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WO2024180521A1 - Treatment for inflammatory bowel disease - Google Patents

Treatment for inflammatory bowel disease Download PDF

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Publication number
WO2024180521A1
WO2024180521A1 PCT/IB2024/052001 IB2024052001W WO2024180521A1 WO 2024180521 A1 WO2024180521 A1 WO 2024180521A1 IB 2024052001 W IB2024052001 W IB 2024052001W WO 2024180521 A1 WO2024180521 A1 WO 2024180521A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
indacen
carbamoyl
hexahydro
Prior art date
Application number
PCT/IB2024/052001
Other languages
French (fr)
Inventor
Sameer Agarwal
Abhijit Chatterjee
Mukul Jain
Rajiv Sharma
Deven V. PARMAR
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Zydus Lifesciences Limited
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Publication of WO2024180521A1 publication Critical patent/WO2024180521A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients

Definitions

  • the present invention relates to the development of therapeutic compound for the treatment of inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the present invention provides a NLRP3 inhibitors or its pharmaceutically acceptable salt or suitable composition useful in the treatment of inflammatory bowel diseases.
  • severe and persistent illnesses include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • NLRP3 pyrin domain-containing 3
  • IL-1 ⁇ mucosal interleukin-1 ⁇
  • NLRP3 pyrin domain-containing 3
  • IL mucosal interleukin-1 ⁇
  • IL-1 ⁇ mucosal interleukin-1 ⁇
  • NLRP3 is a cytosolic pattern recognition receptor (PRR) that senses exogenous and endogenous danger signals.
  • PRR cytosolic pattern recognition receptor
  • the NLRP3 protein is made up of three domains: a leucine-rich repeat domain (LRR), a NOD containing a caspase activation and recruitment domain (CARD) (NACHT), and a pyrin domain (PYD).
  • LRR leucine-rich repeat domain
  • CARD caspase activation and recruitment domain
  • PYD pyrin domain
  • NLRP3 oligomerizes and triggers assembly of the adapter apoptosis-associated speck-like protein containing a CARD (ASC) via PYD–PYD interactions.
  • ASC fibrils assemble into large structures, called ASC specks, and recruit pro-caspase-1, leading to its autoproteolytic activation.
  • the activated caspase-1 is able to cleave pro-IL-1 ⁇ and pro-IL-18 to generate the inflammatory cytokines IL-1 ⁇ and IL-18 (Guo et al., 2015; Dinarello et al., 2012).
  • NLRP3 inflammasome Involvement of the NLRP3 inflammasome in different kinds of diseases provides new avenues to design drugs targeting NLRP3 inflammasome.
  • clinical treatment of NLRP3-related diseases targets IL-1 ⁇ with IL-1 ⁇ antibodies or recombinant IL-1 ⁇ receptor antagonist, such as canakinumab and anakinra, respectively.
  • IL-1 ⁇ antibodies or recombinant IL-1 ⁇ receptor antagonist such as canakinumab and anakinra
  • a few small-molecule compounds have shown anti-inflammatory effects on NLRP3 inflammasome activation in vitro, including MCC950, ⁇ -hydroxybutyrate (BHB), Bay 11-7082, dimethyl sulfoxide (DMSO), and type I interferon.
  • BHB ⁇ -hydroxybutyrate
  • DMSO dimethyl sulfoxide
  • type I interferon type I interferon
  • IL-1 ⁇ secretion is not the only product of NLRP3 inflammasome activation; instead, other proinflammatory cytokines, including high-mobility group box 1 (HMGB1) and IL-18 may participate in the pathogenesis of these diseases.
  • HMGB1 high-mobility group box 1
  • IL-18 may participate in the pathogenesis of these diseases.
  • IL- 1 ⁇ can be produced by inflammasome-independent pathways or other inflammasomes. Therefore, inhibitors targeting IL-1 ⁇ may lead to unintended immunosuppressive effects besides preventing NLRP3 inflammasome activation itself.
  • Pharmacological inhibitors specific to NLRP3 inflammasome may be the best choice for treatment of NLRP3-related diseases (Yang et al., 2019).
  • IBD ulcerative colitis
  • CD Crohn’s disease
  • IFLX Infliximab
  • TNF tumor necrosis factor
  • FDA US Food and Drug Administration
  • Anti-interleukin (IL)- 12/IL-23 therapy small molecule inhibitors to sphingosine-1-phosphate, Janus kinase, purinergic receptor P2X, ligand-gated ion channel 7 receptor, and Bruton tyrosine kinase (BTK), are currently in the IBD pipeline.
  • IL interleukin
  • P2X purinergic receptor
  • P2X ligand-gated ion channel 7 receptor
  • novel therapy with distinct mechanisms of action is of urgent need for the long-term treatment of IBD patients in remission and/or to improve quality of life of the affected patients. (Biomedicine & Pharmacotherapy, June 2021, 111442).
  • Activation of NLRP3 is considered as an important inducing factor that triggers pathogenesis of IBD, such as sterile inflammation activation in intestinal epithelial cells and sustained activation of macrophages.
  • the present invention provides a therapeutic compound of formula (I) and their pharmaceutically acceptable salts for the prevention and treatment of inflammatory bowel diseases. These severe and persistent illnesses include such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides a therapeutic compound of formula (I) suitable for the treatment and prevention of treatment of Inflammatory bowel diseases.
  • These severe and persistent illnesses include such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides a compound of formula (I) and their pharmaceutically acceptable salts suitable for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease and eosinophilic gastrointestinal disease and other related forms of disorders.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease and eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides the administration of therapeutic compound of formula (I) and their pharmaceutically acceptable salts alone or in combination with suitable for the treatment and prevention of treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides a suitable composition comprising the compound of formula (I) or their suitable pharmaceutical compositions for the treatment and prevention of treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • BRIEF DESRIPTION OF THE FIGURE Figure 1 Effect of compound of Formula (11) in 2, 4, 6- trinitrobenzenesulfonic acid (TNBS) induced IBD model in rat.
  • TNBS trinitrobenzenesulfonic acid
  • DETAIL DESCRIPTION OF THE INVENTION "Patient” includes both human and animals. "Mammal
  • preventing refers to barring a subject from acquiring a disorder or disease in the first place.
  • a "subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • veterinary treatment e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • treating includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome.
  • Delaying, inhibiting or preventing the progression of the disease, disorder or syndrome includes for example, delaying, inhibiting or preventing the progression of inflammatory bowel diseases.
  • the present invention describes a method of treating a subject suffering from inflammatory bowel diseases.
  • the present invention describes a method of treating a subject suffering from inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides use of the compound of formula (I) or their suitable pharmaceutical compositions for the treatment or prevention of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • inflammatory bowel disease is ulcerative colitis.
  • the present invention provides a compound of formula (I) and their pharmaceutically acceptable salts suitable for the treatment of IBD.
  • the method comprises administering to a subject an effective amount of a compound according to Formula (I), their tautomeric forms, their their metabolites, their deuterium analogs, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof wherein X is O, NH or N-R3 wherein R3 at each occurrence independently represents hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, amine, optionally substituted groups selected from (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, SO 2 (C 1 -C 6 )alkyl, thiol, thioalkyl, thio-alkoxy, SO(C 1 -C 6 )alkyl, benzyl, aryl, heteroaryl, heterocycly
  • R x and R y at each occurrence are independently selected from hydrogen, halogen, optionally substituted groups selected from (C 1 -C 6 )alkyl; alternatively R x and R y together may form a 4- to 7-membered heterocyclic ring system; ‘M’ is selected from aryl, heteroaryl, heterocyclyl; When any of above defined group is substituted the substitutions on them may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, optionally substituted group selected from (C 1 - C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 10 )cycloalkyl, C 1 -C 6 alkoxy, aryl, heterocyclyl, heteroaryl, -COR 11, -CSR 11, C(O)OR 11, C(O
  • alkyl group examples include but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. - butyl, pentyl, hexyl etc.
  • alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C 1-6 is intended.
  • Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo ⁇ e.g., CI, F, Br, and I); halogenated alkyl ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2 CF 3 , or CF 2 CF 3 ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those described under the definition of ‘Optionally substituted’.
  • halo ⁇ e.g., CI, F, Br, and I
  • halogenated alkyl ⁇ e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
  • alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l -propenyl, 2-butenyl, 2-methyl -2-butenyl etc.
  • the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, (C 2-6 ) is intended.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl- l -pentynyl etc. When no number of carbon atoms is specified, is intended.
  • carbocycle or “carbocyclic residue” is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
  • cycloalkyl and cycloalkenyl refers to optionally substituted, saturated and unsaturated mono-cyclic, bicyclic or tricyclic carbon groups.
  • the cycloalkyl or cycloalkenyl group may have a specified number of carbon atoms, for example, C 3 -C 6 cycloalkyl or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms.
  • substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.
  • Substituted cycloalkyl or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo (e.g. , CI, F, Br, and I); halogenated alkyl (e.g.
  • alkoxy refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • Heterocyclyl means a saturated, partially saturated or unsaturated aromatic or non- aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including the oxidized forms of sulfur, namely SO & SO 2 Heterocyclyl systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated.
  • heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4- dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, etc.
  • THF tetrahydrofuran
  • dihydrofuran 1,4- dioxane
  • morpholine 1,4-dithiane
  • 1,4-dithiane piperazine
  • piperidine 1,3-dioxolane
  • imidazoline imidazolidine
  • pyrrolidine pyrroline
  • tetrahydropyran dihydropyran
  • heterocycloalkyl refers to a heterocyclic group as defined above connected to an alkyl group as defined above;
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
  • heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolin
  • haloalkyl means an alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another.
  • the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; In certain other embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
  • Aryloxyalkyl means an alkyl radical substituted with aryloxy group as defined herein.
  • Aryloxyaryl means an aryl radical substituted with aryloxy group as defined herein.
  • “Aryloxyheteroaryl” means a heteroaryl radical substituted with aryloxy group as defined herein.
  • Halo/ Halogen refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • substituted means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
  • Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1 , 2- ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromie, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic
  • optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'.
  • an optionally substituted group includes an unsubstituted group.
  • Particularly useful compounds may be selected from but not limited to the following: N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide; N'-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide; N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2- yl)furan-2-sulfonimidamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbam
  • the present invention provides a suitable composition comprising the compound of formula (I) or their suitable pharmaceutical compositions for the treatment and prevention of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • pharmaceutical composition refers to a mixture of an NLRP3 antagonist or other compound described herein with other chemical components (referred to collectively herein as “excipients”) such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • the pharmaceutical composition facilitates administration of the NLRP3 antagonist or other compound to an organism.
  • the present invention provides effective amount of compound of formula (I) or its pharmaceutically acceptable salts may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment and prevention of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1mg to about 25 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject. In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.
  • the amount of dose in the range of about 1 mg to about 500 mg according to present disclosure include each integer and non-integer number between a particular range.
  • the present invention provides effective amount of compound of formula (I) or its pharmaceutically acceptable salt may be administered by oral, topical, parenteral, intravenous or intramuscular route of administration.
  • the present invention provides effective amount of formula (I) or its pharmaceutically acceptable salts is administered by oral route of administration.
  • the compound of formula (I) or its pharmaceutically acceptable salts may be provided to the subject daily, weekly, as prescribed by physician to the person in need thereof.
  • the present invention provides a method of treating a subject suffering from IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably Crohn's disease and ulcerative colitis which comprises treatment of a patient in need of such therapy, with compound of formula (I) or its pharmaceutically acceptable salts or suitable pharmaceutical compositions containing them.
  • IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably Crohn's disease and ulcerative colitis
  • the present invention provides the combination of compound of formula (I) or its pharmaceutically acceptable salts with other suitable agents as therapeutic agent for the treatment of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders
  • the additional therapeutic agent used is selected from Inhibitors of interleukin-1 ⁇ (e.g.
  • Rilonacept Canakinumab, and Anakinra
  • immune-suppressants e.g., Methotrexate, Mercaptopurine, Cyclophosphamide
  • metabolic disorders drugs e.g., glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF- ⁇ binding proteins (e.g.,Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; anti-viral drugs, for example: Remdesivir, Lopinavir/Ritonavir, Favipiravir, Molnupiravir,Tamiflu; anti-malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts.
  • Non-Alcoholic Steato- Hepatitis and fibrosis drugs
  • anticancer antibiotics, for example Azithromycin
  • Drugs originally developed for SARS (ACE2 protein decoy) Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR/ABL antagonist.
  • the compound of formula (I) of the present invention or its pharmaceutically acceptable salts may be used further in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combinations.
  • MAO B inhibitors selegiline (Zelapar), rasagiline (Azilect) and safinamide (Xadago); Catechol O-methyltransferase (COMT) inhibitors, Entacapone (Comtan) and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, Amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon), Memantine (Namenda), aducanumab (Aduhelm); Riluzole (Rilutek), Edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; t
  • the compounds and compositions of the present invention are also intended for use with general care provided patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including Metronidazole and Cephalosporin antibiotics, such as Ceftriaxone and Cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as Metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin C or/and K and zinc sulfate), anti-inflammatory agents (such as Ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including Artemether and Artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as Ciprofloxacin, macrolide antibiotics, such as Azithromycin, cephalosporin antibiotics, such as Ceftri
  • compound of formula (I) or its pharmaceutically acceptable salts is provided in the form of pharmaceutical composition.
  • present invention provides a pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts for treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis wherein compound of formula (I) is
  • the present invention provides pharmaceutical composition comprising compound of formula (I) and suitable pharmaceutically acceptable excipients for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis
  • the pharmaceutically acceptable excipients may be selected at least one from dilu
  • the present invention provides a pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts wherein effective amount of compound of formula (I) or its pharmaceutically acceptable salt may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis
  • the present invention provides pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts may be administered by oral, topical, parenteral, intravenous or intramuscular route of administration.
  • the pharmaceutical composition may be administered by oral route of administration.
  • a process for the preparation of a stable pharmaceutical composition of compounds of formula (1) or its pharmaceutically acceptable salts may be made by dry mixing, wet granulation or dry granulation methods by techniques known to persons skilled in the art.
  • the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules, the wet granules are dried and optionally sieved.
  • the dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.
  • the drug In dry mixing process, the drug is mixed with all the pharmaceutical excipients required. The blend is mixed with one or more suitable excipients from those described elsewhere and then final blend is either compressed into tablets or filled in capsules.
  • dry granulation process the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.
  • One or more solvents or vehicle used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof and other such materials known to those of ordinary skill in the art.
  • the present invention further discloses use of said compound of formula (I) or their suitable pharmaceutical compositions for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • the present invention provides a method of treating Inflammatory bowel diseases using pharmaceutical composition of compound of formula (I) or its pharmaceutically acceptable salts.
  • a method of treating Inflammatory bowel diseases using compound of formula (I) or its pharmaceutical composition a preferred embodiment, the present invention provides compound of formula (11) or its pharmaceutically acceptable salts suitable for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides use of the compound of formula (11) or their suitable pharmaceutical compositions for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the present invention provides effective amount of compound of formula (11) or its pharmaceutically acceptable salt may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject. In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject.
  • the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.
  • the amount of dose in the range of about 1 mg to about 500 mg according to present disclosure includes each integer and non-integer number between a particular range.
  • the present invention provides effective amount of compound of formula (11) or its pharmaceutically acceptable salt may be administered by oral, topical, parenteral, intravenous or intramuscular route of administration.
  • the present invention provides effective amount of formula (11) or its pharmaceutically acceptable salt is administered by oral route of administration.
  • the compound of formula (11) or its pharmaceutically acceptable salts may be provided to the subject daily, weekly, as prescribed by physician to the person in need thereof.
  • the present invention provides the combination of compound of formula (11) and their pharmaceutically acceptable salts with other suitable agents as therapeutic agent for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • suitable therapeutic agents may be selected from Inhibitors of interleukin- 1 ⁇ (e.g.
  • Rilonacept Canakinumab, and Anakinra
  • immune-suppressants e.g., Methotrexate, Mercaptopurine, Cyclophosphamide
  • metabolic disorders drugs e.g., glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF- ⁇ binding proteins (e.g.,Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; anti-viral drugs, for example: Remdesivir, Lopinavir/Ritonavir, Favipiravir, Molnupiravir, Tamiflu; anti-malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts.
  • Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs include anticancer; antibiotics, for example Azithromycin; hormones, Aromatase inhibitors, Colchicine, Anticoagulants, antibodies, cytokines, anti- IL6 drugs; Antiparasitics; vaccines; Interferons; drug conjugates; Drugs originally developed for SARS (ACE2 protein decoy); Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR/ABL antagonist may also be used in combination with compound of formula (11) for treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis
  • the compound of formula (11) of the present invention or its pharmaceutically acceptable salts may be used further in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combinations.
  • MAO B inhibitors selegiline (Zelapar), rasagiline (Azilect) and safinamide (Xadago); Catechol O-methyltransferase (COMT) inhibitors, Entacapone (Comtan) and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, Amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon), Memantine (Namenda), aducanumab (Aduhelm); Riluzole (Rilutek), Edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; te
  • the compounds of formula (11) and its compositions of the present invention are also intended for use with general care provided patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including Metronidazole and Cephalosporin antibiotics, such as Ceftriaxone and Cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as Metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin C or/and K and zinc sulfate), anti-inflammatory agents (such as Ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including Artemether and Artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as Ciprofloxacin, macrolide antibiotics, such as Azithromycin, cephalosporin antibiotics,
  • present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising compound of formula (11) or its pharmaceutically acceptable salts for treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • the present invention provides pharmaceutical composition
  • pharmaceutical composition comprising compound of formula (11) and suitable pharmaceutically acceptable excipients for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • the pharmaceutically acceptable excipients may be selected at least one from diluents, carriers, binders, disintegrating agents, lubricating agents, surface active agents and the like.
  • the present invention further discloses use of said compound of formula (11) or their suitable pharmaceutical compositions for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis.
  • the present invention provides a method of treating Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis using pharmaceutical composition of compound of formula (11) or its pharmaceutically acceptable salts.
  • Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis using pharmaceutical composition of compound of formula (11) or its pharmaceutically acceptable salts.
  • a method of treating Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis using compound of formula (11) or its pharmaceutical composition.
  • the stable pharmaceutical composition may be made by dry mixing, wet granulation or dry granulation methods by techniques known to persons skilled in the art.
  • the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules, the wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.
  • dry mixing process the drug is mixed with all the pharmaceutical excipients required. The blend is mixed with one or more suitable excipients from those described elsewhere and then final blend is either compressed into tablets or filled in capsules.
  • dry granulation process the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required sieve.
  • the sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.
  • One or more solvents or vehicle used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof and other such materials known to those of ordinary skill in the art.
  • the pharmaceutically acceptable excipients described in the present invention are selected at least one from diluents, carriers, binders, disintegrating agents, lubricating agents, surface active agents and the like.
  • Diluents include, but are not limited to lactose monohydrate, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose, combinations thereof and other such materials known to those of ordinary skill in the art.
  • Carriers include, but are not limited to lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose and silicic acid, combinations thereof and other such materials known to those of ordinary skill in the art.
  • Binders include, but are not limited to carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein, combinations thereof and other such materials known to those of ordinary skill in the art.
  • Disintegrating agents include, but are not limited to, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate sodium, combinations thereof and other such materials known to those of ordinary skill in the art.
  • Lubricating agents used include, but are not limited to, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic acid, combinations thereof and other such materials known to those of ordinary skill in the art.
  • Nonionic surfactant selected from alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside
  • anionic surfactant selected from arachnidan acid and arachidonic acid
  • cationic surfactant selected from cetyl trimethylammonium bromide and cetylpyridinium chloride, combinations thereof and other such materials known to those of ordinary skill in the art.
  • General Process for Preparation The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
  • Biological Activity In-vitro assays: THP1 monocytes were differentiated with PMA (100ng/ml) and incubated at 37 °C for 20 hrs in presence of 5% CO 2 . 2X105 differentiated cells were plated per well of 96 well tissue culture plates. The cells were primed using 500ng/mL Lipopolysaccharide and incubating for 4h under the same condition. The cells were then treated with various concentrations of the compounds for 30 min followed by treatment with 5mM ATP for 1hr.
  • DAI Disease activity index
  • the compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of NLRP3 activity and suitable for humans and other warm-blooded animals, and may be administered either by oral, topical or parenteral administration.
  • Evaluation of effect of compound of Formula (11) in 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) induced IBD model in rat TNBS-IBD is a chemical-induced IBD model with an overall etiology, including some immunological and histological changes in the GI tract that resembles human disease.
  • TNBS 6-trinitrobenzenesulfonic acid
  • Dose Mean % No Treatment (m /k ) colon SEM inhibition in Protocol Title: A randomised, double blind, parallel, interventional phase II-a proof of concept trial to evaluate the efficacy and safety of compound 11 for the treatment of patients with mild to moderately active Ulcerative Colitis (UC) resistant to high doses of mesalamine treatment.
  • Objectives and Endpoints The purpose of this study is to evaluate efficacy and safety of compound 11 oral capsule twice a day for 12 weeks for treatment of mild to moderate active ulcerative colitis resistant to high doses of mesalamine.
  • Vital Signs Vital sign measurements include sitting blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature and should be taken in resting condition. Electrocardiograms 12-lead ECGs are performed. Clinical Safety Laboratory Tests Clinical Laboratory assessment includes: ⁇ Hematology: Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular volume, MCHC, platelet count, red blood cell count, white blood cell count, differential WBC count, red cell distribution width.
  • ⁇ Liver function test Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, serum protein, albumin and total bilirubin (with Direct & Indirect bilirubin).
  • Renal function test Blood urea nitrogen, serum creatinine / creatinine clearance and uric acid.
  • Urine microscopy Epithelial cells, red blood cells, pus cells, cast and crystals; physical examination of urine to include: appearance and colour.
  • Urine Chemistry pH, Specific gravity, Protein, Glucose, Bilirubin, albumin, Urobilinogen, Ketone bodies and nitrite.
  • Pregnancy Testing Serum pregnancy test / Urine pregnancy test will be performed for female participants with child bearing potential. Adverse Events Frequency and severity of adverse events (AEs) for all the participants enrolled are recorded. All AEs, are classified using ⁇ Causality ⁇ Severity ⁇ Seriousness Note: All the safety assessments are performed at the specified time-points as mentioned in the protocol. Methodology: This is a Phase IIa, randomized, two arms, double blind, double dummy, parallel, multicentre study to evaluate efficacy and safety of compound 11 oral capsules for the treatment of mild to moderately active ulcerative colitis resistant to high doses of mesalamine.
  • the study consists of: screening period of upto 4 weeks, treatment period of 12 weeks (first 6 weeks period: Induction period and remaining 6 weeks: Maintenance period), and end of the study at Week 13.
  • Eligible participants are randomly assigned to one of the two following study arms: Eligible participants are screened within 4 weeks prior to enrolment. Informed consent is obtained from all eligible participants before any study related activity according to the regulatory requirements. During Visit 1 and Visit 2, eligibility is verified. Eligible participants are randomly assigned in a 1:1 ratio on Day 0 to one of following: ⁇ Arm 1: Compound 11 capsules 25 mg for oral administration + 50 mg placebo twice daily for 6 weeks ⁇ Arm 2: Compound 11 capsules 50 mg for oral administration + 25 mg placebo twice daily for 6 weeks This trial is conducted over a period of 12 weeks.
  • Treatment period consist of two periods: blinded induction period of 6 weeks followed by an open label maintenance period of 6 weeks. Participants are received treatment as described above for 6 weeks. At the end of 6 weeks, participants are assessed for achievement of clinical remission. Participants in either arm who show clinical remission are continued to receive the same dose for another 6 weeks in maintenance period. Those participants who do not achieve in clinical remission (non-responders) at 6 weeks in 25 mg compound 11 arm are entered the follow-up period to receive capsule compound 1150 mg for 6 weeks. Participants in compound 11 50 mg arm, who do not achieve clinical remission are offered rescue / standard of care medicine (steroid or biological agent) and withdrawn from the study. Assessment of efficacy is performed by a tool modified Mayo Score (mMS).
  • mMS Mayo Score
  • the mMS is a composite instrument which consists of three subscores: 1. Stool frequency, 2. Rectal Bleeding & 3. Endoscopic findings assessed by central reviewer. Detailed assessment procedure is described in Section 8. During the treatment period, dose adjustment is not permitted. All the participants are evaluated for adverse event at all visits during treatment period. If further investigations are required in case of any AE, Investigator is advised to assess the AE and take necessary action. Participants are advised to contact the Investigator for any discomfort. No. of subjects in treatment arm: A total of 24 participants (12 participants per arm) have been planned to be enrolled in the study. Duration of treatment: 12 weeks (Induction period: 6 weeks and Maintenance period: 6 weeks) Study Duration: 119 days including screening period of 28 days

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Abstract

The present invention relates to the development of therapeutic compound for the treatment of inflammatory bowel diseases. Specifically, the present invention provides an NLRP3 inhibitor or its pharmaceutically acceptable salt or suitable composition useful in the treatment of inflammatory bowel diseases. These severe and persistent illnesses include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.

Description

TREATMENT FOR INFLAMMATORY BOWEL DISEASE FIELD OF THE INVENTION The present invention relates to the development of therapeutic compound for the treatment of inflammatory bowel disease (IBD). Specifically, the present invention provides a NLRP3 inhibitors or its pharmaceutically acceptable salt or suitable composition useful in the treatment of inflammatory bowel diseases. These severe and persistent illnesses include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. BACKGROUND OF THE INVENTION The nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3 or NALP3) inflammasome are a major source of mucosal interleukin (IL)-1β and the inflammasomes are mostly subject to activation by multiple aspects of inflammation-associated stress. NLRP3 is a cytosolic pattern recognition receptor (PRR) that senses exogenous and endogenous danger signals. The NLRP3 protein is made up of three domains: a leucine-rich repeat domain (LRR), a NOD containing a caspase activation and recruitment domain (CARD) (NACHT), and a pyrin domain (PYD). Upon activation, NLRP3 oligomerizes and triggers assembly of the adapter apoptosis-associated speck-like protein containing a CARD (ASC) via PYD–PYD interactions. ASC fibrils assemble into large structures, called ASC specks, and recruit pro-caspase-1, leading to its autoproteolytic activation. The activated caspase-1 is able to cleave pro-IL-1β and pro-IL-18 to generate the inflammatory cytokines IL-1β and IL-18 (Guo et al., 2015; Dinarello et al., 2012). Involvement of the NLRP3 inflammasome in different kinds of diseases provides new avenues to design drugs targeting NLRP3 inflammasome. To date, clinical treatment of NLRP3-related diseases targets IL-1β with IL-1β antibodies or recombinant IL-1β receptor antagonist, such as canakinumab and anakinra, respectively. In addition, a few small-molecule compounds have shown anti-inflammatory effects on NLRP3 inflammasome activation in vitro, including MCC950, β-hydroxybutyrate (BHB), Bay 11-7082, dimethyl sulfoxide (DMSO), and type I interferon. However, most of these inhibitors are relatively nonspecific and have low efficacy. For inhibitors targeting IL-1β, it should be noted that IL-1β secretion is not the only product of NLRP3 inflammasome activation; instead, other proinflammatory cytokines, including high-mobility group box 1 (HMGB1) and IL-18 may participate in the pathogenesis of these diseases. Moreover, IL- 1β can be produced by inflammasome-independent pathways or other inflammasomes. Therefore, inhibitors targeting IL-1β may lead to unintended immunosuppressive effects besides preventing NLRP3 inflammasome activation itself. Pharmacological inhibitors specific to NLRP3 inflammasome may be the best choice for treatment of NLRP3-related diseases (Yang et al., 2019). IBD is a chronic gastrointestinal inflammatory disease that affects the entire gastrointestinal tract and the colon. Two of the most common types of IBD include ulcerative colitis (UC) and Crohn’s disease (CD). Approximately more than 5 million people in the industrialized world suffer from IBD. In Europe, the incidence of UC and CD was 0.5% and 1%, respectively. The number of IBD patients increases dramatically worldwide, especially in China and other Asian countries. Major symptoms of IBD include abdominal pain, abdominal distension, diarrhea, and mucous pus blood, which have a significant impact on the quality of life of these patients. Current treatment for IBD mainly includes steroids and immune suppressive agents, especially antibodies to inflammatory cytokines. These biological agents exert their function by neutralizing inflammatory cytokines. For example, Infliximab (IFLX), the first anti-tumor necrosis factor (TNF)-α monoclonal antibody approved by the US Food and Drug Administration (FDA), eliminates the biological activity of cytosolic and membrane-bound pro- inflammatory cytokine TNF-α. Subsequently, IFLX induces apoptotic cell death of pro- inflammatory cells. IFLX increases clinical remission in CD and UC patients, and heals fistulas in CD. However, the long-term use of IFLX and other biological agents leads to relapse, generation of anti-drug antibodies, or malignancy. Anti-interleukin (IL)- 12/IL-23 therapy, small molecule inhibitors to sphingosine-1-phosphate, Janus kinase, purinergic receptor P2X, ligand-gated ion channel 7 receptor, and Bruton tyrosine kinase (BTK), are currently in the IBD pipeline. However, detailed pathogenic factors that trigger IBD are tremendously complicated and remain largely unresolved. The combination of drugs with different activities could increase clinical efficacy and/or safety profile. Therefore, novel therapy with distinct mechanisms of action is of urgent need for the long-term treatment of IBD patients in remission and/or to improve quality of life of the affected patients. (Biomedicine & Pharmacotherapy, June 2021, 111442). Activation of NLRP3 is considered as an important inducing factor that triggers pathogenesis of IBD, such as sterile inflammation activation in intestinal epithelial cells and sustained activation of macrophages. SUMMARY OF THE INVENTION The present invention provides a therapeutic compound of formula (I) and their pharmaceutically acceptable salts for the prevention and treatment of inflammatory bowel diseases. These severe and persistent illnesses include such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. EMBODIMENTS OF THE INVENTION In an embodiment, the present invention provides a therapeutic compound of formula (I)
Figure imgf000005_0001
suitable for the treatment and prevention of treatment of Inflammatory bowel diseases. These severe and persistent illnesses include such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In an embodiment, the present invention provides a compound of formula (I) and their pharmaceutically acceptable salts suitable for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease and eosinophilic gastrointestinal disease and other related forms of disorders. In yet another embodiment, the present invention provides the administration of therapeutic compound of formula (I) and their pharmaceutically acceptable salts alone or in combination with suitable for the treatment and prevention of treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In yet another embodiment, the present invention provides a suitable composition comprising the compound of formula (I) or their suitable pharmaceutical compositions for the treatment and prevention of treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. BRIEF DESRIPTION OF THE FIGURE Figure 1: Effect of compound of Formula (11) in 2, 4, 6- trinitrobenzenesulfonic acid (TNBS) induced IBD model in rat. DETAIL DESCRIPTION OF THE INVENTION "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. The term "preventing" refers to barring a subject from acquiring a disorder or disease in the first place. A "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). As used herein "treating" includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome. Delaying, inhibiting or preventing the progression of the disease, disorder or syndrome includes for example, delaying, inhibiting or preventing the progression of inflammatory bowel diseases. The present invention describes a method of treating a subject suffering from inflammatory bowel diseases. The present invention describes a method of treating a subject suffering from inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In a further embodiment the present invention provides use of the compound of formula (I) or their suitable pharmaceutical compositions for the treatment or prevention of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In a preferred embodiment, inflammatory bowel disease is ulcerative colitis. In an embodiment, the present invention provides a compound of formula (I) and their pharmaceutically acceptable salts suitable for the treatment of IBD. These severe and persistent illnesses include such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. The method comprises administering to a subject an effective amount of a compound according to Formula (I), their tautomeric forms, their
Figure imgf000007_0001
their metabolites, their deuterium analogs, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof wherein X is O, NH or N-R3 wherein R3 at each occurrence independently represents hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, amine, optionally substituted groups selected from (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, SO2(C1-C6)alkyl, thiol, thioalkyl, thio-alkoxy, SO(C1-C6)alkyl, benzyl, aryl, heteroaryl, heterocyclyl; Y is O, S; R1 at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl,(C1-C6)alkylSO2(C1- C6)alkyl,(C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C2- C6)alkenyl, N((C2-C6)alkenyl)2, -N-heterocyclyl, N(C1-C6)alkyl-heterocyclyl, NR’R’’, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, - CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms; In an embodiment R1 represents: , each of R’ , R” , R1’, R1’’, R2’ and R2” at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1- C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3- C7)cycloalkyl, (C1-C6)alkylSO2(C1-C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1- C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, - CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms; In an embodiment R’ and R” optionally forms 4- to 7-membered heterocyclic ring system; R2 is selected from the following ring system
Figure imgf000008_0001
wherein X, Y, Z at each occurrence independently represents C, N, S, SO2, and O, which may be optionally substituted; R4 at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, bicyclic heterocyclic ring system, substituted amines, thiol, mercapto alkyl, (C1-C6)thio-alkoxy groups; each of R7, R8, R9, R10 11 12 , R and R at each occurrence are independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; In one embodiment each of R8 and R9 9 10 , R and R , R10 and R11and R11 and R12 wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p; p = 1-2. Rx and Ry at each occurrence are independently selected from hydrogen, halogen, optionally substituted groups selected from (C1-C6)alkyl; alternatively Rx and Ry together may form a 4- to 7-membered heterocyclic ring system; ‘M’ is selected from aryl, heteroaryl, heterocyclyl; When any of above defined group is substituted the substitutions on them may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, optionally substituted group selected from (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, C1-C6 alkoxy, aryl, heterocyclyl, heteroaryl, -COR11,-CSR11, C(O)OR11, C(O)-R11, -C(O)-NR11R12, -C(S)- NR11R12, -SO2R11group, wherein each of, R11 and R12 is independently selected from hydrogen, optionally substituted group selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups; In a preferred embodiment, the groups, radicals described above may be selected from: "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means a carbon chain which may further be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. - butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C1-6 is intended. Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo {e.g., CI, F, Br, and I); halogenated alkyl {e.g., CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those described under the definition of ‘Optionally substituted’. "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l -propenyl, 2-butenyl, 2-methyl -2-butenyl etc. Where the specified number of carbon atoms permits, e.g., from C5-10, the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, (C2-6) is intended. "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl- l -pentynyl etc. When no number of carbon atoms is specified, is intended. The “thioalkyl” group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula –SR’, (sulfur and its oxidized forms) where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues; The terms "cycloalkyl" and "cycloalkenyl" refers to optionally substituted, saturated and unsaturated mono-cyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group may have a specified number of carbon atoms, for example, C3-C6 cycloalkyl or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Substituted cycloalkyl or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo (e.g. , CI, F, Br, and I); halogenated alkyl (e.g. , CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those described under the definition of ‘Optionally substituted’. The "alkoxy" refers to the straight or branched chain alkoxides of the number of carbon atoms specified. "Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. “Heterocyclyl” means a saturated, partially saturated or unsaturated aromatic or non- aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including the oxidized forms of sulfur, namely SO & SO2 Heterocyclyl systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4- dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, etc. The term "heterocycloalkyl" refers to a heterocyclic group as defined above connected to an alkyl group as defined above; "Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyt, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl; and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings. The term "haloalkyl "means an alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like; In certain other embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another. "Aryloxyalkyl" means an alkyl radical substituted with aryloxy group as defined herein. "Aryloxyaryl" means an aryl radical substituted with aryloxy group as defined herein. "Aryloxyheteroaryl" means a heteroaryl radical substituted with aryloxy group as defined herein. "Halo/ Halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. The term "substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1 , 2- ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromie, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, -lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic. The term 'optional' or ‘optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'. Further an optionally substituted group includes an unsubstituted group. Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Particularly useful compounds may be selected from but not limited to the following: N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide; N'-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide; N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2- yl)furan-2-sulfonimidamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide; (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide; (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide; (R,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- ethanesulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1- sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2- yl)ethene-1-sulfonamide; (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- ethanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; sodium(S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)amide; potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)amide; Sodium(R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)amide; (E)-N'-cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonimidamide; (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1- methylpyrrolidin-2-yl)ethene-1-sulfonimidamide; (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1- methylpyrrolidin-2-yl)ethene-1-sulfonimidamide; (E)-N'-cyano-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonimidamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a- trimethyloctahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a- tetramethyloctahydropyrrolo[1,2-a]pyrazin-4-yl)methanesulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene- 1-sulfonamide; sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)amide; (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl- d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl- d)pyrrolidin-2-yl)ethene-1-sulfonamide (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2- yl)ethene-1-sulfonamide; (E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3- methylbut-1-ene-1-sulfonamide; Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1- (methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2- (methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide; or pharmaceutically acceptable salts of any of the compounds above. In one embodiment, the present invention provides a suitable composition comprising the compound of formula (I) or their suitable pharmaceutical compositions for the treatment and prevention of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. The term “pharmaceutical composition” refers to a mixture of an NLRP3 antagonist or other compound described herein with other chemical components (referred to collectively herein as “excipients”) such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the NLRP3 antagonist or other compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to rectal, oral, and intravenous, aerosol, and parenteral, ophthalmic, pulmonary, and topical administration. In an embodiment, the present invention provides effective amount of compound of formula (I) or its pharmaceutically acceptable salts may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment and prevention of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject. In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject. The amount of dose in the range of about 1 mg to about 500 mg according to present disclosure include each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.254.5, 4.75, 5, etc.). In an embodiment, the present invention provides effective amount of compound of formula (I) or its pharmaceutically acceptable salt may be administered by oral, topical, parenteral, intravenous or intramuscular route of administration. In a preferred embodiment, the present invention provides effective amount of formula (I) or its pharmaceutically acceptable salts is administered by oral route of administration. The compound of formula (I) or its pharmaceutically acceptable salts may be provided to the subject daily, weekly, as prescribed by physician to the person in need thereof. In another embodiment, the present invention provides a method of treating a subject suffering from IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably Crohn's disease and ulcerative colitis which comprises treatment of a patient in need of such therapy, with compound of formula (I) or its pharmaceutically acceptable salts or suitable pharmaceutical compositions containing them. In an embodiment, the present invention provides the combination of compound of formula (I) or its pharmaceutically acceptable salts with other suitable agents as therapeutic agent for the treatment of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders In an embodiment, the additional therapeutic agent used is selected from Inhibitors of interleukin-1β (e.g. Rilonacept, Canakinumab, and Anakinra); immune-suppressants (e.g., Methotrexate, Mercaptopurine, Cyclophosphamide), metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g.,Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; anti-viral drugs, for example: Remdesivir, Lopinavir/Ritonavir, Favipiravir, Molnupiravir,Tamiflu; anti-malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts. Further examples for use in combination with Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs; anticancer; antibiotics, for example Azithromycin; hormones, Aromatase inhibitors, Colchicine, Anticoagulants, antibodies, cytokines, anti- IL6 drugs; Antiparasitics; vaccines; Interferons; drug conjugates; Drugs originally developed for SARS (ACE2 protein decoy); Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR/ABL antagonist. The compound of formula (I) of the present invention or its pharmaceutically acceptable salts may be used further in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combinations. MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect) and safinamide (Xadago); Catechol O-methyltransferase (COMT) inhibitors, Entacapone (Comtan) and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, Amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon), Memantine (Namenda), aducanumab (Aduhelm); Riluzole (Rilutek), Edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austedo), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel), levetiracetam (Keppra, Elepsia XR, Spritam) and clonazepam (Klonopin); citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex (Depakote), carbamazepine (Carbatrol, Epitol) and lamotrigine (Lamictal). The compounds and compositions of the present invention are also intended for use with general care provided patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including Metronidazole and Cephalosporin antibiotics, such as Ceftriaxone and Cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as Metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin C or/and K and zinc sulfate), anti-inflammatory agents ( such as Ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including Artemether and Artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as Ciprofloxacin, macrolide antibiotics, such as Azithromycin, cephalosporin antibiotics, such as Ceftriaxone, or aminopenicillins, such as Ampicillin), or shigellosis. In yet another embodiment, compound of formula (I) or its pharmaceutically acceptable salts is provided in the form of pharmaceutical composition. In an embodiment, present invention provides a pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts for treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis wherein compound of formula (I) is
Figure imgf000019_0001
In an embodiment, the present invention provides pharmaceutical composition comprising compound of formula (I) and suitable pharmaceutically acceptable excipients for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis The pharmaceutically acceptable excipients may be selected at least one from diluents, carriers, binders, disintegrating agents, lubricating agents, surface active agents and the like. In an embodiment, the present invention provides a pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts wherein effective amount of compound of formula (I) or its pharmaceutically acceptable salt may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis In an embodiment, the present invention provides pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts may be administered by oral, topical, parenteral, intravenous or intramuscular route of administration. In a preferred embodiment, the pharmaceutical composition may be administered by oral route of administration. In another embodiment of the present invention provides a process for the preparation of a stable pharmaceutical composition of compounds of formula (1) or its pharmaceutically acceptable salts. The stable pharmaceutical composition may be made by dry mixing, wet granulation or dry granulation methods by techniques known to persons skilled in the art. Thus, for example, In wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules, the wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules. In dry mixing process, the drug is mixed with all the pharmaceutical excipients required. The blend is mixed with one or more suitable excipients from those described elsewhere and then final blend is either compressed into tablets or filled in capsules. In dry granulation process, the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules. One or more solvents or vehicle used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof and other such materials known to those of ordinary skill in the art. The present invention further discloses use of said compound of formula (I) or their suitable pharmaceutical compositions for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis. In another embodiment, the present invention provides a method of treating Inflammatory bowel diseases using pharmaceutical composition of compound of formula (I) or its pharmaceutically acceptable salts. In a preferred embodiment, a method of treating Inflammatory bowel diseases using compound of formula (I) or its pharmaceutical composition. In a preferred embodiment, the present invention provides compound of formula (11)
Figure imgf000021_0001
or its pharmaceutically acceptable salts suitable for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In a further preferred embodiment, the present invention provides use of the compound of formula (11) or their suitable pharmaceutical compositions for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In another preferred embodiment, the present invention provides effective amount of compound of formula (11) or its pharmaceutically acceptable salt may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject. In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject. The amount of dose in the range of about 1 mg to about 500 mg according to present disclosure includes each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.254.5, 4.75, 5, etc.). In another preferred embodiment, the present invention provides effective amount of compound of formula (11) or its pharmaceutically acceptable salt may be administered by oral, topical, parenteral, intravenous or intramuscular route of administration. In a preferred embodiment, the present invention provides effective amount of formula (11) or its pharmaceutically acceptable salt is administered by oral route of administration. The compound of formula (11) or its pharmaceutically acceptable salts may be provided to the subject daily, weekly, as prescribed by physician to the person in need thereof. In one of the preferred embodiment, the present invention provides the combination of compound of formula (11) and their pharmaceutically acceptable salts with other suitable agents as therapeutic agent for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis. Wherein other suitable therapeutic agents may be selected from Inhibitors of interleukin- 1β (e.g. Rilonacept, Canakinumab, and Anakinra); immune-suppressants (e.g., Methotrexate, Mercaptopurine, Cyclophosphamide), metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g.,Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; anti-viral drugs, for example: Remdesivir, Lopinavir/Ritonavir, Favipiravir, Molnupiravir, Tamiflu; anti-malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts. Further examples for use in combination with Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs; anticancer; antibiotics, for example Azithromycin; hormones, Aromatase inhibitors, Colchicine, Anticoagulants, antibodies, cytokines, anti- IL6 drugs; Antiparasitics; vaccines; Interferons; drug conjugates; Drugs originally developed for SARS (ACE2 protein decoy); Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR/ABL antagonist may also be used in combination with compound of formula (11) for treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis. The compound of formula (11) of the present invention or its pharmaceutically acceptable salts may be used further in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combinations. MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect) and safinamide (Xadago); Catechol O-methyltransferase (COMT) inhibitors, Entacapone (Comtan) and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, Amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon), Memantine (Namenda), aducanumab (Aduhelm); Riluzole (Rilutek), Edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austedo), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel), levetiracetam (Keppra, Elepsia XR, Spritam) and clonazepam (Klonopin); citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex (Depakote), carbamazepine (Carbatrol, Epitol) and lamotrigine (Lamictal). The compounds of formula (11) and its compositions of the present invention are also intended for use with general care provided patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including Metronidazole and Cephalosporin antibiotics, such as Ceftriaxone and Cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as Metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin C or/and K and zinc sulfate), anti-inflammatory agents ( such as Ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including Artemether and Artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as Ciprofloxacin, macrolide antibiotics, such as Azithromycin, cephalosporin antibiotics, such as Ceftriaxone, or aminopenicillins, such as Ampicillin), or shigellosis. In a preferred embodiment, present invention provides a pharmaceutical composition comprising compound of formula (11) or its pharmaceutically acceptable salts for treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis. In another preferred embodiment, the present invention provides pharmaceutical composition comprising compound of formula (11) and suitable pharmaceutically acceptable excipients for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis. The pharmaceutically acceptable excipients may be selected at least one from diluents, carriers, binders, disintegrating agents, lubricating agents, surface active agents and the like. In another embodiment, the present invention further discloses use of said compound of formula (11) or their suitable pharmaceutical compositions for the treatment of Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis. In another preferred embodiment, the present invention provides a method of treating Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis using pharmaceutical composition of compound of formula (11) or its pharmaceutically acceptable salts. In a preferred embodiment, a method of treating Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders preferably ulcerative colitis using compound of formula (11) or its pharmaceutical composition. In another preferred embodiment of the present invention provides a process for the preparation of a stable pharmaceutical composition of compounds of formula (11). The stable pharmaceutical composition may be made by dry mixing, wet granulation or dry granulation methods by techniques known to persons skilled in the art. Thus, for example, In wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules, the wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules. In dry mixing process, the drug is mixed with all the pharmaceutical excipients required. The blend is mixed with one or more suitable excipients from those described elsewhere and then final blend is either compressed into tablets or filled in capsules. In dry granulation process, the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules. One or more solvents or vehicle used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof and other such materials known to those of ordinary skill in the art. In an embodiment, the pharmaceutically acceptable excipients described in the present invention are selected at least one from diluents, carriers, binders, disintegrating agents, lubricating agents, surface active agents and the like. Diluents include, but are not limited to lactose monohydrate, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose, combinations thereof and other such materials known to those of ordinary skill in the art. Carriers include, but are not limited to lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose and silicic acid, combinations thereof and other such materials known to those of ordinary skill in the art. Binders include, but are not limited to carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein, combinations thereof and other such materials known to those of ordinary skill in the art. Disintegrating agents include, but are not limited to, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate sodium, combinations thereof and other such materials known to those of ordinary skill in the art. Lubricating agents used include, but are not limited to, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic acid, combinations thereof and other such materials known to those of ordinary skill in the art. Surface active agents include but are not limited to, nonionic surfactant selected from alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside; anionic surfactant selected from arachnidan acid and arachidonic acid; cationic surfactant selected from cetyl trimethylammonium bromide and cetylpyridinium chloride, combinations thereof and other such materials known to those of ordinary skill in the art. General Process for Preparation The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art. The reactions can be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being affected. Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below. The compounds of the general formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art. Scheme 1
Figure imgf000028_0001
Wherein each of R1 , R2 , X, and Y, are as defined earlier. Compound 1 and Compound 2 can be prepared by variety of methods familiar to those skilled in art using reported procedures. Compound (1), on treatment with isocyanato derivative (2) under suitable conditions in presence of base like sodium hydride and appropriate solvent to afford compound of formula (I). Specific reaction conditions, solvents and other parameters necessary for carrying out the process steps as described above are well within the capabilities of a person skilled in the art. The invention is further illustrated by the following non-limiting examples which describe the preferred way of carrying out the present invention. These are provided without limiting the scope of the present invention in any way. 1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCl3 using TMS as the internal standard. Example – 1 N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide 1
Figure imgf000028_0002
H NMR (400 MHz, = , J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.81 (s, 1H), 5.63 (s, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.68 – 2.65 (m, 4H), 1.94 (qui, J = 7.2 Hz, 4H), 1.49 (s, 6H); MS (ESI): m/z (%) = 445.10 (100%) (M+H)+ , 443.10 (100%) (M-H). Example 2 N'-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2- hydroxypropan-2-yl)benzenesulfonimidamide 1H NMR (400 MHz,
Figure imgf000029_0001
1H), 8.00 (bs, 1H), 7.68- 7.64 (m, 1H), 7.24-7.19 (m, 2H), 6.79 (s, 1H), 2.76-2.60 (m, 8H), 1.95-1.85 (m, 4H), 1.50 (s, 3H), 1.48 (s, 3H); MS (ESI): m/z (%) = 456.88 (100%) (M+H)+ . Example – 3 N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)furan-2-sulfonimidamide 1H NMR (400 MHz,
Figure imgf000029_0002
(s, 1H), 6.82 (s, 1H), 6.79 (s, 1H), 5.03 (s, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 1.94 (qui, J = 7.2 Hz, 4H), 1.38 (s, 6H); MS (ESI): m/z (%) = 429.20 (100%) (M+H)+ , 427.30 (100%) (M-H). Example 4 (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide 1H NMR (400 MHz, DMSO-d6, D2O-X): δ = 10.7 (br, s, 1H), 8.23 (s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 15.2 Hz, 1H), 7.58 (d, J = 15.2 Hz, 1H), 6.96 (s, 1H), 2.79 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 1.98 – 1.91 (m, 4H); MS (ESI): m/z (%) = 389.92 (100%) (M+H)+ , 411.90 (20%) (M+Na+). Example 5 (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide 1H NMR (400 MHz, DMSO)
Figure imgf000030_0001
= , (s, 1H), 7.46-7.42 (m, 2H), 7.29 (d, J=14.8Hz, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 4.16 (q, J=7.2Hz, 2H), 2.82-2.78 (m, 4H), 2.67-2.64 (m, 4H), 1.98-1.91 (m, 4H), 4.16 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 401.15 (100%) (M+H)+; 423.15 (50%) (M+Na)+ . Example 6 (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide
Figure imgf000030_0002
1H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 8.16 (s, 1H), 7.36 (d, J = 14.8 Hz, 1H), 7.21 (d, J = 14.8 Hz, 1H), 7.17 (s, 1H), 6.95 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 2.12 (s, 3H), 1.98 – 1.91 (m, 4H), 1.27 (d, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 415.18 (100%) (M+H)+ . Example-7 (R,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- ethanesulfonamide 1H NMR (400 MHz, DMS s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60-6.54 (m, 1H), 3.27-3.1 H), 2.67 (t, J=7.2Hz, 4H), 2.35- 2.33 (m, 2H), 2.09-1.94 (m, 6H), 1.81-1.73 (m, 2H), 1.03 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)+ . Example-8 (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1- sulfonamide 1H NMR (400 MHz,
Figure imgf000031_0001
(s, 1H), 6.95 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.36 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 4.08 – 4.02 (m, 1H), 3.18 – 3.03 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.14 – 2.07 (m, 4H), 2.03 – 1.80 (m, 6H), 1.70 – 1.60 (m, 1H); MS (ESI): m/z (%) = 376.10 (100%) (M+H)+, 374.05 (100%) (M-1). Example-9 (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2- yl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000031_0002
, (s, 1H), 6.92 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.53 (dd, J = 7.6 Hz, J = 15.2 Hz, 1H), 3.13 – 3.04 (m, 1H), 3.05 – 2.92 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 – 2.28 (m, 1H), 2.26 (s, 3H), 2.05 – 1.91 (m, 5H), 1.79 – 1.72 (m, 2H), 1.59 – 1.54 (m, 1H); MS (ESI): m/z (%) = 390.17 (100%) (M+H)+ , 388.07 (30%) (M-1). Example-10 (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-ethanesulfonamide 1H NMR (400 MHz, DMS (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60-6.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.35- 2.33 (m, 2H), 2.09-1.94 (m, 6H), 1.81-1.73 (m, 2H), 1.03 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)+ . Example-11 (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide 1H NMR (400 MHz, DMSO-
Figure imgf000032_0001
1H), 6.74 (d, J = 15.6 Hz, 1H), 6.65 (d, J = 15.2 Hz, 1H), 2.93 – 2.86 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.19 (s, 3H), 1.99 – 1.91 (m, 5H), 1.80 – 1.69 (m, 4H), 1.13 (s, 3H), MS (ESI): m/z (%) = 404.16 (100%) (M+H)+ . Example-12 (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000032_0002
1H), 6.73 (d, J = 15.2 Hz, 1H), 6.65 (d, J= 15.2 Hz, 1H), 2.80 (t, J = 7.2 Hz, 4H) , 2.68 (t, J = 7.2 Hz, 4H) , 2.20 (s, 3H), 1.96 (m, 4H), 1.72 (m, 4H), 1.13 (s, 3H); MS (ESI): m/z (%) = 404.25 (100%) (M+1). Example-13 sodium(S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)amide 1H NMR (400 MHz, DMS , 1H), 6.56 (d, J = 15.2 Hz, 1H), 6.16 (d, J= 16 Hz, 1H), 2.7 J = 7.2 Hz, 4H) , 2.62 (m, 1H), 2.08 (s, 3H), 1.90 (m, 4H), 1.72 (m, 4H), 1.60 (m, 3H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+1). Example-14 potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)amide 1H NMR (400 MHz, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H),
Figure imgf000033_0001
– , = 7.2 Hz, 4H), 2.64 – 2.58 (m, 1H), 2.08 (s, 3H), 1.90 (quin, J = 7.6 Hz, 4H), 1.75 – 1.70 (m, 3H), 1.62 – 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.21 (100%) (M-K)+ . Example-15 Sodium(R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)amide 1H NMR (400 MHz,
Figure imgf000033_0002
1H), 6.57 (d, J = 15.6 Hz, 1H), 6.19 (d, J = 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.64 – 2.59 (m, 1H), 2.08 (s, 3H), 1.91 (quin, J = 7.6 Hz, 4H), 1.74 – 1.68 (m, 3H), 1.62 – 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.17 (100%) (M-Na)+ . Example-16 (E)-N'-cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide 1H NMR (400 MHz, DMSO , 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.83 (s, 1H), 6.56 – 6.48 (m, .12 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 7H), 2.10 – 1.99 (m, 3H), 1.95 – 1.88 (m, 5H), 1.53 – 1.36 (m, 3H); ESI-Q-TOF-MS: m/z [M-HCl+H]+ calcd for [C22H30N5O2S]+: 428.2120; found: 428.2052 Example-17 (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1- methylpyrrolidin-2-yl)ethene-1-sulfonimidamide 1H NMR (400 MHz,
Figure imgf000034_0001
1H), 7.11 – 7.02 (m, 1H), 6.83 (s, 1H), 6.43 – 6.35 (m, 1H), 4.99 (br s, 1H), 3.62 – 3.61 (m, 1H), 3.09 – 3.07 (m, 1H), 2.77 (t, J = 7.2 Hz, 7H), 2.70 (t, J = 7.2 Hz, 4H), 2.33 – 2.27 (m, 1H), 2. 1 – 1.88 (m, 7H); MS (TOF): m/z (%) = 414.1897 (100%) (M+H)+ , 412.1765 (100%) (M-1)- . Example-18 (E)-N'-cyano-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide 1H NMR (400 MHz,
Figure imgf000034_0002
, 1H), 6.94 – 6.90 (m, 1H), 6.83 (s, 1H), 6.54 – 6.51 (m, 1H), 2.77 (t, J = 7.2 Hz, 5H), 2.70 (t, J = 7.2 Hz, 5H), 2.62 (br s, 3H), 1.99 – 1.90 (br s, 2H), 1.97 – 1.93 (m, 6H), 1.48 – 1.46 (m, 3H); MS (TOF): m/z (%) = 428.2097 (100%) (M+H)+ , 426.1941 (60%) (M-1)- . Example-19 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a- trimethyloctahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide 1H NMR (400 MHz, DMSO- s, 1H), 3.42 - 3.26 (m, 5H), 3.07 - 3.01 (m, 1H), 2.89 - 2.80 (m, 1H), 2.89 - 2.80 (m, 1H), 2.77 (t, J=7.2Hz, 4H), 2.73 - 2.67 (m, 4H), 2.58 - 2.44 (m, 1H), 2.38 - 2.33 (m, 1H), 1.98 - 1.92 (m, 4H), 1.69 - 1.61 (m, 2H), 1.31 (s, 3H), 1.18 (s, 3H), 0.78 (s, 3H); MS (TOF): m/z (%) = 461.2537 (100%) (M+H)+ . Example-20 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a- tetramethyloctahydropyrrolo[1,2-a]pyrazin-4-yl)methanesulfonamide 1H NMR (400 MHz, DMSO- (s, 1H), 3.52 – 3.48 (m, 2H), 3.18 – 3.09 (m, 1H), 3.09 – 3.01
Figure imgf000035_0001
, – , 2.81 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.36 – 2.33 (m, 2H), 2.19 (s, 3H), 2.01 – 1.93 (m, 4H), 1.76– 1.69 (m, 1H), 1.67 – 1.54 (m, 3H), 1.01 – 1.04 (m, 6H), 0.86 (s, 3H); MS (TOF): m/z (%) = 475.2709 (100%) (M+H)+ ,473.2593 (20%) (M-1). Example-21 (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1- ene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000035_0002
, (s, 1H), 6.91 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.62 – 6.55 (m, 1H), 3.27 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.30 (s, 6H), 1.99 – 1.91 (m, 4H); MS (ESI): m/z (%) = 364.1513 (100%) (M+H)+ . Example-22 sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)amide 1H NMR (400 MHz,
Figure imgf000036_0001
(s, 1H), 6.51 (d, J = 15.6 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.11 (s, 1H), 1.94 – 1.87 (m, 4H), 1.06 (s, 6H); MS (TOF): m/z (%) = 392.1987 (100%) (M+H)+ ,390.1841 (20%) (M-1). Example-23 (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl- d)pyrrolidin-2-yl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000036_0002
1H), 6.71 (d, J = 15.2 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 2.85 – 2.83 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.73 – 2.71 (m, 1H), 2.67 (t, J = 7.2 Hz, 4H), 2.15 (s, 2H), 1.95 (quin, J = 7.2 Hz, 4H), 1.81 – 1.69 (m, 4H), 1.10 (s, 3H). ESI-Q-TOF-MS: m/z 405.2268 (100%) [M+H]+ , 403.1901 (100%) [M- H]- . Example-24 (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl- d)pyrrolidin-2-yl)ethene-1-sulfonamide 1
Figure imgf000036_0003
H NMR (400 MHz, : = , , 6.72 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 15.2 Hz, 1H), 2.88 – 2.83 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 – 2.71 (m, 1H), 2.67 (t, J = 7.2 Hz, 4H), 2.15 (s, 2H), 1.95 (quin, J = 7.2 Hz, 4H), 1.82 – 1.69 (m, 4H), 1.11 (s, 3H), ESI-Q-TOF-MS: m/z 405.2104 (100%) [M+H]+ , 403.1915 (100%) [M- H]- . Example-25 (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2- yl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000037_0001
1H), 6.92 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.56 (dd, J1 = 7.6 Hz, J2 = 15.2 Hz, 1H), 3.12 – 3.06 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.38 – 2.32 (m, 1H), 2.25 (s, 2H), 2.08 – 2.01 (m, 1H), 1.95 (quin, J = 7.2 Hz, 4H), 1.80 – 1.73 (m, 2H), 1.63 – 1.54 (m, 1H), ESI-Q-TOF- MS: m/z 391.1956 (100%) [M+H]+ , 389.1756 (100%) [M-H]- . Example-26 (E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3- methylbut-1-ene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000037_0002
, , 6.73 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 15.2 Hz, 1H), 2.79 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.30 (s, 4H), 1.97 – 1.93 (m, 4H), 1.21 (s, 6H), ESI-Q-TOF-MS: m/z 394.2150 (100%) [M+H]+, 392.1980 (100%) [M-H]- . Example-27 Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1- (methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide 1H NMR (400 MHz, DM (s, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 2.78 – 2.68 (m, 9H), 2.64 – 2.59 (m, 1H), 2.06 (s, 2H), 1.94 – 1.87 (m, 4H), 1.74 – 1.70 (m, 3H), 1.60 – 1.57 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 405.2101 (100%) (M+H)+ ,403.1921 (100%) (M-1). Example-28 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2- (methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide 1H NMR (400 MHz,
Figure imgf000038_0001
1H), 3.54 (s, 2H), 2.98 - 2.50 (m, 10H), 2.45 - 2.09 (m, 5H), 1.99 - 1.91 (m, 4H), 1.81 - 1.65 (m, 4H), 1.10 (s, 6H), 0.8 (s, 3H); MS (TOF): m/z (%) = 476.2797 (100%) (M+H)+; 474.2623 (100%) (M-1)- . Example-29 (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000038_0002
, 1H), 6.79 - 6.73 (m, 2H), 6.66 - 6.62 (m, 1H), 6.46 - 6.45 (m, 1H), 3.34 - 3.22 (m, 2H), 2.90 - 2.86 (m, 3H), 2.78 - 2.72 (m, 3H), 2.22 (s, 3H), 2.03 - 1.96 (m, 2H), 1.88 - 1.73 (m, 4H), 1.15 (s, 3H); MS (TOF): m/z (%) = 402.25 (100%) (M+H)+ . Example-30 (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide 1H NMR (400 MHz, DMS (s, 1H), 6.91 (s, 1H), 6.77 - 6.65 (m, 2H), 4.79 (d, J=3.6Hz, 1H), 4.43 (d, J=2.8Hz, 1H), 3.03 - 2.97 (m, 3H), 2.81 - 2.78 (m, 7H), 2.33 (s, 3H), 1.99 - 1.76 (m, 6H), 1.16 (s, 3H); MS (TOF): m/z (%) = 420.19 (100%) (M+H)+ . Example-31 (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000039_0001
1H), 6.75 (t, J = 15.2 Hz, 1H), 6.60 (t, J = 15.6 Hz, 1H), 5.01 (t, J = 3.2 Hz, 1H), 3.18 – 2.89 (m, 2H), 2.87 – 2.67 (m, 3H), 2.68 – 2.60 (m, 2H), 2.32 – 2.19 (m, 4H), 2.07 – 1.93 (m, 2H), 1.90 – 1.79 (m, 6H), 1.17 (s, 3H);MS (TOF): m/z (%) = 420.1937 (50%) (M+H)+ ,418.1843 (5%) (M-1). Example-32 (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)ethene-1-sulfonamide 1H NMR (400 MHz,
Figure imgf000039_0002
= , 1H), 7.02 (s, 1H), 6.75 (t, J = 15.2 Hz, 1H), 6.65 (t, J = 15.6 Hz, 1H), 5.13 (d, J = 4.4 Hz, 1H), 4.98 (d, J = 3.6 Hz, 1H), 2.88 – 2.79 (m, 3H), 2.77 – 2.60 (m, 4H), 2.56 – 2.54 (m, 1H), 2.30 – 2.24 (m, 1H), 2.20 (s, 3H), 2.00 – 1.91 (m, 2H), 1.84 – 1.67 (m, 5H), 1.13 (s, 3H);MS (TOF): m/z (%) = 420.1947 (100%) (M+H)+ , 418.1800 (20%) (M-1). While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Biological Activity: In-vitro assays: THP1 monocytes were differentiated with PMA (100ng/ml) and incubated at 37 °C for 20 hrs in presence of 5% CO2. 2X105 differentiated cells were plated per well of 96 well tissue culture plates. The cells were primed using 500ng/mL Lipopolysaccharide and incubating for 4h under the same condition. The cells were then treated with various concentrations of the compounds for 30 min followed by treatment with 5mM ATP for 1hr. The supernatants were collected and analyzed by IL-1β (Mabtech Cat # 3415-1H-20) or TNF-a (Mabtech; Cat # 3510-1H-20) detection kit. The data were analyzed using GraphPad Prism V7.0. Dose Response Curve (DRC) was constructed to determine the IC50 value by fitting percentage cell survival data to the GraphPad Prism using nonlinear regression analysis. The in vitro IL-1β inhibitory activity (IC50) for representative compounds are listed in Table 1. Table 1: Compound IL-1β (IC50) (nM)
Figure imgf000040_0001
Example 16 1.5 Exam le 17 23
Figure imgf000041_0001
In-vivo efficacy studies: The effect of compound of formula (11) was investigated in dextran sodium sulphate (DSS) induced inflammatory model in mice. Female C57BL/6 mice were housed in our facility for one week before DSS experiments were run. Colitis was induced by administration of DSS (molecular weight [MW] =36,000–50,000 Da; MP Biomedicals). Three groups of animals were treated twice daily for eight days with various doses (1, 5 and 10 mg/kg, p.o.) of compound of formula (11). Control group animals received vehicle only. Mice were treated with 2% DSS dissolved in drinking water for 5 days, followed by regular access to water till the end of study. Weight loss and mortality were monitored daily until study termination. A scoring system was applied to assess diarrhea and the presence of occult or overt blood in the stool in the last day of the study. Changes in body weight were indicated as loss of baseline body weight as a percentage. Disease activity index (DAI) was determined based on a scoring system. The scoring criteria included that for (a) body weight where 0 corresponded to no loss of weight and 4 corresponding to >20% weight loss; (b) Stool consistency where 0 is normal and 3 is diarrhea; rectal bleeding where 0 is no abnormalities and 4 is severe. Results Dextran sodium sulphate (DSS) (diseased control) caused an increase in DAI score associated with shrinkage of colon length as compared to normal control group. Treatment with compound of formula (11) was found to lower disease activity index (DAI) associated with an improvement in colon length. Groups Disease % Colon % activity index inhibition length improvement
Figure imgf000042_0001
The compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of NLRP3 activity and suitable for humans and other warm-blooded animals, and may be administered either by oral, topical or parenteral administration. Evaluation of effect of compound of Formula (11) in 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) induced IBD model in rat TNBS-IBD is a chemical-induced IBD model with an overall etiology, including some immunological and histological changes in the GI tract that resembles human disease. We aimed to evaluate the effect of Formula (11) in TNBS-induced IBD model in rat. Male Sprague Dawley rats randomized into various treatment groups were subjected to colitis induction by rectal administration of TNBS in 50% ethanol. Different groups of animals were treated twice daily for six days with various doses (1, 5, 25 and 50 mg/kg, p.o.) of Formula (11). Control group animals received vehicle only. On 7th day, body weight was recorded, animals were sacrificed and colon was removed, washed and length & weight were recorded. Results Treatment with compound of formula (11) showed dose-related improvement in body weight loss (Figure-1) and shortening of colon length due to TNBS challenge (as shown in the following table). Gr. Dose Mean % No Treatment (m /k ) (colon SEM inhibition in
Figure imgf000043_0001
Protocol Title: A randomised, double blind, parallel, interventional phase II-a proof of concept trial to evaluate the efficacy and safety of compound 11 for the treatment of patients with mild to moderately active Ulcerative Colitis (UC) resistant to high doses of mesalamine treatment. Objectives and Endpoints: The purpose of this study is to evaluate efficacy and safety of compound 11 oral capsule twice a day for 12 weeks for treatment of mild to moderate active ulcerative colitis resistant to high doses of mesalamine. OBJECTIVES ENDPOINTS of 6, g: al ad
Figure imgf000043_0002
Secondary al as of a a of at ic a y al in Es t, ry al in m is or al ee
Figure imgf000044_0001
2) Rectal bleeding subscore = 0 3) Centrally read endoscopy subscore = 0 or 1 (score of 1 modified to exclude friability) ed 1 ng nt
Figure imgf000045_0001
Criteria for Safety: Physical Examinations A complete physical examination is include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological systems. Height and weight are also be measured and recorded. A brief physical examination is include, evaluation of the head, neck, eyes, ears, nose, throat, chest, heart, lungs, abdomen, and skin. Vital Signs Vital sign measurements include sitting blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature and should be taken in resting condition. Electrocardiograms 12-lead ECGs are performed. Clinical Safety Laboratory Tests Clinical Laboratory assessment includes: ^ Hematology: Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular volume, MCHC, platelet count, red blood cell count, white blood cell count, differential WBC count, red cell distribution width. ^ Liver function test: Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, serum protein, albumin and total bilirubin (with Direct & Indirect bilirubin). ^ Renal function test: Blood urea nitrogen, serum creatinine / creatinine clearance and uric acid. ^ Urine microscopy: Epithelial cells, red blood cells, pus cells, cast and crystals; physical examination of urine to include: appearance and colour. ^ Urine Chemistry: pH, Specific gravity, Protein, Glucose, Bilirubin, albumin, Urobilinogen, Ketone bodies and nitrite. Pregnancy Testing: Serum pregnancy test / Urine pregnancy test will be performed for female participants with child bearing potential. Adverse Events Frequency and severity of adverse events (AEs) for all the participants enrolled are recorded. All AEs, are classified using ^ Causality ^ Severity ^ Seriousness Note: All the safety assessments are performed at the specified time-points as mentioned in the protocol. Methodology: This is a Phase IIa, randomized, two arms, double blind, double dummy, parallel, multicentre study to evaluate efficacy and safety of compound 11 oral capsules for the treatment of mild to moderately active ulcerative colitis resistant to high doses of mesalamine. The study consists of: screening period of upto 4 weeks, treatment period of 12 weeks (first 6 weeks period: Induction period and remaining 6 weeks: Maintenance period), and end of the study at Week 13. Eligible participants are randomly assigned to one of the two following study arms: Eligible participants are screened within 4 weeks prior to enrolment. Informed consent is obtained from all eligible participants before any study related activity according to the regulatory requirements. During Visit 1 and Visit 2, eligibility is verified. Eligible participants are randomly assigned in a 1:1 ratio on Day 0 to one of following: ^ Arm 1: Compound 11 capsules 25 mg for oral administration + 50 mg placebo twice daily for 6 weeks ^ Arm 2: Compound 11 capsules 50 mg for oral administration + 25 mg placebo twice daily for 6 weeks This trial is conducted over a period of 12 weeks. Treatment period consist of two periods: blinded induction period of 6 weeks followed by an open label maintenance period of 6 weeks. Participants are received treatment as described above for 6 weeks. At the end of 6 weeks, participants are assessed for achievement of clinical remission. Participants in either arm who show clinical remission are continued to receive the same dose for another 6 weeks in maintenance period. Those participants who do not achieve in clinical remission (non-responders) at 6 weeks in 25 mg compound 11 arm are entered the follow-up period to receive capsule compound 1150 mg for 6 weeks. Participants in compound 11 50 mg arm, who do not achieve clinical remission are offered rescue / standard of care medicine (steroid or biological agent) and withdrawn from the study. Assessment of efficacy is performed by a tool modified Mayo Score (mMS). The mMS is a composite instrument which consists of three subscores: 1. Stool frequency, 2. Rectal Bleeding & 3. Endoscopic findings assessed by central reviewer. Detailed assessment procedure is described in Section 8. During the treatment period, dose adjustment is not permitted. All the participants are evaluated for adverse event at all visits during treatment period. If further investigations are required in case of any AE, Investigator is advised to assess the AE and take necessary action. Participants are advised to contact the Investigator for any discomfort. No. of subjects in treatment arm: A total of 24 participants (12 participants per arm) have been planned to be enrolled in the study. Duration of treatment: 12 weeks (Induction period: 6 weeks and Maintenance period: 6 weeks) Study Duration: 119 days including screening period of 28 days

Claims

We claim: 1. A method for the treatment of Inflammatory bowel diseases, which comprises administering a compound of formula (I)
Figure imgf000048_0001
Formula (I) or its pharmaceutically acceptable salts wherein X is O, NH, or N-R3 wherein R3 at each occurrence is independently selected from hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, optionally substituted groups selected from (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, SO2(C1-C6)alkyl, thiol, thioalkyl, thio-alkoxy, SO(C1-C6)alkyl, benzyl, aryl, heteroaryl, heterocyclyl; Y is O, S; R1 at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl,(C1- C6)alkylSO2(C1-C6)alkyl,(C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3- C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, NH(C1- C6)alkyl, N((C1-C6)alkyl)2, NH(C2-C6)alkenyl, N((C2-C6)alkenyl)2, -N- heterocyclyl, N(C1-C6)alkyl-heterocyclyl, NR’R’’, thiol, mercaptoalkyl, SO2(C1- C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1- C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1- C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms; Alternatively R1 is selected from ,
Figure imgf000048_0002
n, is independently selected from integer 0-3; each of R’ , R” , R1’, R1’’, R2’ and R2” at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1- C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-C6)alkyl, (C1-C6)alkylN(C1- C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3- C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, - CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14- membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms; In an embodiment R’ and R” optionally forms 4- to 7-membered heterocyclic ring system. R2 is selected from the following ring system
Figure imgf000049_0001
wherein X, Y, Z at each occurrence independently represents C, N, S, SO2, and O, which may be optionally substituted; each of R7, R8, R9, R10 , R11 and R12 at each occurrence are independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C -C )alkoxy, benzyl, aryl, heteroaryl, het 8 1 6 erocyclyl; In one embodiment each of R and R9 , R9 and R10, R10 and R11 and R11 and R12 wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p; p = 1-2. Rx and Ry at each occurrence are independently selected from hydrogen, halogen, optionally substituted groups selected from (C1-C6)alkyl; Alternatively Rx and Ry together may form a 4- to 7-membered heterocyclic ring system; ‘M’ is selected from aryl, heteroaryl, heterocyclyl; and wherein when any of above defined group is substituted the substitutions on them are selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, optionally substituted group selected from (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, C1-C6 alkoxy, aryl, heterocyclyl, heteroaryl, -COR11, -CSR11, C(O)OR11, C(O)-R11, -C(O)-NR11R12, - C(S)-NR11R12, -SO2R11 group, wherein each of, R11 and R12 is independently selected from hydrogen, optionally substituted group selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups.
2. The method as claimed in claim 1, wherein inflammatory bowel diseases are selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
3. The method as claimed in claim 1 and 2, wherein Inflammatory bowel disease is ulcerative colitis.
4. The method as claimed in claim 1, wherein said compound of Formula (I) is selected from the group: N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2-N'-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide; N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)furan-2-sulfonimidamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2- yl)ethenesulfonamide; (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide; (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethenesulfonamide; (R,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-ethanesulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2- yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin- 2-yl)ethene-1-sulfonamide; (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-ethanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1-sulfonamide; sodium(S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)amide; potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)amide; Sodium(R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)amide; (E)-N'-cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide; (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1- methylpyrrolidin-2-yl)ethene-1-sulfonimidamide; (E)-N'-cyano-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a- trimethyloctahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a- tetramethyloctahydropyrrolo[1,2-a]pyrazin-4-yl)methanesulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop- 1-ene-1-sulfonamide; sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)amide; (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl- d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1- (methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl- d)pyrrolidin-2-yl)ethene-1-sulfonamide; or pharmaceutically acceptable salts of any of the compounds above.
5. The method as claimed in claim 1, wherein therapeutically effective amount of compound of formula (I) or its pharmaceutically acceptable salt is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.
6. The method as claimed in claim 1, wherein compound of formula (I) or its pharmaceutically acceptable salt is administered by oral, topical or parenteral route of administration, preferably administered by an oral route of administration.
7. The method as claimed in claim 1, wherein compound of formula (I) or its pharmaceutically acceptable salt is administered in combination with other suitable therapeutic agents.
8. The method as claimed in claim 1, wherein compound of formula (I) or its pharmaceutically acceptable salt is administered in the form of pharmaceutical composition.
9. Use of the compound of formula (I) as claimed in claim 1 and 4 for the preparation of a medicament for the treatment of Inflammatory bowel diseases.
10. Use of the compound of formula (I) as claimed in claim 1 and 4, wherein the compound is administrated in a daily dosage range is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.
11. A pharmaceutical composition comprising compound of formula (I) or its pharmaceutically acceptable salts for the treatment of Inflammatory bowel diseases wherein compound of formula (I) is
Figure imgf000052_0001
12. The pharmaceutical composition as claimed in claim 11, wherein Inflammatory bowel diseases are selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
13. The pharmaceutical composition as claimed in claim 11 and 12, wherein inflammatory bowel disease is ulcerative colitis.
14. The pharmaceutical composition as claimed in claim 11, wherein therapeutically effective amount of compound of formula (I) or its pharmaceutically acceptable salt is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.
15. The pharmaceutical composition as claimed in claim 11 comprising compound of formula (I) and other pharmaceutically acceptable excipients for the treatment of Inflammatory bowel diseases.
16. The pharmaceutical composition as claimed in claim 11, wherein compound of formula (I) or its pharmaceutically acceptable salt is administered in combination with other suitable therapeutic agents.
17. Use of the pharmaceutical composition as claimed in claim 11 for the preparation of medicament for the treatment of inflammatory bowel diseases.
18. A method for the treatment of inflammatory bowel diseases which comprises administering a compound of formula (11)
Figure imgf000052_0002
Formula 11 or its pharmaceutically acceptable salts.
19. The method as claimed in claim 18, wherein Inflammatory bowel diseases is selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
20. The method as claimed in claim 18 and 19, wherein inflammatory bowel disease is ulcerative colitis.
21. The method as claimed in claim 18, wherein therapeutically effective amount of compound of formula (11) or its pharmaceutically acceptable salt is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.
22. The method as claimed in claim 18, wherein compound of formula (11) or its pharmaceutically acceptable salt is administered by oral, topical or parenteral route of administration, preferably administered by an oral route of administration.
23. The method as claimed in claim 18, wherein compound of formula (11) or its pharmaceutically acceptable salt is administered in combination with other suitable therapeutic agents.
24. The method as claimed in claim 18, wherein compound of formula (11) or its pharmaceutically acceptable salt is administered in the form of pharmaceutical composition.
25. Use of the compound of formula (11) as claimed in any one of the preceding claims for the preparation of a medicament for the treatment of inflammatory bowel diseases.
26. Use of the compound of formula (11) as claimed in any one of the preceding claims wherein the compound is administrated in a daily dosage range is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.
27. A pharmaceutical composition comprising compound of formula (11) or its pharmaceutically acceptable salts for the treatment of inflammatory bowel diseases, wherein compound of formula (11) is
Figure imgf000053_0001
Formula (11)
28. The pharmaceutical composition as claimed in claim 27, wherein inflammatory bowel diseases are selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease and other related forms of disorders.
29. The pharmaceutical composition as claimed in claim 27 and 28, wherein inflammatory bowel disease is ulcerative colitis.
30. The pharmaceutical composition as claimed in claim 27, wherein therapeutically effective amount of compound of formula (11) or its pharmaceutically acceptable salt is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.
31. The pharmaceutical composition as claimed in claim 27 comprising compound of formula (11) and other pharmaceutically acceptable excipients for the treatment of inflammatory bowel diseases.
32. The pharmaceutical composition as claimed in claim 27, wherein compound of formula (11) or its pharmaceutically acceptable salt is administered in combination with other suitable therapeutic agents.
33. Use of the pharmaceutical composition as claimed in claim 27 for the preparation of medicament for the treatment of inflammatory bowel diseases.
34. The pharmaceutical composition as claimed in claim 31, wherein other pharmaceutically acceptable excipients are selected from diluents, carriers, binders, disintegrating agents, lubricating agents and surface active agents.
35. The pharmaceutical composition as claimed in any one of the preceding claims, wherein diluents are selected from lactose monohydrate, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose and suitable combination thereof.
36. The pharmaceutical composition as claimed in as claimed in any one of the preceding claims, wherein carriers are selected from lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose, silicic acid and suitable combination thereof.
37. The pharmaceutical composition as claimed in as claimed in any one of the preceding claims, wherein binders are carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein and suitable combination thereof.
38. The pharmaceutical composition as claimed in any one of the preceding claims, wherein disintegrating agents are selected from bicarbonate salt, chitin, gellan gum, polacrillin potassium, docusate sodium and suitable combination thereof.
39. The pharmaceutical composition as claimed in any one of the preceding claims, wherein lubricating agents are selected from glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate, myristic acid and suitable combination thereof.
40. The pharmaceutical composition as claimed in any one of the preceding claims wherein surface active agents are nonionic surfactant selected from alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside; anionic surfactant selected from arachnidan acid and arachidonic acid; cationic surfactant selected from cetyl trimethylammonium bromide and cetyl pyridinium chloride and suitable combination thereof.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018225018A1 (en) * 2017-06-09 2018-12-13 Cadila Healthcare Limited Novel substituted sulfoximine compounds
WO2019043610A1 (en) * 2017-08-31 2019-03-07 Cadila Healthcare Limited Novel substituted sulfonylurea derivatives
WO2020148619A1 (en) * 2019-01-14 2020-07-23 Cadila Healthcare Limited Novel substituted sulfonylurea derivatives
WO2021048809A1 (en) * 2019-09-12 2021-03-18 Cadila Healthcare Limited Novel substituted sulfoximine derivatives
WO2021111351A1 (en) * 2019-12-03 2021-06-10 Cadila Healthcare Limited Novel substituted sulfonylurea and sulfoximineurea derivatives
WO2021171230A1 (en) * 2020-02-28 2021-09-02 Cadila Healthcare Limited Novel substituted sulfonylurea and sulfoximineurea derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018225018A1 (en) * 2017-06-09 2018-12-13 Cadila Healthcare Limited Novel substituted sulfoximine compounds
WO2019043610A1 (en) * 2017-08-31 2019-03-07 Cadila Healthcare Limited Novel substituted sulfonylurea derivatives
WO2020148619A1 (en) * 2019-01-14 2020-07-23 Cadila Healthcare Limited Novel substituted sulfonylurea derivatives
WO2021048809A1 (en) * 2019-09-12 2021-03-18 Cadila Healthcare Limited Novel substituted sulfoximine derivatives
WO2021111351A1 (en) * 2019-12-03 2021-06-10 Cadila Healthcare Limited Novel substituted sulfonylurea and sulfoximineurea derivatives
WO2021171230A1 (en) * 2020-02-28 2021-09-02 Cadila Healthcare Limited Novel substituted sulfonylurea and sulfoximineurea derivatives

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