# US 9,750,720 B2 · γ-aminobutyric acid (GABA) analogues for the treatment of pain and other disorders

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- Number: US 9,750,720 B2
- Document ID: US9750720B2
- Status: Granted
- Kind: B2
- Application number: 15/359,120
- Filed: 2016-11-22
- Published: 2017-03-16
- Granted: 2017-09-05
- Earliest claimed: 2013-12-18
- Assignees: Novassay S.A.
- Applicants: Novassay S.A.
- Inventors: Premji Meghani; Franz Kricek
- Web page: https://patentgrep.com/patent/US9750720B2

## CPC

- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/4245: Oxadiazoles
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- 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
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 205/50: having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 233/10: with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
- C07C 255/31: having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
- C07C 259/14: having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 257/04: Five-membered rings
- C07D 271/07: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07B 2200/07: Optical isomers
- C07C 2602/20: the ring system containing seven carbon atoms
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

A compound of Formula 1 wherein R1 represents hydrogen, halo, a C1-C4 alkyl group, a C1-C4 alkylhalide group, a C1-C4 alkoxy-C2-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group or a C3-C7 cycloalkyl group; R2 represents or a tautomer thereof; and R3 represents hydrogen, a C1-C4 alkyl group, a C1-C4 alkoxy-C2-C4 alkyl group or a C3-C7 cycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof. Processes to prepare said compounds and novel intermediates are also claimed. Such compound finds utility in treating neuropathic pain and disorders of the central nervous system.

## Claims

### Claim 1

A method of administering to a human subject a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula 1
wherein R1 represents hydrogen, halo, a C1-4 alkyl group, a C1-4 alkylhalide group, a (C1-4 alkoxy)(C2-4 alkyl) group, a C2-4 alkenyl group, a C2-4 alkynyl group or a C3-7 cycloalkyl group;
R2 represents
or a tautomer thereof; and
R3 represents hydrogen, a C1-4 alkyl group, a (C1-4 alkoxy)(C2-4 alkyl) group or a C3-7 cycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof; wherein the method comprises: (i) providing the human subject with the pharmaceutical composition, wherein the pharmaceutical composition is in a form for administration to a human subject, the form selected from the group consisting of a capsule, a caplet, a tablet, and a topical ointment; (ii) administering the form to the human subject, wherein the administering is selected from the group consisting of orally, rectally, parenterally, and topically; and (iii) allowing the compound to bind to an α2δ-1subunit of a voltage-gated calcium channel, wherein the voltage-gated calcium channel is embedded within a cell plasma membrane of the human subject.

### Claim 2 (depends on 1)

The method according to claim 1, the compound having the Formula 2
wherein R1 represents hydrogen, halo, a C1-4 alkyl group, a C1-4 alkylhalide group, a (C1-4 alkoxy)(C2-4 alkyl) group, a C2-4 alkenyl group, a C2-4 alkynyl group or a C3-7 cycloalkyl group;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 3 (depends on 1)

The method according to claim 1, the compound having the Formula 3
wherein R1 represents hydrogen, halo, a C1-4 alkyl group, a C1-4 alkylhalide group, a (C1-4 alkoxy)(C2-4 alkyl) group, a C2-4 alkenyl group, a C2-4 alkynyl group or a C3-7 cycloalkyl group;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 4 (depends on 1)

The method according to claim 1, the compound in which R1 represents ethyl.

### Claim 5 (depends on 1)

The method according to claim 1, the compound having the Formula 4

### Claim 6 (depends on 5)

The method according to claim 5, the compound having the Formula 4a

### Claim 7 (depends on 3)

The method according to claim 3, the compound having the Formula 5

### Claim 8 (depends on 1)

The method according to claim 1, wherein the human subject has neuropathic pain.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the human subject has a disorder of the central nervous system.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the human subject has a disease of the central nervous system and/or the peripheral nervous system.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the human subject has a headache and/or a migraine.

### Claim 12 (depends on 1)

A method of treating neuropathic pain in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof as defined in claim 1.

### Claim 13 (depends on 1)

A method of treating disorders of the central nervous system in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof as defined in claim 1.

### Claim 14 (depends on 1)

A compound of Formula 1 as defined in claim 1 for use in the treatment of neuropathic pain.

### Claim 15 (depends on 1)

A compound of Formula 1 as defined in claim 1 for use in the treatment of diseases of the central and/or the peripheral nervous system.

### Claim 16 (depends on 15)

A compound for the use according to claim 15 for use in the treatment of diseases of the central nervous system.

### Claim 17 (depends on 16)

A compound of Formula 1 as defined in claim 16 for use in the treatment headache and migraine.