# US 2014/0155403 A1 · Cyclic triazo and diazo sodium channel blockers

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2014/0155403 A1
- Document ID: US20140155403A1
- Status: Published application
- Kind: A1
- Application number: 14/174,492
- Filed: 2014-02-06
- Published: 2014-06-05
- Earliest claimed: 2008-01-16
- Assignees: University of Greenwich
- Applicants: University of Greenwich
- Inventors: Michael Leach; Laurence Harbige; Dieter Riddall; Karl Franzmann
- Web page: https://patentgrep.com/patent/US20140155403A1

## CPC

- C07D 253/075: Two hetero atoms, in positions 3 and 5
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- 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 25/00: Drugs for disorders of the nervous system
- 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 25/22: 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 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 253/06: 1,2,4-Triazines
- C07D 253/07: with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 253/10: Condensed 1,2,4-triazines; Hydrogenated condensed 1,2,4-triazines
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

A method of treating a disorder. The method includes administering to a subject in need thereof a compound of formula (I): Each of A, N*, X, Y, Z, R1, and R2 is defined herein. Also disclosed are compounds of the formula and a pharmaceutical composition containing such a compound.

## Claims

### Claim 1

A method of treating a disorder comprising administering to a subject in need thereof a compound of general formula (I), or a salt or solvate thereof,
in which:
X and Y are each N;
Z is a single bond or an optionally substituted linking group;
R1 is hydrogen, or a substituent group, or the Y nitrogen is unsubstituted;
R2 is amino or a substituent group;
N* is amino when R1 is hydrogen or ═NH when R1 is a substituent group; or
N* is a group NRaRb where Ra and Rb are independently H or an alkyl group; or
N* is an optionally substituted piperazinyl ring; and
A is an optionally substituted phenyl group or an optionally substituted sulphur containing heterocycle;
wherein the disorder is epilepsy, multiple sclerosis, glaucoma and uveitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia, or trigeminal autonomic cephalalgias.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the phenyl group or sulphur containing heterocycle is substituted with halogen, alkyl or alkoxy.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the phenyl group or sulphur containing heterocycle is substituted with 1, 2, or 3 chlorine or bromine atoms.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of:
3,5-Diamino-6-(3,4,5 trimethoxyphenyl)-1,2,4-triazine [CEN-095];
3,5-Diamino-6-(2-bromophenyl)-1,2,4-triazine [CEN-068];
3,5-Diamino-6-(3-bromophenyl)-1,2,4-triazine [CEN-069];
3,5-Diamino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine [CEN-092];
3,5-Diamino-6-(2,6-dichlorophenyl)-1,2,4-triazine [CEN-104];
3,5-Diamino-6-(3,4-dimethoxyphenyl)-1,2,4-triazine [CEN-115];
3,5-Diamino-6-(2-bromophenyl)-1,2,4-triazine [CEN-068];
3,5-Diamino-6-(3-bromophenyl)-1,2,4-triazine [CEN-069];
3,5-Diamino-6-(2-trifluoromethoxyphenyl)-1,2,4-triazine [CEN-056];
3,5-Diamino-6-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,2,4-triazine [CEN-108];
3,5-Diamino-6-[2-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,2,4-triazine [CEN-137];
3,5-Diamino-6-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,2,4-triazine [CEN-140];
3,5-Diamino-6-[2-difluoromethoxy)phenyl]-1,2,4-triazine [CEN-142];
3,5-Diamino-6-(3-chloro-5-trifluoromethylphenyl)-1,2,4-triazine [CEN-172];
3,5-Diamino-6-[3,5 (bis-trifluoromethyl) phenyl]-1,2,4-triazine [CEN-175];
3,5-Diamino-6-(2-chloro-3-trifluoromethylphenyl)-1,2,4-triazine [CEN-176];
3,5-Diamino-6-[2-chloro-4-(methylsulphonyl) phenyl]-1,2,4-triazine [CEN-179];
3,5-Diamino-6-(2,4,6-triisopropylphenyl)-1,2,4-triazine [CEN-180];
3,5-Diamino-6-(4-tertbutylphenyl)-1,2,4-triazine [CEN-181];
3,5-Diamino-6-(4-n-butylphenyl)-1,2,4-triazine [CEN-183];
3,5-Diamino-6-(3,5-di-tert-butylphenyl)-1,2,4-triazine [CEN-187];
3,5-Diamino-6-(3,5-dimethoxyphenyl)-1,2,4-triazine [CEN-192];
3,5-Diamino-6-[3,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,2,4-triazine [CEN-193];
3,5-Diamino-6-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-1,2,4-triazine [CEN-197];
3,5-Diamino-6-[2,5-bis(trifluoromethyl)phenyl]-1,2,4-triazine [CEN-198];
3,5-Diamino-6-(2-chloro-3-trifluoromethylphenyl)-1,2,4-triazine [CEN-199];
3,5-Diamino-6-(5-chloro-2-trifluoromethylphenyl)-1,2,4-triazine [CEN-200];
3,5-Diamino-6-(2,3,4-trifluorophenyl)-1,2,4-triazine [CEN-206];
3,5-Diamino-6-(2-chloro-4,5-difluorophenyl)-1,2,4-triazine [CEN-207];
3,5-Diamino-6-(2,3,4,5-tetrafluorophenyl)-1,2,4-triazine [CEN-208];
3,5-Diamino-6-(2,3-dichloro-6-trifluoromethylphenyl)-1,2,4-triazine [CEN209;
3,5-Diamino-6-(2,3,4,5,6-pentafluorophenyl)-1,2,4-triazine [CEN-212;
3,5-Diamino-6-(2,3,6-trichlorophenyl)-1,2,4-triazine [CEN-214];
5(3)-Amino-6-(2,3,5-trichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-(2,2-difluoroethyl)-1,2,4-triazine [CEN-085];
5(3)-Amino-6-(2,3,-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-(2,2,2-trifluoroethyl)-1,2,4-triazine [CEN-067];
5(3)-Amino-6-(2,3,-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-(2-isopropoxy)ethyl-1,2,4-triazine [CEN-091];
5(3)-Amino-6-phenyl-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine methanesulfonate [CEN-051];
5(3)-Amino-6-(2,5-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-053];
5(3)-Amino-6-(3,5-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-059];
5(3)-Amino-6-(2-difluoromethoxyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-146];
5(3)-Amino-6-(2-chloro-3-trifluoromethyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-177];
5(3)-Amino-6-(3-chloro-2-fluoro-5-trifluoromethyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-202];
5(3)-Amino-6-(2-chloro-4,5-difluoro-5-phenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-204];
5(3)-Amino-6-phenyl-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-052];
5(3)-Amino-6-(2,5-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-054];
5(3)-Amino-6-(2,3,5-trichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-055];
5(3)-Amino-6-(3,5-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-060];
5(3)-Amino-6-(2-naphthyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-075];
5(3)-Amino-6-(3,4,5-trimethoxyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-119];
5(3)-Amino-6-(2-chloro-3-trifluoromethyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-178];
5(3)-Amino-6-(3,5-bis-tert-butylphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine[CEN-189];
5(3)-Amino-6-(3-chloro-2-fluoro-5-trifluoromethyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-203];
5(3)-Amino-6-(2-chloro-4,5-difluoro-5-phenyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-205];
5(3)-Amino-6-(3,4,5-trimethoxyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-101];
5(3)-Amino-6-[3,5-(bis-trifluoromethyl)phenyl]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-099];
5(3)-Amino-6-(3-chloro-2-fluoro-5-trifluoromethyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-(2,2,3,3-tetrafluoropropyl)-1,2,4-triazine [CEN-210]; and
5(3)-Amino-6-(3-chloro-2-fluoro-5-trifluoromethyphenyl)-2,3(2,5)-dihydro-3(5)-imino-2-(2,2,3,3,3-pentafluoropropyl)-1,2,4-triazine [CEN-211].

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of:
3,5-Diamino-6-(2-thienyl)-1,2,4-triazine [CEN-057];
3,5-Diamino-6-(3-thienyl)-1,2,4-triazine [CEN-064];
3,5-Diamino-6-[3-(2,5 dichlorothienyl)]-1,2,4-triazine [CEN-071];
3,5-Diamino-6-[2-(3,4,5 trichlorothienyl)]-1,2,4-triazine [CEN-079];
5(3)-Amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-061];
5(3)-Amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-062];
5(3)-Amino-6-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-080];
5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-194];
5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-195];
3,5-Diamino-6-[2-(4,5-dibromothienyl)]-1,2,4-triazine [CEN-122];
3,5-Diamino-6-[2-(5-bromothienyl)]-1,2,4-triazine [CEN-124];
3,5-Diamino-6-[2-(3-bromothienyl)]-1,2,4-triazine [CEN-125];
3,5-Diamino-6-[2-(5-chlorothienyl)]-1,2,4-triazine [CEN-138];
3,5-Diamino-6-[2-(benzo[b]thiophenyl)]-1,2,4-triazine [CEN-113]; and
3,5-Diamino-6-[2-(3-chlorobenzo[b]thiophenyl)]-1,2,4-triazine [CEN-114].

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound is 3,5-Diamino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine [CEN-092].

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound is 3,5-Diamino-6-[2-(3,4,5 trichlorothienyl)]-1,2,4-triazine [CEN-079].

### Claim 8 (depends on 1)

The method according to claim 1, wherein the disorder is epilepsy, multiple sclerosis, motorneurone disease, or neuropathic pain.

### Claim 9 (depends on 4)

The method according to claim 4, wherein the disorder is epilepsy, multiple sclerosis, motorneurone disease, or neuropathic pain.

### Claim 10 (depends on 5)

The method according to claim 5, wherein the disorder is epilepsy, multiple sclerosis, motorneurone disease, or neuropathic pain.

### Claim 11

A compound of general formula (I), or a salt or solvate thereof,
in which:
X and Y are each N;
Z is a single bond or an optionally substituted linking group;
R1 is hydrogen, or a substituent group, or the Y nitrogen is unsubstituted;
R2 is amino or a substituent group;
N* is amino when R1 is hydrogen or ═NH when R1 is a substituent group; or
N* is a group NRaRb wherein Ra and Rb are independently H or an alkyl group; or
N* is an optionally substituted piperazinyl ring; and
A is an optionally substituted sulphur containing heterocycle.

### Claim 12 (depends on 11)

The compound according to claim 11, wherein the sulphur containing heterocycle is substituted with halogen, alkyl or alkoxy.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein the sulphur containing heterocycle is optionally substituted with 1, 2, or 3 chlorine or bromine atoms.

### Claim 14 (depends on 11)

The compound according to claim 11, wherein the compound is selected from the group consisting of:
3,5-Diamino-6-(2-thienyl)-1,2,4-triazine [CEN-057];
3,5-Diamino-6-(3-thienyl)-1,2,4-triazine [CEN-064];
3,5-Diamino-6-[3-(2,5 dichlorothienyl)]-1,2,4-triazine [CEN-071];
3,5-Diamino-6-[2-(3,4,5 trichlorothienyl)]-1,2,4-triazine [CEN-079];
5(3)-Amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-061];
5(3)-Amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-062];
5(3)-Amino-6-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-080];
5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-194];
5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-195];
3,5-Diamino-6-[2-(4,5-dibromothienyl)]-1,2,4-triazine [CEN-122];
3,5-Diamino-6-[2-(5-bromothienyl)]-1,2,4-triazine [CEN-124];
3,5-Diamino-6-[2-(3-bromothienyl)]-1,2,4-triazine [CEN-125];
3,5-Diamino-6-[2-(5-chlorothienyl)]-1,2,4-triazine [CEN-138];
3,5-Diamino-6-[2-(benzo[b]thiophenyl)]-1,2,4-triazine [CEN-113]; and
3,5-Diamino-6-[2-(3-chlorobenzo[b]thiophenyl)]-1,2,4-triazine [CEN-114].

### Claim 15 (depends on 11)

The compound according to claim 11, wherein the compound is 3,5-Diamino-6-[2-(3,4,5 trichlorothienyl)]-1,2,4-triazine [CEN-079].

### Claim 16 (depends on 11)

A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 12, 16)

The pharmaceutical composition according to claim 16, wherein the compound is a compound of claim 12 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 13, 16)

The pharmaceutical composition according to claim 16, wherein the compound is a compound of claim 13 and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 14, 16)

The pharmaceutical composition according to claim 16, wherein the compound is a compound of claim 14 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 15, 16)

The pharmaceutical composition according to claim 16, wherein the compound is a compound of claim 15 and a pharmaceutically acceptable carrier.