Potent phthalate inhibitors of aspartate N-acetyltransferase and selective aspartate pathway inhibitors

• US 10,449,168 B2
• Filed: 08/29/2016
• Issued: 10/22/2019
• Est. Priority Date: 08/31/2015
• Status: Active Grant

• Current Assignee: University of Toledo
• Original Assignee: University of Toledo
• Inventors: Viola, Ronald E., Thangavelu, Bharani, Mutthamsetty, Vinay, Wang, Qinzhe, Bhansali, Pravin
• Primary Examiner(s): Rodriguez-Garcia, Valerie
• Application Number:
  US15/755,447
• Publication Number:
  US 20180250252A1
• Time in Patent Office: 1,149 Days
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: C07C 227/18 by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• CPC Class Codes: C07C 229/38 having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Phthalate derivatives that are aspartate-P-semialdehyde dehydrogenase (ASADH) inhibitor compounds, aspartate N-acetyltransferase (ANAT) inhibitor compounds, or both, are described, as well as methods of making the same, and methods of using the same.

Claims

1. A composition comprising Formula II:

2. The composition of claim 1, wherein R₁ is benzyl.

3. The composition of claim 1, wherein R₁ is naphthyl.

4. The composition of claim 1, wherein n is 1, and R₁ is aryl or aryloxy.

5. The composition of claim 1, wherein n is 2, and R₁ is aryl or aryloxy.

6. The composition of claim 1, wherein R₁ is biphenyl.

10. The composition of claim 1, wherein the composition consists essentially of a sodium salt of Formula II.

11. A pharmaceutical composition comprising:

a composition of claim 1; and

a pharmaceutically acceptable excipient, diluent, or carrier.

12. A method of making a composition of claim 1, the method comprising:

i) esterifying a dicarboxylic methylphthalate to produce a methylphthalate dimethyl ester;

ii) bromonating the methylphthalate dimethyl ester to produce a bromomethylphthalate dimethyl ester by either;

a) coupling the bromomethylphthalate dimethyl ester with glycine methyl ester to produce an esterified N-carboxymethyl dicarboxybenzylamine;

or,

b) coupling the bromomethylphthalate dimethyl ester with β

-alanine methyl ester to produce an esterified N-carboxyethyl dicarboxybenzylamine;

and,

iii) reacting the bromomethylphthalate dimethyl ester with an alkyl halide or a benzyl halide to produce an ester compound.

13. A method of inhibiting ANAT activity in a cell, the method comprising:

administering a composition of claim 1 to a cell, and inhibiting ANAT activity in the cell.

14. The composition of claim 1, wherein the compound is selected from:

N-carboxymethyl-3,4-dicarboxybenzylamine;

N-carboxyethyl-3,4-dicarboxybenzylamine;

N-((2-methyl)carboxymethyl)-3,4-dicarboxybenzylamine;

N-((2-hydroxymethyl)carboxymethyl)-3,4-dicarboxybenzylamine;

N-methyl, N-carboxymethyl-2,3-dicarboxybenzylamine;

N-methyl, N-carboxymethyl-3,4-dicarboxybenzylamine;

N-allyl, N-carboxymethyl-3,4-dicarboxybenzylamine;

N-acetonitrile, N-carboxymethyl-3,4-dicarboxybenzylamine;

N-benzyl, N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(1-naphthyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(2-naphthyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(ethylmorpholino)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-biphenyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(2-bromobenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(3-bromobenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-bromobenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(2-methylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(3-methylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-methylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(2-trifluoromethylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(3-trifluoromethylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-trifluoromethylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(2-trifluoromethyoxybenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(3-trifluoromethoxybenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-trifluoromethoxybenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-difluoromethoxybenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-carboxybenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-carboxamidebenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-t-butylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-(2-perfluoropropyl))-N-carboxymethyl-3,4-dicarboxybenzylamine;

N-(4-bromobenzyl)-N-carboxyethyl-3,4-dicarboxybenzylamine;

N-(4-trifluoromethylbenzyl)-N-carboxymethyl-3,4-dicarboxybenzylamine;

or,

N-acetal-N-carboxymethyl-3,4-dicarboxybenzylamine.

7. A composition comprising Formula III:

8. A composition comprising Formula III:

9. The composition of claim 8, wherein R₂ is selected from the group consisting of:

H, 4-bromo, 4-methyl, 4-trifluoromethyl, 4-trifluoromethoxy, 4-difluoromethoxy, 4-tert-butyl, 4-(2-perfluoropropyl), 4-phenyl, 4-((2-benzyl)vinyl), and 4-trifluoromethyl.