Thiosemicarbazates and uses thereof
View Patent ↗Thioesters, thiocarbamates, thiocarbazates, semithiocarbazates, peptides, aza-amino acid conjugates, and azapeptides; and a chemoselective and site-specific functionalization protocol of protected thiocarbazates and semithiocarbazates are described. The protocol features the use of Mitsunobu reaction to alkylate specifically the nitrogen atom close to the acylthiol moiety with alcohols to produce protected mono-substituted thiocarbazates that can be stored for months, activated under mild conditions at low temperature using halonium reagents and integrated orthogonally to make substituted semicarbazides that can be used, e.g., as synthons in synthesis of aza-amino acid conjugates, azapeptides and other peptidomimetics. Methods for preparing and using ureases, carbazides, semicarbazides, beta-peptides, azapeptides, and other peptidomimetics and azapeptide conjugates, and uses of ureases, carbazides, semicarbazides, beta-peptides, azapeptides in drug discovery, diagnosis, inhibition, prevention and treatment of diseases are also described.
1 . A compound of the Formula (I):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
Y is NR 1 ;
X is NR 5 ;
D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and
R 5 is H, an unsubstituted alkyl, unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted, or an alkyl substituted one or more times by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C 1 -C 6 haloalkyl, and a protecting group, wherein R is an alkyl; or
R 1 and R 5 are together joined by —(CH 2 —CH 2 —CH 2 )—.
2 . The compound according to claim 1 , wherein A is selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and carboxybenzyl.
3 . A compound of the Formula (I):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
Y is NR 1 ;
X is NR 5 ;
D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 is a radical of an amino acid, wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C 1 -C 6 haloalkyl, and a protecting group, wherein R is alkyl; and
R 5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted.
4 . A compound of the Formula (I):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
Y is NR 1 ;
X is NR 5 ;
D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and
R 5 is a radical of an amino acid wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, a C 1 -C 6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C 1 -C 6 haloalkyl, and a protecting group, wherein R is alkyl.
5 . A compound of the Formula (I):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
Y is NR 1 ;
X is NR 5 ;
D is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the substituents are selected from the group consisting of halo, C 1 -C 6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, and C 1 -C 6 haloalkyl, wherein R is alkyl,
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and
R 5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted.
6 . The compound according to claim 1 , A compound of the Formula (I):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
Y is NR 1 ;
X is NR 5 ;
D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
R 1 is a radical of an amino acid wherein the amino acid is an unnatural amino acid, and
R 5 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted.
7 . The compound according to claim 1 , A compound of the Formula (I):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
Y is NR 1 ;
X is NR 5 ;
D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and
R 5 is a radical of an amino acid wherein the amino acid is an unnatural amino acid.
8 . The compound according to claim 1 , which is of the formula:
9 . The compound according to claim 8 , wherein A is selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and carboxybenzyl.
10 . The compound according to claim 1 , which is of the formula:
wherein R 9 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted.
11 . A compound of the Formula (V):
wherein
A is a protecting group selected from the group consisting of tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, 2,2,4,6,7,-pendamethyl-dihydrobenzofuran-5-sulfonyl, triphenylmethyl, tert-butylcarbonyl, t-butoxy, allyloxycarbonyl, methoxytrimethylbenzene sulfonyl, 4,4-dimethoxy benzhydryl, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, 2,4,6-trimethoxybenzyl, allylcarbonyl, and acetamidomethyl;
D is H, Cl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 10 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted.
12 . The compound according to claim 1 , wherein R 1 is a radical of an amino acid, wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C 1 -C 6 haloalkyl, and a protecting group, wherein R is alkyl.
13 . The compound according to claim 12 , wherein R 5 is a radical of an amino acid, wherein the amino acid is selected from the group consisting of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine, which are unsubstituted or substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, —COOR, —COR, methoxy, ethoxy, propoxy, C 1 -C 6 haloalkyl, and a protecting group, wherein R is alkyl.
14 . A process for synthesizing an aza-peptide comprising activating an acyl thiol with TCCA or a combination of TCCA and TBACl to form an acyl chloride and coupling the acyl chloride with an amine, wherein the acyl thiol is a compound according to claim 1 .
15 . A process for preparing a compound according to claim 1 , which comprises forming the compound by reacting a semi-protected hydrazine with chlorothioformate to form an S-alkylthiocarbazate, and alkylating the resulting S-alkylthiocarbazate selectively via Mitsunobu reaction, a direct alkylation with a combination of NaH or Barton's base and an alkyl halide.
16 . The compound according to claim 1 , wherein:
R 1 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is unsubstituted or substituted; and
R 5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkylene, optionally protected alkyl amine, or a side chain radical of an amino acid, which is substituted or unsubstituted.
17 . The compound according to claim 1 , wherein:
R 1 is H, substituted or unsubstituted alkyl, or a side chain radical of an amino acid, which is unsubstituted or substituted; and
R 5 is substituted or unsubstituted alkyl, or a side chain radical of an amino acid, which is substituted or unsubstituted.
18 . The compound according to claim 1 , wherein A is fluorenylmethoxycarbonyl.
19 . The compound according to claim 1 , wherein D is ethyl.
20 . The compound according to claim 1 , wherein A is fluorenylmethoxycarbonyl, and D is ethyl.
21 . The compound according to claim 1 , wherein A is 9-fluorenylmethoxycarbonyl, R 1 is H; and D is ethyl.