POTENT PHTHALATE INHIBITORS OF ASPARTATE N-ACETYLTRANSFERASE AND SELECTIVE ASPARTATE PATHWAY INHIBITORS

• US 20180250252A1
• Filed: 08/29/2016
• Published: 09/06/2018
• 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
• Granted Patent: US 10,449,168 B2
• Time in Patent Office: 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 compound comprising Formula I or Formula II:

2. The compound of claim 1, wherein the compound comprises Formula II, and R₁ comprises benzyl.

3. The compound of claim 1, wherein the compound comprises Formula II, and R₁ comprises naphthyl.

4. The compound of claim 1, wherein the compound comprises Formula II, n is 1, and R₁ comprises naphthyl.

5. The compound of claim 1, wherein the compound comprises Formula II, n is 2, and R₁ comprises naphthyl.

6. The compound of claim 1, the compound comprises Formula and R₁ comprises biphenyl.

7. The compound of claim 1, wherein the compound comprises Formula III:

20. The compound of claim 1, wherein the compound comprises Formula I, and R is hydrogen, a straight or branched alkane having from 1 to 6 carbons, a halogen, a halogenated alkane having from 1 to 6 carbons, a halogenated alkoxy, or a substituted or unsubstituted cyclic alkane.

21. The compound of claim 1, wherein the compound comprises Formula I, and R 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.

23. The compound of claim 1, wherein the compound consists essentially of a sodium salt of Formula I.

25. A pharmaceutical composition comprising:

an effective amount of a compound of claim 1; and

a pharmaceutically acceptable excipient, diluent, or carrier.

26. A method of making a compound of claim 1, the method comprising:

esterifying a dicarboxylic methylphthalate to produce a methylphthalate dimethyl ester;

bromonating the methylphthalate dimethyl ester to produce a bromomethylphthalate dimethyl ester; and

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

28. A method of making a compound of claim 1, the method comprising:

esterifying a dicarboxylic methylphthalate to produce a methylphthalate dimethyl ester;

bromonating the methylphthalate dimethyl ester to produce a bromomethylphthalate dimethyl ester; and

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

30. A method of making a compound of claim 1, the method comprising:

esterifying a dicarboxylic methylphthalate to produce a methylphthalate dimethyl ester;

bromonating the methylphthalate dimethyl ester to produce a bromomethylphthalate dimethyl ester; and

coupling the bromomethylphthalate dimethyl ester with β

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

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

administering an effective amount of a compound of claim 1 to a cell, wherein the compound is a compound of Formula II, and inhibiting ANAT activity in the cell.

33. A method for treating, preventing, or ameliorating Canavan disease, the method comprising:

administering an effective amount of a compound of claim 1 to a patient in need thereof, wherein the compound is a compound of Formula II, and treating, preventing, or ameliorating Canavan disease.

34. A method of treating an infection, the method comprising:

administering an effective amount of a compound of claim 1 to a patient having an infection, wherein the compound is a compound of Formula I, to treat the infection.

39. A method of blocking the aspartate pathway in a pathogen, the method comprising:

exposing cells of a pathogen to an effective amount of a compound of claim 1 to inhibit aspartate-β

-semialdehyde dehydrogenase (ASADH), and blocking the aspartate pathway in the pathogen, wherein the compound is a compound of Formula I.

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46. A kit for preparing an ANAT inhibitor, the kit comprising:

a first container housing a methylphthalate dimethyl ester; and

a second container housing either an alkyl halide or a benzyl halide

47. The kit of claim 46, further comprising a pharmaceutically acceptable excipient, diluent, or carrier.