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Aminothiazole-pyridine heterocyclic compounds with hedgehog pathway antagonist activity

A technology of aminothiazole and hedgehog pathway, applied in the field of pharmaceutical synthesis, can solve the problems of poor physical and chemical properties and low solubility of vismodegib, achieve the effect of blocking tumor cell metastasis and regeneration, and treating tumor diseases

Active Publication Date: 2016-07-13
SUZHOU KINTOR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, vismodegib has poor physical and chemical properties, low solubility, strong side effects and has developed drug resistance, etc.

Method used

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  • Aminothiazole-pyridine heterocyclic compounds with hedgehog pathway antagonist activity
  • Aminothiazole-pyridine heterocyclic compounds with hedgehog pathway antagonist activity
  • Aminothiazole-pyridine heterocyclic compounds with hedgehog pathway antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] This embodiment provides an aminothiazole-pyridine heterocyclic compound C1, which is synthesized by the following method:

[0048]

[0049] 1) Synthesis of intermediate C1-1:

[0050] Add N-tert-butoxycarbonylpiperidone (20g, 100.5mmol), cyanamide (8.7g, 200.9mmol), sublimed sulfur (6.4g, 200mmol) into 100mL of pyridine, and react at 130°C for 90 minutes. After cooling to room temperature, crystals were precipitated, filtered, and the obtained solid was washed twice with diethyl ether (100 mL) to obtain a light yellow solid (19 g, 74.2%). 1 HNMR (400MHz, DMSO-d6) δ6.83 (s, 2H), 4.29 (s, 2H), 3.56 (s, 2H), 2.43 (s, 2H), 1.41 (s, 9H).

[0051] 2) Synthesis of intermediate C1-2:

[0052] Add C1-1 (200mg, 0.78mmol) to 3M hydrogen chloride in ethyl acetate (3mL), stir at room temperature for 3 hours, spin off the solvent under reduced pressure, and add the concentrate to saturated aqueous sodium bicarbonate (5mL) and dichloromethane (20mL), the organic phase was dried...

Embodiment 2

[0056] This embodiment provides an aminothiazole-pyridine heterocyclic compound C2, which is synthesized by the following method:

[0057]

[0058] The intermediate C1 was synthesized according to the method in Example 1, and then the product C2 was prepared.

[0059] C1 (40mg, 0.11mmol), acetic acid (9mg, 0.14mmol), N,N`-diisopropylethylamine (28mg, 0.22mmol) were dissolved in N,N`-dimethylformamide (1.5mL). HATU (53 mg, 0.14 mmol) was added to the solution and stirred at room temperature for 24 hours. The reaction solution was added into ethyl acetate (40 mL), and washed with saturated brine (15 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column (dichloromethane:methanol=70:1) to obtain yellow solid C2 (20 mg, 45%). 1 HNMR (400MHz, CDCl 3 )δ9.55(s,1H),8.35(s,1H),8.22(s,1H),7.43(s,1H),6.66(s,1H),4.68(s,2H),3.96(t,J =5.6Hz,2H),2.83(t,J=5.4Hz,2H),2.38(s,3H)...

Embodiment 3

[0062] This embodiment provides an aminothiazole-pyridine heterocyclic compound C3, which is synthesized by the following method:

[0063]

[0064] The intermediate C1 was synthesized according to the method in Example 1, and then the product C3 was prepared.

[0065] C1 (35mg, 0.094mmol), isobutyric acid (11mg, 0.125mmol), N,N`-diisopropylethylamine (20mg, 0.155mmol) dissolved in N,N`-dimethylformamide (1.5mL ). HATU (49 mg, 0.129 mmol) was added to the solution and stirred at room temperature for 24 hours. The reaction solution was added into ethyl acetate (40 mL), and washed with saturated brine (15 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column (dichloromethane:methanol=80:1 to 50:1) to obtain white solid C3 (13.3 mg, 32%). 1 HNMR (400MHz, CDCl 3 )δ9.89(s,1H),8.36(s,1H),8.22(s,1H),7.43(s,1H),6.67(s,1H),4.67(s,2H),3.96(t,J =5.6Hz,2H),2.82(t,J=5.4Hz...

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Abstract

The invention discloses an amido thiazole-pyridine heterocycle compound with the activity of a hedgehog path antagonist. The amido thiazole-pyridine heterocycle compound comprises a compound, pharmaceutically-acceptable salt, various isotopes, various isomers and various crystal structures. The amido thiazole-pyridine heterocycle compound has a structure shown by a general formula. The amido thiazole-pyridine heterocycle compound has the advantages that the transferring and the regeneration of tumor cells can be blocked by hedgehog path antagonism, and the anti-tumor action is obvious.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to an aminothiazole-pyridine heterocyclic compound with hedgehog pathway antagonist activity. Background technique [0002] Malignant tumors are one of the most important diseases that endanger human health. There are about 10.9 million new cases of malignant tumors in the world every year, and about 6.7 million patients die of malignant tumors every year. The research and development of anticancer drugs has undergone tremendous changes in recent years. In the past, anticancer drugs commonly used in clinical treatment were mainly cytotoxic drugs. This type of anticancer drugs has unavoidable disadvantages such as poor selectivity, strong side effects, and easy drug resistance . In recent years, with the rapid development of life science research, various basic processes such as signal transduction in malignant tumor cells, regulation of cell cycle, induction of apo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/00C07D498/04A61K31/444A61K31/4545A61K31/5377A61K31/496A61P35/00A61P35/04
CPCC07D498/04C07D513/04
Inventor 张小虎
Owner SUZHOU KINTOR PHARMA
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