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Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof

A technology of thrombin inhibitors and heterocyclic compounds, which is applied in the field of chemical synthesis, can solve the problems of low yields of synthetic key intermediate compounds, achieve the effects of inhibiting thrombin production, simple operation and separation, and high yields

Inactive Publication Date: 2010-03-10
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in this route, take CDI as condensing agent to synthesize key intermediate compound (i) productive rate is low, and Chinese patent application (publication number: CN1861596) uses HOBt / EDCI to replace CDI, optimizes part steps simultaneously, has obtained better result

Method used

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  • Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof
  • Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof
  • Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0068] When R 1 When it is 2-pyridine,

[0069] Synthesis of 3-({2-[(4-cyano-phenylimine)-methylene]-1-methylene-1hydro-benzimidazole-5-carbonyl}-pyridine-2-imine)- Ethyl propionate (1)

[0070] Compound 2-(4-cyano-phenylamino)-acetic acid (2.32g, 13.2mmol) was dissolved in 80ml DMF, HOBT (1.96g, 14.5mmol) was added, and EDCI (2.77g, 14.5mmol) was added below 0°C ) stirred for 10-60min, slowly rose to room temperature, added diamine compound 3-(N,N-(2-pyridine)-[3-amino-4-methylamino-benzoyl]-propionic acid ethyl ester (5.0 g, 14.5mmol).Reacted for 2~6h, concentrated, diluted with a large amount of ethyl acetate, washed three times with saturated brine, and washed with Na 2 SO 4 After drying and concentration, the crude product was refluxed in 60ml of acetic acid for 1.5h. After concentration, it was basified and extracted with ethyl acetate (60mL×3) three times. The organic phase was washed once with saturated brine, washed with Na 2 SO 4 After drying and concentration,...

Embodiment 2

[0085] When R 1 For 2-pyridine:

[0086] Synthesis of 3-({2-[(4-nitro-phenylimine)-methylene]-1-methylene-1hydro-benzimidazole-5-carbonyl}-pyridine-2-imine)- Ethyl propionate (7)

[0087] Compound 2-(4-nitro-phenylamino)-acetic acid (3.14g, 15.95mmol) was dissolved in 20ml DMF, HOBT (2.40g, 17.54mmol) was added, and EDCI (3.35g, 17.54mmol) was added below 0°C ) stirred for 5-60min, slowly rose to room temperature, added diamine compound 3-(N,N-(2-pyridine)-[3-amino-4-methylamino-benzoyl]-propionic acid ethyl ester (6.0 g, 17.54mmol).Reacted for 2~6h, concentrated, diluted with a large amount of ethyl acetate, washed three times with saturated brine, and washed with Na 2 SO 4 After drying and concentration, the crude product was refluxed in 30ml of acetic acid for 1.5h, after concentration, it was basified, extracted with ethyl acetate (30mL×3) three times, the organic phase was washed once with saturated brine, washed with Na 2 SO 4 After drying and concentration, the crud...

Embodiment 3

[0099] When R 1 For 4-fluoro-phenyl,

[0100] Synthesis of 3-({2-[(4-methylguanidino-phenylimine)-methylene]-1-methylene-1hydro-benzimidazole-5-carbonyl}-4-fluorophenyl- 2-imino)-propionic acid

[0101] The synthetic method is as embodiment 1,

[0102] 1 H NMRδ (300MHz, DMSO-d 6 ): 7.87(m, 1H), 7.54-7.49(m, 2H), 7.29-7.24(m, 4H), 7.11-7.04(m, 5H), 6.73-6.71(d, 2H), 4.60(s, 2H ), 4.17-4.15(d, 2H), 4.06-4.01(t, 2H), 3.81(s, 3H), 2.58-2.53(t, 2H);

[0103] ESI-MS(M / z): 517.6(M + +1)

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Abstract

The invention belongs to the field of chemosynthesis and relates to a thrombase inhibitor containing guanidyl heterocyclic compound and a preparation method thereof. In the invention, an alkaline group which has high affinity with a thrombase active site is constructed and a compound which has anticoagulation effect and the structural formula is synthesized, and the thrombase inhibitor can be directly prepared. The target compound obtained from the invention undergoes activity tests, and results show that the target compound can obviously inhibit the generation of thrombases. The synthesizingmethod realizes simple step operation separation, utilizes common reagents, has short course and achieves high yield in each step.

Description

technical field [0001] The invention belongs to the field of chemical synthesis and relates to a guanidine-containing heterocyclic compound inhibitor, in particular to a thrombin inhibitor containing a guanidine-containing heterocyclic compound and a preparation method thereof. Background technique [0002] Thromboembolism and its complications are one of the most important causes of morbidity and mortality in today's society. Studies have shown that thrombin plays a very important role in the advancement of blood coagulation, so it has become the preferred target for the development of anticoagulant drugs. Research in the field of anticoagulants has been active and considerable progress has been made over the past few decades. In recent years, the development of anticoagulant drugs with high efficiency, safety, easy oral administration and satisfactory pharmacokinetic and pharmacokinetic properties has been the focus and direction of this field in recent years. [0003] D...

Claims

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Application Information

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IPC IPC(8): C07D235/14C07D401/12A61K31/4184A61K31/454A61P7/02
Inventor 魏邦国马景毅孙逊张岭朱海波林国强王进贤
Owner FUDAN UNIV