Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIA

A technology of heterocycles and compounds, applied in the field of preparation

Inactive Publication Date: 2011-05-11
SANOFI AVENTIS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Just as excessive clotting can lead to serious pathological conditions due to thrombosis, antithrombotic therapy can lead to unwanted bleeding risks due to interference with the formation of essential hemostatic emboli

Method used

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  • Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIA
  • Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIA
  • Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIA

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0307] (S)-6-amino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2] Octadeca-1(17), 14(18), 15-trien-12-yl)ureido]hexanoic acid

[0308]

[0309] A. (S)-3-Methyl-2-{[1-phenylmethylene]amino}butan-1-ol

[0310] Add 2.64ml (2.78g, 26.16mmol) of benzaldehyde to a solution of 2.57g (24.91mmol) of L-valinol (L-valinol) in 28ml of toluene with stirring, and heat the mixture to reflux (using a water trap) for 1 hour . After cooling, it was concentrated and recrystallized from heptane. Suction filtration and drying under reduced pressure gave a colorless solid (3.74g).

[0311] 1 H-NMR (DMSO-d6, 400MHz) δ [ppm] = 8.23 ​​(s, 1H), 7.77 (d, 2H), 7.45-7.40 (m, 3H), 4.49 (t, 1H), 3.68-3.31 (m , 1H), 3.48-3.40 (m, 1H), 2.96 (ddd, 1H), 1.94-1.81 (m, 1H), 0.88 (s, 5H).

[0312] B. (S)-1-allyloxymethyl-2-methylpropylamine

[0313] Add 1.25 g (60%, 31.36 mmol) of sodium hydride to 3.00 g (15.68 mmol) of (S)-3-methyl-2-{[1-phenylmethylene]amino}butan-1-ol in In 28 mL ...

Embodiment 2-1

[0335] (S)-6-amino-2-[3-((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2] Docos-1(21), 18(22), 19-trien-16-yl)ureido]hexanoic acid

[0336] A. (R)-1-(2-hept-6-enyloxyethyl)-2-methylpropylamine

[0337] Prepare 3.00 g (15.68 mmol) of (S)-3-methyl-2-{[1-phenylmethylene]amino}butan-1-ol (1-1A) in 28 ml dry THF under argon To the solution in , 1.50 g (60%, 37.51 mmol) of sodium hydride was added, and the mixture was stirred for 45 minutes. Add 2.83g (15.68mmol) of 7-bromohept-1-ene, then continue to stir overnight, carefully quench with 20ml of methanol, then add 300ml of 1N hydrochloric acid (pH=1), and stir at 40°C for 2h. The mixture was washed with dichloromethane, the aqueous phase was adjusted to pH 14 with 1N aqueous sodium hydroxide solution, and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 0.91 g of crude product were obtained. The crude product was used in further reactions...

Embodiment 3-1

[0349] Example 3-1(S)-6-amino-2-[3-((E)-(9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10- Azabicyclo[12.2.2]octadec-1(17),4,14(18),15-tetraen-12-yl)ureido]hexanoic acid

[0350] The title compound was prepared in a manner analogous to Example 1-1, wherein the hydrogenation step was omitted and the final lyophilization with hydrochloric acid was not carried out, and was obtained directly as the trifluoroacetate salt. LC / MS (Method A): R t =0.89min, m / z: 491.2 [MH + ].

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Abstract

The invention relates to compounds of the formula (I) which are inhibitors of activated thrombin-activable fibrinolysis inhibitor. The compounds of the formula I are suitable for producing medicaments for prophylaxis, secondary prevention and treatment of one or more disorders associated with thromboses, embolisms, hypercoagulability or fibrotic changes.

Description

technical field [0001] The present invention relates to novel compounds of formula I which inhibit the enzyme TAFIa (activated thrombin-activatable fibrinolysis inhibitor), their preparation and their use as medicaments. Background technique [0002] The enzyme TAFIa is generated from the thrombin-activatable fibrinolysis inhibitor zymogen (TAFI) by, for example, thrombin activation. The enzyme TAFI, also known as plasma procarboxypeptidase B, procarboxypeptidase U or procarboxypeptidase R, is a proenzyme similar to carboxypeptidase B (L. Bajzar, Arterioscler. Thromb. Vasc. Biol. 2000, pp. 2511-2518). [0003] During clot formation, thrombin is produced as the end product of the coagulation cascade, which induces the conversion of soluble plasma fibrinogen into an insoluble fibrin matrix. At the same time, thrombin can activate the endogenous fibrinolysis inhibitor TAFI. Thus, during thrombus formation and lysis, activated TAFI (TAFIa) is generated from the zymogen TAFI b...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D273/01A61K31/553A61P7/00
CPCC07D413/14C07D273/01C07D267/00A61K31/395C07D273/02C07D413/12A61P11/00A61P11/08A61P17/02A61P19/02A61P27/00A61P27/02A61P29/00A61P3/00A61P3/04A61P31/04A61P35/00A61P35/04A61P7/00A61P7/02A61P7/04A61P9/00A61P9/06A61P9/10A61P3/10
Inventor 克里斯托弗·卡勒斯马克·不伦斯特拉普安德烈亚斯·埃弗尔斯安贾·格洛比希赫尔曼·施鲁德迈克尔·瓦格纳
Owner SANOFI AVENTIS SA
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