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Amidophenoxypropanolamines

An alkoxy and alkyleneoxy technology, which can be used in drug combinations, anti-infectives, active ingredients of heterocyclic compounds, etc., can solve problems such as harmful antimalarial activity

Inactive Publication Date: 2015-02-18
MEDIZINISCHE UNIVET WIEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But conversion of propafenone (A) to "aza-propafenone" (B) is harmful for antimalarial activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0519] 2-{3-[(adamantan-1-ylmethyl)-amino]-2-hydroxy-propoxy}-N-p-tolyl-benzamide (compound of formula I-40)

[0520] Compounds were prepared according to Reaction Scheme 1 above.

[0521] Step a1) 2-Hydroxy-N-p-tolyl-benzamide

[0522] A drop of boron trifluoride diethyl ether was added to a solution of phenyl 2-hydroxybenzoate (1 g, 46.7 mmol) and 4-toluidine (0.5 g, 46.7 mmol) in toluene (5 mL). The resulting reaction mixture was left overnight at room temperature. A crystalline precipitate formed and the crystals were collected by filtration, washed 3 times with cold MTBE and dried in vacuo to afford 2-hydroxy-N-p-tolyl-benzamide in the form of colorless crystals (theoretically 0.81 g, 76%). Chemical characterization data correspond to data from known compounds (CAS 7164-80-9).

[0523] Step b1) 2-oxiranylmethoxy-N-p-tolyl-benzamide

[0524] Freshly powdered KOH (0.7 g, 13.2 mmol) was added to a solution of 2-hydroxy-N-p-tolyl-benzamide (3 g, 13.2 mmol) in MeOH (20...

example 2

[0528] 2-{2-Hydroxy-3-[4-(3-trifluoromethyl-3H-diaziridin-3-yl)-benzylamino]propoxy}-N-(3-methyl-butyl Base)-5-propyn-2-yloxy-benzamide (compound of formula I-44)

[0529] This compound is prepared according to the following reaction scheme 4:

[0530] Reaction scheme 4

[0531]

[0532] Previous step a1) 2-Hydroxy-5-propyn-2-yloxy-benzoic acid methyl ester

[0533] Propargyl bromide (30.7 mL, 285 mmol) was added to 2,5-dihydroxy-benzoic acid methyl ester (40 g, 237.9 mmol) and K 2 CO 3 (40 g, 285 mmol) was suspended in acetone (250 mL) and the reaction mixture was kept at reflux for 20 h. The resulting heterogeneous mixture was filtered and volatile materials were removed under reduced pressure. The remaining oil was neutralized with 2N HCl. The obtained mixture was extracted with EtOAc, the organic phase was washed with saturated NaHCO 3 - the solution was washed once with MgSO 4 dry. The solvent was removed from the dried solution under reduced pressure and th...

example 3

[0543] 2-[3-(Adamantan-2-yl-methyl-amino)-2-hydroxy-propoxy]-N-[4-(3-trifluoromethyl-3H-diaziridine-3- Base)-benzyl]-benzamide (compound of formula I-43)

[0544] This compound was prepared according to Reaction Scheme 2 above.

[0545] Step a2) 2-oxiranylmethoxy-methylbenzoate

[0546] Freshly powdered KOH (0.74 g, 13.1 mmol) was added to a solution of methyl 2-hydroxybenzoate (2 g, 13.1 mmol) in MeOH (15 mL) and the mixture was kept at 60 °C with a rotary evaporator. The solvent was removed from the resulting homogeneous solution under reduced pressure. Racemic epichlorohydrin (10 mL) was added and the resulting mixture was heated to reflux for 5 min. Excess epichlorohydrin was removed under reduced pressure and the resulting oil was diluted with EtOAc (30 mL). The obtained dilutions were washed three times with brine, washed with Na 2 SO 4 Drying, concentration under reduced pressure and purification by chromatography (MTBE / PE 3:2) gave 2-oxiranylmethoxy-benzoic aci...

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PUM

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Abstract

The use of compounds of formula wherein R2, R3, R4, R5, R6 and R7 have several meanings, for the treatment of disorders mediated by protozoan organisms, novel compounds of the above formula and intermediates for the preparation of such compounds, pharmaceutical compositions comprising such novel compounds, a method of treating disorders mediated by protozoan organisms comprising administering such compounds, optionally together with a second drug substance, to a subject in need thereof and the use of such compounds, whenever comprising a photoaffinity label, for the identification of the molecular target(s) of arylamino alcohol antimalarials.

Description

technical field [0001] The present invention relates to amidophenoxypropanolamines which have been found to be useful in the treatment of diseases caused by infections mediated (e.g., caused) by protists, such as malaria, Chagas disease, African trypanosomiasis, trichomoniasis, leishmaniasis, giardiasis, amoeba, toxoplasmosis, trypanosomiasis (animal African trypanosomiasis), babesiosis, piriplasmosis theileria , coccidiosis) effective. Background technique [0002] Many diseases are mediated (eg, caused) by infection by protists such as Apicomplexa, Zoograms, microspores, Plasmodium. The latter is the main cause of malaria prevalent in South Asia and sub-Saharan Africa. [0003] Malaria is caused by four protozoan parasites of the genus Plasmodium that invade and damage the red blood cells of an infected individual. Plasmodium falciparum is the most common and lethal representative of this class, especially in sub-Saharan Africa. Although malaria appears to be a treatab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/14C07D229/02C07C235/46C07C235/60C07D295/088A61K31/166A61K31/396A61K31/445
CPCC07D211/14C07C235/60C07D229/02C07D295/088C07C235/46C07C235/64C07D211/18C07C2601/02C07C2601/18C07C2601/20C07C2603/74A61P33/02A61P33/04A61P33/06A61K31/166A61K31/396A61K31/445C07C235/66C07C237/28
Inventor 休伯特·施塔赫彼得·千波马蒂亚斯·马斯塔利
Owner MEDIZINISCHE UNIVET WIEN
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