Amide derivatives of squalamine for the treatment of infections

A technology of compounds and mixtures, applied in the direction of anti-infectives, drug combinations, steroids, etc., can solve the problems of cytotoxicity, low activity, etc.

Active Publication Date: 2019-07-09
VIRB AC SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, applicants have observed that these compounds have significant cytotoxicity and that the compounds of formula IIc and IId have low activity against certain Gram-negative bacteria such as E. coli

Method used

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  • Amide derivatives of squalamine for the treatment of infections
  • Amide derivatives of squalamine for the treatment of infections
  • Amide derivatives of squalamine for the treatment of infections

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0232] Example 1 : the preparation of the compound of formula (III) as defined above

Embodiment 11

[0233] Example 1.1 N-isopropyl deoxycholamide 1

[0234]

[0235]2 g (5.1 mmol) of deoxycholic acid dissolved in 20 mL of THF were placed in a two necked round bottom flask equipped with a magnetic bar. Then 1.7 equivalents of HOBT (1.36 g, 8.8 mmol) and 1 equivalent of DCC (1.04 g, 5.1 mmol) were added. 600 [mu]L isopropylamine (13 mmol) was also added and the mixture was stirred at room temperature for 24 hours. After evaporating THF and dissolving the residue in 40 mL CH2Cl2, the precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (eluent: ethyl acetate / methanol (9 / 1)). The desired product 1 was obtained in the form of a white solid (1.9 g).

[0236] 1 H NMR (250MHz, CDCl 3 ):δ(ppm)=4.17(m,2H),2.39-0.63(m,45H). 13 C NMR (63MHz, CDCl 3 ): δ (ppm) = 173.39; 73.17; 71.59; 50.36; 48.93; 48.06; 46.76; 42.09; 41.23; ;26.19;25.62;24.95;23.75;23.10;22.68;17.31;12.69.Yld:79%.C ...

Embodiment 12

[0238] Example 1.2 N-isopropyl chenodeoxycholamide 2

[0239]

[0240] 1 H NMR (250MHz, CDCl 3 ):δ(ppm)=3.96(m,2H),3.69(m,1H),3.31(m,1H),2.30-0.75(m,41H),0.50(s,3H). 13 C NMR (63MHz, CDCl 3 ): δ (ppm) = 172.88, 72.02, 68.53, 60.46, 55.80, 50.45, 42.69, 41.49, 41.28, 39.83, 39.64, 39.41, 35.47, 35.33, 35.06, 34.60, 33.75, 32.83, 31.83, 28.0 ,22.83,20.59,18.42,14.22,11.78.Yld:67%.C 27 h 47 NO 3

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Abstract

The present invention relates to a compound of formula (I), in which R' represents a -(CRaRb)n-X-(CRcRd)m-[Y-(CReRf)o]t-NR9R10 group, and X and Y independently represent a -NR11- group, an -O- group or a divalent heterocyclic group comprising at least one nitrogen atom, with 5 or 6 members; as well as the stereoisomers, stereoisomer mixtures, and / or pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical or veterinary compositions containing same, and to the use of said compositions as a drug, more particularly in the treatment of bacterial, fungal, viral or parasitic infections. The invention further relates to the pharmaceutical or veterinary compositions comprising such a compound of formula (I) in combination with an antibiotic different from such a compound of formula (I).

Description

technical field [0001] The present invention relates to squalamine analogues for use in the treatment of bacterial, fungal, viral or parasitic infections in humans or animals, and also to pharmaceutical or veterinary compositions comprising them. Background technique [0002] In 1993, squalamine, a natural steroid derived mainly from the tissues of the small shark Squalus acanthias, was shown to be a very active substance, which essentially has anti-angiogenic activity against cells as well as antiviral and antibacterial activity. [0003] [0004] Chemically, squalamine is a new amphiphilic molecule. Therefore, it consists of a non-polar central part (cholestane-type backbone) and two polar ends (polyamine chain and sulfate group). [0005] Initially, this water-soluble polyaminosterol was effective against various Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), fungi (Candida a...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07J41/00C07J9/00A61K31/575A61P31/04A61P31/10A61P31/12A61P33/00
CPCC07J9/005C07J41/0005C07J41/0061A61P31/04A61P31/10A61P31/12A61P33/00A61K31/575C07J9/00
InventorJ-M·布鲁内尔M·布兰切特J-P·马克
OwnerVIRB AC SA