Optical isomers used as tyrosine kinase inhibitors

An optical isomer and pharmaceutical technology, applied in the field of medicine, can solve problems such as toxic side effects and no efficacy

Inactive Publication Date: 2015-09-09
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In many cases, the inferior isomer not only has no medicinal effect, but also partially offsets the medicinal effect of the superior enantiomer, and sometimes even produces serious toxic and side effects, showing the complexity of the difference in medicinal effect, which also determines the The therapeutic index of a single enantiomer is quite different from its racemate. For example, the curative effect of the well-known DL-(+-) synmycin is only half of that of D(-) chloramphenicol; propranolol L-isomer The drug activity of the isomer is 100 times greater than that of the D-isomer

Method used

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  • Optical isomers used as tyrosine kinase inhibitors
  • Optical isomers used as tyrosine kinase inhibitors
  • Optical isomers used as tyrosine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Example 1N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylthio)pyrimidin-4-ylamino)phenyl)acrylamide preparation of

[0176]

[0177] (1) Preparation of tert-butyl 3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylthio)pyrimidin-4-ylamino)phenylcarbamate

[0178]

[0179] Dissolve tert-butyl 3-(2-chloro-5-(methylthio)pyrimidin-4-ylamino)phenylcarbamate (0.25g, 0.68mmol) in 10mL of tert-amyl alcohol, then add 2 drops of acetic acid , 4-(2-methoxyethoxy)aniline (0.119g, 0.71mmol), the reaction was stirred at 85°C for 1h. The system was spin-dried, and column chromatography (PE:EA=8:1—2:1) gave 0.15 g of a white solid, with a yield of 44.1%.

[0180] (2)N 4 -(3-Aminophenyl)-N 2 Preparation of -(4-(2-methoxyethoxy)phenyl)-5-(methylthio)pyrimidine-2,4-diamine

[0181]

[0182] tert-butyl 3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylthio)pyrimidin-4-ylamino)phenylcarbamate (0.14g, 0.28mmol ) was dissolved in 10 mL of DCM, reacted with HCl gas under ice bath for 1 h, and...

Embodiment 2

[0188] Example 2N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl) Preparation of acrylamide

[0189]

[0190] N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylthio)pyrimidin-4-ylamino)phenyl)acrylamide (0.045g, 0.1 mmol) was dissolved in methanol and refluxed for 3 h, spin-dried, and the preparative solution was purified by phase phase (methanol / water=57%) to obtain 9 mg of white solid. Yield: 19.3%.

[0191] Molecular formula: C 23 h 25 N 5 o 4 S Molecular weight: 467.16 Mass spectrum (m / z): 468.2 (M+H) +

[0192] 1 H-NMR (DMSO-d 6 ,400MHz)δ(ppm): 10.17(1H,s),9.54(2H,s),8.20(1H,s),7.73(1H,s),7.55-7.45(3H,m),7.39(1H,d ),7.29(1H,t),6.82-6.73(2H,m),6.42(1H,dd),6.24(1H,dd),5.75(1H,dd),4.00(2H,t),3.62(2H, t), 3.29(3H,s), 2.95(3H,s).

Embodiment 3

[0193] Example 3 (R)-N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl ) Acrylamide and (S)-N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl ) C Preparation of enamide

[0194]

[0195] Method 1: Chiral resolution of N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylsulfinyl)pyrimidin-4-ylamino) using chromatographic column ) phenyl) acrylamide, adopt HPLC method, use Daicel's preparation equipment and Daicel chiral column chiral isomer separation, collect its corresponding component, t R =3.694min,t R =4.748min. The solvent was removed by rotary evaporation to obtain the pure product of the optical isomer. HPLC separation conditions:

[0196]

[0197]Method 2: Oxidation of N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylthio)pyrimidin-4-ylamino)phenyl group after addition of chiral reagent ) acrylamide, chiral inducing N-(3-(2-(4-(2-methoxyethoxy)anilino)-5-(methylsulfinyl)pyrimidin-4-ylamino)phenyl ...

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to optical isomers represented by the formula (II) and the formula (III) and used as tyrosine kinase inhibitors, and pharmaceutically acceptable salts thereof. The invention also relates to preparation methods of the optical isomers, pharmaceutical preparations containing the optical isomers, and the optical isomers playing important roles in preparation of drugs for prevention and / or treatment of B cell related leukemia (such as B cell chronic lymphocytic cancer, non-hodgkin lymphoma and the like), inflammatory and autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus and the like).

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an optical isomer as a tyrosine kinase inhibitor and a pharmaceutically acceptable salt thereof, a preparation method of the isomer, a pharmaceutical preparation containing the isomer, and The isomer is used in the preparation for the prevention and / or treatment of B cell-related blood cancers (such as B cell chronic lymphocytic carcinoma, non-Hodgkin's lymphoma), inflammatory and autoimmune diseases (such as rheumatoid arthritis) , systemic lupus erythematosus, etc.) plays an important role. 2. Background technology [0002] Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins (T. Hunter, Cell 198 750:823-829). In particular, tyrosine kinases phosphorylate the phenolic moieties of proteins at tyrosine residues. The tyrosine kinase family includes members th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07B57/00A61K31/505A61P35/00A61P29/00A61P37/02
CPCC07D239/48C07B57/00C07B2200/07
Inventor 王爱臣
Owner KBP BIOSCIENCES CO LTD
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