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3-ureidoisoquinolin-8-yl derivatives

A technology of dimethylamino and alkyl, applied in the field of novel 3-ureidoisoquinolin-8-yl derivatives

Inactive Publication Date: 2013-12-25
ACTELION PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no specific example of any 1-(isoquinolin-3-yl)-3-(alkyl)urea in these documents

Method used

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  • 3-ureidoisoquinolin-8-yl derivatives
  • 3-ureidoisoquinolin-8-yl derivatives
  • 3-ureidoisoquinolin-8-yl derivatives

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0968] Preparation of synthetic intermediates

[0969] Preparation A: 1-[8-(Aminomethyl)isoquinolin-3-yl]-3-ethyl-urea:

[0970] A.1. N-(2-bromo-benzyl)-2,2-diethoxy-acetamidine:

[0971] Starting from 2-bromobenzylamine (20.00 g; commercially available) and methyl 2,2-diethoxy-acetimidate (24.46 g; 85% pure) and proceeding in a similar manner to Procedure A , and the title compound (39.31 g) was obtained as yellow oil.

[0972] MS (ESI, m / z): 315.2 and 317.2 [M+H of the two main isotopes + ].

[0973] A.2.8-Bromo-isoquinolin-3-yl-amine:

[0974] Starting from intermediate A.1 (39.31 g) and proceeding in an analogous manner to procedure B without additional purification, the title compound was obtained as a yellow solid (19.66 g; 82% yield over 2 steps).

[0975] 1 H NMR(d6-DMSO)δ: 8.92(s, 1H); 7.53(d, J=8.3Hz, 1H); 7.41-7.37(m, 1H); 7.33-7.26(m, 1H); 6.61(s, 1H); 6.18(br.s, 2H).

[0976] MS (ESI, m / z): 223.2 and 225.2 [M+H of the two main isotopes + ].

[0977] A.3....

example 1

[1068] Example 1: But-3-ynoic acid [3-(3-ethyl-ureido)-isoquinolin-8-ylmethyl]-amide:

[1069] Starting from the compound of Preparation A and 3-butynoic acid and proceeding in an analogous manner to Procedure G, the title compound was obtained as a white solid (31% yield) after purification by preparative HPLC (basic conditions). ).

[1070] 1 H NMR(d6-DMSO)δ: 9.18(s,1H); 9.01(s,1H); 8.47(t,J=5.7Hz,1H); 8.00(s,1H);7.70-7.64(m,1H) ;7.55(dd,J=8.3,6.9Hz,1H);7.28(d,J=6.4Hz,1H);7.09(t,J=5.4Hz,1H);5.79(t,J=6.6Hz,1H) ; 5.31(d, J=6.6Hz, 2H); 4.79(d, J=5.7Hz, 2H); 3.21-3.11(m, 2H); 1.08(t, J=7.2Hz, 3H).

[1071] LC-MS (01): MS (ESI, m / z): 311.2 [M+H + ];t R =0.58min.

example 2

[1072] Example 2: N-[3-(3-Ethyl-ureido)-isoquinolin-8-ylmethyl]-isonicotine:

[1073] Starting from the compound of Preparation A and isonicotinic acid and proceeding in an analogous manner to Procedure H, the title compound was obtained as an amorphous solid after purification by preparative HPLC (basic conditions) (55% yield) .

[1074] LC-MS (01): MS (ESI, m / z): 350.2 [M+H + ];t R =0.53min.

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Abstract

The invention relates to 3-ureidoisoquinolin-8-yl derivatives of formula II, wherein R1 is alkyl, haloalkyl or cyclopropyl; R2 is H, halogen, pyridazin-4-yl, pyrimidin-5-yl or an optionally substituted pyridin-3-yl, pyridin-4-yl or phenyl group; R3 is alkyl, alkynyl, aminoalkyl, carbamoylalkyl, methylcarbamoylalkyl, alkoxy, haloalkoxy, alkynyloxy, (4-hydroxybut-2-yn-1-yl)oxy, (4-aminobut-2-yn-1-yl)oxy, dimethylaminoalkoxy, carbamoylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkoxy, carboxyalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, aryl, heteroaryl, benzyl, benzyloxy, 2-cyanoethoxy, 2,3-dihydroxypropoxy, 3,4-dihydroxybutoxy, -CH2Ra, -CH2CH2Rb, -(CH2)n-C(O)O-Rd, -(CH2) n -N(Rc)C(O)O-Rd, -O-(CH2)n -N(Rc)C(O)O-Rd, -(CH2)n-Re or -O-(CH2)n-Re; Ra is cyano, acetylamino or N,N-dimethylamino; Rb is cyano or carbamoyl; Rc is H or methyl; Rd is alkyl; Re is pyrrolidin-1-yl, piperidin-1-yl, piperidin-3-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl, 5-oxopyrrolidin-2-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl, 4-(tert-butoxycarbonyl)piperazin-1-yl, 4-(aminomethyl)cyclohexyl or heteroaryl; R4 is H or methyl; and to the salts of such compounds. These compounds are useful for the prevention or the treatment of bacterial infections.

Description

technical field [0001] The present invention relates to novel 3-ureidoisoquinolin-8-yl derivatives, pharmaceutical antibacterial compositions containing them and the use of these compounds in the manufacture of medicaments for the treatment of infections, such as bacterial infections. These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including, inter alia, Gram-positive and Gram-negative aerobic and anaerobic bacteria and mycobacteria. agent. Background technique [0002] The overuse of antibiotics has exerted selective evolutionary pressure on microorganisms to develop genetic-based resistance mechanisms. Modern medical and socio-economic practices present problems by exacerbating resistance to pathogenic micro-organisms through slow growth conditions (eg in artificial joints) and by supporting long-term host reservoirs (eg in immunocompromised patients). [0003] Increasingly, strains of Staphylococcus aureus, S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/22C07D401/04C07D401/12C07D401/14A61K31/472A61K31/4725A61P31/04
CPCC07D401/04C07D401/12C07D401/14C07D217/22A61P31/04A61K31/472
Inventor 马库斯·古德克里斯蒂安·哈伯舒兰菲利普·潘彻德
Owner ACTELION PHARM LTD