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US 7,517,893 B2Granted
Bichalcophenes and their prodrugs as antiprotozoal agents
AssigneesThe University of North Carolina at Chapel Hill, Georgia State University Research Foundation, Inc.
InventorsRichard R. Tidwell, David W. Boykin, Chad Stephens, Mohamed A. Ismail, W. David Wilson, Reto Brun, Karl Werbovetz
Life of this patent
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Abstract
Novel dicationic bichalcophene compounds 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.
Claims33
A compound of Formula (I):
- wherein:
- X1 and X2 are independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1, is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- p is an integer from 0 to 1;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Ar1 and Ar2 are independently selected from the group consisting of phenyl, pyridine, and benzimidazole;
- Am1 and Am2 are each
- wherein:
- each R3 is independently selected from the group consisting of H, hydroxyl, acyloxyl, and alkoxyl;
- each R4, R5, R6, and R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R3 and R4 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R3 and R4 together are:
- wherein s is a number from 1 to 4, and R8 is H or —CONHR9NR10R11, wherein R9 is alkyl, and R10 and R11 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
13 more elements
A method of treating a microbial infection in a subject in need of treatment thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):
- wherein:
- X1 and X2 are independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- p is an integer from 0 to 1;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Ar1 and Ar2 are independently selected from the group consisting of phenyl, pyridine, and benzimidazole;
- Am1 and Am2 are each
- wherein:
- each R3 is independently selected from the group consisting of H, hydroxyl, acyloxyl, and alkoxyl;
- each R4, R5, R6, and R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R3 and R4 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R3 and R4 together are:
- wherein s is a number from 1 to 4, and R8 is H or —CONHR9NR10R1R11, wherein R9 is alkyl, and R10 and R11 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof.
13 more elements
A method for preparing a compound of Formula (I)
- wherein:
- X1 and X2 are independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- p is an integer from 0 to 1;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Ar1 and Ar2 are independently selected from the group consisting of phenyl, pyridine, and benzimidazole;
- Am 1 and Am2 are each
- wherein:
- each R3 is independently selected from the group consisting of H, hydroxyl, acyloxyl, and alkoxyl;
- each R4, R5, R6, and R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R3 and R4 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R3 and R4 together are:
- wherein s is a number from 1 to 4, and R8 is H or —CONHR9NR10R11, wherein R9 is alkyl, and R10 and R11 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof;
- the method comprising:
- (a) contacting a first cyano-substituted heterocyclic compound with N-bromosuccinimide to form a first bromo-heterocyclic compound;
- (b) coupling the first bromo-heterocyclic compound with a second heterocyclic compound to form a third heterocyclic compound;
- (c) reacting the third heterocyclic compound with one of:
- (i) a strong acid and an anhydrous alcohol, followed by ammonia and an anhydrous alcohol to form a compound of Formula (I), wherein the compound of Formula (I) is a bis-amidine;
- (ii) hydroxylamine hydrochloride and a base to form a compound of Formula (I), wherein the compound of Formula (I) is a bis-amidoxime;
- and
- (iii) a lithium bis(trialkylsilyl)amide for a period of time, followed by a strong acid for a period of time to form a compound of Formula (I), wherein the compound of Formula (I) is a bis-amidine.
21 more elements
A method for preparing a compound of Formula (I)
- wherein:
- X1 and X2 are independently selected from the group consisting of O, S, Se, Te, and NR1, wherein R1 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, and substituted aryl;
- p is an integer from 0 to 1;
- each q is independently an integer from 0 to 2;
- each R2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- Ar1 and Ar2 are independently selected from the group consisting of phenyl, pyridine, and benzimidazole;
- Am1 and Am2 are each
- wherein:
- each R3 is independently selected from the group consisting of H, hydroxyl, acyloxyl, and alkoxyl;
- each R4, R5, R6, and R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl;
- or
- R3 and R4 together represent a C2 to C10 alkyl, C2 to C10 hydroxyalkyl, or C2 to C10 alkylene;
- or
- R3 and R4 together are:
- wherein s is a number from 1 to 4, and R8 is H or —CONHR9NR10R11, wherein R9 is alkyl, and R10 and R11 are each independently selected from the group consisting of H and alkyl;
- or a pharmaceutically acceptable salt thereof;
- the method comprising:
- (a) contacting a halo-substituted five-membered aromatic heterocyclic aldehyde with hydroxylamine hydrochloride and acetic anhydride to form a 2-cyano-5-halo-heteroaryl compound;
- (b) coupling the 2-cyano-5-halo-heteroaryl compound with a trialkyltin-substituted five-membered aromatic heterocyclic acetal to form a cyano-substituted diaryl aldehyde,
- (b) contacting the cyano-substituted diaryl aldehyde with 3,4-diaminobenzonitrile and 1,4-benzoquinone to form a benzimidazole;
- (c) contacting the benzimidazole with one of:
- (i) a strong acid and an alcohol to form an intermediate di-imidate, followed by ammonia and an alcohol to form a compound of Formula (I), wherein the compound of Formula (I) is a bis-amidine;
- (ii) hydroxylamine hydrochloride and a base to form a compound of Formula (I), wherein the compound of Formula (I) is a bis-amidoxime;
- and
- (iii) a lithium bis(trialkylsilyl)amide for a period of time, followed by a strong acid for a period of time to form a compound of Formula (I), wherein the compound of Formula (I) is a bis-amidine.
22 more elements
Dependencies are inferred from the claim text.