U.S. patent application number 17/196956 was filed with the patent office on 2021-10-14 for sodium salt of n-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl) -1 -isopropyl-1 h-pyrazole-3-sulfonamide.
The applicant listed for this patent is INFLAZOME LIMITED. Invention is credited to Susana DEL RIO GANCEDO, Angus MACLEOD, David MILLER, Samuel Alexander STRATFORD.
Application Number | 20210315862 17/196956 |
Document ID | / |
Family ID | 1000005657059 |
Filed Date | 2021-10-14 |
United States Patent
Application |
20210315862 |
Kind Code |
A1 |
MILLER; David ; et
al. |
October 14, 2021 |
Sodium Salt Of N-((1,2,3,5,6,7-Hexahydro-S-Indacen-4-Yl) Carbamoyl)
-1 -Isopropyl-1 H-Pyrazole-3-Sulfonamide
Abstract
The present invention relates to a sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide and to hydrates, solvates and polymorphic forms
thereof. The present invention further relates to pharmaceutical
compositions comprising this compound and the use of this compound
in the treatment and prevention of medical disorders and diseases,
most especially by NLRP3 inhibition.
Inventors: |
MILLER; David; (Cambridge,
GB) ; MACLEOD; Angus; (Cambridge, GB) ; DEL
RIO GANCEDO; Susana; (Cambridge, GB) ; STRATFORD;
Samuel Alexander; (Cambridge, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INFLAZOME LIMITED |
Dublin 2 |
|
IE |
|
|
Family ID: |
1000005657059 |
Appl. No.: |
17/196956 |
Filed: |
March 9, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16850978 |
Apr 16, 2020 |
10973803 |
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17196956 |
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PCT/EP2019/060311 |
Apr 23, 2019 |
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16850978 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
A61K 31/415 20130101 |
International
Class: |
A61K 31/415 20060101
A61K031/415 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 23, 2018 |
GB |
1806578.9 |
Claims
1. A sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, or a hydrate or solvate thereof.
2. The salt of claim 1, wherein the salt is a monosodium salt.
3. The salt of claim 1, wherein the salt is a monohydrate.
4. The salt of claim 1, wherein the salt is crystalline.
5. The salt of claim 1, wherein the salt is a crystalline
monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyr-
azole-3-sulfonamide monohydrate.
6. A polymorphic form of the salt of claim 5, having an XRPD
spectrum comprising peaks at approximately: 4.3.degree.2.theta.,
8.7.degree.2.theta., and 20.6.degree.2.theta..
7. A polymorphic form of the salt of claim 5, having an XRPD
spectrum in which the 10 most intense peaks include 5 or more peaks
which have an approximate 2.theta. value selected from:
4.3.degree.2.theta., 6.2.degree.2.theta., 6.7.degree.2.theta.,
7.3.degree.2.theta., 8.7.degree.2.theta., 9.0.degree.2.theta.,
12.1.degree.2.theta., 15.8.degree.2.theta., 16.5.degree.2.theta.,
18.0.degree.2.theta., 18.1.degree.2.theta., 20.6.degree.2.theta.,
21.6.degree.2.theta., and 24.5.degree.2.theta..
8. A process for preparing a sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, comprising: (a) contacting
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid and a source of sodium ions in the
presence of one or more polar solvents to form a mixture; and (b)
obtaining a solid sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide from the mixture.
9. The process of claim 8, wherein the one or more polar solvents
used in step (a) comprise water and a polar aprotic organic
solvent.
10. A process for preparing a crystalline monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monohydrate in the polymorphic form of claim 6,
comprising: (a) contacting
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid and a source of sodium ions in the
presence of water and optionally a polar aprotic organic solvent to
form a solution; or dissolving
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt in a solvent mixture comprising
water and optionally a polar aprotic organic solvent to form a
solution; and (b) obtaining theft crystalline monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monohydrate in the polymorphic form from the
solution.
11. The process of claim 10, wherein the polar aprotic organic
solvent used in step (a) is acetone.
12. The process of claim 10, wherein the sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide is obtained in step (b) by addition of an
antisolvent.
13. The process of claim 12, wherein the antisolvent is tert-butyl
methyl ether.
14. A crystalline monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide obtainable by a process of claim 10.
15. (canceled)
16. A pharmaceutical composition comprising a salt of claim 1, and
a pharmaceutically acceptable excipient.
17. (canceled)
18. A method of treating or preventing a disease, disorder or
condition in a subject, the method comprising the step of
administering an effective amount of the salt of claim 1 to the
subject, thereby treating or preventing the disease, disorder or
condition, wherein the disease, disorder or condition is responsive
to NLRP3 inhibition.
19. The method as claimed in claim 18, wherein the disease,
disorder or condition is selected from: (i) inflammation; (ii) an
auto-immune disease; (iii) cancer; (iv) an infection; (v) a central
nervous system disease; (vi) a metabolic disease; (vii) a
cardiovascular disease; (viii) a respiratory disease; (ix) a liver
disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin
disease; (xiii) a lymphatic condition; (xiv) a psychological
disorder; (xv) graft versus host disease; (xvi) allodynia; (xvii)
any disease where an individual has been determined to carry a
germline or somatic non-silent mutation in NLRP3; (xviii)
cryopyrin-associated periodic syndromes (CAPS); (xix) Muckle-Wells
syndrome (MWS); (xx) familial cold autoinflammatory syndrome
(FCAS); (xxi) neonatal onset multisystem inflammatory disease
(NOMID); (xxii) familial Mediterranean fever (FMF); (xxiii)
pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA);
(xxiv) hyperimmunoglobulinemia D and periodic fever syndrome
(HIDS); (xxv) Tumour Necrosis Factor (TNF) Receptor-Associated
Periodic Syndrome (TRAPS); (xxvi) systemic juvenile idiopathic
arthritis; (xxvii) adult-onset Still's disease (AOSD); (xxviii)
relapsing polychondritis; (xxix) Schnitzler's syndrome; (xxx)
Sweet's syndrome; (xxxi) Behcet's disease; (xxxii) anti-synthetase
syndrome; (xxxiii) deficiency of interleukin 1 receptor antagonist
(DIRA); and (xxxiv) haploinsufficiency of A20 (HA20).
20. (canceled)
21. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide and to hydrates, solvates and polymorphic forms
thereof. The present invention further relates to pharmaceutical
compositions comprising this compound and the use of this compound
in the treatment and prevention of medical disorders and diseases,
most especially by NLRP3 inhibition.
BACKGROUND OF THE INVENTION
[0002] The NOD-like receptor (NLR) family, pyrin domain-containing
protein 3 (NLRP3) inflammasome is a component of the inflammatory
process, and its aberrant activity is pathogenic in inherited
disorders such as cryopyrin-associated periodic syndromes (CAPS)
and complex diseases such as multiple sclerosis, type 2 diabetes,
Alzheimer's disease and atherosclerosis.
[0003] NLRP3 is an intracellular signalling molecule that senses
many pathogen-derived, environmental and host-derived factors. Upon
activation, NLRP3 binds to apoptosis-associated speck-like protein
containing a caspase activation and recruitment domain (ASC). ASC
then polymerises to form a large aggregate known as an ASC speck.
Polymerised ASC in turn interacts with the cysteine protease
caspase-1 to form a complex termed the inflammasome. This results
in the activation of caspase-1, which cleaves the precursor forms
of the proinflammatory cytokines IL-1.beta. and IL-18 (termed
pro-IL-1.beta. and pro-IL-18 respectively) to thereby activate
these cytokines. Caspase-1 also mediates a type of inflammatory
cell death known as pyroptosis. The ASC speck can also recruit and
activate caspase-8, which can process pro-IL-1.beta. and pro-IL-18
and trigger apoptotic cell death.
[0004] Caspase-1 cleaves pro-IL-1.beta. and pro-IL-18 to their
active forms, which are secreted from the cell. Active caspase-1
also cleaves gasdermin-D to trigger pyroptosis. Through its control
of the pyroptotic cell death pathway, caspase-1 also mediates the
release of alarmin molecules such as IL-33 and high mobility group
box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2
resulting in its degradation and allowing the release of
IL-1.alpha.. In human cells caspase-1 may also control the
processing and secretion of IL-37. A number of other caspase-1
substrates such as components of the cytoskeleton and glycolysis
pathway may contribute to caspase-1-dependent inflammation.
[0005] NLRP3-dependent ASC specks are released into the
extracellular environment where they can activate caspase-1, induce
processing of caspase-1 substrates and propagate inflammation.
[0006] Active cytokines derived from NLRP3 inflammasome activation
are important drivers of inflammation and interact with other
cytokine pathways to shape the immune so response to infection and
injury. For example, IL-1.beta. signalling induces the secretion of
the pro-inflammatory cytokines IL-6 and TNF. IL-1.beta. and IL-18
synergise with IL-23 to induce IL-17 production by memory CD4 Th17
cells and by .gamma..delta. T cells in the absence of T cell
receptor engagement. IL-18 and IL-12 also synergise to induce
IFN-.gamma. production from memory T cells and NK cells driving a
Thi response.
[0007] The inherited CAPS diseases Muckle-Wells syndrome (MWS),
familial cold autoinflammatory syndrome (FCAS) and neonatal-onset
multisystem inflammatory disease (NOMID) are caused by
gain-of-function mutations in NLRP3, thus defining NLRP3 as a
critical component of the inflammatory process. NLRP3 has also been
implicated in the pathogenesis of a number of complex diseases,
notably including metabolic disorders such as type 2 diabetes,
atherosclerosis, obesity and gout.
[0008] A role for NLRP3 in diseases of the central nervous system
is emerging, and lung diseases have also been shown to be
influenced by NLRP3. Furthermore, NLRP3 has a role in the
development of liver disease, kidney disease and aging. Many of
these associations were defined using Nlrp3-/- mice, but there have
also been insights into the specific activation of NLRP3 in these
diseases. In type 2 diabetes mellitus (T2D), the deposition of
islet amyloid polypeptide in the pancreas activates NLRP3 and
IL-1.beta. signaling, resulting in cell death and inflammation.
[0009] Several small molecules have been shown to inhibit the NLRP3
inflammasome. Glyburide inhibits IL-1.beta. production at
micromolar concentrations in response to the activation of NLRP3
but not NLRC4 or NLRP1. Other previously characterised weak NLRP3
inhibitors include parthenolide,
3,4-methylenedioxy-.beta.-nitrostyrene and dimethyl sulfoxide
(DMSO), although these agents have limited potency and are
nonspecific.
[0010] Current treatments for NLRP3-related diseases include
biologic agents that target IL-1. These are the recombinant IL-1
receptor antagonist anakinra, the neutralizing IL-1.beta. antibody
canakinumab and the soluble decoy IL-1 receptor rilonacept. These
approaches have proven successful in the treatment of CAPS, and
these biologic agents have been used in clinical trials for other
IL-1.beta.-associated diseases.
[0011] Some diarylsulfonylurea-containing compounds have been
identified as cytokine release inhibitory drugs (CRIDs) (Perregaux
et al.; J. Pharmacol. Exp. Ther. 299, 187-197, 2001). CRIDs area
class of diarylsulfonylurea-containing compounds that inhibit the
post-translational processing of IL-1.beta.. Post-translational
processing of IL-ill is accompanied by activation of caspase-1 and
cell death. CRIDs arrest activated monocytes so that caspase-1
remains inactive and plasma membrane latency is preserved.
[0012] Certain sulfonylurea-containing compounds are also disclosed
as inhibitors of NLRP3 (see for example, Baldwin et al., J. Med.
Chem., 59(5), 1691-1710, 2016; and WO 2016/131098 A1, WO
2017/129897 A1, WO 2017/140778 A1, WO 2017/184604 A1, WO
2017/184623 A1, WO 2017/184624 A1 and WO 2018/015445 WO 2016/131098
A1 discloses
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide.
[0013] There is a need to provide compounds with improved
pharmacological and/or physiological and/or physicochemical
properties and/or those that provide a useful alternative to known
compounds.
SUMMARY OF THE INVENTION
[0014] A first aspect of the present invention provides a sodium
salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, or a hydrate or solvate thereof.
[0015] A second aspect of the present invention provides a
polymorphic form of a sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, or a hydrate or solvate thereof.
[0016] In certain embodiments, the polymorphic form of the second
aspect is a polymorph of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt monohydrate. Examples of such
polymorphs include the polymorph referred to herein as Form 1.
[0017] In certain embodiments, the polymorphic form of the second
aspect is a polymorph of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt anhydrate. Examples of such
polymorphs include the polymorph referred to herein as Form 2.
[0018] A third aspect of the present invention provides a process
for preparing a sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, comprising: [0019] (a) contacting
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-free
acid and a source of sodium ions in the presence of one or more
polar solvents to form a mixture; and [0020] (b) obtaining a solid
sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide from the mixture.
[0021] A fourth aspect of the present invention provides a
pharmaceutical composition comprising a salt, hydrate or solvate of
the first aspect of the invention or a polymorphic form of the
second aspect of the invention, and a pharmaceutically acceptable
excipient.
[0022] Further aspects of the present invention provide medical
uses and methods of treatment or prevention of a disease, disorder
or condition, most especially by NLRP3 inhibition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows XRPD analysis of the salt of Example 2.
[0024] FIG. 2 shows TGA and DSC analysis of the salt of Example
2.
[0025] FIG. 3 shows XRPD analysis of the salt of Example 3.
[0026] FIG. 4 shows TGA and DSC analysis of the salt of Example
3.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Differences between salt forms of an active pharmaceutical
compound can have profound effects on the properties of the solid
form of the compound. For example, differences can arise in the
crystallinity, solubility, intrinsic dissolution rate, stability
under storage, and stability in aqueous media of the solid form of
a substance as compared to the non-salified compound and other salt
forms of the same compound. The salts of the present invention
provide forms of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, and in particular sodium salts, which have
certain advantages over other salts and over the free acid
itself.
[0028] A first aspect of the present invention provides a sodium
salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, or a hydrate or solvate thereof.
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide (also referred to as the free acid) has the
formula:
##STR00001##
[0029] The salts of the first aspect of the present invention
encompass salts having any ratio of the conjugate base of the free
acid to sodium ion, for example monosodium salts, disodium salts
and hemisodium salts. In one embodiment, the sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide is a monosodium salt.
[0030] The salts of the first aspect of the present invention may
be anhydrous or in the form of a hydrate (e.g. a hemihydrate,
monohydrate, dihydrate or trihydrate) or other solvate. Such
solvates may be formed with common organic solvents, including but
not limited to, alcoholic solvents e.g. methanol, ethanol or
isopropanol. In one embodiment, the sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide is a monohydrate or anhydrate. In one embodiment,
the sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide is a monohydrate.
[0031] The salts, hydrates and solvates of the first aspect of the
invention may be in any crystalline or amorphous form or may exist
as any mixture of crystalline and amorphous forms. In embodiments
where a salt, hydrate and/or solvate of the first aspect of the
invention exists as a mixture of crystalline and amorphous forms,
the salt, hydrate and/or solvate may have a degree of
crystallinity. As used herein the degree of crystallinity is the
weight percentage of the salt, hydrate and/or solvate of the first
aspect of the invention which is in one or more crystalline forms,
expressed as a percentage of the total weight of the salt, hydrate
and/or solvate.
[0032] The salts, hydrates and solvates of the first aspect of the
invention preferably have a degree of crystallinity of 50% or more
(e.g. 60% or more, 70% or more, 80% or more, 90% or more, 95% or
more, or 99% or more). More preferably, the salts, hydrates and
solvates of the first aspect of the invention are crystalline. As
used herein a salt, hydrate and/or solvate of the first aspect of
the invention is typically referred to as crystalline, if it has a
degree of crystallinity 90% or more (e.g. 95% or more, or 99% or
more).
[0033] In one embodiment, the sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide is crystalline. In one embodiment, the sodium salt
of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide is a crystalline monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monohydrate.
[0034] A crystalline salt, hydrate and/or solvate of the first
aspect of the invention may exist in one or more polymorphic forms.
Polymorphism refers to the ability of a solid substance to exist in
one or more distinct crystal structures (i.e. with one or more
distinct arrangements of molecules relative to each other in the
crystal lattice). Different polymorphs of a substance may have
different physical properties such as solubility, intrinsic
dissolution rate and calorimetric behaviour (e.g. melting point).
Different polymorphs may also exhibit differences in stability
(e.g. differences in stability with respect to conversion to other
crystalline or amorphous forms). The physical properties of an
active pharmaceutical ingredient may affect the drug product safety
performance and efficacy. It is therefore advantageous to identify
polymorphic forms of a drug substance which have pharmaceutically
acceptable properties.
[0035] Accordingly, a second aspect of the present invention
provides a polymorphic form of a sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide, or a hydrate or solvate thereof.
[0036] The salts, hydrates and solvates of the first aspect of the
invention and the polymorphic forms of the second aspect of the
invention may contain any stable isotope including, but not limited
to .sup.12C, .sup.13C, .sup.1H, .sup.2H (D), .sup.14N, .sup.15N,
.sup.16O, .sup.17O, .sup.18O, .sup.19F and .sup.127I, and any
radioisotope including, but not limited to .sup.13C, .sup.14C,
.sup.3H (T), .sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I,
.sup.125I and .sup.131I.
[0037] In certain embodiments, the polymorphic form of the second
aspect is a polymorph of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt monohydrate. Examples of such
polymorphs include the polymorph referred to herein as Form 1.
[0038] The Form 1 polymorph can be characterised by techniques
including X-Ray Powder Diffraction (XRPD), Differential Scanning
calorimetry (DSC) and/or Thermogravimetric Analysis (TGA).
[0039] As used herein, XRPD data are typically those which can be
obtained using CuK.alpha. radiation at 20.degree. C. As used
herein, the term "approximate" or "approximately" when used in
connection with the position of an XRPD peak typically refers to
the stated position .+-.0.2.degree.2.theta..
[0040] The Form 1 polymorph typically has an XRPD spectrum
comprising peaks at approximately: 4.3.degree.2.theta.,
8.7.degree.2.theta., and 20.6.degree.2.theta.. More typically, the
Form 1 polymorph has an XRPD spectrum comprising peaks at
approximately: 4.3.degree.2.theta., 7.3.degree.2.theta.,
8.7.degree.2.theta., 16.5.degree.2.theta., and
20.6.degree.2.theta.. Still more typically, the Form 1 polymorph
has an XRPD spectrum comprising peaks at approximately:
4.3.degree.2.theta., 6.7.degree.2.theta., 7.3.degree.2.theta.,
8.7.degree.2.theta., 15.8.degree.2.theta., 16.5.degree.2.theta.,
and 20.6.degree.2.theta.. Still further typically, the Form 1
polymorph has an XRPD spectrum comprising peaks at approximately:
4.3.degree.2.theta., 6.7.degree.2.theta., 7.3.degree.2.theta.,
8.7.degree.2.theta., 9.0.degree.2.theta., 15.8.degree.2.theta.,
16.5.degree.2.theta., 18.0.degree.2.theta., and
20.6.degree.2.theta..
[0041] The Form 1 polymorph typically has an XRPD spectrum in which
the 10 most intense peaks include 5 or more (e.g. 6 or more, 7 or
more, 8 or more, 9 or more, or 10) peaks which have an approximate
2.theta. value selected from: 4.3.degree.2.theta.,
6.2.degree.2.theta., 6.7.degree.2.theta., 7.3.degree.2.theta.,
8.7.degree.2.theta., 9.0.degree.2.theta., 12.1.degree.2.theta.,
15.8.degree.2.theta., 16.5.degree.2.theta., 18.0.degree.2.theta.,
18.1.degree.2.theta., 20.6.degree.2.theta., 21.6.degree.2.theta.,
and 2.4.5.degree.2.theta.. More typically, the Form 1 polymorph has
an XRPD spectrum in which the 10 most intense peaks include 5 or
more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks
which have an approximate 2.theta. value selected from:
4.3.degree.2.theta., 6.2.degree.2.theta., 6.7.degree.2.theta.,
7.3.degree.2.theta., 8.7.degree.2.theta., 9.0.degree.2.theta.,
12.1.degree.2.theta., 15.8.degree.2.theta., 16.5.degree.2.theta.,
18.0.degree.2.theta., 20.6.degree.2.theta., and
21.6.degree.2.theta.. Still more typically, the Form 1 polymorph
has an XRPD spectrum in which the 10 most intense peaks include 5
or more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10)
peaks which have an approximate 2.theta. value selected from:
4.3.degree.2.theta., 6.2.degree.2.theta., 6.7.degree.2.theta.,
7.3.degree.2.theta., 8.7.degree.2.theta., 9.0.degree.2.theta.,
15.8.degree.2.theta., 16.5.degree.2.theta., 18.0.degree.2.theta.,
and 20.6.degree.2.theta..
[0042] The Form 1 polymorph may have an XRPD spectrum approximately
as set out in Table 1 below:
TABLE-US-00001 TABLE 1 Form 1 Angle/.degree. 2.theta. Intensity %
4.3 100.0 6.2 25.4 6.7 38.7 7.3 42.0 8.0 16.0 8.7 51.1 9.0 29.8 9.4
13.2 10.0 9.2 10.3 15.3 10.6 6.5 10.9 15.4 12.1 22.5 12.3 18.8 12.7
8.6 13.0 10.6 13.4 6.3 14.0 8.3 14.9 16.9 15.2 16.3 15.8 36.5 16.5
41.8 17.1 11.8 17.6 12.1 18.0 26.4 18.1 21.8 18.7 19.9 19.2 19.1
19.7 16.0 19.9 20.8 20.6 42.2 21.1 13.8 21.6 23.4 22.0 11.7 22.3
12.8 22.8 8.9 23.2 10.4 23.6 16.3 24.0 21.3 24.5 21.6 25.1 10.3
25.4 12.7 26.0 12.7 26.9 10.4 27.3 9.8
[0043] The Form 1 polymorph typically has a TGA profile comprising
weight loss of about 4.6% to about 5.0% (e.g. weight loss of about
4.7% to about 4.9%, or weight loss of about 4.8%) between
20.degree. C. and 100.degree. C.
[0044] The Form 1 polymorph typically has a DSC profile comprising
a first endotherm and a second endotherm. The first endotherm of
the Form 1 polymorph typically has an onset at a temperature in a
range from about 41.degree. C. to about 45.degree. C. (e.g. a
temperature in a to range from about 42.degree. C. to about
44.degree. C., or at a temperature of about 43.degree. C.). The
first endotherm of the Form 1 polymorph typically has a peak at a
temperature in a range from about 72.degree. C. to about 76.degree.
C. (e.g. a temperature in a range from about 73.degree. C. to about
75.degree. C., or at a temperature of about 74.degree. C.). The
first endotherm of the Form 1 polymorph typically has an enthalpy
change of about 69 J/g to about 73 J/g (e.g. about 70 J/g to about
72 J/g, or about 71 J/g). The second endotherm of the Form 1
polymorph typically has an onset at a temperature in a range from
about 177.degree. C. to about 181.degree. C. (e.g. a temperature in
a range from about 178.degree. C. to about 180.degree. C., or at a
temperature of about 179.degree. C.). The second endotherm of the
Form 1 polymorph typically has a peak at a temperature in a range
from about 188.degree. C. to about 192.degree. C. (e.g. a
temperature in a range from about 189.degree. C. to about
191.degree. C., or at a temperature of about 190.degree. C.). The
second endotherm of the Form 1 polymorph typically has an enthalpy
change of about 13 J/g to about 17 J/g (e.g. about 14 J/g to about
16 J/g, or about 15 J/g).
[0045] The Form 1 polymorph can be obtained by a process
comprising: [0046] (a) contacting
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid and a source of sodium ions in the
presence of water and optionally a polar aprotic organic solvent to
form a solution; or dissolving
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt in a solvent mixture comprising
water and optionally a polar aprotic organic solvent to form a
solution; and [0047] (b) obtaining a crystalline monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monohydrate as the Form 1 polymorph from the
solution.
[0048] In a preferred embodiment, the solvent mixture used in step
(a) comprises water and a polar aprotic organic solvent. In a
preferred embodiment, the polar aprotic organic solvent is acetone.
The volume ratio of water to polar aprotic organic solvent is
typically from 1:35 to 1:1 (e.g. from 1:20 to 1:1, or from 1:15 to
1:4, or from 1:13 to 1:6, or from 1:11 to 1:8, or about 1:9). In a
preferred embodiment,
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid is treated with a solvent mixture of
water and a polar aprotic organic solvent, followed by addition of
a source of sodium ions to form a solution.
[0049] In a preferred embodiment, in step (b), the crystalline
monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1-
H-pyrazole-3-sulfonamide monohydrate Form 1 polymorph may be
obtained from the solution by addition of a suitable antisolvent,
or by a combination of addition of a suitable antisolvent and
addition of seed crystals. Preferred antisolvents are diethyl
ether, diisopropyl ether and tert-butyl methyl ether. Particularly
preferred is tert-butyl methyl ether.
[0050] Further preferred processes for obtaining the Form 1
polymorph include those in which the polar aprotic organic solvent,
source of sodium ions, means of obtaining the solid sodium salt and
other features of the process are as described herein with respect
to the process of the third aspect of the present invention.
[0051] In certain embodiments, the polymorphic form of the second
aspect is a polymorph of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt anhydrate. Examples of such
polymorphs include the polymorph referred to herein as Form 2.
[0052] The Form 2 polymorph typically has an XRPD spectrum
comprising peaks at approximately: 5.1.degree.2.theta.,
21.7.degree.2.theta., and 22.7.degree.2.theta.. More typically, the
Form 2 polymorph has an XRPD spectrum comprising peaks at
approximately: 5.1.degree.2.theta., 17.9.degree.2.theta.,
18.7.degree.2.theta., 21.7.degree.2.theta., and
22.7.degree.2.theta.. Still more typically, the Form 2 polymorph
has an XRPD spectrum comprising peaks at approximately:
5.1.degree.2.theta., 17.1.degree.2.theta., 17.9.degree.2.theta.,
18.7.degree.2.theta., 20.1.degree.2.theta., 21.7.degree.2.theta.,
and 22.7.degree.2.theta.. Still further typically, the Form 2
polymorph has an XRPD spectrum comprising peaks at approximately:
5.1.degree.2.theta., 8.9.degree.2.theta., 17.1.degree.2.theta.,
17.9.degree.2.theta., 18.7.degree.2.theta., 20.1.degree.2.theta.,
20.6.degree.2.theta., 21.7.degree.2.theta., and
22.7.degree.2.theta..
[0053] The Form 2 polymorph typically has an XRPD spectrum in which
the 10 most intense peaks include 5 or more (e.g. 6 or more, 7 or
more, 8 or more, 9 or more, or 10) peaks which have an approximate
2.theta. value selected from: 5.1.degree.2.theta.,
6.6.degree.2.theta., 7.7.degree.2.theta., 8.9.degree.2.theta.,
9.3.degree.2.theta., 10.3.degree.2.theta., 16.2.degree.2.theta.,
17.1.degree.2.theta., 17.9.degree.2.theta., 18.7.degree.2.theta.,
20.1.degree.2.theta., 20.6.degree.2.theta., 21.7.degree.2.theta.,
and 22.7.degree.2.theta.. More typically, the Form 2 polymorph has
an XRPD spectrum in which the 10 most intense peaks include 5 or
more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks
which have an approximate 2.theta. value selected from:
5.1.degree.2.theta., 6.6.degree.2.theta., 8.9.degree.2.theta.,
10.3.degree.2.theta., 16.2.degree.2.theta., 17.1.degree.2.theta.,
17.9.degree.2.theta., 18.7.degree.2.theta., 20.1.degree.2.theta.,
20.6.degree.2.theta., 21.7.degree.2.theta., and
22.7.degree.2.theta.. Still more typically, the Form 2 polymorph
has an XRPD spectrum in which the 10 most intense peaks include 5
or more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10)
peaks which have an approximate 2.theta. value selected from:
50.1.degree.2.theta., 8.9.degree.2.theta., 16.2.degree.2.theta.,
17.1.degree.2.theta., 17.9.degree.2.theta., 18.7.degree.2.theta.,
20.1.degree.2.theta., 20.6.degree.2.theta., 21.7.degree.2.theta.,
and 22.7.degree.2.theta..
[0054] The Form 2 polymorph may have an XRPD spectrum approximately
as set out in Table 2 below:
TABLE-US-00002 TABLE 2 Form 2 Angle/.degree. 2.theta. Intensity %
5.1 100.0 6.6 15.3 7.7 15.0 8.9 19.1 9.3 15.0 10.3 15.1 11.0 10.3
11.9 10.5 13.2 10.1 13.9 11.5 14.7 11.4 16.2 15.7 17.1 20.6 17.9
22.5 18.7 21.8 20.1 21.1 20.6 20.4 21.7 22.6 22.7 23.3
[0055] The Form 2 polymorph typically has a TGA profile comprising
weight loss of about 8.5% to about 8.9% (e.g. weight loss of about
8.6% to about 8.8%, or weight loss of about 8.7%) between
20.degree. C. and 160.degree. C.
[0056] The Form 2 polymorph typically has a DSC profile comprising
a first endotherm, a second endotherm and a third endotherm. The
first endotherm of the Form 2 polymorph typically has an onset at a
temperature in a range from about 61.degree. C. to about 65.degree.
C. (e.g. a temperature in a range from about 62.degree. C. to about
64.degree. C., or at a temperature of about 63.degree. C.). The
first endotherm of the Form 2 polymorph typically has a peak at a
temperature in a range from about 73.degree. C. to about 77.degree.
C. (e.g. a temperature in a range from about 74.degree. C. to about
76.degree. C., or at a temperature of about 75.degree. C.). The
first endotherm of the Form 2 polymorph typically has an enthalpy
change of about 1 J/g to about 5 J/g (e.g. about 2 J/g to about 4
J/g, or about 3 J/g). The second endotherm of the Form 2 polymorph
typically has an onset at a temperature in a range from about
93.degree. C. to about 97.degree. C. (e.g. a temperature in a range
from about 94.degree. C. to about 96.degree. C., or at a
temperature of about 95.degree. C.). The second endotherm of the
Form 2 polymorph typically has a peak at a temperature in a range
from about 99.degree. C. to about 103.degree. C. (e.g. a
temperature in a range from about 100.degree. C. to about
102.degree. C., or at a temperature of about 101.degree. C.). The
second endotherm of the Form 2 polymorph typically has an enthalpy
change of about 0.5 J/g to about 4 J/g (e.g. about 1 J/g to about 3
J/g, or about 2 J/g). The third endotherm of the Form 2 polymorph
typically has an onset at a temperature in a range from about
180.degree. C. to about 184.degree. C. (e.g. a temperature in a
range from about 181.degree. C. to about 183.degree. C., or at a
temperature of about 182.degree. C.). The third endotherm of the
Form 2 polymorph typically has a peak at a temperature in a range
from about 196.degree. C. to about 200.degree. C. (e.g. a
temperature in a range from about 197.degree. C. to about
199.degree. C., or at a temperature of about 198.degree. C.). The
third endotherm of the Form 2 polymorph typically has an enthalpy
change of about 25 J/g to about 29 J/g (e.g. about 26 J/g to about
28 J/g, or about 27 J/g).
[0057] The Form 2 polymorph can be obtained by a process
comprising: [0058] (a) contacting
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid and a source of sodium ions in the
presence of water and a polar protic organic solvent to form a
solution; or dissolving
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt in a solvent mixture comprising
water and a polar protic organic solvent to form a solution; and
[0059] (b) obtaining a crystalline monosodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide anhydrate as the Form 2 polymorph from the
solution.
[0060] In a preferred embodiment, in step (a),
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium salt is dissolved in a solvent mixture
comprising water and a polar protic organic solvent to form a
solution.
[0061] In a preferred embodiment, the polar protic organic solvent
used in step (a) is isopropyl alcohol. The volume ratio of water to
polar protic organic solvent is typically from 1:35 to 1:1 (e.g.
from 1:20 to 1:1, or from 1:15 to 1:4, or from 1:13 to 1:6, or from
1:11 to 1:8, or about 1:10).
[0062] Further preferred processes for obtaining the Form 2
polymorph include those in which the polar protic organic solvent,
source of sodium ions, means of obtaining the solid sodium salt and
other features of the process are as described herein with respect
to the process of the third aspect of the present invention.
[0063] A third aspect of the present invention provides a process
for preparing a salt, hydrate or solvate of the first aspect of the
invention or a polymorphic form of the second aspect of the
invention, the process comprising: [0064] (a) contacting
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid and a source of sodium ions in the
presence of one or more polar solvents to form a mixture; and
[0065] (b) obtaining a solid sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide from the mixture.
[0066] In certain embodiments, the one or more polar solvents used
in step (a) are a mixture of polar solvents, e.g. a mixture of
water and a polar organic solvent. In such embodiments, the volume
ratio of water to polar organic solvent is typically from 1:35 to
1:1 (e.g. from 1:20 to 1:1, or from 1:15 to 1:4, or from 1:13 to
1:6, or from 1:11 to 1:8, or about 1:10, or about 1:9).
[0067] The mixture of polar solvents may be, for example, a mixture
of water and a polar protic organic solvent, or a mixture of water
and a polar aprotic organic solvent. Suitable polar protic organic
solvents include acids such as formic acid and acetic acid, and
alcohols such as methanol, ethanol, isopropyl alcohol and
n-butanol. A preferred polar protic organic solvent is isopropyl
alcohol. Suitable polar aprotic organic solvents include
N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran,
ethyl acetate, methyl acetate, acetone, dimethylformamide,
acetonitrile, dimethyl sulfoxide and propylene carbonate. A
preferred polar aprotic organic solvent is acetone.
[0068] In some embodiments, the mixture of polar solvents may be a
mixture of water and isopropyl alcohol. In some embodiments, the
mixture of polar solvents may be a mixture of water and
acetone.
[0069] The source of sodium ions is typically a sodium salt. In
some embodiments, the sodium salt is a solid sodium salt. In other
embodiments, the sodium salt is a solution of a sodium-ion
containing compound. Suitable solid sodium salts include NaCl,
NaOH, Na.sub.2CO.sub.3 and NaHCO.sub.3. Suitable solutions of
sodium-ion containing compounds include sodium methoxide (NaOMe),
sodium ethoxide (NaOEt) and sodium tert-butoxide (NaO.sup.tBu) all
in ethanol, tetrahydrofuran, or acetone or a mixture of any of
these solvents with water. Other suitable solutions of sodium-ion
containing compounds include NaCl, NaOH, Na.sub.2CO.sub.3 and
NaHCO.sub.3 in water. A preferred source of sodium ions is sodium
ethoxide (NaOEt) in ethanol or NaOH in water. A more preferred
source of sodium ions is sodium ethoxide (NaOEt) in ethanol.
[0070] In some embodiments, in step (a), the reaction mixture
formed is a solution. In some embodiments, in step (a),
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide free acid is treated with a polar solvent or a
mixture of polar solvents, followed by addition of a source of
sodium ions to form a solution.
[0071] In some embodiments, step (a) is carried out at a
temperature in the range of 5.degree. C. to 100.degree. C., or a
range of 10.degree. C. to 60.degree. C., or a range of 15.degree.
C. to 30.degree. C.
[0072] In some embodiments, in step (b), the solid sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide may be obtained from the reaction mixture by
evaporation of the solvent or mixture of solvents. In some
embodiments, the solid sodium salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide may be obtained from the reaction mixture by
addition of a suitable antisolvent. In such embodiments, the volume
ratio of solvent or mixture of solvents to antisolvent is typically
from 1:1 to 1:10 (e.g. from 1:1.5 to 1:8, or from 1:2 to 1:6, or
about 1:3, or about 1:5). In some embodiments, the solid sodium
salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide may be obtained from the reaction mixture by
addition of seed crystals. In some embodiments, the solid sodium
salt of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide may be obtained from the reaction mixture by a
combination of addition of a suitable antisolvent and addition of
seed crystals.
[0073] Suitable antisolvents include non-polar solvents such as
hexane, heptane, cyclohexane, toluene, benzene, 1,4-dioxane,
chloroform, dichloromethane, diethyl ether, diisopropyl ether and
tert-butyl methyl ether. Diethyl ether, diisopropyl ether and
tert-butyl methyl ether are preferred. Particularly preferred is
tert-butyl methyl ether.
[0074] In some embodiments, step (b) is carried out at a
temperature in the range of 5.degree. C. to 100.degree. C., or a
range of 10.degree. C. to 60.degree. C., or a range of 15.degree.
C. to 30.degree. C.
[0075] A fourth aspect of the present invention provides a
pharmaceutical composition comprising a salt, hydrate or solvate of
the first aspect of the invention or a polymorphic form of the
second aspect of the invention, and a pharmaceutically acceptable
excipient.
[0076] Conventional procedures for the selection and preparation of
suitable pharmaceutical formulations are described in, for example,
"Aulton's Pharmaceutics--The Design and Manufacture of Medicines",
M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier,
4th Ed., 2013.
[0077] Pharmaceutically acceptable excipients including adjuvants,
diluents or carriers that may be used in the pharmaceutical
compositions of the invention are those conventionally employed in
the field of pharmaceutical formulation, and include, but are not
limited to, sugars, sugar alcohols, starches, ion exchangers,
alumina, aluminium stearate, lecithin, serum proteins such as human
serum albumin, buffer substances such as phosphates, glycerine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinylpyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0078] In one embodiment, the pharmaceutical composition of the
fourth aspect of the invention additionally comprises one or more
further active agents.
[0079] In a further embodiment, the pharmaceutical composition of
the fourth aspect of the invention may be provided as a part of a
kit of parts, wherein the kit of parts comprises the pharmaceutical
composition of the fourth aspect of the invention and one or more
further pharmaceutical compositions, wherein the one or more
further pharmaceutical compositions each comprise a
pharmaceutically acceptable excipient and one or more further
active agents.
[0080] A fifth aspect of the invention provides a salt, hydrate or
solvate of the first aspect of the invention, a polymorphic form of
the second aspect of the invention, or a pharmaceutical composition
of the fourth aspect of the invention, for use in medicine, and/or
for use in the treatment or prevention of a disease, disorder or
condition. Typically, the use comprises the administration of the
salt, hydrate, solvate, polymorphic form or pharmaceutical
composition to a subject. In one embodiment, the use comprises the
co-administration of one or more further active agents.
[0081] The term "treatment" as used herein refers equally to
curative therapy, and ameliorating or palliative therapy. The term
includes obtaining beneficial or desired physiological results,
which may or may not be established clinically. Beneficial or
desired clinical results include, but are not limited to, the
alleviation of symptoms, the prevention of symptoms, the
diminishment of extent of disease, the stabilisation (i.e., not
worsening) of a condition, the delay or slowing of
progression/worsening of a condition/symptoms, the amelioration or
palliation of the condition/symptoms, and remission (whether
partial or total), whether detectable or undetectable. The term
"palliation", and variations thereof, as used herein, means that
the extent and/or undesirable manifestations of a physiological
condition or symptom are lessened and/or time course of the
progression is slowed or lengthened, as compared to not
administering a salt, hydrate, solvate, polymorphic form or
pharmaceutical composition of the present invention. The term
"prevention" as used herein in relation to a disease, disorder or
condition, relates to prophylactic or preventative therapy, as well
as therapy to reduce the risk of developing the disease, disorder
or condition. The term "prevention" includes both the avoidance of
occurrence of the disease, disorder or condition, and the delay in
onset of the disease, disorder or condition. Any statistically
significant (p 0.05) avoidance of occurrence, delay in onset or
reduction in risk as measured by a controlled clinical trial may be
deemed a prevention of the disease, disorder or condition. Subjects
amenable to prevention include those at heightened risk of a
disease, disorder or condition as identified by genetic or
biochemical markers. Typically, the genetic or biochemical markers
are appropriate to the disease, disorder or condition under
consideration and may include for example, inflammatory biomarkers
such as C-reactive protein (CRP) and monocyte chemoattractant
protein (MCP-1) in the case of inflammation; total cholesterol,
triglycerides, insulin resistance and C-peptide in the case of
NAFLD and NASH; and more generally IL1.beta. and IL18 in the case
of a disease, disorder or condition responsive to NLRP3
inhibition.
[0082] A sixth aspect of the invention provides the use of a salt,
hydrate or solvate of the first aspect of the invention or a
polymorphic form of the second aspect of the invention, in the
manufacture of a medicament for the treatment or prevention of a
disease, disorder or condition. Typically, the treatment or
prevention comprises the administration of the salt, hydrate,
solvate, polymorphic form or medicament to a subject. In one
embodiment, the treatment or prevention comprises the
co-administration of one or more further active agents.
[0083] A seventh aspect of the invention provides a method of
treatment or prevention of a disease, disorder or condition, the
method comprising the step of administering an effective amount of
a salt, hydrate or solvate of the first aspect of the invention, a
polymorphic form of the second aspect of the invention, or a
pharmaceutical composition of the fourth aspect, to thereby treat
or prevent the disease, disorder or condition. In one embodiment,
the method further comprises the step of co-administering an
effective amount of one or more further active agents. Typically,
the administration is to a subject in need thereof.
[0084] An eighth aspect of the invention provides a salt, hydrate
or solvate of the first aspect of the invention, a polymorphic form
of the second aspect of the invention, or a pharmaceutical
composition of the fourth aspect of the invention, for use in the
treatment or prevention of a disease, disorder or condition in an
individual, wherein the individual has a germline or somatic
non-silent mutation in NLRP3. The mutation may be, for example, a
gain-of-function or other mutation resulting in increased NLRP3
activity. Typically, the use comprises the administration of the
salt, hydrate, solvate, polymorphic form or pharmaceutical
composition to the individual. In one embodiment, the use comprises
the co-administration of one or more further active agents. The use
may also comprise the diagnosis of an individual having a germline
or somatic non-silent mutation in NLRP3, wherein the salt, hydrate,
solvate, polymorphic form or pharmaceutical composition is
administered to an individual on the basis of a positive diagnosis
for the mutation. Typically, identification of the mutation in
NLRP3 in the individual may be by any suitable genetic or
biochemical means.
[0085] A ninth aspect of the invention provides the use of a salt,
hydrate or solvate of the first aspect of the invention or a
polymorphic form of the second aspect of the invention, in the
manufacture of a medicament for the treatment or prevention of a
disease, disorder or condition in an individual, wherein the
individual has a germline or somatic non-silent mutation in NLRP3.
The mutation may be, for example, a gain-of-function or other
mutation resulting in increased NLRP3 activity. Typically, the
treatment or prevention comprises the administration of the salt,
hydrate, solvate, polymorphic form or medicament to the individual.
In one embodiment, the treatment or prevention comprises the
co-administration of one or more further active agents. The
treatment or prevention may also comprise the diagnosis of an
individual having a germline or somatic non-silent mutation in
NLRP3, wherein the salt, hydrate, solvate, polymorphic form or
medicament is administered to an individual on the basis of a
positive diagnosis for the mutation. Typically, identification of
the mutation in NLRP3 in the individual may be by any suitable
genetic or biochemical means.
[0086] A tenth aspect of the invention provides a method of
treatment or prevention of a disease, disorder or condition, the
method comprising the steps of diagnosing of an individual having a
germline or somatic non-silent mutation in NLRP3, and administering
an effective amount of a salt, hydrate or solvate of the first
aspect of the invention, a polymorphic form of the second aspect of
the invention, or a pharmaceutical composition of the fourth aspect
of the invention, to the positively diagnosed individual, to
thereby treat or prevent the disease, disorder or condition. In one
embodiment, the method further comprises the step of
co-administering an effective amount of one or more further active
agents. Typically, the administration is to a subject in need
thereof.
[0087] In general embodiments, the disease, disorder or condition
may be a disease, disorder or condition of the immune system, the
cardiovascular system, the endocrine system, the gastrointestinal
tract, the renal system, the hepatic system, the metabolic system,
the respiratory system, the central nervous system, may be a cancer
or other malignancy, and/or may be caused by or associated with a
pathogen.
[0088] It will be appreciated that these general embodiments
defined according to broad categories of diseases, disorders and
conditions are not mutually exclusive. In this regard any
particular disease, disorder or condition may be categorized
according to more than one of the above general embodiments. A
non-limiting example is type I diabetes which is an autoimmune
disease and a disease of the endocrine system.
[0089] In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the invention, the disease, disorder or
condition is responsive to NLRP3 inhibition. As used herein, the
term "NLRP3 inhibition" refers to the complete or partial reduction
in the level of activity of NLRP3 and includes, for example, the
inhibition of active NLRP3 and/or the inhibition of activation of
NLRP3.
[0090] There is evidence for a role of NLRP3-induced IL-1 and IL-18
in the inflammatory responses occurring in connection with, or as a
result of, a multitude of different disorders (Menu et al.,
Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et
al., Nature, 481:278-286, 2012).
[0091] NLRP3 has been implicated in a number of autoinflammatory
diseases, including Familial Mediterranean fever (FMF), TNF
receptor associated periodic syndrome (TRAPS),
hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),
pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's
syndrome, chronic nonbacterial osteomyelitis (CNO), and acne
vulgaris (Cook et al., Eur. J. Immunol., 40: 595-653, 2010). In
particular, NLRP3 mutations have been found to be responsible for a
set of rare autoinflammatory diseases known as CAPS (Ozaki et al.,
J. Inflammation Research, 8:15-27, 2015; Schroder et al., Cell,
140: 821-832, 2010; and Menu et al., Clinical and Experimental
Immunology, 166: 1-15, 2011). CAPS are heritable diseases
characterized by recurrent fever and inflammation and are comprised
of three autoinflammatory disorders that form a clinical continuum.
These diseases, in order of increasing severity, are familial cold
autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and
chronic infantile cutaneous neurological articular syndrome (CINCA;
also called neonatal-onset multisystem inflammatory disease,
NOMID), and all have been shown to result from gain-of-function
mutations in the NLRP3 gene, which leads to increased secretion of
IL-1.beta..
[0092] A number of autoimmune diseases have been shown to involve
NLRP3 including, in particular, multiple sclerosis, type-1 diabetes
(T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease,
Schnitzler syndrome, macrophage activation syndrome (Masters Clin.
Immunol. 2013; Braddock et al. Nat. Rev. Drug Disc. 2004 3: 1-10;
Inoue et al., Immunology 139: 11-18, Coll et al. Nat. Med. 2015
21(3):248-55; and Scott et al. Clin. Exp. Rheumatol 2016 34(1):
88-93), systemic lupus erythematosus (Lu et al. J Immunol.
2017198C3): 1119-29), and systemic sclerosis (Artlett et al.
Arthritis Rheum. 2011; 63(11): 3563-74). NLRP3 has also been shown
to play a role in a number of lung diseases including chronic
obstructive pulmonary disorder (COPD), asthma (including
steroid-resistant asthma), asbestosis, and silicosis (De Nardo et
al., Am. J. Pathol., 184: 42-54, 2014 and Kim et al. Am J Respir
Crit Care Med. 2017 196(3): 283-97). NLRP3 has also been suggested
to have a role in a number of central nervous system conditions,
including Parkinson's disease (PD), Alzheimer's disease (AD),
dementia, Huntington's disease, cerebral malaria, brain injury from
pneumococcal meningitis (Walsh et al., Nature Reviews, 15: 84-97,
2014, and Dempsey et al. Brain. Behay. Immun. 2017 61: 306-316),
intracranial aneurysms (Zhang et al. J. Stroke &
Cerebrovascular Dis. 2015 24; 5: 972-979), and traumatic brain
injury (Ismael et al. J Neurotrauma. 2018 Jan. 2). NRLP3 activity
has also been shown to be involved in various metabolic diseases
including type 2 diabetes (T2D), atherosclerosis, obesity, gout,
pseudo-gout, metabolic syndrome (Wen et al., Nature Immunology, 13:
352-357, 2012; Duewell et al., Nature, 464: 1357-1361, 2010;
Strowig et al., Nature, 481: 278-286, 2012), and non-alcoholic
steatohepatitis (Mridha et al. J Hepatol. 2017 66(5): 1037-46). A
role for NLRP3 via IL-1.beta. has also been suggested in
atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart
J. 2017 38(11): 828-36), heart failure (Sano et al. JAM. Coll.
Cardiol. 2018 71(8): 875-66), aortic aneurysm and dissection (Wu et
al. Arterioscler. Thromb. Vasc. Biol. 2017 37(4): 694-706), and
other cardiovascular events (Ridker et al., N Engl J Med., doi:
10.1056/NEJMoa1707914, 2017). Other diseases in which NLRP3 has
been shown to be involved include: ocular diseases such as both wet
and dry age-related macular degeneration (Doyle et al., Nature
Medicine, 18: 791-798, 2012 and Tarallo et al. Cell 2012 149(4):
847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol.
2017; 95(8): 803-808) and optic nerve damage (Puyang et al. Sci
Rep. 2016 Feb. 19; 6:20998); liver diseases including non-alcoholic
steatohepatitis (NASH) (Henao-Meija et al., Nature, 482: 179-185,
2012); inflammatory reactions in the lung and skin (Primiano et al.
J Immunol. 2016 197(6): 2421-33) including contact hypersensitivity
(such as bullous pemphigoid (Fang et al. J Dermatol Sci. 2016;
83(2): 116-23)), atopic dermatitis (Niebuhr et al. Allergy 2014
69(8): 1058-67), Hidradenitis suppurativa (Alikhan et al. 2009 J Am
Acad Dermatol 60(4): 539-61), acne vulgaris (Qin et al. J Invest.
Dermatol. 2014 134(2): 381-88), and sarcoidosis (Jager et al. Am J
Respir Crit Care Med 2015 191: A5816); inflammatory reactions in
the joints (Braddock et al., Nat. Rev. Drug Disc., 3: 1-10, 2004);
amyotrophic lateral sclerosis (Gugliandolo et al. Inflammation 2018
41(1): 93-103); cystic fibrosis (Iannitti et al. Nat. Commun. 2016
7: 10791); stroke (Walsh et al., Nature Reviews, 15: 84-97, 2014);
chronic kidney disease (Granata et al. PLoS One 2015 10(3):
e0122272); and inflammatory bowel diseases including ulcerative
colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc.,
3: 1-10, 2004, Neudecker et al. J Exp. Med. 2017 214(6): 1737-52,
and Lazaridis et al. Dig. Dis. Sci. 2017 62(9): 2348-56). The NLRP3
inflammasome has been found to be activated in response to
oxidative stress, and UVB irradiation (Schroder et al., Science,
327: 296-300, 2010). NLRP3 has also been shown to be involved in
inflammatory hyperalgesia (Dolunay et al., Inflammation, 40:
366-386, 2017).
[0093] The inflammasome, and NLRP3 specifically, has also been
proposed as a target for modulation by various pathogens including
viruses such as DNA viruses (Amsler et al., Future Virol. (2013)
8(4), 357-370).
[0094] NLRP3 has also been implicated in the pathogenesis of many
cancers (Menu et al., Clinical and Experimental Immunology 166:
1-15, 2011; and Masters Clin. Immunol. 2013). For example, several
previous studies have suggested a role for IL-1.beta. in cancer
invasiveness, growth and metastasis, and inhibition of IL-1.beta.
with canakinumab has been shown to reduce the incidence of lung
cancer and total cancer mortality in a randomised, double-blind,
placebo-controlled trial (Ridker et al. Lancet,
S0140-6736(17)32247-X, 2017). Inhibition of the NLRP3 inflammasome
or IL-1.beta. has also been shown to inhibit the proliferation and
migration of lung cancer cells in vitro (Wang et al. Oncol Rep.
2016; 35(4): 2053-64). A role for the NLRP3 inflammasome has been
suggested in myelodysplastic syndromes (Basiorka et al. Blood. 2016
Dec. 22; 128(25):2960-2975) and also in the carcinogenesis of
various other cancers including glioma (Li et al. Am J Cancer Res.
2015; 5(1): 442-449), inflammation-induced tumours (Allen et al. J
Exp Med. 2010; 207(5): 1045-56 and Hu et al. PNAS. 2010; 107(50):
21635-40), multiple myeloma (Li et al. Hematology 2016 21(3):
144-5.sup.1), and squamous cell carcinoma of the head and neck
(Huang et al. J Exp Clin Cancer Res. 2017 2; 36(1): 116).
Activation of the NLRP3 inflammasome has also been shown to mediate
chemoresistance of tumour cells to 5-Fluorouracil (Feng et al. J
Exp Clin Cancer Res. 2017 21; 36(1): 81), and activation of NLRP3
inflammasome in peripheral nerve contributes to
chemotherapy-induced neuropathic pain (Jia et al. Mol Pain. 2017;
13: 1-11).
[0095] NLRP3 has also been shown to be required for the efficient
control of viral, bacterial, fungal, and helminth pathogen
infections (Strowig et al., Nature, 481:278-286, 2012).
[0096] Accordingly, examples of diseases, disorders or conditions
which may be responsive to NLRP3 inhibition and which may be
treated or prevented in accordance with the fifth, sixth, seventh,
eighth, ninth or tenth aspect of the present invention include:
[0097] (i) inflammation, including inflammation occurring as a
result of an inflammatory disorder, e.g. an autoinflammatory
disease, inflammation occurring as a symptom of a non-inflammatory
disorder, inflammation occurring as a result of infection, or
inflammation secondary to trauma, injury or autoimmunity; [0098]
(ii) auto-immune diseases such as acute disseminated encephalitis,
Addison's disease, ankylosing spondylitis, antiphospholipid
antibody syndrome (APS), anti-syndrome, aplastic anemia, autoimmune
adrenalitis, autoimmune hepatitis, autoimmune oophoritis,
autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac
disease, Crohn's disease, type 1 diabetes (TiD), Goodpasture's
syndrome, Graves' disease, Guillain-Barre syndrome (GBS),
Hashimoto's disease, idiopathic thrombocytopenic purpura,
Kawasaki's disease, lupus erythematosus including systemic lupus
erythematosus (SLE), multiple sclerosis (MS) including primary
progressive multiple sclerosis (PPMS), secondary progressive
multiple sclerosis (SPMS) and relapsing remitting multiple
sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome
(OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious
anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid
arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis
or Still's disease, refractory gouty arthritis, Reiter's syndrome,
Sjogren's syndrome, systemic sclerosis a systemic connective tissue
disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, alopecia universalis,
Behcet's disease, Chagas' disease, dysautonomia, endometriosis,
hidradenitis suppurativa (HS), interstitial cystitis,
neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative
colitis, Schnitzler syndrome, macrophage activation syndrome, Blau
syndrome, vitiligo or vulvodynia; [0099] (iii) cancer including
lung cancer, pancreatic cancer, gastric cancer, myelodysplastic
syndrome, leukaemia including acute lymphocytic leukaemia (ALL) and
acute myeloid leukaemia (AML), adrenal cancer, anal cancer, basal
and squamous cell skin cancer, bile duct cancer, bladder cancer,
bone cancer, brain and spinal cord tumours, breast cancer, cervical
cancer, chronic lymphocytic leukaemia (CLL), chronic myeloid
leukaemia (CML), chronic myelomonocytic leukaemia (CMML),
colorectal cancer, endometrial cancer, oesophagus cancer, Ewing
family of tumours, eye cancer, gallbladder cancer, gastrointestinal
carcinoid tumours, gastrointestinal stromal tumour (GIST),
gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi
sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver
cancer, lung carcinoid tumour, lymphoma including cutaneous T cell
lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell
skin cancer, multiple myeloma, nasal cavity and paranasal sinuses
cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,
non-small cell lung cancer, oral cavity and oropharyngeal cancer,
osteosarcoma, ovarian cancer, penile cancer, pituitary tumours,
prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland
cancer, skin cancer, small cell lung cancer, small intestine
cancer, soft tissue sarcoma, stomach cancer, testicular cancer,
thymus cancer, thyroid cancer including anaplastic thyroid cancer,
uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom
macroglobulinemia, and Wilms tumour; (iv) infections including
viral infections (e.g. from influenza virus, human immunodeficiency
virus (HIV), alphavirus (such as Chikungunya and Ross River virus),
flaviviruses (such as Dengue virus and Zika virus), herpes viruses
(such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster
virus, and KSHV), poxviruses (such as vaccinia virus (Modified
vaccinia virus Ankara) and Myxoma virus), adenoviruses (such as
Adenovirus 5), or papillomavirus), bacterial infections (e.g. from
Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis,
Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium
diptheriae, Clostridium tetani, Clostridium botulinum,
Streptococcus pneumoniae, Streptococcus pyogenes, Listeria
monocytogenes, Hemophilus influenzae, Pasteurella multicida,
Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium
leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria
meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii,
Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas
aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia
trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella
typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections
(e.g. from Candida or Aspergillus species), protozoan infections
(e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or
Trypanosomes), helminth infections (e.g. from schistosoma,
roundworms, tapeworms or flukes) and prion infections; [0100] (v)
central nervous system diseases such as Parkinson's disease,
Alzheimer's disease, dementia, motor neuron disease, Huntington's
disease, cerebral malaria, brain injury from pneumococcal
meningitis, intracranial aneurysms, traumatic brain injury, and
amyotrophic lateral sclerosis; [0101] (vi) metabolic diseases such
as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and
pseudo-gout; [0102] (vii) cardiovascular diseases such as
hypertension, ischaemia, reperfusion injury including post-MI
ischemic reperfusion injury, stroke including ischemic stroke,
transient ischemic attack, myocardial infarction including
recurrent myocardial infarction, heart failure including congestive
heart failure and heart failure with preserved ejection fraction,
embolism, aneurysms including abdominal aortic aneurysm, and
pericarditis including Dressler's syndrome; [0103] (viii)
respiratory diseases including chronic obstructive pulmonary
disorder (COPD), asthma such as allergic asthma and
steroid-resistant asthma, asbestosis, silicosis, nanoparticle
induced inflammation, cystic fibrosis and idiopathic pulmonary
fibrosis; [0104] (ix) liver diseases including non-alcoholic fatty
liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
including advanced fibrosis stages F3 and F4, alcoholic fatty liver
disease (AFLD), and alcoholic steatohepatitis (ASH); [0105] (x)
renal diseases including chronic kidney disease, oxalate
nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic
nephropathy; [0106] (xi) ocular diseases including those of the
ocular epithelium, age-related macular degeneration (AMD) (dry and
wet), uveitis, corneal infection, diabetic retinopathy, optic nerve
damage, dry eye, and glaucoma; [0107] (xii) skin diseases including
dermatitis such as contact dermatitis and atopic dermatitis,
contact hypersensitivity, sunburn, skin lesions, hidradenitis
suppurativa (HS), other cyst-causing skin diseases, and acne
conglobata; [0108] (xiii) lymphatic conditions such as lymphangitis
and Castleman's disease; [0109] (xiv) psychological disorders such
as depression and psychological stress; [0110] (xv) graft versus
host disease; [0111] (xvi) allodynia including mechanical
allodynia; and [0112] (xvii) any disease where an individual has
been determined to carry a germline or somatic non-silent mutation
in NLRP3.
[0113] In one embodiment, the disease, disorder or condition is
selected from: [0114] (i) cancer; [0115] (ii) an infection; [0116]
(iii) a central nervous system disease; [0117] (iv) a
cardiovascular disease; [0118] (v) a liver disease; [0119] (vi) an
ocular disease; or [0120] (vii) a skin disease.
[0121] More typically, the disease, disorder or condition is
selected from: [0122] (i) cancer; [0123] (ii) an infection; [0124]
(iii) a central nervous system disease; or [0125] (iv) a
cardiovascular disease.
[0126] In one embodiment, the disease, disorder or condition is
selected from: [0127] (i) acne conglobata; [0128] (ii) atopic
dermatitis; [0129] (iii) Alzheimer's disease; [0130] (iv)
amyotrophic lateral sclerosis; [0131] (v) age-related macular
degeneration (AMD); [0132] (vi) anaplastic thyroid cancer; [0133]
(vii) cryopyrin-associated periodic syndromes (CAPS); [0134] (viii)
contact dermatitis; [0135] (ix) cystic fibrosis; [0136] (x)
congestive heart failure; [0137] (xi) chronic kidney disease;
[0138] (xii) Crohn's disease; [0139] (xiii) familial cold
autoinflammatory syndrome (FCAS); [0140] (xiv) Huntington's
disease; [0141] (xv) heart failure; [0142] (xvi) heart failure with
preserved ejection fraction; [0143] (xvii) ischemic reperfusion
injury; [0144] (xviii) juvenile idiopathic arthritis; [0145] (xix)
myocardial infarction; [0146] (xx) macrophage activation syndrome;
[0147] (xxi) myelodysplastic syndrome; [0148] (xxii) multiple
myeloma; [0149] (xxiii) motor neuron disease; [0150] (xxiv)
multiple sclerosis; [0151] (xxv) Muckle-Wells syndrome; [0152]
(xxvi) non-alcoholic steatohepatitis (NASH); [0153] (xxvii)
neonatal-onset multisystem inflammatory disease (NOMID); [0154]
(xxviii) Parkinson's disease; [0155] (xxix) systemic juvenile
idiopathic arthritis; [0156] (xxx) systemic lupus erythematosus;
[0157] (xxxi) traumatic brain injury; [0158] (xxxii) transient
ischemic attack; and [0159] (xxxiii) ulcerative colitis.
[0160] In a further typical embodiment of the invention, the
disease, disorder or condition is inflammation. Examples of
inflammation that may be treated or prevented in accordance with
the fifth, sixth, seventh, eighth, ninth or tenth aspect of the
present invention include inflammatory responses occurring in
connection with, or as a result of: [0161] (i) a skin condition
such as contact hypersensitivity, bullous pemphigoid, sunburn,
psoriasis, atopical dermatitis, contact dermatitis, allergic
contact dermatitis, seborrhoetic dermatitis, lichen planus,
scleroderma, pemphigus, epidermolysis bullosa, urticaria,
erythemas, or alopecia; [0162] (ii) a joint condition such as
osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset
Still's disease, relapsing polychondritis, rheumatoid arthritis,
juvenile chronic arthritis, gout, or a seronegative
spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic
arthritis or Reiter's disease); [0163] (iii) a muscular condition
such as polymyositis or myasthenia gravis; [0164] (iv) a
gastrointestinal tract condition such as inflammatory bowel disease
(including Crohn's disease and ulcerative colitis), gastric ulcer,
coeliac disease, proctitis, pancreatitis, eosinopilic
gastro-enteritis, mastocytosis, antiphospholipid syndrome, or a
food-related allergy which may have effects remote from the gut
(e.g., migraine, rhinitis or eczema); [0165] (v) a respiratory
system condition such as chronic obstructive pulmonary disease
(COPD), asthma (including bronchial, allergic, intrinsic, extrinsic
or dust asthma, and particularly chronic or inveterate asthma, such
as late asthma and airways hyper-responsiveness), bronchitis,
rhinitis (including acute rhinitis, allergic rhinitis, atrophic
rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic
rhinitis, rhinitis pumlenta, rhinitis sicca, rhinitis
medicamentosa, membranous rhinitis, seasonal rhinitis e.g. hay
fever, and vasomotor rhinitis), sinusitis, idiopathic pulmonary
fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis,
adult respiratory distress syndrome, hypersensitivity pneumonitis,
or idiopathic interstitial pneumonia; [0166] (vi) a vascular
condition such as atherosclerosis, Behcet's disease, vasculitides,
or wegener's granulomatosis; [0167] (vii) an autoimmune condition
such as systemic lupus erythematosus, Sjogren's syndrome, systemic
sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic
thrombocytopenia purpura, or Graves disease; [0168] (viii) an
ocular condition such as uveitis, allergic conjunctivitis, or
vernal conjunctivitis; [0169] (ix) a nervous condition such as
multiple sclerosis or encephalomyelitis; [0170] (x) an infection or
infection-related condition, such as Acquired Immunodeficiency
Syndrome (AIDS), acute or chronic bacterial infection, acute or
chronic parasitic infection, acute or chronic viral infection,
acute or chronic fungal infection, meningitis, hepatitis (A, B or
C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis,
malaria, dengue hemorrhagic fever, leishmaniasis, Streptococcal
myositis, Mycobacterium tuberculosis, Mycobacterium avium
intracellulare, Pneumocystis carinii pneumonia,
orchitis/epidydimitis, legionella, Lyme disease, influenza A,
epstein-barr virus, viral encephalitis/aseptic meningitis, or
pelvic inflammatory disease; [0171] (xi) a renal condition such as
mesangial proliferative glomerulonephritis, nephrotic syndrome,
nephritis, glomerular nephritis, acute renal failure, uremia, or
nephritic syndrome; [0172] (xii) a lymphatic condition such as
Castleman's disease; [0173] (xiii) a condition of, or involving,
the immune system, such as hyper IgE syndrome, lepromatous leprosy,
familial hemophagocytic lymphohistiocytosis, or graft versus host
disease; [0174] (xiv) a hepatic condition such as chronic active
hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced
hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic
fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or
primary biliary cirrhosis; [0175] (xv) a cancer, including those
cancers listed above; [0176] (xvi) a burn, wound, trauma,
haemorrhage or stroke; [0177] (xvii) radiation exposure; and/or
[0178] (xviii) obesity; and/or [0179] (xix) pain such as
inflammatory hyperalgesia.
[0180] In one embodiment of the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention, the disease,
disorder or condition is an autoinflammatory disease such as
cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells
syndrome (MWS), familial cold autoinflammatory syndrome (FCAS),
familial Mediterranean fever (FMF), neonatal onset multisystem
inflammatory disease (NOMID), Tumour Necrosis Factor (TNF)
Receptor-Associated Periodic Syndrome (TRAPS),
hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),
deficiency of interleukin 1 receptor antagonist (DIRA), Majeed
syndrome, pyogenic arthritis, pyoderma gangrenosum and acne
syndrome (PAPA), adult-onset Still's disease (AOSD),
haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis
(PGA), PLCG2-associated antibody deficiency and immune
dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody
deficiency and immune dysregulation (APLAID), or sideroblastic
anaemia with B-cell immunodeficiency, periodic fevers and
developmental delay (SIFD).
[0181] Examples of diseases, disorders or conditions which may be
responsive to NLRP3 inhibition and which may be treated or
prevented in accordance with the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention are listed above.
Some of these diseases, disorders or conditions are substantially
or entirely mediated by NLRP3 inflammasome activity, and
NLRP3-induced IL-1.beta. and/or IL-18. As a result, such diseases,
disorders or conditions may be particularly responsive to NLRP3
inhibition and may be particularly suitable for treatment or
prevention in accordance with the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention. Examples of such
diseases, disorders or conditions include cryopyrin-associated
periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial
cold autoinflammatory syndrome (FCAS), neonatal onset multisystem
inflammatory disease (NOMID), familial Mediterranean fever (FMF),
pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA),
hyperimmunoglobulinemia D and periodic fever syndrome (RIDS),
Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome
(TRAPS), systemic juvenile idiopathic arthritis, adult-onset
Still's disease (AOSD), relapsing polychondritis, Schnitzler's
syndrome, Sweet's syndrome, Behcet's disease, anti-synthetase
syndrome, deficiency of interleukin 1 receptor antagonist (DIRA),
and haploinsufficiency of A20 (HA20).
[0182] Moreover, some of the diseases, disorders or conditions
mentioned above arise due to mutations in NLRP3, in particular,
resulting in increased NLRP3 activity. As a result, such diseases,
disorders or conditions may be particularly responsive to NLRP3
inhibition and may be particularly suitable for treatment or
prevention in accordance with the fifth, sixth, seventh, eighth,
ninth or tenth aspect of the present invention. Examples of such
diseases, disorders or conditions include cryopyrin-associated
periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial
cold autoinflammatory syndrome (FCAS), and neonatal onset
multisystem inflammatory disease (NOMID).
[0183] An eleventh aspect of the invention provides a method of
inhibiting NLRP3, the method comprising the use of a salt, hydrate
or solvate of the first aspect of the invention, a polymorphic form
of the second aspect of the invention, or a pharmaceutical
composition of the fourth aspect of the invention, to inhibit
NLRP3.
[0184] In one embodiment of the eleventh aspect of the present
invention, the method comprises the use of a salt, hydrate or
solvate of the first aspect of the invention, a polymorphic form of
the second aspect of the invention, or a pharmaceutical composition
of the fourth aspect of the invention, in combination with one or
more further active agents.
[0185] In one embodiment of the eleventh aspect of the present
invention, the method is performed ex vivo or in vitro, for example
in order to analyse the effect on cells of NLRP3 inhibition.
[0186] In another embodiment of the eleventh aspect of the present
invention, the method is performed in vivo. For example, the method
may comprise the step of administering an effective amount of a
salt, hydrate or solvate of the first aspect of the invention, a
polymorphic form of the second aspect of the invention, or a
pharmaceutical composition of the fourth aspect of the invention,
to thereby inhibit NLRP3. In one embodiment, the method further
comprises the step of co-administering an effective amount of one
or more further active agents. Typically, the administration is to
a subject in need thereof.
[0187] Alternately, the method of the eleventh aspect of the
invention may be a method of inhibiting NLRP3 in a non-human animal
subject, the method comprising the steps of administering the salt,
hydrate, solvate, polymorphic form or pharmaceutical composition to
the non-human animal subject and optionally subsequently mutilating
or sacrificing the non-human animal subject. Typically, such a
method further comprises the step of analysing one or more tissue
or fluid samples from the optionally mutilated or sacrificed
non-human animal subject. In one embodiment, the method further
comprises the step of co-administering an effective amount of one
or more further active agents.
[0188] A twelfth aspect of the invention provides a salt, hydrate
or solvate of the first aspect of the invention, a polymorphic form
of the second aspect of the invention, or a pharmaceutical
composition of the fourth aspect of the invention, for use in the
inhibition of NLRP3. Typically, the use comprises the
administration of the salt, hydrate, solvate, polymorphic form or
pharmaceutical composition to a subject. In one embodiment, the
salt, hydrate, solvate, polymorphic form or pharmaceutical
composition is co-administered with one or more further active
agents.
[0189] A thirteenth aspect of the invention provides the use of a
salt, hydrate or solvate of the first aspect of the invention or a
polymorphic form of the second aspect of the invention, in the
manufacture of a medicament for the inhibition of NLRP3. Typically,
the inhibition comprises the administration of the salt, hydrate,
solvate, polymorphic form or medicament to a subject. In one
embodiment, the salt, hydrate, solvate, polymorphic form or
medicament is co-administered with one or more further active
agents.
[0190] In any embodiment of any of the fifth to thirteenth aspects
of the present invention that comprises the use or
co-administration of one or more further active agents, the one or
more further active agents may comprise for example one, two or
three different further active agents.
[0191] The one or more further active agents may be used or
administered prior to, simultaneously with, sequentially with or
subsequent to each other and/or to the salt, hydrate or solvate of
the first aspect of the invention, the polymorphic form of the
second aspect of the invention, or the pharmaceutical composition
of the fourth aspect of the invention. Where the one or more
further active agents are administered simultaneously with the
salt, hydrate, solvate, polymorphic form or pharmaceutical
composition of the present invention, a pharmaceutical composition
of the fourth aspect of the invention may be administered wherein
the pharmaceutical composition additionally comprises the one or
more further active agents.
[0192] In one embodiment of any of the fifth to thirteenth aspects
of the present invention that comprises the use or
co-administration of one or more further active agents, the one or
more further active agents are selected from: [0193] (i)
chemotherapeutic agents; [0194] (ii) antibodies; [0195] (iii)
alkylating agents; [0196] (iv) anti-metabolites; [0197] (v)
anti-angiogenic agents; [0198] (vi) plant alkaloids and/or
terpenoids; [0199] (vii) topoisomerase inhibitors; [0200] (viii)
mTOR inhibitors; [0201] (ix) stilbenoids; [0202] (x) STING
agonists; [0203] (xi) cancer vaccines; [0204] (xii)
immunomodulatory agents; [0205] (xiii) antibiotics; [0206] (xiv)
anti-fungal agents; [0207] (xv) anti-helminthic agents; and/or
[0208] (xvi) other active agents.
[0209] It will be appreciated that these general embodiments
defined according to broad categories of active agents are not
mutually exclusive. In this regard any particular active agent may
be categorized according to more than one of the above general
embodiments. A non-limiting example is urelumab which is an
antibody that is an immunomodulatory agent for the treatment of
cancer.
[0210] In some embodiments, the one or more chemotherapeutic agents
are selected from abiraterone acetate, altretamine, amsacrine,
anhydrovinblastine, auristatin, azathioprine, adriamycin,
bexarotene, bicalutamide, BMS 184476, bleomycin,
N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butyla-
mide, cisplatin, carboplatin, carboplatin cyclophosphamide,
chlorambucil, cachectin, cemadotin, cyclophosphamide, carmustine,
cryptophycin, cytarabine, docetaxel, doxetaxel, doxorubicin,
dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine,
dolastatin, etoposide, etoposide phosphate, enzalutamide (MDV3100),
5-fluorouracil, fludarabine, flutamide, gemcitabine, hydroxyurea
and hydroxyureataxanes, idarubicin, ifosfamide, irinotecan,
leucovorin, lonidamine, lomustine (CCNU), larotaxel (RPR109881),
mechlorethamine, mercaptopurine, methotrexate, mitomycin C,
mitoxantrone, melphalan, mivobulin,
3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine, nilutamide,
oxaliplatin, onapristone, prednimustine, procarbazine, paclitaxel,
platinum-containing anti-cancer agents,
2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene
sulfonamide, prednimustine, procarbazine, rhizoxin, sertenef,
streptozocin, stramustine phosphate, tretinoin, tasonermin, taxol,
topotecan, tamoxifen, teniposide, taxane, tegafur/uracil,
vincristine, vinblastine, vinorelbine, vindesine, vindesine
sulfate, and/or vinflunine.
[0211] Alternatively or in addition, the one or more
chemotherapeutic agents may be selected from CD59 complement
fragment, fibronectin fragment, gro-beta (CXCL2), heparinases,
heparin hexasaccharide fragment, human chorionic gonadotropin
(hCG), interferon alpha, interferon beta, interferon gamma,
interferon inducible protein (IP-10), interleukin-12, kringle 5
(plasminogen fragment), metalloproteinase inhibitors (TIMPs),
2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen
activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD
fragment, proliferin-related protein (PRP), various retinoids,
tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth
factor-beta (TGF-.beta.), vasculostatin, vasostatin (calreticulin
fragment), and/or cytokines (including interleukins, such as
interleukin-2 (IL-2), or IL-10).
[0212] In some embodiments, the one or more antibodies may comprise
one or more monoclonal antibodies. In some embodiments, the one or
more antibodies are selected from abciximab, adalimumab,
alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab,
bretuximab vedotin, canakinumab, cetuximab, ceertolizumab pegol,
daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab,
golimumab, ibritumomab tiuxetan, infliximab, ipilimumab,
muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab,
panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab,
and/or trastuzumab.
[0213] In some embodiments, the one or more alkylating agents may
comprise an agent capable of alkylating nucleophilic functional
groups under conditions present in cells, including, for example,
cancer cells. In some embodiments, the one or more alkylating
agents are selected from cisplatin, carboplatin, mechlorethamine,
cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In
some embodiments, the alkylating agent may function by impairing
cell function by forming covalent bonds with amino, carboxyl,
sulfhydryl, and/or phosphate groups in biologically important
molecules. In some embodiments, the alkylating agent may function
by modifying a cell's DNA.
[0214] In some embodiments, the one or more anti-metabolites may
comprise an agent capable of affecting or preventing RNA or DNA
synthesis. In some embodiments, the one or more anti-metabolites
are selected from azathioprine and/or mercaptopurine.
[0215] In some embodiments, the one or more anti-angiogenic agents
are selected from endostatin, angiogenin inhibitors, angiostatin,
angioarrestin, angiostatin (plasminogen fragment),
basement-membrane collagen-derived anti-angiogenic factors
(tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin.
III, and/or cartilage-derived inhibitor (CDI).
[0216] In some embodiments, the one or more plant alkaloids and/or
terpenoids may prevent microtubule function. In some embodiments,
the one or more plant alkaloids and/or terpenoids are selected from
a vinca alkaloid, a podophyllotoxin and/or a taxane. In some
embodiments, the one or more vinca alkaloids may be derived from
the Madagascar periwinkle, Catharanthus roseus (formerly known as
Vinca rosea), and may be selected from vincristine, vinblastine,
vinorelbine and/or vindesine. In some embodiments, the one or more
taxanes are selected from taxol, paclitaxel, docetaxel and/or
ortataxel. In some embodiments, the one or more podophyllotoxins
are selected from an etoposide and/or teniposide.
[0217] In some embodiments, the one or more topoisomerase
inhibitors are selected from a type I topoisomerase inhibitor
and/or a type H topoisomerase inhibitor, and may interfere with
transcription and/or replication of DNA by interfering with DNA
supercoiling. In some embodiments, the one or more type I
topoisomerase inhibitors may comprise a camptothecin, which may be
selected from exatecan, irinotecan, lurtotecan, topotecan, BNP
1350, CKD 602, DB 67 (AR67) and/or ST 1481. In some embodiments,
the one or more type H topoisomerase inhibitors may comprise an
epipodophyllotoxin, which may be selected from an amsacrine,
etoposid, etoposide phosphate and/or teniposide.
[0218] In some embodiments, the one or more mTOR (mammalian target
of rapamycin, also known as the mechanistic target of rapamycin)
inhibitors are selected from rapamycin, everolimus, temsirolimus
and/or deforolimus.
[0219] In some embodiments, the one or more stilbenoids are
selected from resveratrol, piceatannol, pinosylvin, pterostilbene,
alpha-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C,
diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin H,
hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin,
piceid and/or diptoindonesin A.
[0220] In some embodiments, the one or more STING (Stimulator of
interferon genes, also known as transmembrane protein (TMEM) 173)
agonists may comprise cyclic di-nucleotides, such as cAMP, cGMP,
and cGAMP, and/or modified cyclic di-nucleotides that may include
one or more of the following modification features: 2'-O/3'-O
linkage, phosphorothioate linkage, adenine and/or guanine analogue,
and/or 2'-OH modification (e.g. protection of the 2'-OH with a
methyl group or replacement of the 2'-OH by --F or --N.sub.3).
[0221] In some embodiments, the one or more cancer vaccines are
selected from an HPV vaccine, a hepatitis B vaccine, Oncophage,
and/or Provenge.
[0222] In some embodiments, the one or more immunomodulatory agents
may comprise an immune checkpoint inhibitor. The immune checkpoint
inhibitor may target an immune checkpoint receptor, or combination
of receptors comprising, for example, CTLA-4, PD-1, PD-L1, PD-L2, T
cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9,
phosphatidylserine, lymphocyte activation gene 3 protein (LAGS),
MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL,
CD27, CD70, TNFRSF25, TL1A, CD40, CD40L, HVEM, LIGHT, BTLA, CD160,
CD80, CD244, CD48, ICOS, ICOSL, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2,
TMIGD2, a butyrophilin (including BTNL2), a Siglec family member,
TIGIT, PVR, a killer-cell immunoglobulin-like receptor, an ILT, a
leukocyte immunoglobulin-like receptor, NKG2D, NKG2A, MICA, MICB,
CD28, CD86, SIRPA, CD47, VEGF, neuropilin, CD30, CD39, CD73, CXCR4,
and/or CXCL12.
[0223] In some embodiments, the immune checkpoint inhibitor is
selected from urelumab, PF-05082566, MEDI6469, TRX518, varlilumab,
CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab
(formerly MPDL3280A) (PD-Li), MEDI4736 (PD-Li), avelumab (PD-Li),
PDRooi (PM), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab,
INCBo24360, galunisertib, ulocuplumab, BKT140, bavituximab,
CC-90002, bevacizumab, and/or MNRP1685A.
[0224] In some embodiments, the one or more antibiotics are
selected from amikacin, gentamicin, kanamycin, neomycin,
netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin,
geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem,
doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin,
cefalotin, cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin,
cefprozil, cefuroxime, cefixime, cefdinir, cefditoren,
cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,
ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil,
ceftobiprole, teicoplanin, vancomycin, telavancin, dalbavancin,
oritavancin, clindamycin, lincomycin, daptomycin, azithromycin,
clarithromycin, dirithromycin, erythromycin, roxithromycin,
troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone,
nitrofurantoin, linezolid, posizolid, radezolid, torezolid,
amoxicillin, ampicillin, Yo azlocillin, carbenicillin, cloxacillin,
dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin,
oxacillin, penicillin G, penicillin V, piperacillin, temocillin,
ticarcillin, calvulanate, ampicillin, subbactam, tazobactam,
ticarcillin, clavulanate, bacitracin, colistin, polymyxin B,
ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin,
lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin,
trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide,
sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine,
sulfamethoxazole, sulfanamide, sulfasalazine, sulfisoxazole,
trimethoprim-sulfamethoxazole, sulfonamideochrysoidine,
demeclocycline, minocycline, oytetracycline, tetracycline,
clofazimine, dapsone, dapreomycin, cycloserine, ethambutol,
ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin,
rifapentine, streptomycin, arsphenamine, chloramphenicol,
fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin,
quinupristin, dalopristin, thiamphenicol, tigecycyline, tinidazole,
trimethoprim, and/or teixobactin.
[0225] In some embodiments, the one or more antibiotics may
comprise one or more cytotoxic antibiotics. In some embodiments,
the one or more cytotoxic antibiotics are selected from an
actinomycin, an anthracenedione, an anthracycline, thalidomide,
dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or
chlofazimine. In some embodiments, the one or more actinomycins are
selected from actinomycin D, bacitracin, colistin (polymyxin E)
and/or polymyxin B. In some embodiments, the one or more
antracenediones are selected from mitoxantrone and/or pixantrone.
In some embodiments, the one or more anthracyclines are selected
from bleomycin, doxorubicin (Adriamycin), daunorubicin
(daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or
valrubicin.
[0226] In some embodiments, the one or more anti-fungal agents are
selected from bifonazole, butoconazole, clotrimazole, econazole,
ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole,
sertaconazole, sulconazole, tioconazole, albaconazole,
efinaconazole, epoziconazole, fluconazole, isavuconazole,
itraconazole, posaconazole, propiconazole, ravusconazole,
terconazole, voriconazole, abafungin, amorolfin, butenafine,
naftifine, terbinafine, anidulafungin, caspofungin, micafungin,
benzoic acid, ciclopirox, flucytosine, 5-fluorocytosine,
griseofulvin, haloprogin, tolnaflate, undecylenic acid, and/or
balsam of Peru.
[0227] In some embodiments, the one or more anti-helminthic agents
are selected from benzimidazoles (including albendazole,
mebendazole, thiabendazole, fenbendazole, triclabendazole, and
flubendazole), abamectin, diethylcarbamazine, ivermectin, suramin,
pyrantel pamoate, levamisole, salicylanilides (including
niclosamide and oxyclozanide), and/or nitazoxanide.
[0228] In some embodiments, other active agents are selected from
growth inhibitory agents, anti-inflammatory agents (including
nonsteroidal anti-inflammatory agents), anti-psoriatic agents
(including anthralin and its derivatives), vitamins and
vitamin-derivatives (including retinoinds, and VDR receptor
ligands), corticosteroids, ion channel blockers (including
potassium channel blockers), immune system regulators (including
cyclosporin, FK 506, and glucocorticoids), lutenizing hormone
releasing hormone agonists (such as leuprolidine, goserelin,
triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide),
and/or hormones (including estrogen).
[0229] Unless stated otherwise, in any of the fifth to thirteenth
aspects of the invention, the subject may be any human or other
animal. Typically, the subject is a mammal, more typically a human
or a domesticated mammal such as a cow, pig, lamb, sheep, goat,
horse, cat, dog, rabbit, mouse etc. Most typically, the subject is
a human.
[0230] Any of the medicaments employed in the present invention can
be administered by oral, parenteral (including intravenous,
subcutaneous, intramuscular, intradermal, intratracheal,
intraperitoneal, intraarticular, intracranial and epidural), airway
(aerosol), rectal, vaginal, ocular or topical (including
transdermal, buccal, mucosal, sublingual and topical ocular)
administration.
[0231] Typically, the mode of administration selected is that most
appropriate to the disorder, disease or condition to be treated or
prevented. Where one or more further active agents are
administered, the mode of administration may be the same as or
different to the mode of administration of the salt, hydrate,
solvate, polymorphic form or pharmaceutical composition of the
invention.
[0232] For oral administration, the salt, hydrate, solvate,
polymorphic form or pharmaceutical composition of the present
invention will generally be provided in the form of tablets,
capsules, hard or soft gelatine capsules, caplets, troches or
lozenges, as a powder or granules, or as an aqueous solution,
suspension or dispersion.
[0233] Tablets for oral use may include the active ingredient mixed
with pharmaceutically acceptable excipients such as inert diluents,
disintegrating agents, binding agents, lubricating agents,
sweetening agents, flavouring agents, colouring agents and
preservatives. Suitable inert diluents include sodium and calcium
carbonate, sodium and calcium phosphate, and lactose. Corn starch
and alginic acid are suitable disintegrating agents. Binding agents
may include starch and gelatine. The lubricating agent, if present,
may be magnesium stearate, stearic acid or talc. If desired, the
tablets may be coated with a material, such as glyceryl
monostearate or glyceryl distearate, to delay absorption in the
gastrointestinal tract. Tablets may also be effervescent and/or
dissolving tablets.
[0234] Capsules for oral use include hard gelatine capsules in
which the active ingredient is mixed with a solid diluent, and soft
gelatine capsules wherein the active ingredient is mixed with water
or an oil such as peanut oil, liquid paraffin or olive oil.
[0235] Powders or granules for oral use may be provided in sachets
or tubs. Aqueous solutions, suspensions or dispersions may be
prepared by the addition of water to powders, granules or
tablets.
[0236] Any form suitable for oral administration may optionally
include sweetening agents such as sugar, flavouring agents,
colouring agents and/or preservatives.
[0237] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising, for example, cocoa
butter or a salicylate.
[0238] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0239] For parenteral use, the salt, hydrate, solvate or
polymorphic form of the present invention will generally be
provided in a sterile aqueous solution or suspension, buffered to
an appropriate pH and isotonicity. Suitable aqueous vehicles
include Ringer's solution and isotonic sodium chloride or glucose.
Aqueous suspensions according to the invention may include
suspending agents such as cellulose derivatives, sodium alginate,
polyvinylpyrrolidone and gum tragacanth, and a wetting agent such
as lecithin. Suitable preservatives for aqueous suspensions include
ethyl and n-propyl p-hydroxybenzoate. The salt, hydrate, solvate,
polymorphic form or pharmaceutical xo composition of the invention
may also be presented as a liposome formulation.
[0240] For ocular administration, the salt, hydrate, solvate or
polymorphic form of the invention will generally be provided in a
form suitable for topical administration, e.g. as eye drops.
Suitable forms may include ophthalmic solutions, gel-forming
solutions, sterile powders for reconstitution, ophthalmic
suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic
gels and ocular inserts. Alternatively, the salt, hydrate, solvate
or polymorphic form of the invention may be provided in a form
suitable for other types of ocular administration, for example as
intraocular preparations (including as irrigating solutions, as
intraocular, intravitreal or juxtascleral injection formulations,
or as intravitreal implants), as packs or corneal shields, as
intracameral, subconjunctival or retrobulbar injection
formulations, or as iontophoresis formulations.
[0241] For transdermal and other topical administration, the salt,
hydrate, solvate, polymorphic form or pharmaceutical composition of
the invention will generally be provided in the form of ointments,
cataplasms (poultices), pastes, powders, dressings, creams,
plasters or patches.
[0242] Suitable suspensions and solutions can be used in inhalers
for airway (aerosol) administration.
[0243] The dose of the salt, hydrate, solvate or polymorphic form
of the present invention will, of course, vary with the disease,
disorder or condition to be treated or prevented. In general, a
suitable dose will be in the range of 0.01 to 500 mg per kilogram
body weight of the recipient per day. The desired dose may be
presented at an appropriate interval such as once every other day,
once a day, twice a day, three times a day or four times a day. The
desired dose may be administered in unit dosage form, for example,
containing 1 mg to 50 g of active ingredient per unit dosage
form.
[0244] For the avoidance of doubt, insofar as is practicable any
embodiment of a given aspect of the present invention may occur in
combination with any other embodiment of the same aspect of the
present invention. In addition, insofar as is practicable it is to
be understood that any preferred, typical or optional embodiment of
any aspect of the present invention should also be considered as a
preferred, typical or optional embodiment of any other aspect of
the present invention.
EXAMPLES
[0245] All solvents, reagents and compounds were purchased and used
without further purification unless stated otherwise.
[0246] X-Ray Powder Diffraction (XRPD), Ion Chromatography (IC),
Karl Fischer titration (KF), Thermogravimetric Analysis (TGA),
Differential Scanning calorimetry (DSC) and high performance liquid
chromatography (HPLC) techniques referred to in the examples were
carried out under the following conditions:
[0247] XRPD diffractograms were collected on a Bruker D8
diffractometer using CuK.alpha. radiation (40 kV, 40 mA) and a
.theta.-2.theta. goniometer fitted with a Ge monochromator. The
incident beam passed through a 2.0 mm divergence slit followed by a
0.2 mm antiscatter slit and knife edge. The diffracted beam passed
through an 8.0 mm receiving slit with 2.5.degree. Soller slits
followed by the Lynxeye Detector. The software used for data
collection and analysis was Diffrac Plus XRD Commander and Diffrac
Plus EVA respectively. Samples were run under ambient conditions as
flat plate specimens using powder as received. The sample was
prepared on a polished, zero-background (510) silicon wafer by
gently pressing onto the flat surface or packed into a cut cavity.
The sample was rotated in its own plane. The details of the s data
collection method used are: [0248] Angular range: 2 to 42.degree.
2.theta. [0249] Step size: 0.05.degree. 2.theta. [0250] Collection
time: 0.5 s/step (total collection time: 6.40 min)
[0251] IC data were collected on a Metrohm 930 Compact IC Flex with
858 Professional autosampler and 800 Dosino dosage unit monitor,
using IC MagicNet software.
[0252] Accurately weighed samples were prepared as stock solutions
in a suitable solvent. Quantification was achieved by comparison
with standard solutions of known concentration of the ion being
analysed. Analyses were performed in duplicate and an average of
the values is given unless otherwise stated.
IC Method for Cation Chromatography
TABLE-US-00003 [0253] Parameter Value Type of method Cation
exchange Column Metrosep C 4-250 (4.0 .times. 250 mm) Column
Temperature (.degree. C.) Ambient Injection (.mu.l) Various
Detection Conductivity detector Flow Rate (ml/min) 0.9 Eluent 1.7
mM nitric acid 0.7 mM dipicolinic acid in a 5% acetone aqueous
solution
IC Method for Anion Chromatography
TABLE-US-00004 [0254] Parameter Value Type of method Anion exchange
Column Metrosep A Supp 5-150 (4.0 .times. 350 mm) Column
Temperature (.degree. C.) Ambient Injection (.mu.l) Various
Detection Conductivity detector Flow Rate (ml/min) 0.7 Eluent 3.2
mM sodium carbonate 1.0 mM sodium hydrogen carbonate in a 5%
acetone aqueous solution
[0255] KF analysis was carried out on a Metrohm 874 Oven Sample
Processor at 150.degree. C. with 851 Titrano Coulometer using
Hydranal Coulomat AG oven reagent and nitrogen purge. Weighed solid
samples were introduced into a sealed sample vial. Approximately 10
mg of sample was used per titration and duplicate determinations
were made. An average of these results is presented unless
otherwise stated. Data collection and analysis were performed using
Tiamo software.
[0256] TGA data were collected on a TA Instruments Discovery TGA,
equipped with a 25 position auto-sampler. Typically, 5-10 mg of
each sample was loaded onto a pre-tared aluminium DSC pan and
heated at 10.degree. C./min from ambient temperature to 350.degree.
C. A nitrogen purge at 25 ml/min was maintained over the sample.
The instrument control software was TRIOS and the data were
analysed using TRIOS or Universal Analysis.
[0257] DSC data were collected on a TA Instruments Q2000 equipped
with a 50 position auto-sampler. Typically, 0.5-3 mg of each
sample, in a pin-holed aluminium pan, was heated at 10.degree.
C./min from 25.degree. C. to 300.degree. C. A purge of dry nitrogen
at 50 ml/min was maintained over the sample. Modulated temperature
DSC was carried out using an underlying heating rate of 2.degree.
C./min and temperature modulation parameters of .+-.0.636.degree.
C. (amplitude) every 60 seconds (period). The instrument control
software was Advantage for Q Series and Thermal Advantage and the
data were analysed using Universal Analysis or TRIOS.
[0258] Reversed phase HPLC purity analysis was performed on an
Agilent HP1100 series system equipped with a diode array detector
and using ChemStation software.
HPLC Method for Chemical Purity Determinations
TABLE-US-00005 [0259] Parameter Value Type of method Reversed phase
with gradient elution Sample Preparation General: 0.5 mg/ml in
acetonitrile: water 1:1 Forced degradation study: 0.2 & 0.5
mg/ml in various media Column Supelco Ascentis Express C18, 100
.times. 4.6 mm, 2.7 .mu.m Column Temperature (.degree. C.) 25
Injection (.mu.l) 5 Wavelength, Bandwidth (nm) 255, 90 Flow Rate
(ml/min) 2 Phase A 0.1% TFA in water Phase B 0.085% TFA in
acetonitrile Timetable (min) % Phase A % Phase B 0 95 5 6 5 95 6.2
95 5 8 95 5
Example 1:
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-
-1H-pyrazole-3-sulfonamide monosodium monohydrate (Form 1)
[0260]
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H--
pyrazole-3-sulfonamide free acid was weighed into four vials (50 mg
per vial). NaOH (1M in water) (see Table 3 for equivalents/volume
added) and water (4 ml) were added to each of the sample vials. The
conditions that these samples were subjected to are summarised in
Table 3. The samples remained stirring in solution for 3 hours.
Then it was attempted to remove the water by rotary evaporator, but
after 3 hours the amount of water removed was very small. The
solutions were then spread on glass slides to evaporate at room
temperature. The solids formed were collected and analysed by XRPD,
.sup.1H-NMR, HPLC, IC and KF. IC and KF analysis confirmed
formation of the monosodium salt, monohydrate. XRPD analysis
confirmed formation of the Form 1 polymorph.
TABLE-US-00006 TABLE 3 Example Reaction conditions HPLC purity 1A
1.1 eq. NaOH (142 .mu.l) 97.1% kept at RT 1B 1.0 eq. NaOH (129
.mu.l) 96.8% addition of base at 50.degree. C., then cooling to
5.degree. C. immediately 1C 1.0 eq. NaOH (129 .mu.l) 96.7% addition
of base at 40.degree. C., then cooling to 5.degree. C. immediately
1D 1.0 eq. NaOH (129 .mu.l) 96.7% addition of base at 25.degree. C.
for 1 hour, then cooling to 5.degree. C.
Example 2:
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-
-1H-pyrazole-3-sulfonamide monosodium monohydrate (Form 1)
[0261]
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H--
pyrazole-3-sulfonamide free acid (50 mg) was treated with a 9:1
(v:v) solvent mixture of acetone and water (0.5 ml). The resulting
suspension was stirred at 25.degree. C. before NaOEt (1.1 eq, EtOH
solution) was added. Further NaOEt solution was added until
complete dissolution (total 1.3 eq NaOEt). t-Butyl methyl ether
antisolvent (0.25 ml) was added to each sample prior to seeds of
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide monosodium monohydrate Form 1 polymorph
(.about.2-4%). Further t-butyl methyl ether antisolvent was added
to give a final solvent: antisolvent ratio of 1:3 (example 2A) and
1:5 (example 2B). The samples were then stirred at 25.degree. C.
for 2 hours prior to isolation of the solids through a PE frit. The
samples were then stored under vacuum at room temperature for 18
hours followed by analysis by XRPD, .sup.1H-NMR, HPLC, IC, KF, TGA
and DSC.
TABLE-US-00007 TABLE 4 Example Final solvent:antisolvent ratio
Yield HPLC purity 2A 1:3 34% 98.1% 2B 1:5 85% 97.6%
[0262] IC and KF analysis confirmed formation of the monosodium
salt, monohydrate. XRPD analysis confirmed formation of the Form 1
polymorph. XRPD spectra are shown in FIG. 1. TGA and DSC spectra
are shown in FIG. 2.
[0263] The XRPD spectra shown in FIG. 1 were obtained directly
after preparation of the product, after storage for 1 week and for
5 weeks at 40.degree. C. and 75% relative humidity, and after
storage for 1 week and for 5 weeks at 25.degree. C. and 97%
relative humidity. The XRPD spectra shown in FIG. 1 indicate that
the product obtained in Example 2 shows stability with respect to
conversion into other polymorphic forms after storage at elevated
temperature and humidity.
Example 3:
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-
-1H-pyrazole-3-sulfonamide monosodium anhydrate (Form 2)
[0264]
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H--
pyrazole-3-sulfonamide monosodium salt (500 mg) was treated with a
10:1 (v:v) solvent mixture of isopropyl alcohol and H.sub.2O (30
ml), and the reaction mixture was left stirring at 25.degree. C.
for 30 minutes. The resulting clear solution was then evaporated to
produce a crystalline solid, which was analysed by XRPD,
.sup.1H-NMR, HPLC, IC, KF, TGA and DSC.
[0265] IC and KF analysis confirmed formation of the monosodium
salt, anhydrate. The HPLC purity was 96.5%. XRPD analysis confirmed
formation of the Form 2 polymorph. XRPD spectra are shown in FIG.
3. TGA and DSC spectra are shown in FIG. 4.
[0266] The XRPD spectra shown in FIG. 3 were obtained directly
after preparation of the product, after storage for 1 week at
40.degree. C. and 75% relative humidity, and after storage for 1
week at 25.degree. C. and 97% relative humidity. FIG. 3 also shows
the XRPD spectrum for Form 1 polymorph for reference. The XRPD
spectra shown in FIG. 3 indicate that the monosodium anhydrite
(Form 2) obtained in Example 3 is stable at elevated temperature
(40.degree. C.), and converts to the monosodium monohydrate (Form
1) at elevated humidity (97% RH).
Comparative Example 1:
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-1-sulfonamide free acid
[0267]
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H--
pyrazole-3-sulfonamide free acid was prepared as described in WO
2016/131098 A1.
Comparative Example 2:
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazo-
le-3-sulfonamide potassium salt
[0268]
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H--
pyrazole-3-sulfonamide free acid (100 mg) was weighed out and KOH
(1.1 eq, 1M aqueous solution, 283 .mu.l) was added. Water was added
and the reaction mixture was stirred at room temperature until a
clear solution was obtained. The reaction mixture was left stirring
for 2 hours, and then the water was removed by rotary evaporation
overnight to produce a solid, which was analysed by XRPD, HPLC and
IC.
[0269] IC analysis confirmed formation of the potassium salt. The
HPLC purity was 96.3%. XRPD analysis revealed a fully amorphous
material with no distinct diffraction peaks.
[0270] Attempts to convert the potassium salt into a crystalline
substance by evaporation from acetonitrile or isopropyl alcohol
were not successful, producing a gum in each case.
Evaluation Example 1
[0271] The sodium salt of Example 2 and the free acid of
Comparative Example 1 were evaluated for solubility in water,
stability in aqueous media and intrinsic dissolution rate. The
results are set out in Table 5.
TABLE-US-00008 TABLE 5 Comparative Analysis Example 2 Example 1
Aqueous Solubility 81 mg/ml <0.5 mg/ml Stability in aqueous
media No significant 37% degradation (24 hrs at room temperature)
degradation Stability in aqueous media 2.7% degradation 94%
degradation (24 hrs at 50.degree. C.) Intrinsic dissolution rate 10
.mu.g/min mm.sup.2 4 .mu.g/min mm.sup.2 (at pH 2)
[0272] The thermodynamic aqueous solubility was measured in water.
The sodium salt was found to be soluble in water (81 mg/ml) with a
resulting pH of 9.7. The free acid was found to be very poorly
soluble in water (<0.5 mg/ml).
[0273] To measure the stability in aqueous media, the sodium salt
was dissolved in water at a concentration of 0.2 mg/ml. Due to the
very poor aqueous solubility of the free acid, the free acid was
dissolved in a 1:1 mixture of water and acetonitrile at the same
concentration of 0.2 mg/ml. Samples were kept at 50.degree. C. in
an amber vial and at room temperature in an amber vial as well as a
clear vial. The sodium salt was found to be stable in aqueous
media, whereas the free acid was found to be unstable.
[0274] The intrinsic dissolution rate was measured by the procedure
set out in the US Pharmacopoeia, chapter 1087. The intrinsic
dissolution rate of the sodium salt was found to be at least twice
as high as that of the free acid.
[0275] The sodium salts of Examples 1, 2 and 3 have improved
properties as compared to the free acid and potassium salt of
Comparative Examples 1 and 2. These improved properties include
crystallinity, aqueous solubility, intrinsic dissolution rate,
stability under storage at elevated temperature and/or relative
humidity, and stability in aqueous media.
[0276] It will be understood that the present invention has been
described above by way of example only. The examples are not
intended to limit the scope of the invention. Various modifications
and embodiments can be made without departing from the scope and
spirit of the invention, which is defined by the following claims
only.
* * * * *