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US 11,591,284 B2Granted
Compounds for the treatment of neuromuscular disorders
AssigneeNmd Pharma A/S
InventorsLars J. S. Knutsen, Thomas Holm Pedersen, Claus Elsborg Olesen, Marc A. Labelle, Paul Brian Little, Martin E. Cooper, Neerja Saraswat, Dastagiri Dudekula, Rafiq A. Taj
Life of this patent
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Abstract
The present invention relates to compounds suitable for treating, ameliorating and/or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade. The compounds as defined herein preferably inhibit the CIC-1 ion channel. The compounds include phenoxy propanoic acid, phenoxy propanoate, and phenoxy butanoate compounds.
Claims20
A compound of Formula (I.3.4):
- wherein:
- R1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF3, —CCl3, —CHF2, —CHCl2, —CH2F, —CH2Cl, —OCF3 and —OCCl3;
- R2 is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, C5-6 cycloalkenyl, —C(═O)—C1-5 alkyl, —C(═O)—C2-5 alkenyl, —C(═O)—C2-5 alkynyl, —C(═O)—C3-5 cycloalkyl and —C(═O)—C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;
- R3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, —CF3, —CCl3, —CHF2, —CHCl2, —CH2F, —CH2Cl, —OCF3, —OCCl3 and isocyanide;
- R4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, and C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;
- R5 is selected from the group consisting of H, C1-5 alkyl, C2-5 alkenyl and C2-5 alkynyl;
- R6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C1-3 alkyl, —S—C1-3 alkyl, —CH2—OH, —CH2—O—C1-3 alkyl, —O—CH2-Ph, —CH2—SH and —CH2—S—C1-3 alkyl;
- R7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C1-3 alkyl, —S—C1-3 alkyl, —CH2—O—C1-3 alkyl and —CH2—S—C1-3 alkyl;
- n is an integer 0, 1, 2 or 3;
- or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof with the proviso that when R2 is C(═O)—CH3, R1 is Br and R5 is H then R4 is not Me or CH2CHMe2;
- with the proviso that when R1 is Br, R2 is C(═O)—CH3, R4 is Me, and n is 0, then R5 is not H or Me.
8 more elements
A compound of Formula (I.3.4):
- wherein:
- R1 is selected from the group consisting of F, Cl, Br and I;
- R2 is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, C5 cycloalkenyl, —C(═O)—C1-5 alkyl, —C(═O)—C2-5 alkenyl, —C(═O)—C2-5 alkynyl, —C(═O)—C3-5 cycloalkyl and —C(═O)—C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;
- R3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, —CF3, —CCl3, —CHF2, —CHCl2, —CH2F, —CH2Cl, —OCF3, —OCCl3 and isocyanide;
- R4 is selected from the group consisting of C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, and C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;
- R5 is selected from the group consisting of H and C1-5 alkyl;
- R6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C1-3 alkyl, —S—C1-3 alkyl, —CH2—OH, —CH2—O—C1-3 alkyl, —O—CH2-Ph, —CH2—SH and —CH2—S—C1-3 alkyl;
- R7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C1-3 alkyl, —S—C1-3 alkyl, —CH2—O—C1-3 alkyl and —CH2—S—C1-3 alkyl;
- n is an integer 0, 1, 2 or 3;
- or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, with the proviso that when R2 is C(═O)—CH3, R1 is Br and R5 is H then R4 is not Me or CH2CHMe2;
- with the proviso that when R1 is Br, R2 is C(═O)—CH3, R4 is Me, and n is 0, then R5 is not H or Me.
8 more elements
A compound selected from the group consisting of:
- (2S)-2-{4-bromo-2-[2-(methoxymethyl)cyclopropyl]phenoxy}propanoic acid;
- (2S)-2-[4-bromo-2-(2,2-dichlorocyclopropyl)phenoxy]propanoic acid;
- (2S)-2-{4-bromo-2-[(1s,3 s)-3-methoxycyclobutyl]phenoxy}propanoic acid;
- (2S)-2-{4-bromo-2-[(E)-2-bromoethenyl]phenoxy}propanoic acid;
- (2R)-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropanoic acid;
- (2S)-2-{4-bromo-2-[(1S,2S)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;
- (2S)-2-{4-bromo-2-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;
- (2S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid;
- (2S)-2-{4-bromo-2-[(1E)-2-cyanoeth-1-en-1-yl]phenoxy}propanoic acid;
- (2S)-2-(4-bromo-2-cyclopropylphenoxy)propanoic acid;
- (2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid;
- (2S)-2-(2-cyclopropyl-4-fluorophenoxy)propanoic acid;
- (2S)-2-(2-cyclobutyl-4-fluorophenoxy)propanoic acid;
- (2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid;
- (2S)-2-(4-chloro-2-cyclobutylphenoxy)propanoic acid;
- tert-butyl (2S)-2-(4-chloro-2-propanoylphenoxy)propanoate;
- (2S)-2-{4-chloro-2-[(2,2-2H2)propanoyl]phenoxy}propanoic acid;
- (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoic acid;
- methyl (2S)-2-[4-chloro-2-(cyclopent-1-en-1-yl)phenoxy]propanoate;
- methyl (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoate;
- (2S)-2-(4-chloro-2-ethynylphenoxy)propanoic acid;
- (2S)-2-(4-chloro-2-propanoylphenoxy)propanoic acid;
- sodium (2S)-2-(4-chloro-2-ethenylphenoxy)propanoate;
- (2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid;
- (2R)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)-3-fluoropropanoic acid;
- (2S)-2-(2-cyclopropyl-4,6-difluorophenoxy)propanoic acid;
- (2S)-2-(4-bromo-2-propanoylphenoxy)propanoic acid;
- (2S)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)propanoic acid;
- (2S)-2-(2,4-difluoro-6-propanoylphenoxy)propanoic acid;
- (2S)-2-(2-acetyl-4-chlorophenoxy)propanoic acid;
- (2S)-2-(4-fluoro-2-propanoylphenoxy)propanoic acid;
- (2S)-2-[4-bromo-2-(cyclopent-1-en-1-yl)phenoxy]propanoic acid;
- (2S)-2-[4-bromo-2-(2,2-difluoroethenyl)phenoxy]propanoic acid;
- (2S)-2-{2-[2-(benzyloxy)cyclobutyl]-4-chlorophenoxy}propanoic acid;
- and
- (2S)-2-[4-bromo-2-(cyclopent-1-en-1-yl)phenoxy]propanoic acid,
- or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
34 more elements
Dependencies are inferred from the claim text.