U.S. patent application number 15/945854 was filed with the patent office on 2018-08-09 for cftr corrector for the treatment of genetic disorders affecting striated muscle.
This patent application is currently assigned to UNIVERSITA' DEGLI STUDI DI PADOVA. The applicant listed for this patent is UNIVERSITA' DEGLI STUDI DI PADOVA. Invention is credited to Romeo Betto, Elisa Bianchini, Francesco Mascarello, Roberta Sacchetto, Dorianna Sandona', Pompeo Volpe.
Application Number | 20180221347 15/945854 |
Document ID | / |
Family ID | 47561727 |
Filed Date | 2018-08-09 |
United States Patent
Application |
20180221347 |
Kind Code |
A1 |
Sandona'; Dorianna ; et
al. |
August 9, 2018 |
CFTR CORRECTOR FOR THE TREATMENT OF GENETIC DISORDERS AFFECTING
STRIATED MUSCLE
Abstract
The present invention relates to the use of CFTR correctors in
the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
Inventors: |
Sandona'; Dorianna;
(Polverara, IT) ; Sacchetto; Roberta; (Legnaro,
IT) ; Bianchini; Elisa; (Vigasio, IT) ; Volpe;
Pompeo; (Mira, IT) ; Betto; Romeo; (Padova,
IT) ; Mascarello; Francesco; (Padova, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITA' DEGLI STUDI DI PADOVA |
Padova |
|
IT |
|
|
Assignee: |
UNIVERSITA' DEGLI STUDI DI
PADOVA
Padova
IT
|
Family ID: |
47561727 |
Appl. No.: |
15/945854 |
Filed: |
April 5, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14647773 |
May 27, 2015 |
9987256 |
|
|
PCT/EP2013/075158 |
Nov 29, 2013 |
|
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15945854 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/517 20130101;
A61K 31/443 20130101; A61K 31/496 20130101; A61K 31/426 20130101;
A61P 21/00 20180101; A61K 31/472 20130101; A61K 31/427 20130101;
A61K 31/4709 20130101; A61K 31/404 20130101; A61K 31/47 20130101;
A61K 31/506 20130101 |
International
Class: |
A61K 31/426 20060101
A61K031/426; A61K 31/517 20060101 A61K031/517; A61K 31/496 20060101
A61K031/496; A61K 31/427 20060101 A61K031/427; A61K 31/404 20060101
A61K031/404; A61K 31/472 20060101 A61K031/472; A61K 31/4709
20060101 A61K031/4709; A61K 31/47 20060101 A61K031/47; A61K 31/443
20060101 A61K031/443; A61K 31/506 20060101 A61K031/506 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 3, 2012 |
IT |
MI2012A002065 |
Claims
1. A method of treating of genetic disorders affecting striated
muscle selected from Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT),
said method comprising administering an effective amount of a CFTR
corrector to a patient in need thereof.
2. A method according to claim 1, wherein the genetic disorder
affecting striated muscle is Brody's disease (BD).
3. A method according to claim 1, wherein the genetic disorder
affecting striated muscle is the recessive forms of
Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT).
4. A method according to claim 1, wherein the CFTR corrector is
selected from:
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl-
)pivalamide (Compound A);
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B);
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E);
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); 4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound
H); N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L);
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline (Compound
N); N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine (Compound P);
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q);
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound
S);
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U);
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-
-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarbox-
amide (Compound V); or a pharmaceutically acceptable salt
thereof.
5. A method according to claim 1, wherein the CFTR corrector is
selected from:
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl-
)pivalamide (Compound A);
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B);
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E);
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); 4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound
H); N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q);
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound
S);
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T) or a pharmaceutically acceptable salt thereof.
6. A method of treating of genetic disorders affecting striated
muscle selected from Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT),
said method comprising administering an effective amount of a
pharmaceutical composition comprising a CFTR corrector and one or
more pharmaceutically acceptable excipients to a patient in need
thereof.
7. A method according to claim 6, wherein the genetic disorder
affecting striated muscle is Brody's disease (BD).
8. A method according to claim 6, wherein the genetic disorder
affecting striated muscle is the recessive forms of
Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT).
9. A method according to claim 6, wherein the CFTR corrector is
selected from:
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl-
)pivalamide (Compound A);
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B);
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C);
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrr-
olidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound
D);
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E);
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); 4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound
H); N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L);
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline (Compound
N); N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine (Compound P);
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q);
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound
S);
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V); or a pharmaceutically acceptable salt thereof.
10. A method according to claim 6, wherein the CFTR corrector is
selected from:
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl-
)pivalamide (Compound A);
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B);
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E);
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); 4,5,7-trimethyl-N-phenylquinolin-2-amine (Compound
H); N-(4-bromophenyl)-4-methylquinolin-2-amine (Compound I);
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q);
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (Compound
S);
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-e
(Compound T); or a pharmaceutically acceptable salt thereof.
Description
[0001] This U.S. Non-Provisional application is a Continuation of
U.S. Non-Provisional application Ser. No. 14/647,773 filed on May
27, 2015, which is a U.S. national stage of PCT/EP2013/075158 filed
on 29 Nov. 2013, which claims priority to and the benefit of
Italian Patent Application No. MI2012A002065 filed on 3 Dec. 2012,
the contents of which are incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention is directed to compounds and
pharmaceutically acceptable salts thereof which are correctors of
the cellular processing of cystic fibrosis transmembrane
conductance regulator protein (hereinafter CFTR), for use in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
BACKGROUND OF THE INVENTION
[0003] Genetic disorders are pathologies caused by macroscopic
alteration in chromosomes or microscopic lesions (point mutations,
deletions or insertion) in genes. A genetic disorder is heritable
when the genomic alteration is present in progenitors and can be
transferred to the progeny. A genetic disorder is autosomal
dominant when only one mutated copy of the gene (inherited by one
progenitor) is necessary and sufficient for an organism to be
affected, A genetic disorder is autosomal recessive when two copies
of the gene (inherited by both progenitors) must be mutated for an
organism to be affected. Over 4000 human diseases are due to single
gene mutations, many of them affecting striated muscle tissues.
Among these, sarcoglycanopathies are severe muscular dystrophies
caused mainly by missense mutations in either .alpha.-, .beta.-,
.gamma.- or .delta. sarcoglycan coding genes and are identified as
Limb Girdle Muscular Dystrophy type 2D, 2E, 2C and 2F, respectively
(Laval and Bushby 2004). Sarcoglycans (SGs) form a tetrameric
complex linked to the dystrophin-associated protein complex and, in
addition to the main structural role, they are involved in
signaling [Barton 2006, Yoshida et al 1998]. In particular,
.alpha.-SG is an ecto-ATPase enzyme [Sandona et al 2004] possibly
implicated in the extracellular ATP-dependent modulation of
skeletal muscle contractility [Sandona et al 2005]. Gene defects in
a single sarcoglycan result in the absence or reduced expression of
all SG subunits, with impaired tetramer formation and plasma
membrane localization [Sandona and Betto 2009]. About 75% of
.alpha.-SG, 59% of .beta.-SG, 40% of .gamma.-SG and 57% of
.delta.-SG genetic defects are missense mutations, known to
generate full length proteins with single aminoacid substitution
[Leiden Open Variation database]. Recently, it has been
demonstrated that .alpha.-SG missense mutants are substrates of the
ER quality control and are prematurely disposed of by the
ubiquitin-proteasome system [Gastaldello et al 2008, Bartoli et al
2008].
[0004] In 1969, Brody first described in a human patient a muscular
disorder characterized by an "exercise-induced impairment of muscle
relaxation": muscle contraction was normal but relaxation appeared
delayed after repetitive contractions [Brody 1969]. So far, Brody's
disease (BD) is known as a rare inherited disorder of skeletal
muscle due to a sarco(endo)plasmic reticulum Ca.sup.2+-ATPase
(SERCA) deficiency, resulting from missense, non sense mutations
and in frame deletions of ATP2A1 gene, coding for SERCA1 isoform
[Bertchtold et al 2000].
[0005] Three isoforms of SERCA proteins are differentially
expressed by three genes. The SERCA1 isoform is expressed in
fast-twitch (type 2) skeletal muscle. SERCA1 deficiency results in
delayed muscle relaxation due to prolonged increase of calcium
concentration in skeletal muscle fibres cytoplasm.
[0006] A muscular disorder defined as "congenital pseudomyotonia"
(PMT) [Testoni et al 2008] has been described in bovine species.
Clinical symptoms are exercise-induced muscle stiffness. DNA
sequencing provided evidence of a missense mutations (R164H) in
bovine ATP2A1 gene [Drogemuller et al 2008]. Moreover, biochemical
results clearly demonstrated that cattle pathological muscles are
characterized by a selective reduction in the expression level of
SERCA1 protein, which accounts for the reduced Ca.sup.2+-ATPase
activity. By contrast, SERCA1 mRNA levels found in all affected
animals were comparable with mRNA expression in normal samples
[Sacchetto et al 2009].
[0007] For both Brody disease and cattle PMT a defect of ATP2A1
gene, resulting in selective reduction in SERCA1 expression level,
has been indicated as causative of the disease and cattle PMT has
been defined as the true counterpart of human Brody disease.
[0008] Since the mutations of ATP2A1 gene do not affect the
transcription [Sacchetto et al 2009], it has been hypothesized that
the resulting protein could be corrupted and could have an enhanced
susceptibility to the protein degradation via ubiquitin-proteasomal
pathway before being embedded into Sarcoplasmic Reticulum (SR)
bilayer. This hypothesis turned out to be correct: results have
demonstrated that SERCA1 R164H mutant is substrate of the quality
control system and prematurely disposed of by the
ubiquitin-proteasome pathway (Bianchini et al submitted for
publication).
[0009] Catecholaminergic polymorphic ventricular tachycardia (CPVT)
is an inherited, potentially fatal, arrhythmogenic disease
characterized by stress- and/or emotion-induced life-threatening
cardiac arrhythmias [Liu et al 2008]. Mutations in the cardiac
ryanodine receptor (RyR2) gene have been associated with the
autosomal dominant form of CPVT.1 whereas the autosomal recessive
form of CPVT has been linked to mutations in CASQ2 and, recently,
TRDN genes, encoding calsequestrin2 and triadin, respectively
[Beard et al 2004; Roux-Buisson et al. 2012]. These proteins,
together with RyR2 and junctin, form a quaternary macromolecular
complex at the junctional SR of cardiomyocytes responsible for SR
Ca.sup.2+ release during cardiac muscle contraction. Investigations
performed in knock-in models of dominant CPVT and recessive CPVT
have demonstrated that abnormal Ca.sup.2+ release induces cell-wide
Ca.sup.2+ waves, delayed after depolarizations and triggered
activity, all of which lead to arrhythmogenesis [Liu et al 2009].
In the knock-in mouse model (CASQ2.sup.R33Q/R33Q), drastic
reduction of CASQ2 is accompanied by decrease of triadin (25%) and
junctin (70%) without any change of the relative transcripts [Rizzi
et al 2008]. It has been demonstrated that the strong reduction of
the D307H CASQ2 mutant, also linked to the recessive form of human
CPVT, is due to the activity of the ubiquitin-proteasome system. In
the knock in mouse model CASQ2.sup.D307H/D307H, the cardiac
arrhythmia developed as consequence of CASQ2 mutant degradation,
can be counteracted by systemic administration of the proteasome
inhibitor Velcade that allows partial rescue of the mutant CSAQ2,
i.e., 20% increase over not treated mice [Katz G et al 2013].
Similar results have been obtained by our group in the
CASQ2.sup.R33Q/R33Q knock-in mouse by systemic delivery of Velcade
(unpublished data). The T59R triadin mutant, recently identified in
a CPVT patient, has been studied in both cellular and animal models
suggesting it is prematurely disposed of by the
ubiquitin-proteasome system of the cell [Roux-Buisson N et al.
2012].
[0010] Sarcoglycanopathies, BD and CPVT, even though affecting
striated muscle, are very different genetic disorders both for
symptoms and etiology. However, it is possible to recognize as
common trait of these disorders the posttranscriptional removal of
the mutated gene product because of folding problems, that leads to
a de facto loss of function.
[0011] At present, there are no effective treatments for
sarcoglycanopathies, Brody's disease (BD) or the recessive forms of
Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT).
[0012] Recessive CPVT, for example, shows an incomplete response to
3-blockers, that results in the recurrence of ventricular
arrhythmias and cardiac arrest [Hayashi et al 2009]. BD patients
are usually treated with dantrolene [Vattemi et al. 2010], a muscle
relaxant (blocker of the dihydro-pyridine receptor-RyR complex),
but due to liver toxicity, dantrolene is unsuitable for long-term
treatment. Both gene and cell therapy strategies are under
evaluation for the cure of sarcoglycanopathies and CPVT, but are
far from being amenable of clinical trial [Daniel et al 2007;
Denegri et al 2012]. Exon skipping strategy, very promising in
Duchenne Muscular Dystrophy [Hoffman et al 2011] is not appropriate
for sarcoglycanopathies, CPVT and BD since mutant proteins don't
have dispensable sequence that could be skipped away. The use of
molecules able to promote stop-codon-read-through is potentially
applicable in these disorders when a nonsense mutation is present.
However, in sarcoglycanopathies, for example, the percentage of
missense mutations is considerably higher than that of other gene
defects.
[0013] There are no drugs currently approved to treat
sarcoglycanopathies, Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT) and
therefore there is a great unmet need for the treatment of such
diseases.
[0014] We have now found that small molecules known as "CFTR
correctors" are able to reverse the pathological phenotype of
sarcoglycanopathies BD and CPVT by promoting folding and proper
targeting of the mutated misfolded proteins and thus can be used in
the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
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pseudomyotonia in Chianina cattle. Am J Pathol 2009, 174:565-73.
[0033] Sandona D, Gastaldello S, Martinello T, Betto R.
Characterization of the ATP-hydrolyzing activity of
.alpha.-sarcoglycan. Biochem J 2004, 381:105-12. [0034] Sandona D,
Danieli-Betto D, Germinario E, Biral D, Martinello T, Lioy A,
Tarricone E, Gastaldello S, Betto R. The T-tubule membrane
ATP-operated P2X4 receptor influences contractility of skeletal
muscle. FASEB Journal 2005, 19:1184-1186. [0035] Sandona D, Betto
R. Sarcoglycanopathies: molecular pathogenesis and therapeutic
prospects. Expert Rev Mol Med 2009, 11:e28. [0036] Testoni S, Boni
P, Gentile A. Congenital pseudomyotonia in Chianina cattle. Vet Rec
2008, 163:252. [0037] Vattemi G, Gualandi F, Oosterhof A, Marini M,
Tonin P, Rimessi P, Neri M, Guglielmi V, Russignan A, Poli C, van
Kuppevelt T H, Ferlini A, Tomelleri G. Brody Disease: Insights Into
Biochemical Features of SERCA1 and Identification of a Novel
Mutation. J Neuropathol Exp Neurol 2010, 69:246-52. [0038] Yoshida
T, Pan Y, Hanada H, Iwata Y, Shigekawa M. Bidirectional signaling
between sarcoglycans and the integrin adhesion system in cultured
L6 myocytes. J. Biol. Chem. 1998, 273: 1583-1590.
SUMMARY OF THE INVENTION
[0039] The solution provided by the present invention is the use of
CFTR correctors that promote folding and trafficking of CFTR, in
the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
[0040] Thus, the present invention provides a CFTR corrector for
use in the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
[0041] In another aspect, the present invention provides a method
of treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT) comprising administering a safe and effective
amount of a CFTR corrector to a patient in need thereof.
[0042] In another aspect, the present invention provides
pharmaceutical compositions comprising a CFTR corrector and one or
more pharmaceutically acceptable excipients for use in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
BRIEF DESCRIPTION OF THE FIGURES
[0043] FIG. 1 CFTR correctors (Compounds A to F) promote the rescue
of R98H mutant of alpha-sarcoglycan in HEK293 cell model.
Alpha-sarcoglycan (.alpha.-SG) protein level has been determined by
western blot (a representative experiment is shown in the top
panel) on total protein content purified from cells expressing the
R98H mutant treated with either CFTR correctors (compound A, B, C,
D, E and F as indicated), MG132 (proteasome inhibitor) used as
positive control, or correctors vehicle (DMSO) used as negative
control. Cells expressing the wild type form of alpha-sarcoglycan
have also been analyzed, for comparison. To normalize protein
content, the expression of .beta.-actin has been used as an
internal marker. The graph in the lower part of the figure shows
the average values (+/-standard error) of alpha-sarcoglycan
expression determined by densitometric analyses of at least three
independent experiments. Values are expressed as percentage of the
alpha-sarcoglycan protein content present in cells expressing the
R98H mutant treated with vehicle. **, P.ltoreq.0.01; *,
P.ltoreq.0.05.
[0044] FIG. 2 CFTR correctors (Compounds E and D) promote the
correct membrane localization of V247M alpha-sarcoglycan in HEK293
cells. Cells expressing the V247M mutant of alpha-sarcoglycan
cultivated on glass coverslips have been treated with either
correctors vehicle (DMSO) used as negative control, MG132 used as
positive control, compound E and compound D. Cells expressing the
wild type form of alpha-sarcoglycan have also been utilized
(.alpha.-SG WT) for comparison. After treatments, intact cells have
been immunodecorated with an antibody specific for an extracellular
epitope of alpha-sarcoglycan in order to mark only the membrane
resident protein. The bounded antibody has been visualized by a
secondary antibody conjugated with the fluorescence dye TRITC.
Images have been recorder with a Leica laser scanning confocal
microscope. Behind each fluorescence image, the same field
collected in transmission light, is reported.
[0045] FIG. 3 CFTR correctors (Compounds A to F) promote the rescue
of R164H mutant of SERCA1 in HEK293 cells. SERCA1 protein level has
been determined by western blot (a representative experiment is
shown in the top panel) on total protein of lysates from HEK 293
cells expressing the R164H mutant treated with either CFTR
correctors (compound A, B, C, D, E and F as indicated), MG132 or
correctors vehicle (DMSO). Cells expressing the wild type form of
SERCA1 have also been utilized, for comparison. To normalized
protein loading, the expression of .beta.-actin has been used as an
internal marker. The graph in the lower part of the figure shows
the average values (+/-standard error) of SERCA1 expression
determined by densitometric analyses of at least three independent
experiments. Values are expressed as percentage of the SERCA
protein content present in cells expressing the wild type form.
***, P.ltoreq.0.001; **, P.ltoreq.0.01.
[0046] FIG. 4 CFTR correctors (Compounds H, I, T and A) promote the
rescue of R98H mutant of alpha-sarcoglycan in HEK293 cell model.
Alpha-sarcoglycan protein level has been determined by western blot
(a representative experiment is shown in the top panel) on total
protein content purified from cells expressing the R98H mutant
treated with either compound H 15 .mu.M, I 10 .mu.M, T 15 .mu.M,
and A 2 .mu.M (as indicated), or DMSO (vehicle), used as negative
control. Cells expressing the wild type form of alpha-sarcoglycan
(.alpha.-WT) have been analyzed for comparison. Blot has been
probed with .alpha.-sarcoglycan (.alpha.-SG) specific antibody. To
normalize protein content, the expression of .beta.-actin
(.beta.-act) has been used as an internal marker. The graph in the
lower part of the figure shows the average values (+/-standard
error) of alpha-sarcoglycan expression determined by densitometric
analyses of at least three independent experiments. Values are
expressed as percentage of the alpha-sarcoglycan protein content
present in untreated cells expressing the WT protein. ***,
P.ltoreq.0.001; **, P.ltoreq.0.01.
[0047] FIG. 5 The Compound R promotes the rescue of R98H mutant of
alpha-sarcoglycan in HEK293 cell model in dose dependent manner.
Alpha-sarcoglycan protein level has been determined by western blot
(a representative experiment is shown in the top panel) on total
protein content purified from cells expressing the R98H mutant
treated with either increasing concentrations (as indicated) of
compound R, or DMSO (vehicle) used as negative control. Cells
expressing the wild type form of alpha-sarcoglycan (.alpha.-WT)
have been analyzed, for comparison. Blot has been probed with
.alpha.-sarcoglycan (.alpha.-SG) specific antibody. To normalize
protein content, the expression of .beta.-actin (.beta.-act) has
been used as an internal marker. The graph in the lower part of the
figure shows the average values (+/-standard error) of
alpha-sarcoglycan expression determined by densitometric analyses
of at least three independent experiments. Values are expressed as
percentage of the alpha-sarcoglycan protein content present in
untreated cells expressing the WT protein. **, P.ltoreq.0.01; *,
P.ltoreq.0.05.
[0048] FIG. 6 Compounds Q and S promote the rescue of R98H mutant
of alpha-sarcoglycan in HEK293 cell model in dose dependent manner.
Alpha-sarcoglycan protein level has been determined by western blot
(a representative experiment is shown in the top panel) on total
protein content purified from cells expressing the R98H mutant
treated with either increasing concentrations (as indicated) of
compounds Q and S, or DMSO (vehicle) used as negative control.
Cells expressing the wild type form of alpha-sarcoglycan
(.alpha.-WT) have been analyzed, for comparison. Blot has been
probed with .alpha.-sarcoglycan (.alpha.-SG) specific antibody. To
normalize protein content, the expression of .beta.-actin
(.beta.-act) has been used as an internal marker. The graph in the
lower part of the figure shows the average values (+/-standard
error) of alpha-sarcoglycan expression determined by densitometric
analyses of at least three independent experiments. Values are
expressed as percentage of the alpha-sarcoglycan protein content
present in untreated cells expressing the WT protein. **,
P.ltoreq.0.01; *, P.ltoreq.0.05.
[0049] FIG. 7 CFTR correctors (Compounds E, H, I, Q, F, R, S, T and
A) promote the rescue of D97G mutant of alpha-sarcoglycan in HEK293
cell model. Alpha-sarcoglycan protein level has been determined by
western blot on total protein content purified from cells
expressing the D97G mutant treated with either compound E 10 .mu.M,
H 15 .mu.M, I 10 .mu.M, Q 10 .mu.M, F 10 .mu.M, R 5 .mu.M, S 15
.mu.M, T 15 .mu.M, and A 2 .mu.M (as indicated), or DMSO (vehicle)
used as negative control. Cells expressing the wild type form of
alpha-sarcoglycan (.alpha.-WT) have been analyzed for comparison.
The graph shows the average values (+/-standard error) of
alpha-sarcoglycan expression determined by densitometric analyses
of at least three independent experiments. Values are expressed as
percentage of the alpha-sarcoglycan protein content present in
untreated cells expressing the WT protein. ***, P.ltoreq.0.001; **,
P.ltoreq.0.01; *, P.ltoreq.0.05.
[0050] FIG. 8 Compounds H, I, Q, and A promote the correct membrane
localization of R98H alpha-sarcoglycan in HEK293 cells. Cells
expressing the R98H mutant of alpha-sarcoglycan cultivated on glass
coverslips have been treated with either DMSO (vehicle) used as
negative control, or compound H 15 .mu.M, I 10 .mu.M, Q 10 .mu.M
and A 2 .mu.M, for 24 hours. Cells expressing the wild type form of
alpha-sarcoglycan (.alpha.-SG WT) have been utilized for
comparison. After treatments, intact cells have been
immunodecorated with an antibody specific for an extracellular
epitope of alpha-sarcoglycan in order to mark only the membrane
resident protein. Membrane-bound antibodies have been visualized by
a secondary antibody conjugated with the fluorescence dye TRITC.
Images have been recorded, at the same magnification, with a Leica
laser scanning confocal microscope. Behind each fluorescence image,
the same field collected in transmission light, is reported to
estimate the number of cells present.
[0051] FIG. 9 Compound R promote the correct membrane localization
of R98H alpha-sarcoglycan in HEK293 cells. Cells expressing the
R98H mutant of alpha-sarcoglycan cultivated on glass coverslips
have been treated with either DMSO (vehicle), used as negative
control, or compound R at different concentrations (as indicated),
for 24 hours. Cells expressing the wild type form of
alpha-sarcoglycan (.alpha.-SG WT) have been utilized for
comparison. After treatments, intact cells have been
immunodecorated with an antibody specific for an extracellular
epitope of alpha-sarcoglycan in order to mark only the membrane
resident protein. Membrane-bound antibodies have been visualized by
a secondary antibody conjugated with the fluorescence dye TRITC.
All images have been recorded, at the same magnification, with a
Leica laser scanning confocal microscope. Behind each fluorescence
image, the same field collected in transmission light, is reported
to estimate the number of cells present.
[0052] FIG. 10 CFTR correctors (compounds H, I, Q, R, S and T)
promote the rescue of R164H mutant of SERCA1 in HEK293 cell model.
SERCA1 protein level has been determined by western blot on total
protein content purified from cells expressing the R164H mutant
treated with either compound H 15 .mu.M, I 10 .mu.M, Q 10 .mu.M, R
5 .mu.M, S 15 .mu.M and T 15 .mu.M (as indicated), or DMSO
(vehicle) used as negative control. Cells expressing the wild type
form of SERCA1 (WT) have been analyzed for comparison. The graph
shows the average values (+/-standard error) of SERCA1 expression
determined by densitometric analyses of at least three independent
experiments. Values are expressed as percentage of the SERCA1
protein content present in untreated cells expressing the WT
protein. ***, P.ltoreq.0.001; **, P.ltoreq.0.01; *,
P.ltoreq.0.05.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0053] The term "CFTR" as used herein means cystic fibrosis
transmembrane regulator or a mutation thereof capable of regulator
activity, including, but not limited, to .DELTA.F508 CFTR.
[0054] The term "CFTR correctors" as used herein means a molecule,
correcting the defective cellular processing, able to increase the
number of CFTR in a cellular membrane.
[0055] The term "SERCA1" as used herein is the acronym of
sarco(endo)plasmic reticulum Ca.sup.2+-ATPase isoform 1.
[0056] The term "CASQ2" as used herein is the acronym of
calsequestrin isoform 2.
[0057] "Protein folding" as used herein means the process by which
a polypeptide chain folds to a specific three-dimensional protein
structure assuming its functional shape or conformation.
[0058] Protein trafficking is the mechanism by which proteins
destined either to the plasma membrane or secretion transit through
Endoplasmic Reticulum, Golgi apparatus and by transport vesicles
reach the final destination.
[0059] Misfoded protein as used herein means a protein unable to
reach its functional shape or conformation because of the presence
of missing or incorrect amino acids. The term "missense mutation"
as used herein means a point mutation in which a single nucleotide
is changed, resulting in a codon that codes for a different amino
acid, thus for example: R98H mutant of .alpha.-sarcoglycan means
that at position 98 of .alpha.-sarcoglycan sequence the amino acid
R (Arginine) has been changed in H (Histidine); V247M mutant of
.alpha.-sarcoglycan means that at position 247 of x-sarcoglycan
sequence the amino acid V (Valine) has been changed in M
(Methionine); R33Q mutant of CASQ2 means that at position 33 of
calsequestrin 2 the amino acid R (Arginine) has been changed in Q
(Glutamine); R164H mutant of SERCA1 means that at position 164 of
SERCA1 sequence the amino acid R (Arginine) has been changed in H
(Histidine).
[0060] The term "non sense mutation" as used herein means a point
mutation in which a single nucleotide is changed, resulting in a
stop codon.
[0061] The term "in frame deletion" as used herein means a genetic
mutation caused by deletions of three or multiple of three
nucleotides from a DNA sequence leading to the loss of one of more
amino acids with no other consequence on protein sequence.
[0062] The term "ubiquitin" refers to a small regulatory protein
that can be attached to proteins and label them for destruction
through proteasome.
[0063] The term "proteasome" refers to a macromolecular protein
complex responsible of the ATP dependent degradation of ubiquitin
tagged proteins.
[0064] The term "primary culture" as used herein means cells either
of human or animal origin prepared by mechanical or enzymatic
dissociation of a specific tissue or bioptic fragment of
tissue.
[0065] The term "muscular biopsy" as used herein means a fragment
of skeletal muscle tissue removed from either a human or animal
subject that can be used to diagnose a diseases involving muscle
tissue and that can be also used, after acquisition of informed
consent, for research experiments.
[0066] The term "disease animal model" means a living, non-human
animal that, because of naturally occurring variation of its genome
or because its genome has been artificially modified, develops a
disease similar to a human condition.
[0067] The term "Knock out (KO) mouse" means a genetically
engineered mouse in which an existing gene has been inactivated, or
"knocked out," by replacing it or disrupting it with an artificial
piece of DNA. The loss of gene activity often causes changes in
mouse's phenotype and can lead to the development of a disease
similar to a human condition.
[0068] The term "Knock in (KI) mouse" as used herein means a
genetically engineered mouse in which the protein coding region of
a gene has been replaced by the same coding region containing point
mutations. The expression of the mutated gene can causes changes in
mouse's phenotype and can lead to the development of a disease
similar to a human condition.
[0069] The term LGMD-2D means Limb Girdle Muscular Dystrophy type
2D (sarcoglycanopathy) caused by mutations of the SGCA gene coding
for alpha-sarcoglycan.
[0070] The term LGMD-2E means Limb Girdle Muscular Dystrophy type
2E (sarcoglycanopathy) caused by mutations of the SGCB gene coding
for beta-sarcoglycan.
[0071] The term LGMD-2C means Limb Girdle Muscular Dystrophy type
2C (sarcoglycanopathy) caused by mutations of the SGCG gene coding
for gamma-sarcgoglycan.
[0072] The term LGMD-2F means Limb Girdle Muscular Dystrophy type
2F (sarcoglycanopathy) caused by mutations of the SGCD gene coding
for delta-sarcoglycan.
[0073] As used herein, "treat" in reference to a disorder means:
(1) to ameliorate the disorder or one or more of the biological
manifestations of the disorder, (2) to interfere with (a) one or
more points in the biological cascade that leads to or is
responsible for the disorder or (b) one or more of the biological
manifestations of the disorder, (3) to alleviate one or more of the
symptoms or effects associated with the disorder, or (4) to slow
the progression of the disorder or one or more of the biological
manifestations of the disorder.
[0074] "Treatment," thus, for example, covers any treatment of a
condition or disease in a mammal, particularly in a human, and
includes: (a) preventing the condition or disease, disorder or
symptom thereof from occurring in a subject which may be
predisposed to the condition or disease or disorder but has not yet
been diagnosed as having it; (b) inhibiting the condition or
disease, disorder or symptom thereof, such as, arresting its
development; and (c) relieving, alleviating or ameliorating the
condition or disease or disorder or symptom thereof, such as, for
example, causing regression of the condition or disease or disorder
or symptom thereof.
[0075] As used herein, "safe and effective amount" in reference to
CFTR correctors or a pharmaceutically acceptable salt thereof, or
other pharmaceutically-active agent, means an amount of the
compound sufficient to treat the patient's condition but low enough
to avoid serious side effects (at a reasonable benefit/risk ratio)
within the scope of sound medical judgment. A safe and effective
amount of a compound will vary with the particular compound chosen
(e.g. consider the potency, efficacy, and half-life of the
compound); the route of administration chosen; the disorder being
treated; the severity of the disorder being treated; the age, size,
weight, and physical condition of the patient being treated; the
medical history of the patient to be treated; the duration of the
treatment; the nature of concurrent therapy; the desired
therapeutic effect.
[0076] As used herein, "patient" refers to a human (including
adults and children) or other animal affected by a disease. In one
embodiment, "patient" refers to a human.
[0077] As used herein, "pharmaceutically acceptable excipient"
means a pharmaceutically acceptable material, composition or
vehicle involved in giving form or consistency to the
pharmaceutical composition. Each excipient must be compatible with
the other ingredients of the pharmaceutical composition when
commingled such that interactions which would substantially reduce
the efficacy of a compound of use according to the invention or a
pharmaceutically acceptable salt thereof when administered to a
patient and interactions which would result in pharmaceutical
compositions that are not pharmaceutically acceptable are avoided.
In addition, each excipient must of course be
pharmaceutically-acceptable eg of sufficiently high purity.
[0078] As used herein, the term "pharmaceutically acceptable salt"
refers to a salt that retains the desired biological activity of
the compound and exhibits minimal undesired toxicological effects.
Pharmaceutically acceptable salts of compounds may be used to
impart greater stability or solubility to a molecule thereby
facilitating formulation into a dosage form.
[0079] In one embodiment, the present invention provides correctors
of the cellular processing of cystic fibrosis transmembrane
conductance regulator protein (hereinafter CFTR), in the treatment
of genetic disorder affecting striated muscle selected from
sarcoglycanopathies, Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0080] In one embodiment the genetic disorders affecting striated
muscle are sarcoglycanopathies or Brody's disease (BD).
[0081] CFRT correctors of use in the present invention are fully
described, for example in US patent Nos U.S. Pat. No. 8,227,615,
U.S. Pat. No. 8,143,295, U.S. Pat. No. 7,977,322, U.S. Pat. No.
7,939,558, U.S. Pat. No. 7,645,789 U.S. Pat. No. 6,770,663; in US
patent application Nos US20120184583, US20120101143, US20120004405,
US2011257223, US20110281873, US20110257223, US20110245322,
US20110201544, US20110177999, US20110071206, US20110060024,
US20100331297, US20100273839, US20100144798, US20100113555,
US20090246137, US20090253736, US20090221597, US20090131492,
US20080319008, US20080318984, US20080176899, US20080161371,
US20060052358, US20050113423; US20050176761 in European Patent No
EP1912983 B1; in Japanese application No 2009057364; in PCT
international patent applications WO2012021974 WO2012036573
WO2011137427, WO2011133956, WO2011133953, WO2011133951,
WO2011008931, WO2010151747, WO2010068863, WO2010066912,
WO2010048125, WO2010054138, WO2009123896, WO2009105234,
WO2009108657, WO2009062118, WO2009051909, WO2009051910,
WO2009039567, WO2009023509, WO2008141119, WO2008127399,
WO2007117715, WO2007075946, WO2007021982, WO2007056341,
WO2006101740, WO2006099256, WO2006052821, WO2005120497,
WO2005075435, WO2004080972, WO2004111014.
[0082] The preparation of such compounds is fully described in the
afore-mentioned publications the subject matter of which is
incorporated herein by reference in its entirety.
[0083] A representative first class of CFTR correctors is as
disclosed in WO2009051909 as a compound of formula (I)
##STR00001##
or the salts, solvates, hydrates, and prodrug forms thereof, and
stereoisomers thereof, wherein: A and B are aromatic rings each
independently selected from thiazole and oxazole, with X1, X2, X3
and X4 being heteroatoms selected from N, O and S, with each dotted
line connecting X1 to X2 within ring A and X3 to X4 within ring B
being a single or double bond provided that when one bond is a
double bond then the other bond is a single bond, and with the
dotted line connecting R4 and R5 indicating rotational isomers
around the solid line bond connecting rings A and B. R1 is a
substituted or unsubstituted group selected from aliphatic and
aryl, with the proviso that when R1 is an unsubstituted phenyl then
R3 or R5 is other than hydrogen; R2 is a substituted or
unsubstituted aryl; R3 is hydrogen or substituted or unsubstituted
aliphatic; and R4 and R5 are each independently hydrogen, a
substituted or unsubstituted lower aliphatic, or form a bridge
comprising a heteroatom or a substituted or unsubstituted lower
aliphatic chain, with the dotted line connecting R4 and R5 further
indicating either no bridge for unbridged R4 and R5 or said bridge
for bridged R4 and R5.
[0084] A particularly preferred compound of formula (I) is
##STR00002##
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide. (hereinafter Compound A).
[0085] A representative second class of CFTR correctors is as
disclosed in WO2004111014 as a compound of formulae (V-A, V-B and
V-E)
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein RA and RB
are each independently V--RV, or RA and RB, taken together with the
nitrogen atom, form an optionally substituted 3-12 membered
saturated, partially unsaturated, or fully unsaturated monocyclic
or bicyclic ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, wherein V is a bond or is an
optionally substituted C1-C6 alkylidene chain wherein up to two
methyleneunits of V are optionally and independently replaced by
--CO--, --CS--, --COCO--, --CONR'--, --CONR'NR'--, --CO2-, --OCO--,
--NR'CO2-, --O--, --NR'CONR'--, --OCONR'--, --NR'NR', --NR'NR'CO--,
--NR'CO-'-S--, --SO, --SO2-, --NR'--, --SO2NR'--, --NR'SO2-,
--NR'SO2NR'--, and each occurrence of RV is independently R',
halogen, NO2, or CN, and wherein RA and RB, or any ring formed by
RA and RB taken together with the nitrogen atom, are optionally and
independently substituted by q occurrences of U--RU, wherein q is
0-5; U is a bond or is an optionally substituted C1-C6 alkylidene
chain wherein up to two methylene units of U are optionally and
independently replaced by --CO--, --CS--, --COCO--, --CONR'--,
--CONR'NR'--, --CO2-, --OCO--, --NR--CO2-, --O--, --NR'CONR'--,
--OCONR'--, --NR'NR', --NR'NR'CO--, --NR'CO--, --S--, --SO, --SO2--
--NR'--, --SO2NR'--, --NR'SO2-, --NR'SO2NR'--, and each occurrence
of RU is independently R', halogen, NO2, or CN; R1 is absent or is
Y--RY; Y is a bond or is an optionally substituted C1-C6 alkylidene
chain wherein up to two methylene units of Y are optionally and
independently replaced by --CO--, --CONR--, --O--NRCO--, --S--,
--SO2-, --NR--, --SO2NR--, or --NRSO2-, and each occurrence of RY
is independently R', OR', SR', N(R')2, halogen, NO2, or CN,
provided that when R1 is present, it is always bonded to the
nitrogen atom through a carbon atom; each occurrence of R is
independently selected from hydrogen or an optionally substituted
C1-8 aliphatic group; and each occurrence of R' is independently
selected from hydrogen or an optionally substituted group selected
from a C1-C8 aliphatic group, a 3-8-membered saturated, partially
unsaturated, or fully unsaturated monocyclic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or an 8-12 membered saturated, partially unsaturated, or
fully unsaturated bicyclic ring system having 0-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; or two
occurrences of R', or two occurrences of R, are taken together with
the atoms) to which they are bound to form an optionally
substituted 3-12 membered saturated, partially unsaturated, or
fully unsaturated monocyclic or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; Q is a bond or is an optionally substituted C1-C6
alkylidene chain wherein up to two methylene units of Q
areoptionally and independently replaced by --CO--, --CS--,
--COCO--, --CONR--, --CONRNRCO2-, --OCO--, --NRCO2-, --O--,
--NRCONR--, --OCONR--, --NRNR, --NRNRCO--, --NRCO--, --S--, --SO,
--SO2-, --NR--, --SO2NR--, --NRSO2-, --NRSO2NR--, and each
occurrence of RX is independently R', halogen, NO2, or CN; wherein
x is 0-5; wherein G2 and G3 are each independently absent or an
optionally substituted C1-C6 alkylidene chain, wherein one or two
methylene units are optionally and independently replaced with
--CO--, --CS--, --SO--, --SO2-, --NR'--, NSO2R')--, NCOR')--,
--O--, or --S--, and wherein one or two hydrogen atoms of one or
more methylene units are optionally substituted with R'Ar1 is
absent or is a 3-8 membered saturated, partially unsaturated, or
fully unsaturated monocyclic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or an 8-12
membered saturated, partially unsaturated, or fully unsaturated
bicyclic ring system having 0-5 heteroatoms independently selected
from nitrogen, oxygen, or sulfur; wherein Ar1 is optionally
substituted with m independent occurrences of WRW, wherein m is 0-5
and W is a bond or is an optionally substituted C1-C6 alkylidene
chain wherein up to two methylene units of T are optionally and
independently replaced by --CO--, --CS--, --COCO--, --CONR--,
--CONRNR--, --CO2-, --OCO--, --NRCO2-, --O--, --NRCONR--,
--OCONR--, --NRNR, --NRNRCO--, --NRCO--, --S--, --SO, --SO2-,
--NR--, --SO2NR--, --NRSO2-, --NRSO2NR--, and each occurrence of RW
is independently R', halogen, NO2, or CN; wherein n is 0, 1, or 2;
X2 and X5 are each independently CR' or N; and each occurrence of
X1, when present, and X3, X4 and X6 are each independently, as
valency and stability permit, C(R')2, --O--, --NR--, S, C.dbd.O, or
C.dbd.S.
[0086] A particularly preferred compounds of formula (V-B) is
##STR00004##
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (hereinafter Compound B), individual stereoisomers
thereof or a pharmaceutically acceptable salt thereof.
[0087] A particularly preferred compounds of formula (V-E) is
##STR00005##
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (hereinafter Compound C), individual stereoisomers
thereof or a pharmaceutically acceptable salt thereof.
[0088] A representative third class of CFTR correctors is as
disclosed in WO2007021982 as a compound of formula (III) or
(IIIa)
##STR00006##
or a pharmaceutically acceptable salt thereof, wherein: each
R.sup.x is independently hydrogen, halo, CF3, C1-C4 alkyl, or
--OC1-C4 alkyl; provided that both R.sup.x are not simultaneously
hydrogen; or the two R.sup.x, taken together form ring (a):
##STR00007##
X is CH2, CF2, CH2-CH2, or CF2-CF2; ring A is 3-7 membered
monocyclic cycloalkyl ring; R.sup.AA and R.sup.BB, taken together
with the nitrogen atom, form a pyrrolidinyl ring substituted with
OR'; R' is hydrogen or C1-C6 aliphatic, wherein up to two carbon
units of said aliphatic are optionally and independently replaced
by --CO--, --CS--, --COCO--, --CONR--, --CONRNR--, --CO2-, --OCO--,
--NRCO2-, --O--, --NRCONR--, --OCONR--, --NRNR, --NRNRCO--,
--NRCO--, --S--, --SO, --SO2-, --NR--, --SO2NR--, NRSO2-, or
--NRSO2NR--; R is hydrogen or C1-C6 aliphatic; Z is an electron
withdrawing substituent; and q is 0-3. A particularly preferred
compound of formula (III) is
##STR00008##
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrr-
olidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide
(hereinafter Compound D) or a pharmaceutically acceptable salt
thereof.
[0089] A representative fourth class of CFTR correctors is as
disclosed in WO2006101740 as a compound of formula (II):
##STR00009##
wherein R1 is independently selected from a substituted or
unsubstituted phenyl group, R2 is independently selected from a
hydrogen or an alkyl group, R3 is independently selected from a
substituted or unsubstituted phenyl group, a substituted or
unsubstituted heteroaromatic group, a substituted amino group, a
substituted acyl group; or a pharmaceutically acceptable derivative
thereof, as an individual stereoisomer or a mixture thereof; or a
pharmaceutically acceptable salt thereof.
[0090] In one embodiment, R1 is chosen from an unsubstituted phenyl
group, a unsubstituted biphenyl group, a 3-, 4-di(methyl)phenyl
group, a 4-(methyl)phenyl group, a 3-, 4-di(methoxy)phenyl group, a
3-, 4-di(hydroxy)phenyl group, a 4-(bromo)phenyl group, a
4-(propene)phenyl group, a 3-(methyl)-4-(methoxy)phenyl group, or a
3-(nitro)-4(methyl)phenyl group.
[0091] In another embodiment, R2 is chosen from a hydrogen or a
methyl group. In yet another embodiment, R3 is chosen from a
unsubstituted phenyl group, as a 3-(chloro)phenyl group, a
4-(fluoro)phenyl group, a 2-(methyl)phenyl group, a
2-(ethoxy)phenyl group, a 2-,5-di(methoxy)-4-(chloro)phenyl group,
a 4-(acetamide)phenyl group, a unsubstituted pyrimidine group, a
3-(methyl)pyridine group, a di(methyl)butylideneamine group, an
acyl-thiophene group, an acyl(4-t-butyl-phenyl) group, or an
acyl-methylthio-imidazol-5-phenyl group.
[0092] In representative embodiments, the compound is chosen
from:
##STR00010## ##STR00011##
[0093] A particularly preferred compound of formula (II) is
##STR00012##
N-phenyl-4-(4-vinylphenyl)thiazol-2-amine (hereinafter Compound S)
or a pharmaceutically acceptable salt thereof. or as a compound of
formula (III):
##STR00013##
wherein R1 is chosen from a hydrogen, an alkyl group, or an alkoxy
group; R2 is chosen from a hydrogen, an alkyl group, or an alkoxy
group; R3 is an alkyl group; R4 is chosen from a hydroxyl group or
a carbonyl group; R5 and R6 are chosen from a fused cycloalkyl
group, a hydrogen, an alkyl group, or a substituted or
unsubstituted phenyl group; or a pharmaceutically acceptable
derivative thereof, as an individual stereoisomer or a mixture
thereof; or a pharmaceutically acceptable salt thereof.
[0094] In one embodiment, R1 chosen from a hydrogen, a methyl
group, an ethyl group, a methoxy group, or an ethoxy group. In
another embodiment, R2 is chosen from a hydrogen, a methyl group,
an ethyl group, a methoxy group, or an ethoxy group. In yet another
embodiment, R3 is chosen from a methyl group or an ethyl group. In
yet another embodiment, R4 is chosen from a hydroxyl group or a
carbonyl group. In yet another embodiment, R5 is chosen from a
hydrogen, a methyl group, an ethyl group, a unsubstituted phenyl
group, or a 2-methylthio-1H-benzoimidazole group. In yet another
embodiment, R6 is chosen from a hydrogen, a methyl group, an ethyl
group, a unsubstituted phenyl group, or a
2-methylthio-1H-benzoimidazole group. In yet another embodiment, R5
and R6 are a fused cyclopenyl group.
[0095] In representative embodiments, the compound is chosen
from:
##STR00014##
[0096] A particularly preferred compound of formula (III) is
##STR00015##
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (hereinafter Compound T) or a pharmaceutically acceptable salt
thereof. or as a compound of formula (IV):
##STR00016##
wherein R1 is a alkyl group and R2 is a substituted or
unsubstituted phenyl group; or a substituted or unsubstituted
phenyl group; or a pharmaceutically acceptable derivative thereof,
as an individual stereoisomer or a mixture thereof;
[0097] In one embodiment, R1 is a methyl group. In another
embodiment, R2 is chosen from a 3-(nitro)phenyl group, a
2-methoxyphenyl, a 2-ethoxyphenyl, a 1-phenylethyl-1-one group, or
a 3-chloro-6-methoxyphenyl group.
[0098] In representative embodiments, the compound is chosen
from:
##STR00017##
[0099] A particularly preferred compound of formula (IV) is
selected form
##STR00018##
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (hereinafter Compound E);
##STR00019##
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(hereinafter compound Q);
##STR00020##
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(hereinafter Compound R); or a pharmaceutically acceptable salt
thereof. or as a compound of formula (V):
##STR00021##
wherein R1 is chosen from a hydrogen, or an alkyl group; R2 is
chosen from a hydrogen, or an alkyl group; R3 is an alkyl group; R4
is chosen from a hydrogen, an alkyl group, an alkoxy group, or a
halogen group; and R5 is chosen from a hydrogen, an alkyl group, an
alkoxy group, or a halogen group; or a pharmaceutically acceptable
derivative thereof, as an individual stereoisomer or a mixture
thereof; or a pharmaceutically acceptable salt thereof.
[0100] In one embodiment, R1 is chosen from a hydrogen or a methyl
group. In another embodiment, R2 is chosen from a hydrogen or a
methyl group. In yet another embodiment, R3 is chosen from a
hydrogen or a methyl group. In yet another embodiment, R4 is chosen
from a hydrogen, a brominde group, a chloride group, or a methoxyl
group. In yet another embodiment, R5 is chosen from a hydrogen, a
brominde group, a chloride group, or a methoxyl group. In
representative embodiments, the compound is chosen from:
##STR00022##
[0101] A particularly preferred compound of Formula (V) is selected
from
##STR00023##
N-(4-bromophenyl)-4-methylquinolin-2-amine (hereinafter Compound
I);
##STR00024##
4,5,7-trimethyl-N-phenylquinolin-2-amine (hereinafter Compound H);
or a pharmaceutically acceptable salt thereof.
[0102] A representative fifth class of CFTR correctors is as
disclosed in WO2007056341 a compound of formula V-A-i or V-B-i:
##STR00025##
or a pharmaceutically acceptable salt thereof, wherein
T is --CH2-, --CF2-, or --C(CH3)2-.
[0103] Ri' is selected in several embodiments from the group
consisting of H, C1-6 aliphatic, halo, CF3, CHF2, -0(Cj-5
aliphatic), C3-C5 cycloalkyl, or C4-C6 heterocycloalkyl containing
one oxygen atom.
[0104] Exemplary embodiments include H, methyl, ethyl, i-propyl,
t-butyl, F. Cl, CF3, CHF2, --OCH3, --OCH2CH3, --O-(i-[propyl),
--O-(t-butyl), cyclopropyl, or oxetanyl. More preferably, R1' is H.
Or, R1' is methyl. Or, ethyl. Or, CF3. Or, oxetanyl. In several
embodiments R.sup.D1 is Z.sup.DR9, wherein Z.sup.D is selected from
CONH, NHCO, SO2NH, SO2N(Ci-6 alkyl), NHSO2, CH2NHSO2, CH2N(CH3)SO2,
CH2NHCO, COO, SO2, or CO;
[0105] In several examples, RD2 is H, halo, C1-4 alkyl, or C1-4
alkoxy. A particularly preferred compound of formula V-A-i is
##STR00026##
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(hereinafter Compound U) or a pharmaceutically acceptable salt
thereof.
[0106] In another embodiment, the present invention provide CFTR
correctors for the use in the treatment of genetic disorders
affecting striated muscle selected from sarcoglycanopathies,
Brody's disease (BD) and the recessive forms of Cathecolaminergic
Polymorphic Ventricular Tachycardia (CPVT) which are selected
from:
##STR00027##
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(hereinafter Compound F);
##STR00028##
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (hereinafter Compound L);
##STR00029##
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide; (hereinafter
Compound M);
##STR00030##
7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline (hereinafter
Compound N);
##STR00031##
N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine (hereinafter Compound
P);
##STR00032##
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-
-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarbox-
amide (hereinafter Compound V); or a pharmaceutically acceptable
salt thereof.
[0107] Compounds of the invention may be administered as a
pharmaceutically acceptable salt. These pharmaceutically acceptable
salts may be prepared in situ during the final isolation and
purification of the compound, or by separately reacting the
purified compound, or a non-pharmaceutically acceptable salt
thereof, with a suitable base or acid. For a review on suitable
salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.
[0108] Such salts include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like; or (2) salts formed when an acidic proton present in
the parent compound either is replaced by a metal ion, e.g., an
alkali metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
and the like.
Compounds Preparation
[0109] The compounds for use according to the invention may be made
by a variety of methods, including standard chemistry. Certain of
the compounds for use according to the invention are well known and
readily available from chemical supply houses. Thus for example,
Compound A may be prepared according to the procedure as described
in WO 2009051909.
[0110] Compound B and C and may be prepared according to the
procedure as described in WO200411104.
[0111] Compound D may be prepared according to the procedure as
described in WO 2007021982.
[0112] Compounds E, H, I, P, Q, R, S and T may be prepared
according to the procedure as described in WO2006101740.
[0113] Compound L may be prepared according to the procedure as
described in US20050176761.
[0114] Compound M may be prepared according to the procedure as
described in WO2006699256.
[0115] Compounds U and V may be prepared according to the
procedures as described in WO2007056341 and WO2007117715
respectively.
[0116] Alternatively certain compounds for use according to the
invention are commercially available such as for example Compounds
F, H, I, N O, P, Q, R, S, T, U and V are available from Exclusive
Chemistry Ltd, Selleckchem or Medchem Express LLC.
Methods of Use
[0117] The methods of treatment of the invention comprise
administering a safe and effective amount of a corrector of CFTR to
a patient in need thereof.
[0118] A corrector of CFTR according to the invention may be
administered by any suitable route of administration, in particular
oral administration.
[0119] A corrector of CFTR according to the invention may be
administered according to a dosing regimen wherein a number of
doses are administered at varying intervals of time for a given
period of time. For example, doses may be administered one, two,
three, or four times per day.
[0120] Doses may be administered until the desired therapeutic
effect is achieved or indefinitely to maintain the desired
therapeutic effect. Suitable dosing regimens, including the
duration such regimens are administered, may depend on the severity
of the disorder being treated, the age and physical condition of
the patient being treated, the medical history of the patient to be
treated, the nature of concurrent therapy, the desired therapeutic
effect, and like factors within the knowledge and expertise of the
skilled artisan. It will be further understood by such skilled
artisans that suitable dosing regimens may require adjustment given
an individual patient's response to the dosing regimen or over time
as individual patient needs change.
[0121] In one aspect, the invention provides a CFTR corrector for
use in the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
[0122] In one aspect, the invention provides a CFTR corrector for
use in the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, and Brody's disease (BD).
[0123] In one aspect, the invention provides a CFTR corrector for
use in the treatment of sarcoglycanopathies.
[0124] In one aspect, the invention provides a CFTR corrector for
use in the treatment of, Brody's disease (BD).
[0125] In one aspect, the invention provides a CFTR corrector for
use in the recessive forms of Cathecolaminergic Polymorphic
Ventricular Tachycardia (CPVT).
[0126] In one embodiment, the invention provides the use of a CFTR
corrector in the manufacture of a medicament for the treatment of
genetic disorders affecting striated muscle selected from
sarcoglycanopathies, Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0127] In one embodiment, the invention provides the use of a CFTR
corrector in the manufacture of a medicament for the treatment of
genetic disorders affecting striated muscle selected from
sarcoglycanopathies and Brody's disease (BD).
[0128] In a further embodiment, the invention provides a method of
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT) comprising administering a safe and effective amount of a
CFTR corrector to a patient in need thereof.
[0129] In a further embodiment, the invention provides a method of
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) comprising
administering a safe and effective amount of a CFTR corrector to a
patient in need thereof.
[0130] In one embodiment, the invention provides a CFTR corrector
selected from: [0131]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0132]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0133]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0134] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0135]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0136]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0137] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0138] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0139]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0140]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0141] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0142] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0143]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0144]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0145] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0146]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e [0147] (Compound T); [0148]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0149]
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypr-
opyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropan-
ecarboxamide (Compound V); for use in the treatment of genetic
disorders affecting striated muscle selected from
sarcoglycanopathies, Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0150] In one embodiment, the invention provides a CFTR corrector
selected from: [0151]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0152]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0153]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0154] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0155]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0156]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0157] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0158] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0159]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0160]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0161] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0162] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0163]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(Compound Q); [0164]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(Compound R); [0165] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0166]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0167]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0168]
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypr-
opyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropan-
ecarboxamide (Compound V); or pharmaceutically acceptable salt
thereof for use in the treatment of genetic disorders affecting
striated muscle selected from sarcoglycanopathies, Brody's disease
(BD) and the recessive forms of Cathecolaminergic Polymorphic
Ventricular Tachycardia (CPVT).
[0169] In one embodiment, the invention provides a CFTR corrector
selected from: [0170]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0171]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0172]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0173] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0174]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0175]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0176] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0177] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0178]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0179]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0180] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0181]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); for use in the treatment of genetic disorders
affecting striated muscle selected from sarcoglycanopathies and
Brody's disease (BD)
[0182] In one embodiment, the invention provides a CFTR corrector
selected from: [0183]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0184]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0185]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0186] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0187]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0188]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0189] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0190] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0191]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0192]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0193] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0194]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); or pharmaceutically acceptable salt thereof for use
in the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies and Brody's disease (BD).
[0195] In one embodiment, the invention provides the use of a CFTR
corrector selected from: [0196]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0197]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0198]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0199] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0200]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0201]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) in the manufacture of a medicament in the treatment of
genetic disorders affecting striated muscle selected from
sarcoglycanopathies, Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0202] In one embodiment, the invention provides the use of a CFTR
corrector selected from: [0203]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0204]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0205]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0206] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0207]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0208]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0209] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0210] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0211]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0212]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0213] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0214] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0215]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(Compound Q); [0216]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(Compound R); [0217] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0218]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0219]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0220] (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V); or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament in the treatment of genetic disorders
affecting striated muscle selected from sarcoglycanopathies and
Brody's disease (BD) and the recessive forms of Cathecolaminergic
Polymorphic Ventricular Tachycardia (CPVT).
[0221] In one embodiment, the invention provides the use of a CFTR
corrector selected from: [0222]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0223]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0224]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0225] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chorophenyl)
((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide
(Compound D); [0226]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0227]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0228] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0229] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0230]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0231]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0232] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0233] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0234]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(Compound Q); [0235]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)-benzamide
(Compound R); [0236] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0237]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0238]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0239] (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V) in the manufacture of a medicament in the treatment of genetic
disorders affecting striated muscle selected from
sarcoglycanopathies and Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0240] In one embodiment, the invention provides the use of a CFTR
corrector selected from: [0241]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0242]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0243]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0244] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0245]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0246]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0247] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0248] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0249]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0250]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0251] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0252]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); in the manufacture of a medicament in the treatment
of genetic disorders affecting striated muscle selected from
sarcoglycanopathies and Brody's disease (BD).
[0253] In one embodiment, the invention provides the use of a CFTR
corrector selected from: [0254]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0255]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0256]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0257] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0258]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0259]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0260] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0261] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0262]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0263]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'yl)benzamide
(Compound R); [0264] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0265]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e [0266] (Compound T); or a salt thereof in the manufacture of a
medicament in the treatment of genetic disorders affecting striated
muscle selected from sarcoglycanopathies and Brody's disease
(BD).
[0267] In a further embodiment, the invention provides a method of
treating of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT) comprising administering a safe and effective amount of
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0268]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0269]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0270] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0271]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0272]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) to a patient in need thereof.
[0273] In a further embodiment, the invention provides a method of
treating of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT) comprising administering a safe and effective amount of
[0274]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0275]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0276]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0277] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0278]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0279]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0280] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0281] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0282]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0283]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0284] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0285] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0286]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0287]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0288] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0289]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0290]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0291] (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V) to a patient in need thereof.
[0292] In a further embodiment, the invention provides a method of
treating of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT) comprising administering a safe and effective amount of
[0293]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0294]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0295]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0296] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0297]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0298]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0299] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0300] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0301]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0302]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0303] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0304] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0305]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0306]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0307] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0308]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0309]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0310] (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V); or a pharmaceutically acceptable salt thereof to a patient in
need thereof.
[0311] In a further embodiment, the invention provides a method of
treating of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) comprising
administering a safe and effective amount of [0312]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0313]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0314]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0315] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0316]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0317]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0318] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0319] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0320]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0321]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0322] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0323]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T) to a patient in need thereof.
[0324] In a further embodiment, the invention provides a method of
treating of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) comprising
administering a safe and effective amount of [0325]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0326]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0327]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0328] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0329]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0330]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F); [0331] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0332] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0333]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0334]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'yl)benzamide
(Compound R); [0335] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0336]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); or a pharmaceutically acceptable salt thereof to a
patient in need thereof.
[0337] In a further embodiment, the invention provides a method of
treating of genetic disorders affecting striated muscle selected
from sarcoglycanopathies and Brody's disease (BD) comprising
administering a safe and effective amount of
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0338]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0339]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0340] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0341]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0342]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) or a pharmaceutically acceptable salt thereof to a
patient in need thereof.
Compositions
[0343] CFTR correctors may be formulated into a pharmaceutical
composition prior to administration to a patient.
[0344] Accordingly, in one aspect the invention is directed to
pharmaceutical compositions comprising a CFTR corrector and one or
more pharmaceutically acceptable excipients for use in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0345] In one embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector and one or
more pharmaceutically acceptable excipients for use in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies and Brody's disease (BD)
[0346] In one embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector selected
from: [0347]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0348]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0349]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0350] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0351]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0352]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) [0353] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0354] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0355]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0356]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0357] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0358] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0359]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0360]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0361] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0362]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0363]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0364] (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V) and one or more pharmaceutically acceptable excipients for use
in the treatment of genetic disorders affecting striated muscle
selected from sarcoglycanopathies, Brody's disease (BD) and the
recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
[0365] In another embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector selected
from: [0366]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0367]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0368]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0369] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0370]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0371]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) [0372] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0373] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0374]
2-(4-isopropoxypicolinoyl)-N-(4-pentylphenyl)-1,2,3,4-tetrahydroisoquinol-
ine-3-carboxamide (Compound L); [0375]
N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide (Compound M);
[0376] 7-chloro-4-(4-(phenylsulfonyl)piperazin-1-yl)quinoline
(Compound N); [0377] N-(4-fluorophenyl)-4-p-tolylthiazol-2-amine
(Compound P); [0378]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0379]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0380] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0381]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T); [0382]
3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)
cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
(Compound U); [0383] (R)-1-(2,2-difluorobenzo
[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m-
ethylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound
V); or a pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients for use in the treatment of
genetic disorders affecting striated muscle selected from
sarcoglycanopathies, Brody's disease (BD) and the recessive forms
of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0384] In another embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector selected
from: [0385]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0386]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0387]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0388] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0389]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0390]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) and one or more pharmaceutically acceptable excipients
for use in the treatment of genetic disorders affecting striated
muscle selected from sarcoglycanopathies, Brody's disease (BD) and
the recessive forms of Cathecolaminergic Polymorphic Ventricular
Tachycardia (CPVT).
[0391] In another embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector selected
from: [0392]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0393]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0394]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0395] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0396]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0397]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) or a pharmaceutically acceptable salt thereof and one
or more pharmaceutically acceptable excipients for use in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
[0398] In another embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector selected
from: [0399]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0400]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0401]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0402] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0403]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0404]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) [0405] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0406] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0407]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0408]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0409] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0410]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T) and one or more pharmaceutically acceptable
excipients for use in the treatment of genetic disorders affecting
striated muscle selected from sarcoglycanopathies and Brody's
disease (BD).
[0411] In another embodiment, the invention is directed to
pharmaceutical compositions comprising a CFTR corrector selected
from: [0412]
N-(2-(5-chloro-2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)pival-
amide (Compound A); [0413]
4-Cyclohexyloxy-2-{1-[4-(4-methoxy-benzensulfonyl)-piperazin-1-yl]-ethyl}-
-quinazoline (Compound B); [0414]
2-{1-[4-(4-Chloro-benzensulfonyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-
-quinazoline (Compound C); [0415] 1-(benzo
[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-
-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (Compound D);
[0416]
N-[2-(5-Chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]--
benzamide (Compound E); [0417]
7-chloro-4-(4-(4-chlorophenylsulfonyl)piperazin-1-yl)quinoline
(Compound F) [0418] 4,5,7-trimethyl-N-phenylquinolin-2-amine
(Compound H); [0419] N-(4-bromophenyl)-4-methylquinolin-2-amine
(Compound I); [0420]
N-(2-(3-acetylphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound Q); [0421]
N-(2-(2-methoxyphenylamino)-4'-methyl-4,5'-bithiazol-2'-yl)benzamide
(Compound R); [0422] N-phenyl-4-(4-vinylphenyl)thiazol-2-amine
(Compound S); [0423]
2-(6-methoxy-4-methylquinazolin-2-ylamino)-5,6-dimethylpyrimidin-4(1H)-on-
e (Compound T) or a pharmaceutically acceptable salt thereof and
one or more pharmaceutically acceptable excipients for use in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies and Brody's disease (BD).
[0424] CFTR correctors according to the invention are capable of
existing in stereoisomeric forms. It will be understood that the
compounds of use according to the invention encompasses all
geometric and optical isomers of these compounds and the mixtures
thereof including racemates.
[0425] CFTR correctors according to the invention and the
pharmaceutically acceptable excipient or excipients will typically
be formulated into a dosage form adapted for administration to the
patient by the desired route of administration. For example, dosage
forms include those adapted for oral administration such as
tablets, capsules, caplets, pills, troches, powders, syrups,
elixirs, suspensions, solutions, emulsions, sachets, and cachets),
or those adapted for inhalation such as aerosols, solutions, and
dry powders.
[0426] Suitable pharmaceutically acceptable excipients will vary
depending upon the particular dosage form chosen. In addition,
suitable pharmaceutically acceptable excipients may be chosen for a
particular function that they may serve in the composition. For
example, certain pharmaceutically acceptable excipients may be
chosen for their ability to facilitate the production of uniform
dosage forms. Certain pharmaceutically acceptable excipients may be
chosen for their ability to facilitate the production of stable
dosage forms. Certain pharmaceutically acceptable excipients may be
chosen for their ability to facilitate the carrying or transporting
of a CFTR corrector thereof once administered to the patient from
one organ, or portion of the body, to another organ, or portion of
the body. Certain pharmaceutically acceptable excipients may be
chosen for their ability to enhance patient compliance.
[0427] Suitable pharmaceutically acceptable excipients include the
following types of excipients: diluents, fillers, binders,
disintegrants, lubricants, glidants, granulating agents, coating
agents, wetting agents, solvents, co-solvents, suspending agents,
emulsifiers, sweetners, flavoring agents, flavour masking agents,
colouring agents, anticaking agents, humectants, chelating agents,
plasticizers, viscosity increasing agents, antioxidants,
preservatives, stabilizers, surfactants, and buffering agents. The
skilled artisan will appreciate that certain pharmaceutically
acceptable excipients may serve more than one function and may
serve alternative functions depending on how much of the excipient
is present in the formulation and what other excipients are present
in the formulation.
[0428] Skilled artisans possess the knowledge and skill in the art
to enable them to select suitable pharmaceutically-acceptable
excipients in appropriate amounts for use in the invention. In
addition, there are a number of resources that are available to the
skilled artisan which describe pharmaceutically acceptable
excipients and may be useful in selecting suitable pharmaceutically
acceptable excipients. Examples include Remington's Pharmaceutical
Sciences (Mack Publishing Company), The Handbook of Pharmaceutical
Additives (Gower Publishing Limited), and The Handbook of
Pharmaceutical Excipients (the American Pharmaceutical Association
and the Pharmaceutical Press).
[0429] The pharmaceutical compositions for use according to the
invention are prepared using techniques and methods known to those
skilled in the art. Some of the methods commonly used in the art
are described in Remington's Pharmaceutical Sciences (Mack
Publishing Company).
[0430] A pharmaceutical composition comprising a CFTR corrector may
be prepared by, for example, admixture at ambient temperature and
atmospheric pressure.
[0431] In one aspect, the composition for use according to the
invention is a solid oral dosage form such as a tablet or capsule
comprising a safe and effective amount of a CFTR corrector and a
diluent or filler. Suitable diluents and fillers include lactose,
sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch,
potato starch, and pre-gelatinized starch), cellulose and its
derivatives (e.g. microcrystalline cellulose), calcium sulfate, and
dibasic calcium phosphate. The oral solid dosage form may further
comprise a binder. Suitable binders include starch (e.g. corn
starch, potato starch, and pre-gelatinized starch), gelatin,
acacia, sodium alginate, alginic acid, tragacanth, guar gum,
povidone, and cellulose and its derivatives (e.g. microcrystalline
cellulose). The oral solid dosage form may further comprise a
disintegrant. Suitable disintegrants include crospovidone, sodium
starch glycolate, croscarmelose, alginic acid, and sodium
carboxymethyl cellulose. The oral solid dosage form may further
comprise a lubricant. Suitable lubricants include stearic acid,
magnesuim stearate, calcium stearate, and talc.
[0432] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The composition can also
be prepared to prolong or sustain the release as for example by
coating or embedding particulate material in polymers, wax or the
like.
[0433] CFTR correctors may also be coupled with soluble polymers as
targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds of
use according to the invention or a pharmaceutically acceptable
salt thereof may be coupled to a class of biodegradable polymers
useful in achieving controlled release of a drug, for example,
polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates
and cross-linked or amphipathic block copolymers of hydrogels.
[0434] CFTR correctors according to the invention may be formulated
for parenteral administration by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form e.g. in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilising
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form for constitution with a suitable vehicle, e.g.
sterile pyrogen-free water, before use.
[0435] In another aspect, the composition for use according to the
invention is a liquid oral dosage form. Oral liquids such as
solution, syrups and elixirs can be prepared in dosage unit form so
that a given quantity contains a predetermined amount of a CFTR
corrector. Syrups can be prepared by dissolving a compound of use
according to the invention or a pharmaceutically acceptable salt
thereof in a suitably flavored aqueous solution, while elixirs are
prepared through the use of a non-toxic alcoholic vehicle.
Suspensions can be formulated by dispersing a compound of use
according to the invention or a pharmaceutically acceptable salt
thereof in a non-toxic vehicle. Solubilizers and emulsifiers such
as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and
the like can also be added. The compound of use according to the
invention or its pharmaceutically acceptable salts may be
formulated for parenteral administration by bolus injection or
continuous infusion. Formulations for injection may be presented in
unit dosage form e.g. in ampoules or in multi-dose containers, with
an added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilising
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form for constitution with a suitable vehicle, e.g.
sterile pyrogen-free water, before use.
[0436] In another aspect, the invention is directed to a dosage
form adapted for administration to a patient by inhalation, for
example as a dry powder, an aerosol, a suspension, or a solution
composition. In one embodiment, the invention is directed to a
dosage form adapted for administration to a patient by inhalation
as a dry powder. In a further embodiment, the invention is directed
to a dosage form adapted for administration to a patient by
inhalation via a nebulizer.
[0437] Alternatively, the dry powder may be presented in capsules
(e.g. gelatin or plastic), cartridges, or blister packs for use in
a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein
the medicament is comprised within a multi-dose pack containing (or
otherwise carrying) multiple defined doses (or parts thereof) of
medicament. When the dry powder is presented as a blister pack, it
comprises multiple blisters for containment of the medicament in
dry powder form. The blisters are typically arranged in regular
fashion for ease of release of the medicament therefrom. For
example, the blisters may be arranged in a generally circular
fashion on a disc-form blister pack, or the blisters may be
elongate in form, for example comprising a strip or a tape. Each
capsule, cartridge, or blister may, for example, contain between 20
.mu.g-10 mg of the compound of use according to the invention or a
pharmaceutically acceptable salt thereof.
[0438] According to the invention, a CFTR corrector may be used in
combination with one or more other therapeutic agents, in the
treatment of genetic disorders affecting striated muscle selected
from sarcoglycanopathies, Brody's disease (BD) and the recessive
forms of Cathecolaminergic Polymorphic Ventricular Tachycardia
(CPVT).
Biological Data
In Vitro Results
[0439] The following examples illustrate the invention without
limiting the scope thereof.
Example 1
[0440] HEK293 cells expressing different .alpha.-SG mutants have
been treated with the Compounds A, B, C, D, E, F, H, I, Q, R, S and
T according to protocols developed in CF studies [Loo and Clarke
2011; Becq et al 2011, Pedemonte et al 2005; Wang et al 2006].
Concentration and time-dependent recovery of treated mutants have
been evaluated by Western blotting. The proteasome inhibitor MG132,
at the concentration of 10 .mu.M, or DMSO at 1.Salinity.
concentration, have been used as positive and negative control,
respectively.
[0441] In FIG. 1 the result obtained by treating cells expressing
the R98H mutant of (.alpha.-SG for 24 hours with Compound C 5
.mu.M, Compound B 10 .mu.M, Compound E 10 .mu.M, Compound F 10
.mu.M, Compound A 2 .mu.M, Compound D 10 .mu.M are shown. At the
end of treatments, cells were lysed and total proteins resolved by
SDS-PAGE. Western blotting has been performed by using .alpha.-SG
specific antibody and .beta.-actin specific antibody, used to
normalize loaded proteins (in FIG. 1, upper panel, a representative
experiment is shown). The expression of .alpha.-SG in different
samples has been determined by densitometric analysis of the
western blotting experiments and indicated as percentage of the
protein present in cells expressing the R98H mutant treated with
DMSO (negative control). The graph in the lower part of FIG. 1
shows the average values (+/-standard error) of three independent
experiments. All the compounds tested induce the recovery of the
mutant to an extent comparable to that obtained by proteasomal
inhibition (MG132 treated D98H expressing cells).
[0442] In FIG. 4 the result obtained by treating cells expressing
the R98H mutant of (.alpha.-SG for 24 hours with either Compound H
15 .mu.M, Compound I 10 .mu.M, Compound T 15 .mu.M, Compound A 2
.mu.M, or DMSO at 1.Salinity. concentration, used as negative
control, are shown. Cells expressing the wild type form of
.alpha.-sarcoglycan have been used for comparison. At the end of
treatments, cells were lysed and total proteins resolved by
SDS-PAGE. Western blotting has been performed by using (.alpha.-SG
specific antibody and .beta.-actin specific antibody, used to
normalize loaded proteins (in upper panel of FIG. 4, a
representative experiment is shown). The expression of .alpha.-SG
in different samples has been determined by densitometric analysis
of the western blotting experiments and indicated as percentage of
the protein present in cells expressing the wild type form of
.alpha.-sarcoglycan. The graph in the lower part of FIG. 4 shows
the average values (+/-standard error) of at least three
independent experiments. The compounds tested induced the recovery
of the R98H mutant to levels that in some cases were even greater
than those present in HEK cells expressing the wild type
protein.
[0443] In FIG. 5 the result obtained by treating cells expressing
the R98H mutant of .alpha.-SG for 24 hours with either increasing
concentration of Compound R (1, 2, 5, 5 .mu.M) or DMSO at
1.Salinity. concentration, used as negative control, are shown.
Cells expressing the wild type form of .alpha.-sarcoglycan have
been used for comparison. At the end of treatments, cells were
lysed and total proteins resolved by SDS-PAGE. Western blotting has
been performed by using .alpha.-SG specific antibody and
.beta.-actin specific antibody, used to normalize loaded proteins
(in upper panel of FIG. 5, a representative experiment is shown).
The expression of .alpha.-SG in different samples has been
determined by densitometric analysis of western blotting
experiments and indicated as percentage of the protein present in
cells expressing the wild type form of .alpha.-sarcoglycan. The
graph in the lower part of FIG. 5 shows the average values
(+/-standard error) of at least three independent experiments. The
R compound induced a dose dependent recovery of the R98H mutant
that, at the highest concentration (5 .mu.M), reached the level of
the wild type protein.
[0444] In FIG. 6 the result obtained by treating cells expressing
the R98H mutant of (.alpha.-SG for 24 hours with either increasing
concentration of Compound Q (5, 10 .mu.M), increasing concentration
of Compound S (10, 15 .mu.M) or DMSO at 1.Salinity. concentration,
used as negative control, are shown. Cells expressing the wild type
form of .alpha.-sarcoglycan have been used for comparison. At the
end of treatments, cells were lysed and total proteins resolved by
SDS-PAGE. Western blotting has been performed by using .alpha.-SG
specific antibody and .beta.-actin specific antibody, used to
normalize loaded proteins (in upper panel of FIG. 6, a
representative experiment is shown). The expression of .alpha.-SG
in different samples has been determined by densitometric analysis
of western blotting experiments and indicated as percentage of the
protein present in cells expressing the wild type form of
.alpha.-sarcoglycan. The graph in the lower part of FIG. 6 shows
the average values (+/-standard error) of at least three
independent experiments. Both Q and S compounds induced a dose
dependent recovery of the R98H mutant that, at the highest
concentrations, reached the level of the wild type protein.
[0445] In FIG. 7 is shown the content of .alpha.-sarcoglycan
protein present in HEK cells transfected with the D97G mutant of
.alpha.-SG treated for 24 hours with either Compound E 10 .mu.M,
Compound H 15 .mu.M, Compound I 10 .mu.M, Compound Q 10 .mu.M,
Compound F 10 .mu.M, Compound R 5 .mu.M, Compound S 15 .mu.M,
Compound T 15 .mu.M, Compound A 2 .mu.M, or DMSO at 1.Salinity.
concentration, used as negative control, are shown. Cells
expressing the wild type form of .alpha.-sarcoglycan have been used
for comparison. At the end of treatments, cells were lysed and
total proteins resolved by SDS-PAGE. Western blotting has been
performed by using (.alpha.-SG specific antibody and .beta.-actin
specific antibody, used to normalize loaded proteins. The
expression of .alpha.-SG in different samples has been determined
by densitometric analysis of western blotting experiments and
indicated as percentage of the protein present in cells expressing
the wild type form of .alpha.-sarcoglycan. The graph of FIG. 7
shows the average values (+/-standard error) of at least three
independent experiments. The compounds tested induce the recovery
of the D97G mutant that in some cases reached the level present in
HEK cells expressing the wild type protein.
Example 2
[0446] The cellular localization of either the V247M or R98H
mutants, upon corrector treatments, has been verified by confocal
immunofluorescence.
[0447] In the experiment reported in FIG. 2, HEK 293 cells
expressing the V247M mutant have been treated for 24 hours with
either Compound E (10 .mu.M) or Compound D (10 .mu.M), MG132
(positive control) or DMSO at 1.Salinity. concentration (negative
control). At the end of treatments, not permeabilized cells were
incubated with a monoclonal antibody specific for an extracellular
epitope of .alpha.-sarcoglycan in order to mark only the membrane
resident .alpha.-sarcoglycan. By comparison, cells expressing the
wild type form of .alpha.-sarcoglycan have also been used. Laser
scanning microscopy analysis shows that, in the absence of drug
treatment (DMSO) the wild type form of .alpha.-sarcoglycan
correctly localized at the plasmamembrane, whereas only traces of
the mutant protein were visible on the cell surface. As previously
demonstrated, proteasomal inhibition (MG132), by reducing the
degradation of mutant protein, promoted V247M membrane localization
(Gastaldello et al 2008). Treatments with compound E and D promoted
the correct plasma membrane localization of the V247M mutant as
well.
[0448] In the experiment reported in FIG. 8, HEK 293 cells
expressing the R98H mutant have been treated for 24 hours with
either Compound H (15 .mu.M), Compound I (10 .mu.M), Compound Q (10
.mu.M), Compound A (2 .mu.M) or the vehicle DMSO at 1.Salinity.
concentration used as negative control. By comparison, cells
expressing the wild type form of .alpha.-sarcoglycan have also been
used. At the end of treatments, not permeabilized cells were
incubated with a monoclonal antibody specific for an extracellular
epitope of .alpha.-sarcoglycan in order to mark only the membrane
resident .alpha.-sarcoglycan. Laser scanning microscopy analysis
shows that, the wild type form of .alpha.-sarcoglycan correctly
localized at the plasma-membrane. In the absence of treatment
(vehicle) only traces of the R98H mutant protein were visible on
the cell surface whereas, treatments with the indicated compounds
promoted the correct plasma-membrane localization of the mutant
protein.
[0449] In the experiment reported in FIG. 9, HEK 293 cells
expressing the R98H mutant have been treated for 24 hours with
either two different concentration of Compound R (2.5 and 5 .mu.M),
or the vehicle DMSO at 1.Salinity. concentration used as negative
control. By comparison, cells expressing the wild type form of
x-sarcoglycan have also been used. At the end of treatments, not
permeabilized cells were incubated with a monoclonal antibody
specific for an extracellular epitope of .alpha.-sarcoglycan in
order to mark only the membrane resident .alpha.-sarcoglycan. Laser
scanning microscopy analysis shows that, the wild type form of
.alpha.-sarcoglycan correctly localized at the plasma-membrane. In
the absence of treatment (vehicle) only traces of the R98H mutant
protein were visible on the cell surface whereas, treatments with
the compound R promoted the correct plasma-membrane localization of
the mutant protein.
Example 3
[0450] Recently, a muscular disorder defined congenital
pseudomyotonia (PMT), has been described in Chianina cattle. In
affected animals, PMT is due to a missense mutation in ATP2A1 gene
(R164H) that causes a drastic reduction of SERCA1 protein
[Sacchetto et al. 2009]. Genetic and biochemical data have
indicated that Chianina PMT is the true counterpart of human BD and
it could represent a suitable, non-conventional, animal model for
the investigation of the pathogenesis of BD.
[0451] In FIG. 3 are reported the results obtained with HEK 293
cells expressing the R164H mutant of SERCA1 treated for 24 hours
with either Compound C 5 .mu.M, Compound B 10 .mu.M, Compound E 10
.mu.M, compound F 10 .mu.M, Compound A 2 .mu.M, compound D 10
.mu.M, MG132 (proteasome inhibitor) 10 .mu.M, used as positive
control or the vehicle DMSO at 1.Salinity. concentration, used as
negative control. At the end of treatments, cells were lysed and
total protein resolved by SDS-PAGE. Western blotting analysis has
been performed by using SERCA1 specific antibody and .beta.-actin
specific antibody, to normalize loaded proteins. In the upper panel
of FIG. 3 is reported a representative Western blotting experiment.
The expression of SERCA1 in different samples has been determined
by densitometric analysis and indicated as percentage of SERCA 1
content present in wild type expressing cells treated with DMSO.
The densitometric analyses (reported in FIG. 3 lower panel) show
that the Compounds tested were able to promote R164H mutant rescue
to an extent comparable to that of wild type SERCA1.
[0452] In FIG. 10 is reported the content of SERCA1 protein present
in HEK 293 cells transfected with the R164H mutant of SERCA1 and
treated for 24 hours with either Compound H 15 .mu.M, Compound I 10
.mu.M, compound Q 10 .mu.M, Compound R 5 .mu.M, Compound S 15
.mu.M, Compound T 15 .mu.M or the vehicle DMSO at 1.Salinity.
concentration, used as negative control. Cells expressing the wild
type form of SERCA1 have also been used for comparison. At the end
of treatments, cells were lysed and total protein resolved by
SDS-PAGE. Western blotting analysis has been performed by using
SERCA1 specific antibody and .beta.-actin specific antibody, to
normalize loaded proteins. The expression of SERCA1 in different
samples has been determined by densitometric analysis and indicated
as percentage of SERCA 1 content present in wild type expressing
cells. The graph of FIG. 10 reports the average values (+/-standard
error) of at least three independent experiments. The compounds
tested were able to promote R164H mutant rescue to an extent that
in some cases is comparable to that of wild type SERCA1.
Preclinical Studies
[0453] The preclinical effect of a CFTR correctors according to the
invention in sarcoglycanopathies can be assessed, for example, in
one or more animal models of the diseases as described here
below.
[0454] As animal model for LGMD2D is available the KO .alpha.-SG
mice (Liu and Engvall 1999), for LGMD2E the KO .beta.-SG mice
(Araishi et al. 1999), for LGMD2C the KO .gamma.-SG mice (Hack et
al. 2000) for LGMD2F the KO .delta.-SG mice (Hack et al. 2000).
However these animal models are unsuitable for studying the
preclinical effect of the invention as they don't produce the
sarcoglycan proteins at all. Knock In (KI) mice, expressing the
mutated forms of each sarcoglycan should be necessary. To overcome
time consuming and management problems of transgenic mouse
production, and, importantly, to easily obtain animals expressing
as many different sarcoglycan missense mutations as those necessary
for the study, we intend to transduce specific sarcoglycan KO mice
with Adeno Associated Viruses (AAVs) expressing either the wild
type or the mutant forms of .alpha.-SG, .beta.-SG .gamma.-SG and
.delta.-SG. The procedure for AAV production is described in
[McClure et al 2011; Shin et al 2012] however virus production is
committed to a specialized company, whereas animal transduction is
accomplish like described in [Cordier et al 2000; Vitiello et al
2009 Roux-Buisson et al. 2012]
[0455] Thus, for example:
[0456] Ex vivo experiments are performed on explanted
gastrocnemious muscles from sarcoglycanopathy animal models as
described above. As described in Assereto et al. 2005, the
explanted muscles are quickly cleaned from fat, connective tissue,
and blood; divided bundles of about 5-10 muscle fibers and
incubated with either a suitable dosage of a CFTR correctors
according to the invention, the proteasome inhibitor bortezomib
(Velcade) (Gastaldello et al 2008, Bonuccelli et al 2007) used as
positive control or drugs vehicle used as negative control. After
24 to 48 hours of treatments, explants are rapidly homogenized and
the expression of sarcoglycans is tested by western blotting
analyses.
[0457] In vivo experiments are performed by localized injection in
gastrocnemious muscles of sarcoglycanopathy animal models of either
a CFTR corrector or Velcade used as positive control, the
contralateral muscles, injected with the drug vehicles, represent
the negative control. After treatments, animals are sacrificed and
muscles are either rapidly frozen to further immunofluorescent
analysis concerning the localization of the rescued sarcoglycans or
homogenized and analyzed by western blotting to verify the
expression of the mutated proteins.
[0458] In vivo experiments are performed by systemic administration
of drugs in sarcoglycanopathy animal models thanks to the use of
subcutaneously implanted Alzet Minipumps as described in [Bonucelli
et al. 2007]. In this case, animals of matched age and sex are
treated with either the CFTR correctors, the proteasome inhibitor
Velcade (positive control) or the vehicle (negative control). After
treatments, animal are sacrificed, limb girdle muscles are rapidly
frozen or homogenized and the expression of sarcoglycans are
analyzed by western blotting whereas their localization are tested
by immunofluorescent analysis. The wild type animals are always
used for comparison.
[0459] The preclinical effect of a CFTR correctors according to the
invention in Brody's disease (BD) can be assessed, for example in
the PMT affected Chianina cattle representing the animal model of
the disease (housed at the Veterinary Hospital of the University of
Padova) [Sacchetto et al. 2009].
[0460] Thus, for example:
[0461] Ex vivo experiments are performed on freshly isolated
biopsies from the semimembranosus muscle of the PMT affected cow.
As described in Assereto et al. 2005 bundles of 5-10 muscle fibers
are incubated with either a suitable dosage of CFTR correctors
according to the invention, the proteasome inhibitor bortezomib
(Velcade) used as positive control or the drugs vehicle used as
negative controls. After treatments, explants are rapidly
homogenized the expression of the different proteins are tested by
western blotting analysis whereas the functional recovery of SERCA1
is determined accordingly to (Sacchetto et al 2009)
[0462] The preclinical effect of a CFTR correctors according to the
invention in the recessive forms of Cathecolaminergic Polymorphic
Ventricular Tachycardia (CPVT) can be assessed, for example in CPVT
animal models like the Knock In CASQ.sup.R33Q/R33Q mice [Rizzi et
al. 2008] and the Triadin-/- mice transduced with AAVs expressing
either wild type or mutant forms of the cardiac triadin
[Roux-Buisson et al. 2012].
[0463] Thus, for example:
[0464] Ex vivo experiments are performed in explanted hearts from
CPVT animal models perfused with either suitable dosages of CFTR
correctors according to the invention, the proteasome inhibitor
bortezomib (Velcade) used as positive control or the drugs vehicles
used as negative controls. After treatments, hearts are rapidly
homogenized and the expression of CASQ2, triadin, junction and RyR1
are tested by western blotting analyses.
[0465] In vivo experiments are performed by systemic administration
of drugs in CPVT animal models subcutaneously implanted with a
Alzet Minipumps as described in [Bonucelli et al. 2007]. In this
case, animals of matched age and sex are treated with either CFTR
correctors, the proteasome inhibitor Velcade (positive control) or
the vehicle (negative control). After treatments, animal are
sacrificed, hearts, rapidly frozen, are homogenized and the
expression of the different proteins are analyzed by western
blotting whereas their localization are tested by immunofluorescent
analysis. The wild type animals are always used for comparison.
[0466] The wild type animals of each pathological model as
described above will always be used for comparison.
[0467] Propedeutic to plan clinical trials, the effects of CFTR
correctors according to the invention in sarcoglycanopathies and
Brody's disease can be assessed in primary culture of myoblasts
obtained from sarcoglycanopathy and BD affected patients. This
possibility is based on the collaborations stated with Prof. G. P.
Comi, responsible of the collection of sarcoglycanopathy biopsies
stored at the Department of Neurological Sciences, University of
Milan and with Dr, G. Vattemi of the Department of Neurological
Sciences and Vision, Section of Clinical Neurology, University of
Verona. Myoblasts obtained from biopsies of healthy subjects are
already available in our laboratory. Myoblasts either from healthy
and affected patients will be incubated with either CFTR
correctors, the proteasome inhibitor Velcade used as positive
control or the drug vehicles used as negative control.
Quantitative, topological and functional rescue of sarcoglycans and
SERCA1 will be determined by western blotting, immunofluorescence
analyses and functional assays.
Clinical Study
[0468] 1. local treatments: patients with sarcoglycanopathies, BD
and CPVT linked to triadin defects, selected according to the
clinical phenotype and the type of missense mutations of which they
are carriers, are monitored for 30 days before the beginning of the
treatment. The conditions of the anterior tibialis muscle receiving
treatment, are determined by electromyography and magnetic
resonance imaging and a muscle biopsy planned just before the
beginning of treatment. Patients are then locally injected in the
anterior tibialis muscle with suitable dosage of CFTR correctors
according to the invention. At the end of the treatment a biopsy is
carried out and muscle samples are used to determine the
quantitative recovery and the localization of the rescued of either
sarcoglycan, SERCA1, CASQ2, triadin junctin or RyR1 proteins.
[0469] 2. systemic treatments: patients with sarcoglycanopathies,
BD and CPVT are selected and monitored as above described, a
suitable dosage of a CFTR correctors according to the invention
will be administered. Dose formulation and length of treatments are
determined according to the results obtained by local treatments
and to the information present in the literature regarding cystic
fibrosis treatments, The phenotype improvement are evaluated by
clinical investigations (MRI, EMG, ECG, enzyme assays).
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