Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase

• US 10,513,499 B2
• Filed: 06/02/2017
• Issued: 12/24/2019
• Est. Priority Date: 08/29/2014
• Status: Active Grant

• Current Assignee: TES Pharma SRL
• Original Assignee: TES Pharma SRL
• Inventors: Pellicciari, Roberto, Auwerx, Johan, Raffaelli, Nadia
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US15/612,877
• Publication Number:
  US 20170362185A1
• Time in Patent Office: 935 Days
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 233/68 Halogen atoms
• CPC Class Codes: C07D 233/84 Sulfur atoms
• CPC Class Codes: C07D 233/96 having three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 239/38 One sulfur atom
• CPC Class Codes: C07D 239/56 One oxygen atom and one sulfur atom
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD⁺ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.

Claims

1. A method of treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD⁺) levels selected from the group consisting of a metabolic disorder, a neurodegenerative disease, a chronic inflammatory disease, a fatty liver disease, and a kidney disorder in a subject, the method comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD⁺ levels a therapeutically effective amount of a compound represented by Formula (I):

3. The method of claim 1, wherein the compound is of Formula (Ib):

4. The method of claim 1, wherein the compound is of Formula (II):

5. The method of claim 1, wherein R^c is —

CN or halogen.

6. The method of claim 1, wherein R^d is methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl, or optionally substituted phenyl.

7. The method of claim 1, wherein R^b is hydrogen and R^a is CH₂CO₂H, tetrazole, or oxadiazolone (1,2,4-oxadiazol-5(4H)-one).

8. The method of claim 1, having Formula (Ia):

9. The method of claim 1, wherein R^d is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl, or thienyl.

10. The method of claim 1, wherein R^a is hydrogen, CH₂CO₂H, tetrazole, or oxadiazolone (1,2,4-oxadiazol-5(4H)-one).

11. The method of claim 1, wherein R^b is hydrogen, CH₂CO₂H, tetrazole, or oxadiazolone (1,2,4-oxadiazol-5(4H)-one).

2. A method of treating a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD⁺) levels selected from the group consisting of a metabolic disorder, a neurodegenerative disease, a chronic inflammatory disease, a fatty liver disease, and a kidney disorder in a subject, the method comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD⁺levels a therapeutically effective amount of a compound selected from the group consisting of: