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Crystalline modifications of n-a-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or salts thereof

A technology of triisopropylbenzene, ethoxycarbonylpiperazine for oral application

Active Publication Date: 2012-11-14
LINK HEALTH GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For this reason, it is not suitable for large-scale preparations and must first be protected from heat and moisture

Method used

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  • Crystalline modifications of n-a-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or salts thereof
  • Crystalline modifications of n-a-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or salts thereof
  • Crystalline modifications of n-a-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or salts thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0069] Preparation of various salts of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazid

[0070] These salts were prepared by dissolving 6.0 g of WX-671 in 50 ml of acetone. The acid used was added without dilution in a 25% excess and stirred at room temperature for 2 hours.

[0071] Crystallization conditions

[0072] Table 1.1

[0073] acid equivalent Crystallization conditions dry HCl H 2 SO 4 MsOH BsOH tartaric acid 1.25 molar equivalents 1.25 molar equivalents 1.25 molar equivalents 1.25 molar equivalents 1.25 molar equivalents Clear solution Crystallization from acetone solution Crystallization from acetone solution Clear solution Clear solution High Vacuum High Vacuum High Vacuum High Vacuum High Vacuum

[0074] MsOH: methanesulfonic acid; BsOH: benzenesulfonic acid

[0075] In the second step, the salt is suspended in a suitable solvent for 7 days, filtered, and dried at room t...

Embodiment 2

[0085] Crystallization and Single Crystal X-ray Structure Analysis of WX-671.2(Sulfate)

[0086] A new form of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazid-sulfate is Obtained by suspending the bisulfate salt of compound WX-671 (WX-671.1) in water and by isolating the crystalline compound formed.

[0087] Crystal WX-671.2 was obtained in two different ways:

[0088] a) About 50 mg of WX-671.1 is suspended in about 0.5 ml of water. The suspension was allowed to stand at room temperature. After 6 days the suspension was filtered and the residue was dried in air at room temperature.

[0089] b) About 0.2g of WX-671.1 is suspended in about 2ml of water. The suspension was shaken at 25°C. After 3 days the residue was filtered off and the crystals of WX-671.2 were dried in air at room temperature.

[0090] The X-ray structure was determined from the crystalline material (WX-671.2) prepared here. Single crystals were also...

Embodiment 3

[0101] X-ray Diffraction Method of WX-671.2 (Sulfate)

[0102] The X-ray diffraction pattern was obtained using a Debye-Scherrer diffractometer STOE STADI-P equipped with a position-sensitive detector (PSD, 5°), a germanium [111]-primary monochromator ( Monochromator) and CuKα1.6kW ceramic X-ray tube (1.5406 ). Program used: Stoe WinXpow, version 2.03 (2003).

[0103] chart 3.1

[0104] X-ray Diffraction Method of WX-671.2 - Peak List

[0105]

[0106]

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Abstract

The invention relates to novel crystalline modifications of N-a-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonylpiperazide and / or salts thereof, which can be used as pharmaceutical agents. The invention also relates to said novel crystalline modifications containing pharmaceutical compositions and to pharmaceutical uses.

Description

technical field [0001] The present invention relates to N-alpha-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl useful as a medicament Novel crystal modification (kristalline Modifikationen) of piperazine (piperazid) and / or salt thereof, and pharmaceutical composition and pharmaceutical use containing said new crystal modification. Background technique [0002] From the known chemical name N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxy-carbonyl- The novel crystal variants of the compounds of piperazid according to the invention are potent inhibitors of the serine protease urokinase and are therefore particularly suitable for the treatment of urokinase-associated diseases, such as tumors and metastases, especially for oral application. The free base form is designated WX-671. [0003] The urokinase-type plasminogen activator (uPA) plays a key role in tumor invasion and metastasis formation (Schmitt ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/185
CPCC07D295/185C07D295/205A61P1/00A61P9/10A61P9/12A61P17/00A61P19/02A61P19/10A61P27/02A61P29/00A61P31/00A61P35/00A61P35/04A61P43/00A61K31/495
Inventor A·戈鲁尼比尔格J·伦兹
Owner LINK HEALTH GRP