Compositions and methods for synthesizing heterocyclic therapeutic compounds
Methods for the synthesis of various novel substituted dipeptide derived nitrogen-containing heterocyclic compounds and their pharmaceutically acceptable salt derivatives are provided. The compounds of the invention are useful as medicaments for the treatment or prevention of disease in a mammal, for example a human. In particular the compounds are useful as immunotherapeutics and anti-microbial drugs or vaccines. These heterocyclic derivatives can be used as an active agent in a pharmaceutical, as well as a diagnostic utility.
1 . A compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein,
W is a member selected from the group consisting of —C(R 5 )(R 5a )—; —C(R 6 )(R 6a )—C(R 7 )(R 7a )—; —C(R 8 )═C(R 9 )—; and —N(R 10 );
X is a member selected from the group consisting of —N(R 1a )C(═Y)N(R 4 )—; —OC(═Y)N(R 4 )—; —N(R 1a )C(═Y)O—; —N(R 1a )S(═O)N(R 4 )—; —N(R 1a )S(═O) 2 N(R 4 )—; and —C(R 1a )(R 3a )C(═Y)N(R 4 )—;
Y and Z represent, each independent from the other, a member selected from the group consisting of oxygen (“O”) or Sulfur (“S”); and
R 1 , R 1a , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 9 , and R 10 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom;
an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof
2 . The compound of claim 1 , wherein W is —C(R 6 )(R 6a )—C(R 7 )(R 7a )—.
3 . The compound of claim 1 , wherein X is —OC(═Y)N(R 4 )—.
4 . The compound of claim 1 , wherein Z is oxygen.
5 . The compound of claim 1 , wherein Z is a sulfur.
6 . The compound of claim 1 , wherein R1 comprises an amino acid side chain.
7 . A process for producing the nitrogen-heterocyclic compound of claim 1 , comprising cyclizing intramolecularly at least one of a dipeptide, dipeptide derivative or a combination thereof, having the general structure (A) in the presence of at least one acid and at least one amine;
where R 1 , R 2 , and R 5 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof.
8 . A process for producing the nitrogen-heterocyclic compound of claim 1 , comprising cyclizing intramolecularly at least one of a dipeptide, dipeptide derivative or a combination thereof, having the general structure (B) in the presence of at least one acid and at least one amine;
where R 1 , R 2 , and R 5 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof.
9 . A process for producing the nitrogen-heterocyclic compound of claim 1 , comprising cyclizing intramolecularly at least one of a dipeptide, dipeptide derivative or combination thereof, having the general structure (C) in the presence of at least one acid and at least one amine;
where R 1 , R 2 , R 6 , and R 7 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C 1 -C 10 ) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof.
10 . A process for producing the nitrogen-heterocyclic compound of claim 1 , comprising cyclizing intramolecularly at least one of a dipeptide, dipeptide derivative or combination thereof, having the general structure (D) in the presence of at least one acid and at least one amine:
where R 1 , R 2 , R 4 , R 6 , and R 7 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof.