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Pyrimidinamine and pyridinamine Hedgehog signal conduction inhibitors

A compound and alkyl technology, applied in the field of Hedgehog signaling pathway inhibitors and heterocyclic amine derivatives, can solve problems such as narrow indications, underdeveloped medical value of Hh inhibitors, and drug resistance problems

Active Publication Date: 2014-06-18
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these and other compounds have been studied, the great medical value of Hh inhibitors has not been fully exploited, only the indications are relatively narrow, and the possibility of drug resistance has been reported, so the Hh signaling pathway is still needed effective inhibitor of

Method used

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  • Pyrimidinamine and pyridinamine Hedgehog signal conduction inhibitors
  • Pyrimidinamine and pyridinamine Hedgehog signal conduction inhibitors
  • Pyrimidinamine and pyridinamine Hedgehog signal conduction inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0180] Preparation of compound 1

[0181]

[0182] Preparation of 3-nitro-6-((2S,6R)-2,6-dimethylmorpholinyl)pyridine (intermediate 1-b)

[0183] Weigh 2-chloro-5-nitropyridine (1-a, 1.58g, 1eq) and DMF (10mL) into a 50mL three-necked flask, add 2,6-dimethylmorpholine (1.15g, 1eq) , K 2 CO 3 (2.76g, 2eq), after the addition was completed, the temperature was raised to 80°C under the protection of nitrogen, and the reaction was refluxed for 12h. After cooling, ice water (50mL) was added and filtered to obtain a yellow solid (2.30g, 97%). MS(ESI)m / z:[M+H] + =238.0. 1 H-NMR (400M, DMSO-d 6 )δ8.97(d,1H,ArH),8.24(dd,1H,ArH),7.00(d,1H,ArH),4.45(m,2H,(CH) 2 O),3.37-3.62(m,2H,CH 2 ),2.62-2.68(m,2H,CH 2 ),1.18(s,3H,CH 3 ),1.16(s,3H,CH 3 ) ppm.

[0184] Preparation of 3-amino-6-((2S,6R)-2,6-dimethylmorpholinyl)pyridine (intermediate 1-c)

[0185] Weigh intermediate 1-b (2.1g, 1eq) and place it in a 50mL bottle, add methanol (20mL), add 5% Pd / C (0.2g) in a hydrogen atmosph...

Embodiment 2

[0191] Preparation of Compound 2

[0192]

[0193] Preparation of N-(5-methyl-4-(4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)-1H-indazol-5-amine (2)

[0194] Compound 2 (58 mg, 43%) was prepared in a similar manner to compound 1. MS(ESI)m / z:[M+H] + =386.0. 1 H-NMR (400M, DMSO-d 6 )δ12.89(s,1H,indazole-NH),9.57(s,1H,NH),8.43(s,1H,ArH),8.26(s,1H,ArH),7.98(s,1H,ArH), 7.85(d,2H,ArH),7.59(m,1H,ArH),7.52(d,2H,ArH),7.43(m,1H,ArH),2.22(s,3H,ArCH 3 )ppm, HPLC: 93.98%.

Embodiment 3

[0196] Preparation of compound 3

[0197]

[0198] Preparation of methyl 4-((5-methyl-4-p-trifluoromethoxyphenyl)pyrimidine-2-amino)benzoate (intermediate 3-a)

[0199] Weigh intermediate 1-f (81mg, 1eq) and place it in a microwave tube, add isopropanol (2mL), add methyl p-aminobenzoate (60mg, 1.5eq) and 1 drop of hydrochloric acid, react in microwave at 170°C for 2h, Filtration afforded an off-white solid (110 mg, 97%). MS(ESI)m / z:[M+H] + =404.0.

[0200] Preparation of 4-((5-methyl-4-p-trifluoromethoxyphenyl)pyrimidine-2-amino)benzoic acid (intermediate 3-b)

[0201] Weigh 3-a (7mg, 1eq) and NaOH (18mg, 2.5eq) into a 10mL bottle, add MeOH (5mL), H 2 O (1 mL), reacted at 65°C for 1 h, poured the reaction solution into ice water, adjusted pH=7, a solid precipitated out, filtered to obtain a white solid (70 mg, 97%). MS(ESI)m / z:[M+H] + =390.0. 1 H-NMR (400M, DMSO-d 6 )δ12.53(s,1H,COOH),10.08(s,1H,NH),8.53(s,1H,ArH),7.92-7.85(m,6H,ArH),7.56(d,2H,ArH), 2.52(s,3H,ArCH ...

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Abstract

The invention relates to pyrimidinamine and pyridinamine Hedgehog signal conduction inhibitors. The inhibitors are compounds with the structure represented by formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to a medicinal use of the above compounds as hedgehog signal conduction inhibitors.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of heterocyclic amine derivatives with a structure of formula (I), and the medical use of these compounds as Hedgehog signal pathway inhibitors. Background technique [0002] The Hedgehog (Hh) signaling pathway is a very important pathway in mammals, controlling cell growth and survival. During embryonic development, the Hh pathway plays an important role in cell differentiation and proliferation, organ formation, etc.; in adults, the Hh pathway is closely related to tissue wound repair and stem cell maintenance. Studies have shown that Hh signal transduction is related to the generation, invasion and metastasis of various tumors, including skin basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, pancreatic cancer, colon cancer, gastric cancer, non-small cell lung cancer, prostate cancer, esophageal cancer cancer, breast cancer, ovarian cancer, leukemia, etc. [0003] Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D403/12C07D239/42C07D401/04C07D403/04C07D401/12C07D405/04C07D413/12C07D405/12C07D487/04C07D495/04C07D401/14C07D491/113C07D487/08A61K31/5377A61K31/506A61K31/505A61K31/541A61P35/00A61P35/02
CPCC07D239/42C07D401/04C07D401/12C07D401/14C07D403/04C07D403/12C07D405/04C07D405/12C07D413/12C07D413/14C07D471/04C07D487/04C07D487/08C07D491/107C07D495/04
Inventor 辛敏行唐锋黄伟文珺沈晗刘肇彧涂崇兴赵兴俄
Owner HAINAN SIMCERE PHARMA CO LTD
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