Polymorphs of phenyl pyrrole aminoguandium salts

Abstract

The present disclosure relates to crystalline forms of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salts having high solubility. The disclosure also relates to use of said crystalline forms in medicine.

What is claimed is: 
     
         1 . A crystalline Form of an N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt selected from the group consisting of:
 i. a crystalline Form A of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 11.5±0.2, 23.5±0.2, and 27.0±0.2,   ii. a crystalline Form B of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium succinate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 9.7±0.2, 22.8±0.2, and 26.7±0.2,   iii. a crystalline Form C of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium tosylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 14.5±0.2, 21.0±0.2, and 25.2±0.2,   iv. a crystalline Form D of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium fumarate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 17.6±0.2, 21.2±0.2, and 26.3±0.2,   v. a crystalline Form I of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate exhibiting X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 23.5±0.2, 24.2±0.2, and 26.9±0.2,   vi. a crystalline Form II of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium exhibiting X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 13.3±0.2, 21.1±0.2, and 23.1±0.2,   vii. a crystalline Form III of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium napadisylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 13.4±0.2, 22.2±0.2, and 26.8±0.2,   viii. a crystalline Form IV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium napadisylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 5.4±0.2, 15.6±0.2, and 23.4±0.2,   ix. a crystalline Form V of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium esylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 14.5±0.2, 16.5±0.2, and 18.6±0.2,   x. a crystalline Form VI of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium edisylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 4.8±0.2, 12.8±0.2, and 16.5±0.2,   xi. a crystalline Form VII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium edisylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 6.1±0.2, 15.7±0.2, and 23.6±0.2,   xii. a crystalline Form VIII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium edisylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 15.5±0.2, 20.7±0.2, and 21.7±0.2,   xiii. a crystalline Form IX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium edisylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 4.5±0.2, 16.7±0.2, and 24.7±0.2,   xiv. a crystalline Form X of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium nitrate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 15.3±0.2, 21.4±0.2, and 25.1±0.2,   xv. a crystalline Form XI of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium cyclamate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 7.0±0.2, 13.8±0.2, and 15.7±0.2,   xvi. a crystalline Form XII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium cyclamate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 7.3±0.2, 15.3±0.2, and 17.9±0.2,   xvii. a crystalline Form XIII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium cyclamate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 15.3±0.2, 18.5±0.2, and 18.7±0.2,   xviii. a crystalline Form XIV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium besylate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 13.0±0.2, 15.1±0.2, and 19.9±0.2,   xix. a crystalline Form XV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium oxalate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 19.5±0.2, 23.3±0.2, and 25.8±0.2,   xx. a crystalline Form XVI of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium oxalate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 17.1±0.2, 17.9±0.2, and 19.6±0.2,   xxi. a crystalline Form XVII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium oxalate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 6.3±0.2, 10.6±0.2, and 19.8±0.2,   xxii. a crystalline Form XVIII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine (+)-camphor-10-sulfonic acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 6.5±0.2, 11.5±0.2, and 14.8±0.2,   xxiii. a crystalline Form XIX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium oxoglutarate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 16.8±0.2, 23.4±0.2, and 23.6±0.2,   xxiv. a crystalline Form XX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine DL-mandelic acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 14.8±0.2, 24.2±0.2, and 25.5±0.2,   xxv. a crystalline Form XXI of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine DL-mandelic acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 5.4±0.2, 10.0±0.2, and 24.6±0.2,   xxvi. a crystalline Form XXII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine hippuric acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 20.1±0.2, 24.1±0.2, and 24.5±0.2,   xxvii. a crystalline Form XXIII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium formate exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 13.3±0.2, 15.1±0.2, and 25.6±0.2,   xxviii. a crystalline Form XXIV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine L-lactic acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 3.8±0.2, 9.9±0.2, and 11.9±0.2,   xxix. a crystalline Form XXV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine DL-lactic acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 9.8±0.2, 11.9±0.2, and 27.6±0.2,   xxx. a crystalline Form XXVI of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine glutaric acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 8.3±0.2, 15.9±0.2, and 21.9±0.2,   xxxi. a crystalline Form XXVII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine glutaric acid further exhibiting one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation selected from the group consisting of 16.9±0.2, 25.6±0.2, 27.1±0.2, 28.2±0.2, and 28.7±0.2,   xxxii. a crystalline Form XXVIII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine glutaric acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 14.2±0.2, 16.9±0.2, and 24.5±0.2, and   xxxiii. a crystalline Form XXIX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine adipic acid exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K α  radiation at 13.4±0.2, 14.5±0.2, and 25.5±0.2.   
     
     
         2 . The crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt according to  claim 1 , wherein the crystalline Form is selected from the group consisting of:
 i. the crystalline Form A of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate,   ii. the crystalline Form B of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium succinate,   iii. the crystalline Form XIV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium besylate,   iv. the crystalline Form XIX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium oxoglutarate,   v. the crystalline Form XX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine DL-mandelic acid,   vi. the crystalline Form XXII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine hippuric acid,   vii. the crystalline Form XXIII of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium formate,   viii. the crystalline Form XXIV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine L-lactic acid,   ix. the crystalline Form XXV of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine DL-lactic acid,   x. the crystalline Form XXVI of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine glutaric acid, and   xi. the crystalline Form XXIX of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine adipic acid.   
     
     
         3 . A method of treating a disease or disorder in a subject in need thereof, said method comprising administering the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt according to  claim 1  to the subject. 
     
     
         4 . The method according to  claim 3 , wherein the disease or disorder is an arthritic disease, a kidney disease, a cardiovascular disease, atherosclerosis, a viral disease or disorder, or a systemic inflammatory disorder. 
     
     
         5 . The method according to  claim 4 , wherein the arthritic disease is selected from the group consisting of:
 i. an auto-immune disease and/or an inflammatory disease that presents with joint inflammation,   ii. inflammatory arthritis,   iii. degenerative arthritis,   iv. metabolic arthritis,   v. reactive arthritis,   vi. infectious arthritis, and   vii. arthritis as part of a systemic inflammatory disease.   
     
     
         6 . The method according to  claim 5 , wherein the inflammatory arthritis is Rheumatoid Arthritis, optionally wherein said subject is a subject with an inappropriate response to methotrexate (MTX). 
     
     
         7 . The method according to  claim 4 , wherein the kidney disease is selected from the group consisting of:
 i. kidney disease presenting with proteinuria,   ii. proteinuric kidney disease,   iii. glomerular disease,   iv. nephrotic syndrome (glomerulonephrosis),   v. primary nephrotic syndrome (primary glomerulonephrosis),   vi. secondary nephrotic syndrome (secondary glomerulonephrosis),   vii. an inflammatory kidney disease,   viii. glomerulonephritis (GN), and   ix. idiopathic membranous nephropathy (iMN).   
     
     
         8 . The method according to  claim 4 , wherein the viral disease or disorder is selected from the group consisting of:
 i. a symptomatic viral disease or disorder,   ii. a symptomatic viral disease or disorder with inflammation,   iii. an inflammatory viral disease or disorder,   iv. a viral respiratory infection,   v. a viral respiratory disease or disorder,   vi. a viral disease or disorder of the lung,   vii. a viral disease or disorder with inflammation in the respiratory system,   viii. a viral disease or disorder with one or more respiratory symptoms,   ix. severe disease,   x. critical disease,   xi. viral pneumonia,   xii. viral bronchiolitis,   xiii. viral diseases or disorders with respiratory failure,   xiv. acute respiratory distress syndrome (ARDS),   xv. viral acute respiratory distress syndrome (ARDS),   xvi. symptomatic COVID-19 with acute respiratory distress syndrome (ARDS),   xvii. a viral disease or disorder with systemic inflammatory distress syndrome (SIDS) and/or sepsis,   xviii. a viral disease or disorder with pulmonary insufficiency,   xix. a viral disease or disorder with cytokine release syndrome (CRS) and/or a cytokine storm (hypercytokinemia), and   xx. a viral disease or disorder caused by a viral infection selected from the group consisting of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2); SARS-CoV, MERS-CoV, the dengue virus and influenza virus (including Type A, Type B and Type C).   
     
     
         9 . A method for producing the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt according to  claim 1 , comprising:
 i. mixing
 i. N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and an acid or salt thereof in a solvent to form a mixture, 
 ii. an N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt and an acid or salt thereof in a solvent to form a mixture, 
 iii. an amorphous form or a second crystalline form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt in a solvent to form a composition, 
 iv. 3-[1-(2-nitrophenyl)-1-H-pyrrole-2-yl]-propanal, amino guanidine or a salt thereof, and an acid or a salt thereof in a solvent to form a mixture, or 
 v. N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a second N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt and a counter ion of an acid on an ion exchange column; and 
   ii. isolating the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt from said mixture, composition, or ion exchange column.   
     
     
         10 . The method according to  claim 9 , said method comprising:
 i. mixing N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine and an acid or salt thereof in a solvent to form a mixture; and   ii. isolating the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt from said mixture.   
     
     
         11 . The method according to  claim 9 , said method comprising:
 i. mixing a second N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt and an acid or a salt thereof in a solvent to form a mixture; and   ii. isolating the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt from the mixture.   
     
     
         12 . The method according to  claim 9 , said method comprising:
 i. mixing an amorphous form or a second crystalline form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt in a solvent to form a composition; and   ii. isolating the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt from said composition.   
     
     
         13 . The method according to  claim 9 , said method comprising:
 i. mixing 3-[1-(2-nitrophenyl)-1-H-pyrrole-2-yl]-propanal, amino guanidine or a salt thereof, and an acid or a salt thereof in a solvent, and   ii. isolating the crystalline form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt from said composition.   
     
     
         14 . The method according to  claim 9 , said method comprising:
 i. providing N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine or a second N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt,   ii. introducing a counter ion of an acid ion using ion exchange, and   iii. isolating the crystalline Form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt.   
     
     
         15 . The method according to  claim 9 , wherein the acid or the salt thereof is selected from the group consisting of: acetic acid, succinic acid, fumaric acid, toluene sulfonic acid, naphthalene-1,5-disulfonic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, nitric acid, cyclohexylsulfamic acid, benzenesulfonic acid, oxalic acid, (+)-camphor-10-sulfonic acid, 2-oxoglutaric acid, hydroxy(phenyl)acetic acid such as DL-hydroxy(phenyl)acetic acid, N-benzoylglycine, formic acid, 2-hydroxypropanoic acid such as L-2-hydroxypropanoic acid or DL-2-hydroxypropanoic acid, pentanedioic acid, and hexanedioic acid, and salts thereof. 
     
     
         16 . The method according to  claim 9 , wherein the solvent is a protic or a polar aprotic solvent. 
     
     
         17 . The method according to  claim 9 , wherein the mixture or the composition is heated at least once before the isolating step. 
     
     
         18 . The method according to  claim 9 , wherein the mixture or the composition is heated and cooled in cycles for 15 min to 72 hours before the isolating step. 
     
     
         19 . The method according to  claim 9 , further comprising a step of adding an anti-solvent to the mixture or the composition before the isolation step. 
     
     
         20 . The method according to  claim 9 , wherein the isolation is carried out using filtration, centrifugation, and/or evaporation of the solvent or solvents.