JP-2022509965-A5 -

Dates

Publication Date

20221202

Application Date

20191127

Description

Compounds 1a2, 1b2, 2a2, and 2b2 were incubated in human plasma as described above, and their half-lives of 0.5 to 1.5 hours were determined by the formation of 15 to 35% of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine and 4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl- d3 )piperazine, respectively. The present invention may include the following embodiments. [1] Prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine in form 1a or 1b, or 4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl- d3 )piperazine in forms 2a and 2b (wherein X- is a counterion selected from the group consisting of halide anions such as chloride, bromide, or iodide, optionally fluorinated C1-C10 sulfonates such as mesylate, tosylate, trifluoromethanesulfonate, or nonafluorobutanesulfonate, and optionally fluorinated linear or branched C1-C11 carboxylates such as trifluoroacetate ) ; or a pharmaceutically acceptable salt thereof. [2] The prodrug according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of linear or branched C1 - C11 alkyl and C3 - C10 cycloalkyl groups. [3] A prodrug according to any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of methyl, tert-butyl, n-undecane, and cyclohexylmethyl. [4] The prodrug according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of salts formed from hydrochloric acid, hydrobromic acid, phosphoric acid, nitrite, sulfuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid. [5] Each of these is a halide anion such as chloride, bromide, or iodide; an optionally fluorinated C1-C10 sulfonate such as mesylate, tosylate, trifluoromethanesulfonate, or nonafluorobutanesulfonate; and an optionally fluorinated linear or branched C1-C10 sulfonate such as trifluoroacetate . ( R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine-1-ium, (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine-1-ium, (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl- d3) )piperazine-1-ium,(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl- d3 )piperazine-1-ium,(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazine-1-ium,(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazine-1-ium,(R)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl- d3 )-1-((pivaloyloxy)methyl)piperazine-1-ium,(S)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl- d3 )-1-((pivaloyloxy)methyl)piperazine-1-ium,(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazine-1-ium,(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazine-1-ium,(R)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl- d3 )piperazine-1-ium,(S)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl- d3 )piperazine-1-ium,(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazine-1-ium,(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazine-1-ium,(R)-4-((1R,3S)-6-chloro-3-(phenyl- d5 )-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl- d3 A prodrug according to any one of claims 1 to 4, selected from the group consisting of piperazine-1-ium, (S)-4-((1R,3S)-6-chloro-3-( phenyl -d5)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl- 1-(methyl- d3 )piperazine-1-ium; or a pharmaceutically acceptable salt thereof. [6] A pharmaceutical composition comprising a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and one or more pharmaceutically acceptable excipients. [7] A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for use in therapeutic purposes. [8] Use of a compound or salt thereof according to any one of claims 1 to 5 or a phar