Compounds for the treatment of neuromuscular disorders
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.
1. A compound of Formula (I.3.4):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 2 is selected from the group consisting of C 2-6 alkenyl, C 2-6 alkynyl, C 3-4 cycloalkyl, C 5-6 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl and —C(═O)—C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 , —OCCl 3 and isocyanide;
R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, and C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
R 5 is selected from the group consisting of H, C 1-5 alkyl, C 2-5 alkenyl and C 2-5 alkynyl;
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl;
R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 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 R 2 is C(═O)—CH 3 , R 1 is Br and R 5 is H then R 4 is not Me or CH 2 CHMe 2 ; with the proviso that when R 1 is Br, R 2 is C(═O)—CH 3 , R 4 is Me, and n is 0, then R 5 is not H or Me.
2. The compound according to claim 1 , wherein:
R 1 is selected from the group consisting of F, Cl, Br and I;
R 2 is selected from the group consisting of vinyl, ethynyl, cyclopropyl, cyclobutyl, —C(═O)-methyl and —C(═O)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;
R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, and C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
R 5 is H;
R 6 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, CH 2 —SH and —CH 2 —S—C 1-3 alkyl;
R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br and I;
n is an integer 0 or 1,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
3. The compound according to claim 1 , wherein the compound is of Formula (II.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 4 is methyl, ethyl, n-propyl, isopropyl or —CH 2 F;
R 8 and R 9 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —CH 2 —SH, —CH 2 —S—C 1-3 alkyl, C 1-4 alkyl and C 2-4 alkenyl and wherein the C 1-4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
4. The compound according to claim 1 , wherein the compound is of Formula (III.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 4 is methyl, ethyl, n-propyl, isopropyl or —CH 2 F;
R 8 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —CH 2 —SH, —CH 2 —S—C 1-3 alkyl, and C 1-4 alkyl and wherein the C 1-4 alkyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
5. The compound according to claim 1 , wherein the compound is of Formula (IV.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 4 is methyl, ethyl, n-propyl, isopropyl or —CH 2 F;
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl; and
R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —CH 2 —SH, —CH 2 —S—C 1-3 alkyl, C 1-4 alkyl and C 2-4 alkenyl and
wherein the C 1-4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
6. The compound according to claim 1 , wherein the compound is of Formula (V.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 4 is methyl, ethyl, n-propyl, isopropyl or —CH 2 F; and
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
7. The compound according to claim 1 , wherein the compound is of Formula (VI.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 4 is methyl, ethyl, n-propyl, isopropyl or —CH 2 F; and
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
8. The compound according to claim 1 , wherein the compound is of Formula (VII.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 2 is selected from the group consisting of C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl and —C(═O)—C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl; and
R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
9. The compound according to claim 1 , wherein the compound is of Formula (VIII.3):
wherein:
R 1 is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 and —OCCl 3 ;
R 2 is selected from the group consisting of C 2-6 alkenyl, C 2-6 alkynyl, C 3-4 cycloalkyl, C 5-6 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl and —C(═O)—C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 , —OCCl 3 and isocyanide; and
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
10. The compound according to claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
11. The compound according to claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
12. A method of inhibiting a ClC-1 receptor in a patient, comprising administering to a patient in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
13. The method of claim 12 , wherein the patient is suffering from a neuromuscular disorder, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or a solvate thereof.
14. The method of claim 12 , wherein the patient requires a reversing and/or ameliorating a neuromuscular blockade, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or a solvate thereof.
15. The method according to claim 13 , wherein the neuromuscular disorder is selected from the group consisting of myasthenia gravis, Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), reversal diabetic polyneuropathy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, and critical illness polyneuropathy.
16. The method according to claim 13 , wherein the neuromuscular disorder has been induced by a neuromuscular blocking agent.
17. A compound of Formula (I.3.4):
wherein:
R 1 is selected from the group consisting of F, Cl, Br and I;
R 2 is selected from the group consisting of C 2-6 alkenyl, C 2-6 alkynyl, C 3-4 cycloalkyl, C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl and —C(═O)—C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, —CF 3 , —CCl 3 , —CHF 2 , —CHCl 2 , —CH 2 F, —CH 2 Cl, —OCF 3 , —OCCl 3 and isocyanide;
R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, and C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
R 5 is selected from the group consisting of H and C 1-5 alkyl;
R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl;
R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 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 R 2 is C(═O)—CH 3 , R 1 is Br and R 5 is H then R 4 is not Me or CH 2 CHMe 2 ; with the proviso that when R 1 is Br, R 2 is C(═O)—CH 3 , R 4 is Me, and n is 0, then R 5 is not H or Me.
18. The compound according to claim 17 , wherein:
R 1 is selected from the group consisting of F, Cl, Br and I;
R 2 is selected from the group consisting of vinyl, ethynyl, cyclopropyl, cyclobutyl, —C(═O)-methyl and —C(═O)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;
R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;
R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, and C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;
R 5 is selected from the group consisting of H and C 1-5 alkyl;
R 6 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, —CN, isocyanide, —O—C 1-3 alkyl, —S—C 1-3 alkyl, —CH 2 —OH, —CH 2 —O—C 1-3 alkyl, —O—CH 2 -Ph, —CH 2 —SH and —CH 2 —S—C 1-3 alkyl;
R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br and I;
n is an integer 0 or 1,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
19. 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- 2 H 2 )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.
20. The compound according to claim 1 , wherein R 2 is selected from the group consisting of vinyl, ethynyl, —C(═O)-methyl and —C(═O)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .