Novel bichalcophenes and their prodrugs as antiprotozoal agents

A C2-C10, pharmaceutical technology, applied in anti-infective drugs, anti-infective drugs, and resistance to vector-borne diseases, etc., can solve serious side effects and other problems

Inactive Publication Date: 2007-03-28
THE UNIV OF NORTH CAROLINA AT CHAPEL HILL +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, pentamidine must be administered parenterally and causes potentially serious side effects

Method used

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  • Novel bichalcophenes and their prodrugs as antiprotozoal agents
  • Novel bichalcophenes and their prodrugs as antiprotozoal agents
  • Novel bichalcophenes and their prodrugs as antiprotozoal agents

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preparation example Construction

[0344] In some embodiments, the present invention provides a method for preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof, the method comprising:

[0345] (a) contacting a first cyano-substituted heterocyclic compound with N-bromosuccinimide to form a first brominated heterocyclic compound;

[0346] (b) coupling said first brominated heterocyclic compound with a second heterocyclic compound to form a third heterocyclic compound;

[0347] (c) reacting the third heterocyclic compound with one of the following:

[0348] (i) reacting with a strong acid and anhydrous alcohol, followed by reaction with ammonia and anhydrous alcohol, to form a compound of formula (I), wherein the compound of formula (I) is a bisamidine;

[0349] (ii) react with hydroxylamine hydrochloride and base, form the compound of formula (I), wherein the compound of said formula (I) is bisamidoxime; With

[0350] (iii) reacting with lithium bis(trialkylsilyl)amide for a period...

Embodiment 1

[0404] 5'-(4-amidinophenyl)-2,2'-bifuran-5-carboxamidine

[0405]

[0406] Reagents and conditions: (i) NBS, DMF; (ii) 2-tributyltinfuran, Pd(PPh 3 ) 4 ; (iii) CuCN, DMF, 110-120 ° C; (iv) NH 2 OH·HCl, KO-t-Bu, DMSO; (v) AcOH / Ac 2 O; (vi)H 2 / Pd-C, AcOH.

[0407] Synthesis of route 2.5'-(4-amidinophenyl)-2,2'-bifuran-5-carboxamidine

[0408] 4-(5-Bromofuran-2-yl)-benzonitrile (2). Now referring to route 2 above, to 1 (8.45 g, 50 mmol) in DMF (30 ml) was added N-bromo Subsuccinimide (9.79 g, 55 mmol). The reaction mixture was stirred overnight, then poured onto cold water. The formed precipitate was collected, washed with water, and dried to give analytically pure product 2 in 94.2% yield, mp 94-94.5 °C. 1 H NMR (CDCl 3 ): δ6.45(d, J=3.6 Hz, 1H), 6.76(d, J=3.6 Hz, 1H), 7.66(d, J=8.4Hz, 2H), 7.70(d, J=8.4Hz, 2H ). 13 C NMR (CDCl 3 ): δ153.7, 133.5, 132.6, 123.8, 123.6, 118.7, 114.0, 110.7, 110.3. EIMS (m / z, rel.int.): 247 (M + , 50), 140(100), 113(10). C 11 h ...

Embodiment 2

[0417] 6-(5'-amidino-2,2'-bifuran-5-yl)-nicotinamide

[0418] (6-(5'-Amidino-2,2'-bifuran-5-yl)-nicotinamidine)

[0419]

[0420] Reagents and conditions: (i) 2-tributyltinfuran, Pd(PPh 3 ) 4 ; (ii) NBS, DMF; (iii) CuCN, DMF110-120 ° C; (iv) NH 2 OH·HCl, KO-t-Bu, DMSO; (v)a) AcOH / Ac 2 O; b) H 2 / Pd-C,A c Oh.

[0421] Route 3. Synthesis of 6-(5'-amidino-2,2'-bifuran-5-yl)-nicotinamide

[0422] 6-(2,2'-Bifuran-5-yl)-nicotinonitrile (10). Referring now to Scheme 3, start from 9 using the same procedure as described for 3. Yield 78%, mp 169-170°C. 1 H NMR (CDCl 3 ): δ6.52(dd, J=3.6Hz, J=1.8Hz, 1H), 6.74(m, 2H), 7.31(d, J=3.6Hz, 1H), 7.49(d, J=1.8Hz, 1H ), 7.79(d, J=8.4Hz, 1H), 7.95(dd, J=8.4, 2.1Hz, 1H), 8.80(d, J=2.1Hz, 1H). 13 C NMR: δ152.5, 151.3, 151.0, 148.7, 145.5, 142.9, 139.6, 117.6, 117.0, 114.3, 111.7, 108.1, 107.1, 106.6. C 14 h 8 N 2 o 2 Calculated: C, 71.18; H, 3.41; N, 11.85. Found: C, 70.83; H, 3.61; N, 11.84.

[0423] 6-(5'-Bromo-2,2'-bifuran...

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Abstract

Novel dicationic bichalcophene compounds of formula (I) are described. The presently disclosed novel dicationic bichalcophene compounds exhibit in vitro activity versus Trypanosoma brucei rhodesiense, Plasmodium falciparum, or Leishmania donovani comparable to that of pentamidine and furamidine. Some of the novel dicationic bichalcophene compounds displayed good activity in vivo in a murine model of a Trypanosoma brucei rhodesiense infection.

Description

technical field [0001] The present invention relates to methods for combating microbial infections with novel dicative bichalcophene compounds and their prodrugs, methods for the synthesis of novel dicative bichalcophene compounds and their prodrugs, and the novel dicative bichalcophene compounds and their prodrugs themselves. [0002] abbreviation [0003] δ = chemical shift [0004] Ac = acetyl [0005] AcO = acetoxy [0006] AcOH = acetic acid [0007] Ac 2 O = acetic anhydride [0008] Am = amidine [0009] AmOH = amidoxime [0010] Bu = butyl [0011] ℃ = degrees Celsius [0012] calcd = calculated value [0013] cm = centimeter [0014] Cs 2 CO 3 = cesium carbonate [0015] dec = decomposition point [0016] DIBAL = diisobutylaluminum hydride [0017] DMF = dimethylformamide [0018] DMSO = dimethyl sulfoxide [0019] D. 2 O = deuterium oxide [0020] EIMS = Electrospray Ionization Mass Spectrometry [0021] EtOAc = ethyl acetate [0022] EtOH = et...

Claims

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Application Information

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IPC IPC(8): C07D307/54C07D405/14C07D409/14C07D345/00C07D421/14C07D333/24A61K31/34A61K31/381A61K31/4427A61K31/33A61K31/4184A61P33/02
CPCC07D421/14C07D333/24C07D405/14C07D307/54C07D333/38C07D405/12C07D405/04C07D409/14C07D307/68C07D345/00A61P31/00A61P33/02A61P33/06Y02A50/30
Inventor 理查德·R.·蒂德韦尔戴维·W.·博伊金查德·E.·斯蒂芬斯穆罕默德·A.·伊斯梅尔W.·戴维·威尔逊雷托·布隆卡尔·韦尔鲍沃茨
Owner THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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