.0 eq.) in DMF (500 mL) was added potassium carbonate (68.0 g, 492.1 mmol, 2.0 eq.) and compounds 1, 2, 3, 4,5-Pentafluorobenzene (49.6 g, 295.3 mmol, 1.2 eq.). The reaction solution was stirred at 100°C for 12 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed twice with water (100 mL) and once with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and spin-dried to o...

Embodiment 1

[0159] LC / MS (Method: UFLC): RT = 3.002 min; m / z = 531.1 [M+H] + ; The total run time is 7 minutes.

[0160] 1 H NMR (400MHz, CDCl 3 ) 8.36(s, 1H), 7.58(t, J=8.4Hz, 1H), 7.09-7.04(m, 1H), 6.94-6.88(m, 2H), 6.62-6.54(m, 1H), 6.32- 6.25(m, 1H), 5.73-5.63(m, 1H), 5.56-5.51(m, 1H), 4.90-4.85(m, 1.5H), 4.59-4.56(m, 0.5H), 4.21-4.17(m , 0.5H), 4.04-4.01(m, 0.5H), 3.76-3.71(m, 0.5H), 3.40-3.35(m, 0.5H), 3.22-3.15(m, 0.5H), 2.93-2.87(m , 0.5H), 2.39-2.27(m, 2H), 2.04-1.68(m, 2H).

Embodiment 2

[0162] LC / MS (Method: UFLC): RT = 3.006 min; m / z = 531.1 [M+H] + ; The total run time is 7 minutes.

[0163] 1 H NMR (400MHz, CD 3 OD) 8.24 (s, 1H), 7.62 (t, J=8.4Hz, 1H), 7.50-7.45 (m, 1H), 7.09-7.01 (m, 2H), 6.85-6.63 (m, 1H), 6.21 -6.09(m, 1H), 5.77-5.61(m, 1H), 4.63-4.59(m, 1H), 4.23-4.07(m, 1.5H), 3.90-3.85(m, 0.5H), 3.51-3.45( m, 0.5H), 3.34-3.17(m, 1.5H), 2.40-2.23(m, 2H), 2.08-2.05(m, 1H), 1.75-1.71(m, 1H).

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Abstract

The invention provides a series of new multi-fluorine-substituted pyrazolopyrimidine type compounds or salts. The compounds are Bruton's tyrosine kinase (BTK) inhibitors, and can have better kinase inhibition selectivity and pharmacokinetic property. The invention discloses a preparation method of the compounds and also discloses medicine combination containing the compounds with other target medicine compositions or other medicines. The optimized medicine combination has a synergistic effect, can greatly inhibit the existence of tumors as compared with a single target medicine, and can completely eliminate certain tumors. The optimized medicine combination can greatly treat the medicine resistance of the tumors and prevent the cancer recurrence as compared with the single target medicine, and the treatment period is shorter. The invention further relates to combined compounds and medicine preparations using the compounds as active elements, and at a lower dosage, the compounds are safer and have the curative effect of the synergistic effect. The invention further comprises methods for treating and inhibiting the autoimmune diseases or symptoms, heterogeneous immune diseases or symptoms, inflammatory diseases and cancer or symptoms by using the compounds and preparations of the compounds.

Description

[0001] technical field of invention [0002] The invention relates to a series of novel polyfluorinated substituted pyrazolopyrimidine compounds and their preparation method, a pharmaceutical composition containing them as active ingredients and a method for inhibiting the activity of brutonine kinase. The invention also relates to the optimization screening of multi-class drugs in vitro tumor cell viability and in vivo tumor suppression combination drug. The optimized combined drug of the present invention has a synergistic effect, can better inhibit the survival of tumors than a single targeted drug, and can cause some tumors to disappear completely, and the optimized combined drug can better treat drug resistance of tumors than a single targeted drug and cancer recurrence. Optimized drug combinations are safer due to lower doses, and better efficacy results in shorter treatment cycles. Background of the invention [0003] Cancer treatment has developed from toxic chemothe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61K45/06A61P37/02A61P29/00A61P5/14A61P3/10A61P21/04A61P1/04A61P1/00A61P13/12A61P1/16A61P25/00A61P19/02A61P17/06A61P17/00A61P19/04A61P7/06A61P9/00A61P27/02A61P11/02A61P1/02A61P11/04A61P11/00A61P7/00A61P11/06A61P37/08A61P35/00A61P35/02
CPCA61K45/06C07D487/04A61K31/519A61P1/04A61P1/16A61P3/10A61P5/14A61P13/12A61P21/04A61P25/00A61P29/00A61P37/02A61P35/00A61K31/52A61K31/4162A61K31/436A61K31/454A61K31/635A61K2300/00A61K31/496A61P37/00A61P19/02
Inventor 何伟
Owner ZHEJIANG DTRM BIOPHARMA