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Isoquinoline-3- formyl-LARGD (aa) aa as well as preparation, antivenous thrombotic activity and application thereof

A technology of venous thrombosis and isoquinoline, which is applied in the field of anti-venous thrombosis activity and preparation of anti-venous thrombosis drugs, can solve problems such as little effect, narrow safety window, bleeding, etc.

Inactive Publication Date: 2019-05-28
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although warfarin has been used clinically since 1941, its safety window is narrow
Low doses can cause pulmonary embolism, high doses can cause fatal bleeding
Over the past 50 years, although a lot of effort has been devoted to the invention of safe anti-venous thrombosis drugs, the results have been minimal
In antithrombotic drug research, the inventor once disclosed that intravenous injection of N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-Arg- Gly-Asp(Ser)-Ser,N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-Arg-Gly-Asp(Val)-Val and N -[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-formyl]-Leu-Arg-Gly-Asp(Phe)-Phe can effectively inhibit rat arterial thrombosis, and has no effect on venous thrombosis Therapeutic effect

Method used

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  • Isoquinoline-3- formyl-LARGD (aa) aa as well as preparation, antivenous thrombotic activity and application thereof
  • Isoquinoline-3- formyl-LARGD (aa) aa as well as preparation, antivenous thrombotic activity and application thereof
  • Isoquinoline-3- formyl-LARGD (aa) aa as well as preparation, antivenous thrombotic activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Example 1 Preparation of N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-Ala-Arg-Gly-Asp(aa)-aa

[0013] Prepare N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-Ala-Arg-Gly-Asp(aa)-aa (wherein aa is a Ser, Val or Phe residue).

Embodiment 2

[0014] Example 2 Preparation of isoquinoline-3-formyl-Leu-Ala-Arg-Gly-Asp-(Ser)-Ser(10a)

[0015] 50mg (0.04mmol) N-[(3S)-N-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-Ala-Arg-Gly-Asp(Ser)-Ser in Dissolve with 1mL rat serum at 37°C, shake the obtained solution at a constant temperature of 37°C for 4 hours, and monitor the disappearance of raw materials by TLC. Add 2 mL of methanol to the serum solution and shake at a constant temperature of 37°C for 10 minutes, and the resulting mixed solution is centrifuged at 3000 rpm for 10 minutes. The residue obtained by centrifugation was fully extracted with ultrapure water, and the extract was separated and centrifuged. The supernatant obtained by centrifugation was concentrated under reduced pressure at 37°C, the residue was fully extracted with ultrapure water, and the extract was separated. The combined extracts were lyophilized to yield 33 mg (96%) of the title compound. ESI(+)-FT-MS:860.60580[M+H] + .Mp 138-139℃.[α] D 25 =-...

Embodiment 3

[0016] Example 3 Preparation of isoquinoline-3-formyl-Leu-Ala-Arg-Gly-Asp(Val)-Val(10b)

[0017] According to the method of Example 1, by 50mg (0.04mmol) N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-Ala-Arg-Gly-Asp(Val )-Val yielded 33 mg (96%) of the title compound. ESI(-)-FT-MS:866.41722[M-H] - .Mp 162-163℃.[α] D 25 =-13.1 (c=1.6, CH 3 OH).IR(cm -1 )3448,3250,2965,2383,1656,1544,1458,1392,1250,1170,1027,765,643,514,439. 1 H NMR (300MHz, DMSO) δ / ppm=11.06(s,2H),9.22(s,1H),8.55(s,1H),8.04-8.45(m,7H),7.92(d,J=5.5Hz, 1H), 7.63(d, J=8.0Hz, 1H), 7.49(m, 1H), 7.42(m, 1H), 4.38(d, J=3.9Hz, 1H), 4.37-4.26(m, 3H), 3.21-3.11(m,2H),2.80(d,J=4.8Hz,1H),2.14-2.03(m,2H),1.91-1.77(m,2H),1.91-1.77(m,1H),1.67- 1.53 (m, 5H), 1.35 (d, J=2.1Hz, 3H), 0.91-0.76 (m, 18H).

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Abstract

The invention discloses isoquinoline-3-formyl-Leu-Ala-Arg-Gly-Asp (aa) aa in the following formula as well as a preparation method and antivenous thrombotic activity thereof, wherein aa in the formulais Phe, Ser or Val residue. Therefore, the invention discloses application of the isoquinoline-3-formyl-Leu-Ala-Arg-Gly-Asp (aa) aa in preparing antivenous thrombotic drugs. (The formula is shown inthe description).

Description

technical field [0001] The present invention relates to isoquinoline-3-formyl-Leu-Ala-Arg-Gly-Asp(aa)-aa, to their preparation method, to their anti-venous thrombosis activity, thus the present invention relates to their use in the preparation of anti-venous thrombosis Use in thrombotic drugs. The invention belongs to the field of biomedicine. Background technique [0002] Thrombosis has become a disease with high morbidity and mortality. The number of patients with venous thrombosis, including deep vein thrombosis and pulmonary embolism, exceeds the total incidence of myocardial infarction and stroke, and is higher than the total number of deaths caused by breast cancer and AIDS. The incidence of thrombosis increases exponentially with age, which poses a serious threat to people's health in aging countries like my country. If included in the population base, the absolute negative impact of venous thrombosis on my country's national economy and people's livelihood is part...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/02A61K38/08A61P7/02
Inventor 赵明彭师奇桂琳张筱宜
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES