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

Patent metadata

Field	Value
Publication number	US-10844076-B2
Application number	US-201816182387-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	Dec 21, 2013
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

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

What is claimed is:

1. A 6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine compound having a structure of Formula B,

wherein M is NR 6 R 7 ,
wherein R 6 and R 7 are each independently selected from the group consisting of H, (CH 2 CH 2 O) m R 8 , —CH 2 CH 2 -(3-7 membered heterocycloalkyl), —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 , —CR 11 R 12 CH 2 OH, —CR 11 R 12 CH 2 O(CH 2 CH 2 O) 1-7 R 10 , —CH—[CH 2 OH] 2 ; —CCH 3 (CH 2 OH) 2 , —CCH 3 (CH 2 OH)CH 2 O(CH 2 CH 2 O) 1-7 R 10 , alkylamino, hydroxyalkylamino, —CH 2 CH 2 NCH 3 C(O)CH 2 (OCH 2 CH 2 ) 1-7 R 10 , —CH 2 CH 2 NCH 3 C(O)CH 2 OCH 2 C(O)NH 2 , —CH 2 CH 2 NCH 3 (CH 2 CH 2 O) 1-7 R 10 , —CR 11 R 12 CH(O), —CR 11 R 12 (CH 2 ) 1 or 2 SO 2 − CH 2 CH 2 O) 1-7 R 10 , —CCH 3 (CH 2 OCH 2 CH 2 OCH 3 ) 2 , —OCH 2 CR 9 HCH 2 OR 10 , —CH 2 CR 9 HCH 2 NHC(O)CH 2 O(CH 2 CH 2 O) m R 10 , —CH 2 CR 9 HCH 2 NHC(O)CH 2 OCH 2 C(O)NH 2 , and —(OCH 2 CH 2 ) m OR 10 , with the proviso that R 6 and R 7 are not both H,
wherein when R 6 is H and W is 0, R 7 does not equal (CH 2 CH 2 O) 2-11 CH 3 ,
m is an integer selected from 0-29,
R 8 is selected from H, a C 1 -C 6 alkyl, fluoro-substituted methyl, —CH 2 COOR 10 , —CH 2 COCH 3 , —C(O)OCH 3 , C 1 -C 6 alkyl substituted with one or more of hydroxyl, amino, alkylamino, amido, alkylamide, amidoalkylamine, acylamino, carboxyalkylamino, sulfonamide, alkylsulfone, alkoxyalkyl sulfone, alkyloxyalklsulfoxide, a 3-7 membered heterocycloalkyl, a 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 , wherein when R 6 is H and m is 0, R 8 does not equal H;
R 9 is selected from H, lower alkyl, and 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 (—OCH 2 CH 2 ) n OR, where n is an integer selected from 1-7 and R is selected from H, lower alkyl and fluoro-substituted methyl,
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 (—OCH 2 CH 2 ) n OR, where n is an integer from 1-7 and R is selected from H, lower alkyl, methyl, and fluoro-substituted methyl.

3. The compound of claim 1 , wherein R or R 10 is selected from methyl and —CF 3 .

4. The compound of claim 1 , wherein W is fluoro.

5. The compound of claim 4 , wherein W is a fluoro group positioned at the 5-position of the phenyl ring.

6. The compound of claim 1 , wherein R 6 is H.

7. The compound of claim 6 , wherein R 7 is selected from the group consisting of —(CH 2 CH 2 O) m R 8 , —CH 2 CH 2 -(3-7 membered heterocycloalkyl), —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 , —CR 11 R 12 CH 2 OH, —CR 11 R 12 CH 2 O(CH 2 CH 2 O) 1-7 R 10 , —CH—[CH 2 OH]2, —CCH 3 (CH 2 OH) 2 , —CCH 3 (CH 2 OH)CH 2 O(CH 2 CH 2 O) 1-7 R 10 , —CH 2 CH 2 NCH 3 C(O)CH 2 (OCH 2 CH 2 ) 1-7 R 10 , —CH 2 CH 2 NCH 3 C(O)CH 2 OCH 2 C(O)NH 2 , —CH 2 CH 2 NCH 3 (CH 2 CH 2 O) 1-7 R 10 , —CR 11 R 12 CH(O), —CR 11 R 12 (CH 2 ) 1 or 2 SO 2 —CH 2 CH 2 O) 1-7 R 10 , —CCH 3 (CH 2 OCH 2 CH 2 OCH 3 ) 2 , —OCH 2 CR 9 HCH 2 OR 10 , —CH 2 CR 9 HCH 2 NHC(O)CH 2 O(CH 2 CH 2 O) m R 10 , —CH 2 CR 9 HCH 2 NHC(O)CH 2 OCH 2 C(O)NH 2 , and —(OCH 2 CH 2 ) m OR 10 .

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

9. The compound of claim 1 , wherein R 6 is H and R 7 is —(CH 2 CH 2 O) m R 8 , where m is selected from 1, 2, 3, 4, 5, 6, and 7, and R 8 is selected from H, methyl, isopropyl, fluoro-substituted methyl, carboxyl, and a 3-7 membered heterocycloalkyl.

10. The compound of claim 9 , wherein the 3-7 membered ring heterocycloalkyl is selected from tetrazole, oxetane and piperazine.

11. The compound of claim 1 , having the following structure

wherein:
A is

G is selected from the group consisting of ˜O˜, ˜CH 2 ˜,

p is 0 or 1 (where a value of 0 indicates the absence of oxygen and a value of 1 indicates its presence); and
J is selected from the group consisting of ˜CH(OH)CH 2 OH, ˜CH(OH)CH 2 OCH 3 , ˜OCH 2 CH 2 OH, ˜CH 2 OCF 3 , ˜CH 2 OCH 3 , ˜OCF 3 , —OH, ˜OCH(CH 2 OCH 3 ) 2 , ˜OCH(CH 2 OH) 2 , ˜(OCH 2 CH 2 ) 0-29 OR 1 , where R 1 is methyl or a fluoro-substituted methyl, ˜CH 2 OCH 2 CH 3 , ˜CH 2 OCH(CH 3 ) 2 ,

and ˜OCH 2 C(OH)HCH 2 OCH 3 ,
or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , wherein R 1 is selected from the group consisting of ˜CF 3 , ˜CF 2 H, and ˜CFH 2 .

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:

14. The compound of claim 1 having a structure:

wherein (n) is an integer of 1 to 30, or pharmaceutically acceptable salts thereof.

15. The compound of claim 1 having a structure selected from the group consisting of:

16. A composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.

17. A method for the treatment of one or more of epilepsy, neuropathic pain, bipolar disorder or a malarial infection comprising:
administering to a therapeutically effective amount of the-composition of claim 16 to a subject in need thereof.

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

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D253/075

  Two hetero atoms, in positions 3 and 5 · 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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title