Bicyclic heterocyclic amine Hedgehog signal pathway inhibitor

A heterocycloalkyl and heteroaryl technology, applied in the field of heterocyclic amine Hedgehog signaling pathway inhibitors, can solve the problems of narrow indications and incomplete development of the medical value of Hh inhibitors

Active Publication Date: 2014-12-03
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although these and other compounds have been studied, the huge medical value of Hh inhibitors has not been fully developed. At present, only the indications are relatively narrow, only BCC, and in solid tumors, especially pancreatic cancer, colon cancer, There are major breakthroughs in gastric cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, breast cancer, ovarian cancer, liver cancer, and many opportunities

Method used

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  • Bicyclic heterocyclic amine Hedgehog signal pathway inhibitor
  • Bicyclic heterocyclic amine Hedgehog signal pathway inhibitor
  • Bicyclic heterocyclic amine Hedgehog signal pathway inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1、2

[0135] Preparation of compound 1 and compound 2

[0136]

[0137] Preparation of 2-chloro-4-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 1-a)

[0138] Weigh 2,4-dichloro-7H-pyrrolopyrimidine (372mg, 1eq), p-trifluoromethoxyphenylboronic acid (1000mg, 1.1eq), triethylamine (1.2eq), bis(triphenylphosphine) Palladium(II) chloride (0.1eq), N,N-dimethylformamide (28.5ml) and water (0.5ml) were added into the flask and heated to 85°C for 4h. After stopping the reaction, add 100ml of water to the reaction solution, stir, extract with ethyl acetate (20ml*4), dry the ester layer with anhydrous sodium sulfate, concentrate, and separate by column chromatography (petroleum ether:ethyl acetate=20:1 ) to give a solid (680mg, 41%). 1 H-NMR (400M, DMSO-d 6 )δ12.56(s,1H,NH),8.31(d,2H,ArH),7.76(d,1H,ArH),7.60(d,2H,ArH),6.98(d,1H,ArH)ppm.

[0139] Preparation of 2-chloro-7-p-toluenesulfonyl-4-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate ...

Embodiment 3

[0148] Preparation of compound 3

[0149]

[0150] Preparation of 2,6-dichloro-9-(4-methoxybenzyl)-9H-purine (intermediate 3-a)

[0151] Dissolve 2,6-dichloro-9H-purine (1g, 5.29mmol) and 1-chloro-4-methoxybenzene (0.91g, 5.82mmol) in N,N-dimethylformamide (10ml) , add potassium carbonate (0.88g, 6.35mmol), react at room temperature for 17 hours, add ethyl acetate to dilute, wash with water, dry, filter, concentrate the filtrate to make sand, and separate by column chromatography (petroleum ether / ethyl acetate=2:1) Intermediate 3-a (823 mg, 50%) was obtained. MS(ESI)m / z:[M+H] + =309.2. 1 H-NMR (400M, DMSO-d 6 )δ8.82(s,1H,ArH),7.33(d,2H,ArH),6.92(d,2H,ArH),5.41(s,2H,CH 2 ),3.73(s,3H,CH 3 ) ppm.

[0152] Preparation of 2-chloro-9-(4-methoxybenzyl)-6-(4-(trifluoromethoxy)phenyl)-9H-purine (intermediate 3-b)

[0153] Weigh intermediate 3-a (760mg, 2.46mmol), 4-trifluoromethoxyphenylboronic acid (760mg, 3.69mmol), bis(triphenylphosphine)palladium(II) chloride dichloromet...

Embodiment 4

[0159] Preparation of Compound 4

[0160]

[0161] Methyl 4-(9-(4-methoxybenzyl)-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-ylamino)benzoate (4-a) preparation of

[0162] Weigh intermediate 3-b (546mg, 1.26mmol), methyl p-aminobenzoate (285mg, 1.88mmol), palladium acetate (28mg, 0.12mmol), 2,2'-bisdiphenylphosphino-1,1 '-Binaphthyl (156mg, 0.24mmol), cesium carbonate (1.23g, 3.78mmol), add dioxane (15ml), microwave at 150°C for 5 hours, add water, extract with ethyl acetate, dry, filter, The filtrate was concentrated to make sand, and separated by column chromatography (petroleum ether / ethyl acetate=10:1) to obtain intermediate 4-a (200 mg, 29%). MS(ESI)m / z:[M+H] + =550.1. 1 H-NMR (400M, DMSO-d 6 )δ10.18(s,1H,NH),8.93(d,2H,ArH),8.56(s,1H,ArH),8.01(d,2H,ArH),7.94(d,2H,ArH),7.63( d,2H,ArH),7.40(d,2H,ArH),6.94(d,2H,ArH),5.41(s,2H,CH 2 ),3.84(s,3H,CH 3 ),3.72(s,3H,CH 3 ) ppm.

[0163] Preparation of 4-(9-(4-methoxybenzyl)-6-(4-(trifluoromethoxy)phenyl)-9H-purin-2-ylami...

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Abstract

The invention relates to the field of biological medicine, and concretely relates to bicyclic heterocyclic amine compounds, and the compounds are a new Hedgehog inhibitor and pharmaceutically acceptable salts shown as a general formula (I). The compounds can be used as a Hedgehog signal conduction inhibitor applied to multiple medical applications.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of heterocyclic amine Hedgehog signal pathway inhibitors with a structure of formula (I), and the medical application of these compounds. Background technique [0002] The Hedgehog (Hh) signaling pathway is a very important pathway that controls the growth and survival of cells in mammals. 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. The Hh signal transduction pathway is mainly composed of secreted glycoprotein ligand Hh, transmembrane protein receptor Patched-1 (Ptch1), transmembrane protein Smoothened (Smo), and nuclear transcription factor Gli protein. Hh signal transduction is a very complicated process: when there is no Hh signal, Ptch1 binds to Smo, inhibits the activity of Smo, and the tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D473/32C07D495/04C07D491/048C07D491/107A61K31/519A61K31/52A61K31/5377A61P35/00A61P35/02
CPCC07D473/32C07D487/04C07D491/048C07D491/107C07D495/04
Inventor 辛敏行唐锋文珺沈晗涂崇兴赵兴俄
Owner HAINAN SIMCERE PHARMA CO LTD
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