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1. WO2020114853 - PRODRUGS OF 4-((1R,3S)-6-CHLORO-3-PHENYL-2,3-DIHYDRO-1H-INDEN-1-YL)-1,2,2-TRIMETHYLPIPERAZINE AND 4-((1/R,3S)-6-CHLORO-3-(PHENYL-D5)-2,3-DIHYDRO-1H-INDEN-1-YL)-2,2-DIMETHY-1-(METHYL-D3)PIPERAZINE

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[ EN ]

CLAIMS

1. A prodrug of 4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro-2/-/-inden-l-yl)-l,2,2-trimethylpipera- zine in the form of la or lb or 4-((2/?,3S)-6-chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l-yl)- 2,2-dimethyl-l-(methyl-c/3)piperazine in the form of 2a and 2b


wherein X is a counter ion selected from the group consisting of halide anion, such as chloride, bromide or iodide, Ci-Cio sulfonate, optionally fluorinated, such as mesylate, tosylate, trifluo- romethanesulfonate or nonafluorobutanesulfonate, and linear or branched Ci-Cn carboxylate, optionally fluorinated, such as trifluoroacetate; or a pharmaceutically acceptable salt thereof.

2. The prodrug according to claim 1, wherein R is selected from the group consisting of linear or branched Ci-Cn alkyl and C3-C10 cycloalkyl, or a pharmaceutically acceptable salt thereof.

3. The prodrug according to any of claims 1 and 2, wherein R is selected from the group consisting of methyl, tertbutyl, n-undecane and cyclohexylmethyl, or a pharmaceutically acceptable salt thereof.

4. The prodrug according to any of claims 1 to 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of salts formed from hydrochloride acid, hydrobromide acid, phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fu- maric acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid, saccharin and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesul- fonic acid.

5. The prodrug according to any of claims 1 to 4 selected from the group consisting of (/?)-l-(ace- toxymethyl)-4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro-2/-/-inden-l-yl)-l,2,2-trimethylpiper- azin-l-ium, (S)-l-(acetoxymethyl)-4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro-2/-/-inden-l-yl)- 1,2,2-trimethylpiperazin-l-ium, (/?)-l-(acetoxymethyl)-4-((2/?,3S)-6-chloro-3-(phenyl-c/5)-2,3- dihydro-2/-/-inden-l-yl)-2,2-dimethyl-l-(methyl-c/3)piperazin-l-ium, (S)-l-(acetoxymethyl)-4- ((1R, 3S)-6-chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l-yl)-2,2-dimethyl-l-(methyl-c/3)piper- azin-l-ium, (/?)-4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro- Z/-/-inden-l-yl)-2,2-dimethyl-l-me- thyl-l-((pivaloyloxy)methyl)piperazin-l-ium, (S)-4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro-2/-/- inden-l-yl)-2,2-dimethyl-l-methyl-l-((pivaloyloxy)methyl)piperazin-l-ium, (R)-4-((lR,3S)-6- chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l-yl)-2,2-dimethyl-l-(methyl-c/3)-l-((pivalo- yloxy)methyl)piperazin-l-ium, (S)-4-((2/?,3S)-6-chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l- yl)-2,2-dimethyl-l-(methyl-c/3)-l-((pivaloyloxy)methyl)piperazin-l-ium, (/?)-4-((2/?,3S)-6-chloro- 3-phenyl-2,3-dihydro-2/-/-inden-l-yl)-l-((dodecanoyloxy)methyl)-l,2,2-trimethylpiperazin-l- ium, (S)-4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro-2/-/-inden-l-yl)-l-((dodecanoyloxy)methyl)- 1,2,2-trimethylpiperazin-l-ium, (/?)-4-((2/?,3S)-6-chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l- yl)-l-((dodecanoyloxy)methyl)-2,2-dimethyl-l-(methyl-c/3)piperazin-l-ium, (S)-4-((lR,3S)-6- chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l-yl)-l-((dodecanoyloxy)methyl)-2,2-dimethyl-l- (methyl-c/3)piperazin-l-ium, (/?)-4-((2/?,3S)-6-chloro-3-phenyl-2,3-dihydro-2/-/-inden-l-yl)-l-((2- cyclohexylacetoxy)methyl)-l,2,2-trimethylpiperazin-l-ium, (S)-4-((2/?,3S)-6-chloro-3-phenyl- 2,3-dihydro-2/-/-inden-l-yl)-l-((2-cyclohexylacetoxy)methyl)-l,2,2-trimethylpiperazin-l-ium, (/?)-4-((2/?,3S)-6-chloro-3-(phenyl-c/5)-2,3-dihydro-2/-/-inden-l-yl)-l-((2-cyclohexylacetoxy)me- thyl)-2,2-dimethyl-l-(methyl-c/3)piperazin-l-ium, (S)-4-((2/?,3S)-6-chloro-3-(phenyl-c/5)-2,3-di- hydro-2/-/-inden-l-yl)-l-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-l-(methyl-c/3)piperazin-l- ium, each of which is combined with a counter ion selected from the group consisting of halide anion, such as chloride, bromide or iodide, Ci-Cio sulfonate, optionally fluorinated, such as me sylate, tosylate, trifluoromethanesulfonate or nonafluorobutanesulfonate, and linear or branched Ci-Cn carboxylate, optionally fluorinated, such as trifluoroacetate; or a pharmaceu tically acceptable salt thereof.

6. A pharmaceutical composition comprising any of the prodrugs of claims 1 to 5, or a pharma ceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

7. The compound according to any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6 for use in therapy.

8. Use of a compound according to any of claims 1 to 5 or a salt thereof, or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment of a Central Nervous System (CNS) disease.

9. A compound according to any of claims 1 to 5 or a pharmaceutical composition according to claim 6 for use in a method for the treatment of a CNS disease.

10. A method for the treatment of a CNS disease, the method comprising the administration of a therapeutically effective amount of a compound according to any of claims 1 to 5 or a pharma- ceutical composition according to claim 6 to a patient in need thereof.