Derivatives of 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine

Patent metadata

Field	Value
Publication number	US-10189859-B2
Application number	US-201415106741-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 21, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The instant disclosure relates to (among other things) compounds that are derivatives of 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine. The compounds provided possess unique effects and differences over other phenyltriazines known in the art.

First claim

The invention claimed is:

1. A 6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine compound having an N-bonded substituent at the 3-position of the triazine ring and an amino (—NH 2 ) group at the 5-position of the triazine ring, wherein the N-bonded substituent is an amino nitrogen covalently attached to the 3-carbon of the triazine ring, wherein the amino nitrogen forms part of a substituted or unsubstituted nitrogen-containing heterocycle selected from the group consisting of a substituted or unsubstituted piperazine, a substituted or an unsubstituted pyrrolidine, a substituted or an unsubstituted azetidine, and a substituted or an unsubstituted diazetidine, where any of the foregoing nitrogen-containing heterocycles may form part of a bi- or a tricylic ring structure,
wherein a substituted nitrogen-containing heterocycle comprises one or more substituents, where the substituent is a linear or a branched alkyl chain, and/or comprises an oligomeric ethylene oxide chain, which may be further substituted with one or more functional groups selected from C 1 -C 6 alkyl ether, amino, hydroxyl, carboxyl, aldehyde, alkylsulfone, tetrazole, oxetane, C 2 -C 6 carbonate ester, alkyl ester, alkylsulfoxide, halo, amido, sulfonamide, cycloalkyl, heterocyclyl, —CF 3 , —CF 2 H, and —CFH 2 , and wherein the dichlorophenyl ring may possess an additional substituent at any one of positions 4, 5 or 6,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the dichlorophenyl ring possesses an additional substituent at any one of positions 4, 5 or 6, where the substituent is selected from halo, hydroxyl, and oligomeric ethylene oxide (—OCH 2 CH 2 ) n OR, where n is in a range from 1-7 and R is selected from H, lower alkyl, —CF 3 , —CHF 2 , and —CH 2 F.

3. A compound in accordance with Formula B,

wherein M is a substituted amino moiety, —NR 6 R 7 , wherein
R 6 and R 7 taken together with N form a heterocycloalkyl ring selected from piperazine and azetidine, which may optionally form part of a bicyclic ring structure, where the heterocycloalkyl ring or bicyclic ring is either unsubstituted or is substituted with a group selected from lower alkyl, —(CH 2 CH 2 O) m R 8 , —C(O)—CH 2 (CH 2 CH 2 O) m R 10 , —CH 2 CR 9 HCH 2 O(CH 2 CH 2 O) m (CH 2 ) 0,1 R 10 , —CH 2 CH 2 SO 2 CH 3 , —NR 9 (CH 2 CH 2 O) m R 10 , tetra-hydro-2H-pyranyl, piperidinyl, —CH 2 OH, —CH 2 R 10 , amino, —CHCH 3 CH 2 OH, hydroxyl, —CR 11 R 12 CH 2 OH, —C(O)OCH 3 , —CF 3 , —CH 2 C(OH)CF 3 , —CH 2 OCH 2 —C 6 H 5 F, and —CH 2 CR 9 HCH 2 O(CH 2 CH 2 O) m (CH 2 ) 0,1 R 13 ,
m is in a range from 0-29,
R 8 is selected from H, C1-C6 alkyl, fluoro-substituted methyl, —CH 2 COOR 10 , —CH 2 COCH 3 , 3-7 membered heterocycloalkyl, 3-7 membered heteroaryl, heteroarylalkyl, —C(O)OCH 3 , C1-C6 alkyl substituted with one or more of hydroxyl, amino, alkylamino, amido, alkylamide, amidoalkylamine, acylamino, carboxyalkylamino, sulfonamide, sulfone, alkylsulfone, alkoxyalkyl sulfone, alkyloxyalklsulfoxide, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, carboxyl, —NHCH 2 CH 2 OCH 3 , —NHCHR 9 COOR 11 ; and —CH—[CH 2 O—(CH 2 CH 2 O) 2-8 CH 3 ] 2 ;
R 9 is H, lower alkyl, hydroxyl,
R 10 is selected from H, lower alkyl and fluoro-substituted methyl,
R 11 and R 12 are each independently selected from H and lower alkyl,
R 13 is cyclopropyl or cyclobutyl, and
W is an optional substituent selected from the group consisting of halo, hydroxyl, and oligomeric ethylene oxide (—OCH 2 CH 2 ) n OR, where n ranges from 1-7 and R is selected from H, -lower alkyl and fluoro-substituted methyl,
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein R or R 10 is methyl.

5. The compound of claim 3 , wherein R or R 10 is —CF 3 .

6. The compound of claim 3 , wherein W is fluoro.

7. The compound of claim 6 , wherein W is a fluoro group positioned at the 5-position of the phenyl ring.

8. The compound of claim 3 , wherein m is selected from 0, 1, 2, 3, 4, 5, 6, and 7.

9. The compound of claim 3 , wherein R 6 and R 7 taken together with N form a heterocycloalkyl ring selected from piperazine and azetidine, which may optionally form part of a bicyclic ring structure, where the heterocycloalkyl ring or bicyclic ring is either unsubstituted or is substituted with a group selected from lower alkyl, —(CH 2 CH 2 O) m R 8 , —C(O)—CH 2 (CH 2 CH 2 O) m R 10 , —CH 2 CR 9 HCH 2 O(CH 2 CH 2 O) m (CH 2 ) 0,1 R 10 , —CH 2 CH 2 SO 2 CH 3 , —NR 9 (CH 2 CH 2 O) m R 10 , tetra-hydro-2H-pyranyl, piperidinyl, —CH 2 OH, —CH 2 R 10 , amino, —CHCH 3 CH 2 OH, hydroxyl, —CR 11 R 12 CH 2 OH, —C(O)OCH 3 , —CF 3 , —CH 2 C(OH)CF 3 , —CH 2 OCH 2 —C 6 H 5 F, and —CH 2 CR 9 HCH 2 O(CH 2 CH 2 O) m (CH 2 ) 0,1 R 13 .

10. The compound of claim 3 , wherein R 6 and R 7 taken together with N form a heterocycloalkyl ring selected from substituted or unsubstituted piperazine and substituted or unsubstituted azetidine.

11. The compound of claim 10 , wherein R 6 and R 7 taken together with N form an unsubstituted or a substituted piperazine.

12. The compound of claim 11 , wherein R 6 and R 7 taken together with N form a substituted piperazine having a N-substituent selected from —(CH 2 CH 2 O) 1-7 C1-C6 alkyl or fluoro-substituted methyl, —(CH 2 CH 2 O) 1-7 CH 2 CH 2 NHSO 2 CH 3 ,

—C(O)CH 2 O(CH 2 CH 2 O) 1-7 CH 3 , —CH 2 CHOHCH 2 OCF 3 , —CH 2 CHOHCH 2 OCH 2 CF 3 —CH 2 CHOHCH 2 OCH 3 , —CH 2 OH, —(CH 2 CH 2 O) 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 CH 2 OCH 2 COOH, —CH 2 CH 2 OCH 2 COOC(CH 3 ) 3 , —CH 2 CH(OH)CH 2 OH, —C(CH 3 ) 2 CH 2 OCH 2 CH 2 OH,

—CH 2 CF 3 , —CHCH 3 CH 2 OH, —C(CH 3 ) 2 CH 2 OH, and —CH 2 CH(OH)CH 2 Cl.

13. The compound of claim 11 , selected from the group consisting of 3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propane-1,2-diol (Compound 92), 3-N-(4′-N-mPEG 3 -piperazinyl) lamotrigine (Compound 103), 3-N-(4′-N-mPEG 3 -piperazinyl) 5-fluoro lamotrigine (Compound 104), 3-N-mPEG 2 -CM-piperazinyl lamotrigine (Compound 105), 3-N-mPEG 2 -CM-piperazinyl 5′-fluoro lamotrigine (Compound 106), 3-N-(4-N,N-methyl-mPEG 3 -amino)piperidin-1-yl) lamotrigine (Compound 113), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl) lamotrigine di HCl (Compound 120) 3-N-(4-(piperidin-4-yl)piperazin-1-yl) lamotrigine 3HCl salt (Compound 121), (R)-5-amino-3-N-[3 (hydroxymethyl) piperazin-1-yl] lamotrigine diHCl (Compound 122), (R)-5-amino-3-N-[3-(hydroxymethyl) piperazin-1-yl] 5′-fluoro lamotrigine di HCl salt (Compound 123), (R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol (Compound 96), (S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol (Compound 97), 6-(2,3-dichlorophenyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2,4-triazin-5-amine (Compound 87), 2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol (Compound 89), 6-(2,3-dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine (Compound 88), 2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methylpropan-1-ol (Compound 90), (R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol (Compound 94), (S)-1-(4-(5-amino-6-(2,3

Assignees

• Nektar Therapeutics

Inventors

• Sharma Pankaj
• Khatri Vijay Kumar
• Gu Xuyuan
• Song Yuan
• Shen Michael Lixin
• Riggs-Sauthier Jennifer
• Anand Neel K
• Kozlowski Antoni
• Odinecs Aleksandrs
• Riley Timothy A
• Ren Zhongxu
• Mu Yongqi
• Shen Xiaoming
• Yuan Xuejun
• Aurrecoechea Natalia
• O'Mahony Donogh John Roger
• Deng Bo-Liang

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D253/075

  Two hetero atoms, in positions 3 and 5 · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P25/28

  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 title