Memantine compounds and their preparation and uses thereof

Patent metadata

Field	Value
Publication number	US-2020399208-A1
Application number	US-202017014746-A
Country	US
Kind code	A1
Filing date	Sep 8, 2020
Priority date	May 7, 2016
Publication date	Dec 24, 2020
Grant date	—

Abstract

Provided are compounds of formula (I), or a stereoisomer, mixture of stereoisomers, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, compositions, method of making and uses thereof.

First claim

1 .- 30 . (canceled)

31 . A compound of formula (I):

or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein:
R 1 is H, an amino-protecting group, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 2 is

R 3 and R 4 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl or aryl; and
R 5 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 , and R 4 are each independently optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, hydroxy, mercapto, alkyl, alkylamino, dialkylamino, alkoxy, alkylacyl, alkenylacyl, alkylthio, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkylacylalkyl, alkenylacylalkyl, alkylthioalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R 5 is independently optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, mercapto, alkyl, alkylamino, dialkylamino, alkoxy, alkylacyl, alkenylacyl, alkylthio, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkylacylalkyl, alkenylacylalkyl, alkylthioalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

32 . The compound of claim 31 , wherein R 1 is H, an amino-protecting group or C 1-6 alkyl optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, hydroxyl, mercapto, C 1-6 alkoxy, C 6-10 aryl, C 2-10 heterocyclyl and C 1-9 heteroaryl.

33 . The compound of claim 31 , wherein R 3 and R 4 are each independently H or C 1-9 alkyl.

34 . The compound of claim 31 , wherein R 5 is C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 6-14 aryl or C 1-9 heteroaryl, wherein the C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 6-14 aryl, C 1-9 heteroaryl is optionally substituted with one or more substituents selected from halo, CN, N 3 , NO 2 , amino, mercapto, C 1-30 alkylamino, C 1-30 dialkylamino, C 1-30 alkoxy, C 1-30 alkylacyl, C 2-30 alkenylacyl, C 1-30 alkylthio, C 6-14 aryl and C 1-9 heteroaryl.

35 . The compound of claim 34 , wherein R 5 is naphthylmethyl, phenyl, benzyl, methyl, propyl, isopropyl, octyl, hendecyl, tridecyl, pentadecyl or heptadecyl.

36 . The compound of claim 31 represented by formula (Ia):

or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R 5 is C 1-30 alkyl, C 6-10 aryl or C 1-30 alkyl substituted with C 6-10 aryl.

37 . A compound selected from the group consisting of:

or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof.

38 . A pharmaceutical composition comprising a compound of claim 31 or a stereoisomer, deuterated analog, tautomer, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

39 . The pharmaceutical composition of claim 38 , further comprising a cholinesterase inhibitor.

40 . The pharmaceutical composition of claim 39 , wherein the cholinesterase inhibitor is tacrine, donepezil, huperzine-A, galantamine, rivastigmine, or a combination thereof.

41 . The pharmaceutical composition of claim 38 , which is a suspension.

42 . The pharmaceutical composition of claim 41 , wherein the compound or the stereoisomer, the deuterated analog, the tautomer, or the solvate is present in the suspension in a nanocrystalline or a microcrystalline form.

43 . A method for treating or ameliorating the symptoms of a neurodegenerative disease in a human in need thereof, wherein the method comprises administering to the human a compound of claim 31 , the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, atrophic myelitis, AIDS dementia, vascular dementia or the combinations thereof.

44 . The method of claim 43 , wherein the human suffers from moderate to severe dementia of the Alzheimer's disease.

45 . A method for inhibiting the activity of N-methyl-D-aspartate (NMDA) receptor in a human in need thereof, wherein the method comprises administering to the human a compound of claim 31 .

46 . A method for treating or ameliorating the symptoms of diabetes in a human in need thereof, wherein the method comprises administering to the human a compound of claim 31 .

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• He Bifei
• Fan Yuping
• Lu Huixiong
• Liu Guangyuan
• Wang Zhongqing
• Luo Zhonghua

Classifications

• C07C271/24 Primary

  with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C269/06

  by reactions not involving the formation of carbamate groups · CPC title

• A61K31/27

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• C07C269/02

  from isocyanates with formation of carbamate groups · CPC title

• C07C2603/74

  Adamantanes · CPC title