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-pyrazole-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.

1 . A sodium salt of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-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-pyrazole-3-sulfonamide monohydrate. 
     
     
         6 . A polymorphic form of the salt of  claim 5 , having an XRPD spectrum comprising peaks at approximately: 4.3°2θ, 8.7°2θ, and 20.6°2θ. 
     
     
         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 2θ value selected from: 4.3°2θ, 6.2°2θ, 6.7°2θ, 7.3°2θ, 8.7°2θ, 9.0°2θ, 12.1°2θ, 15.8°2θ, 16.5°2θ, 18.0°2θ, 18.1°2θ, 20.6°2θ, 21.6°2θ, and 24.5°2θ. 
     
     
         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-pyrazole-3-sulfonamide, comprising:
 (a) contacting N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-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-pyrazole-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-pyrazole-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-pyrazole-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-pyrazole-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-pyrazole-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-pyrazole-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-pyrazole-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)