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Isoquinoline derivatives with angiogenesis inhibiting activity

A technology of compounds and oxides, applied in the direction of organic active ingredients, medical preparations containing active ingredients, drug combinations, etc.

Inactive Publication Date: 2001-10-24
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Isoquinoline derivatives with angiogenesis inhibiting activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] 3-Bromo-5-trifluoromethylaniline (Fluorochem. Old Glossop, Great Britain); 4-chloro-3-trifluoromethylaniline (Fluka, Buchs, Switzerland). Example 1: 1-(3,5-dimethylanilino)-4-[(pyridin-4-yl)-methyl]-isoquinoline (=N-(3,5-dimethyl-benzene base)-[(4-(pyridin-4-yl-methyl)-isoquinolin-1-yl)-amine]

[0160] Moisture was excluded, 100 mg (0.825 mmol) of 3,5-dimethyl-aniline was dissolved in 4 ml of ethanol, and 196 μl (0.784 mmol) of HCL (4N in dioxane) was added. Then 200 mg (0.785 mmol) of 1-chloro-4-[(pyridin-4-yl)-methyl]-isoquinoline were added and the mixture was heated at 90° C. for 8 hours. Then concentrated by evaporation, the residue was taken up in 4 ml of water, 1 ml of saturated ammonia solution and 20 ml of CH 2 Cl 2 Within, the organic phase is separated off, dried over sodium sulfate (anhydrous) and concentrated again by evaporation. Column chromatography (SiO 2 ; ethyl acetate / hexane 3:1) and crystallization from ethyl acetate / hexane to obtain the title ...

Embodiment 132

[0174] Similarly, the following compound was prepared as described above: Example 131: 1-(4-Chloro-anilino)-4-(4-pyridyl-methyl)-5,6,7,8-tetrahydro-iso Quinoline Example 132: 1-(3-Chlorobenzylamino)-4-[(pyridin-4-yl)-methyl]-isoquinoline

[0175] Exclude moisture, stir 1.6ml (13.1mmol) 3-chlorobenzylamine and 800mg (3.14mmol) 1-chloro-4-(pyridin-4-ylmethyl)-isoquinoline (Example 1e) at 150°C 2 hours. The mixture was then suspended in ethyl acetate, 1 ml of concentrated ammonia solution was added, washed with water and brine, and dried (Na 2 SO 4 ) organic phase and concentrated by evaporation. Column chromatography (SiO 2 ; Ethyl acetate) to obtain the title compound: m.p.141-142 ° C; 1 H NMR (DMSO-d 6 )8.39(d,2H),8.31(d,1H),8.03(t,HN),7.82(s,1H),7.69(d,1H),7.61(t,1H),7.50(t,1H), 7.40(s,1H),7.33(m,2H),7.26(m,1H),7.20(d,2H),4.73(d,2H),4.14(s,2H); FAB-MS:(M+H ) + =360; elemental analysis (C 22 h 18 N 3 Cl) C 73.43%, H 5.04%, N 11.68%, Cl 9.85%; found values: C 73.2%,...

Embodiment 142

[0184] Example 142: Soft capsules

[0185] 5000 soft gelatin capsules were prepared as follows, each containing as active ingredient 0.05 g of one of the compounds of formula I mentioned in the previous examples: Composition: active ingredient 250 g Lauroglykol 2 liters

[0186] Preparation method: Suspend the powdered active ingredient in Lauroglykol  (Propylene glycol laurate, Gattefosse S.A., Saint Priest, France), and ground into about 1-3 μm particle size in a wet mill, and then utilize a capsule filling machine to fill each 0.419 g mixture into soft gelatin capsules.

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Abstract

The invention relates to compounds of formula (I) wherein r is from 0 to 2; n is from 0 to 2; m is from 0 to 4; A, B, D and E are each independently of the others N or CH, with the proviso that not more than two of those radicals are N; G is lower alkylene, -CH2-O-, -CH2-S-, -CH2-NH-, oxa (-O-), thia (-S-) or imino (-NH-), or is lower alkylene substituted by acyloxy or by hydroxy; Q is lower alkyl, especially methyl; R is H or lower alkyl; X is imino, oxa or thia; Y is lower alkyl or, especially, aryl, heteroaryl or unsubstituted or substituted cycloalkyl; and Z is amino, mono- or di-substituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, phenylsulphonyl, phenyl-lower alkanesulfonyl or alkylphenylsulfonyl, and where, if more than one radical Z is present (m> / =2), the substituents Z are identical or different; and wherein the bonds indicated by a wavy line are either single bonds or double bonds; or an N-oxide of the mentioned compound, wherein one or more N atoms carry an oxygen atom; or a salt thereof. The compounds inhibit especially angiogenesis.

Description

[0001] The present invention relates to novel isoquinoline derivatives, their preparation and their use in methods of treatment of the human or animal body, their alone or in combination with one or more other pharmaceutically active compounds for the treatment of diseases (especially proliferative diseases) such as tumor diseases, methods for treating such diseases in animals, especially humans, and the use of such compounds alone or in combination with one or more other pharmaceutically active compounds for the preparation of drugs for the treatment of especially proliferative diseases such as tumors Use of a pharmaceutical composition (drug). Background of the invention [0002] The growth of the vasculature of animal organs and tissues and the transient phases of neovascularization, for example during the menstrual cycle, pregnancy or wound healing, involve two processes, the de novo formation of blood vessels (vasculature) from differentiated endothelial or hemangioblast c...

Claims

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Application Information

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IPC IPC(8): A61K31/4725A61K31/506A61P35/00A61P43/00C07D401/06C07D401/12C07D401/14C07D405/14C07D413/14
CPCC07D401/14C07D401/12C07D405/14C07D401/06A61P35/00A61P43/00
Inventor K-H·奥尔特曼G·博尔德P·W·曼利
Owner NOVARTIS AG
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