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.
1. A compound of Formula (I.3.4):
wherein:
R 1 is selected from the group consisting of deuterium, F, Cl, Br and I;
R 2 is a 5-6 membered aromatic heterocycle or an 8-10 membered bicyclic heterocycle each of which may be optionally substituted with one or more, identical or different, substituents R 6 ; or alternatively, R 1 can be H and if R 1 is H, then R 2 is a 5-6 membered aromatic heterocycle or an 8-10 membered aromatic bicyclic heterocycle each of which may be optionally substituted with one or more, identical or different, substituents R 6 and wherein R 2 is not a 3-thiophene, an N-linked pyrrole, a 2,3-dihydro-2-benzothiazolyl or a 2-benzothiazolyl;
R 3 is selected from the group consisting of 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 1-5 alkenyl, C 1-5 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 5 is selected from the group consisting of H, C 1-5 alkyl, C 1-5 alkenyl and C 1-5 alkynyl;
R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl,
—C(═O)—C 1-5 alkenyl, —C(═O)—C 1-5 alkynyl,
—C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 1-5 alkenyl,
—C(═O)—C 1-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;
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.
2. The compound according to claim 1 , wherein R 2 is a 5 membered aromatic heterocycle, wherein each of which 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.
3. The compound according to claim 1 , wherein the compound is of Formula (II.4):
wherein:
R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;
R 3 is selected from the group consisting of 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 1-5 alkenyl, C 1-5 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 5 is selected from the group consisting of H, C 1-5 alkyl, C 1-5 alkenyl and C 1-5 alkynyl;
R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl,
—C(═O)—C 1-5 alkenyl, —C(═O)—C 1-5 alkynyl,
—C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 1-5 alkenyl,
—C(═O)—C 1-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;
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;
m is an integer 0, 1 or 2; and
n is an integer 0, 1, 2 or 3,
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.4):
wherein:
R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;
R 3 is selected from the group consisting of 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 1-5 alkenyl, C 1-5 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 5 is selected from the group consisting of H, C 1-5 alkyl, C 1-5 alkenyl and C 1-5 alkynyl;
R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 1-5 alkenyl, —C(═O)—C 1-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 1-5 alkenyl,
—C(═O)—C 1-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;
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;
m is an integer 0, 1 or 2; and
n is an integer 0, 1, 2 or 3,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
5. The compound according to claim 1 , wherein n is 0, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
6. The compound according to claim 1 , wherein R 4 is C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 7 ,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
7. The compound according to claim 1 , wherein R 5 is hydrogen,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
8. The compound according to claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
9. The compound according to claim 1 , wherein the compound has the following structure:
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
10. A method of inhibiting a CIC-1 ion channel 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.
11. A method of treating or ameliorating a neuromuscular disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the neuromuscular disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy, Kennedy's disorder, multifocal motor neuropathy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, Charcot-Marie Tooth disease (CMT), sarcopenia, critical illness myopathy (CIM), diabetes, chronic fatigue syndrome, systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), critical illness polyneuropathy, metabolic myopathy, mitochondrial myopathy, a myasthenic condition, congenital myasthenia gravis, myasthenia gravis, and Lambert-Eaton syndrome.
12. A method of reversing and/or ameliorating a neuromuscular blockade in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
13. The method according to claim 11 , wherein the neuromuscular disorder is myasthenia gravis.
14. The method according to claim 11 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).
15. The method according to claim 11 , wherein the neuromuscular disorder is selected from the group consisting of spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease (CMT) and sarcopenia.
16. The method according to claim 11 , 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 H, deuterium, F, Cl, Br and I;
R 2 is a 5 membered aromatic heterocycle which may be optionally substituted with one or more, identical or different, substituents R 6 ; and wherein R 2 is not a 3-thiophene or an N-linked pyrrole;
R 3 is selected from the group consisting of 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 1-5 alkenyl, C 1-5 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 5 is selected from the group consisting of H, C 1-5 alkyl, C 1-5 alkenyl and C 1-5 alkynyl;
R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 1-5 alkenyl, —C(═O)—C 1-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, C 3-5 cycloalkyl,
C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 1-5 alkenyl, O—C 1-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 1-5 alkenyl,
—C(═O)—C 1-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;
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.
18. The compound according to claim 17 , wherein the R 2 is selected from the group consisting of isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isthiazol-3-yl, isthiazol-4-yl, isthiazol-5-yl, thiazol-2-yl and thiazol-4-yl, thiazol-5-yl,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
19. The compound according to claim 17 , wherein the compound is selected from the group consisting of:
(2S)-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]butanoic acid;
(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]butanoic acid;
(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]-3-methylbutanoic acid;
(2S)-2-{4-bromo-2-[3-(propan-2-yl)-1,2-oxazol-5-yl]phenoxy}propanoic acid;
(2S)-2-[4-bromo-2-(4-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-chloro-6-(1,2-oxazol-3-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(5-methyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;
(2S)-2-[4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl)phenoxy]propanoic acid;
(2S)-2-[4-chloro-2-(1,3-thiazol-2-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(3-methyl-1,2-oxazol-5-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(1H-imidazol-2-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(1H-imidazol-4-yl)phenoxy]propanoic acid;
(2R)-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]-3-fluoropropanoic acid;
(2S)-2-[4-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenoxy]propanoic acid;
(2S)-2-[4-chloro-2-(1H-pyrazol-3-yl)phenoxy]propanoic acid;
(2S)-2-[4-chloro-2-(thiophen-2-yl)phenoxy]propanoic acid;
(2S)-2-[4-chloro-2-(1,2-oxazol-5-yl)phenoxy]propanoic acid;
(2S)-2-[4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]propanoic acid;
(2S)-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]propanoic acid; and
(2S)-2-[4-chloro-2-(1H-pyrazol-1-yl)phenoxy]propanoic acid,
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.