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  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/16—Sulfur atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to the development of therapeutic compound for the treatment of brain psychiatric diseases.
• the present invention provides a NLRP3 inhibitors or its pharmaceutically acceptable salt or suitable composition useful in the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases.
• These severe and persistent illnesses include Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington 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.
• 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).
• Parkinson’s disease is the most prevalent synucleinopathy and the second most common neurodegenerative disorder worldwide, affecting about 2% of the population over the age of 60 (Nat. Rev. Dis. Primers 3, 17013 (2017)).
• Inflammasomes are multiprotein complexes that function as intracellular sensors of environmental and cellular stress (Nat. Rev. Neurosci.15, 84–97 (2014).).
• the NLR family pyrin domain containing 3 (NLRP3) inflammasome is composed of the NLRP3 sensor, the signaling adapter apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the caspase-1 protease.
• AD interleukin-1 ⁇
• IL-18 interleukin-1 ⁇
• CNS central nervous system
• the inflammasome pathway can potentially be activated by oxidative stress and insoluble ⁇ -synuclein aggregates (PLOS ONE 8, e55375 (2013)).
• the NLRP3 inflammasome plays a key role in PD-like pathophysiology in rodents and might represent a feasible therapeutic target to mitigate neurotoxic ⁇ -synuclein pathology and the resulting nigrostriatal dopaminergic neuron loss in PD (Sci. Transl. Med.10, eaah4066 (2016)).
• microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease- modifying treatments for PD (Sci.
• MCC950 inhibited NLRP3 activation in a mouse model of MWS.
• Peripheral blood mononuclear cells (PBMC) from patients with low penetrance NLRP3 variants (Q703K and V198M) have been shown to display enhanced IL-1 ⁇ levels following inflammasome activation compared to healthy controls.
• release of IL-1 ⁇ has been shown to be NLRP3-dependent as it was blocked by MCC950 (Schuh et al., 2019).
• the IL-1 receptor antagonist anakinra is conventionally used to control the symptoms of the syndrome, but patients relapse when treatment is withdrawn.
• NLRP3 inflammasome activation There are various agents in various stages of Phase 1 and Phase II development that target the NLRP3 inflammasome. (Freeman et al., 2020). Agents like MCC950, CY-09, OLT1177, Tranilast, Oridonin, NT-0167 displayed the good therapeutic properties, as they directly target NLRP3 itself, but not other components (NEK7, ASC, caspase-1, or IL-1 ⁇ ) up-/downstream of NLRP3 inflammasome activation. Furthermore, these inhibitors are being used in clinical practice or are being investigated at phase II clinical trials having shown relatively high safety (Yang et al., 2019). NLRP3 in innate immune cells are activated by Pathogen Associated Molecular Patterns and Death Associated Molecular Patterns.
• NLRP3 inflammasome activates Caspase-1 and in-turn cleave and releases IL-1 ⁇ and IL-18.
• NLRP3 inflammasome inhibitors have potential to negate IL-1 mediated neurodegenerative disorder including Parkinson’s disease.
• All current therapies are limited to injectable biologics that often have limited central nervous system (CNS) penetration, which is particularly important in NOMID patients with severe CNS disease. Therefore, there remains an unmet clinical need for more targeted and preferably small molecule, compounds as an alternative to IL-1 targeted biologics.
• CNS central nervous system
• the present invention provides a therapeutic compound of formula (I) and their pharmaceutically acceptable salts for the prevention and treatment of treatment of neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• TBI Traumatic brain injury
• ALS Amyotrophic lateral sclerosis
• AD Alzheimer disease
• PD Parkinson’s disease
• MS Multiple sclerosis
• Huntington disease Huntington disease and other related forms of disorders.
• EMBODIMENTS OF THE INVENTION the present invention provides a therapeutic compound of formula (I) Formula (I) suitable for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorder diseases.
• Traumatic brain injury TBI
• Amyotrophic lateral sclerosis ALS
• Alzheimer disease AD
• Parkinson’s disease PD
• Multiple sclerosis MS
• Huntington disease Huntington 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 neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington 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 neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• the present invention provides a method of treating neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders using pharmaceutical composition of compound of formula (I) or its pharmaceutically acceptable salts.
• the present invention provides a suitable composition comprising the compound of formula (I) or their suitable pharmaceutical compositions for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• treatment refers to slowing, stopping, or delaying the progression of the disease or clinical symptoms in a patient, as evidenced by a decrease or elimination of a clinical or diagnostic symptom of the disease, disorder or condition.
• Patient includes both human and animals.
• mammal means humans and other mammalian animals.
• 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 neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• the present invention describes a method of treating a subject suffering from neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington 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 or prevention of neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• neuroinflammatory disorders or neurodegenerative disorders disease is Parkinson’s disease (PD).
• the method comprises administering to a subject an effective amount of a compound according to Formula (I), Formula (I) their tautomeric forms, their stereoisomers, their enantiomers, 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
• 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.
• 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.
• 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
• piperazine piperidine
• 1 ,3-dioxolane imidazoline
• imidazolidine imidazoline
• imidazolidine imidazoline
• pyrrolidine pyrroline
• 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)carbamo
• the present invention provides a suitable composition comprising the compound of formula (I) or their suitable pharmaceutical compositions for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington 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.
• 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 neuroinflammatory disorders or neurodegenerative disorder diseases.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• the present invention provides a method of treating a subject suffering from neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders preferably Parkinson’s disease (PD) 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.
• TBI Traumatic brain injury
• ALS Amyotrophic lateral sclerosis
• AD Alzheimer disease
• Parkinson’s disease PD
• MS Multiple sclerosis
• Huntington disease and other related forms of disorders preferably Parkinson’s disease (PD) 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.
• 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 neuroinflammatory disorders or neurodegenerative disorder diseases.
• the additional therapeutic agent used is selected from Inhibitors of interleukin-1 ⁇ (e.g.
• 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 Cef
• 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 neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders preferably Parkinson’s disease (PD) wherein compound of formula (I) is Formula (I)
• the present invention provides pharmaceutical composition comprising compound of formula (I) and suitable pharmaceutically acceptable excipients for the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders preferably Parkinson’s disease (PD).
• 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 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 neuroinflammatory disorders or neurodegenerative disorder diseases.
• 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 neuroinflammatory or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders preferably Parkinson’s disease (PD).
• the present invention provides a method of treating neuroinflammatory disorders or neurodegenerative disorder diseases using pharmaceutical composition of compound of formula (I) or its pharmaceutically acceptable salts.
• a method of treating neuroinflammatory disorders or neurodegenerative disorder diseases using compound of formula (I) or its pharmaceutical composition a preferred embodiment, provides compound of formula (11) Formula (11) or its pharmaceutically acceptable salts suitable for the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases.
• These severe and persistent illnesses include Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• neuroinflammatory disorders or neurodegenerative disorder diseases is Parkinson’s disease (PD).
• the present invention provides use of the compound of formula (11) or their suitable pharmaceutical compositions for the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders preferably Parkinson’s disease (PD).
• 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 neuroinflammatory disorders or neurodegenerative disorder diseases.
• 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. 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.
• 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.
• 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.
• 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.
• 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.
• 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 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 neuroinflammatory disorders or neurodegenerative disorder diseases.
• other 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 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 may also be used in combination with compound of formula (11) for treatment of neuroinflammatory disorders or neurodegenerative disorder diseases.
• 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 comprising compound of formula (11) or its pharmaceutically acceptable salts for treatment of neuroinflammatory disorders or neurodegenerative disorder diseases.
• These severe and persistent illnesses include Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders.
• neuroinflammatory disorders or neurodegenerative disorder diseases is Parkinson’s disease.
• the present invention provides pharmaceutical composition comprising compound of formula (11) and suitable pharmaceutically acceptable excipients for the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases.
• 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 neuroinflammatory disorders or neurodegenerative disorder diseases such as Traumatic brain injury (TBI), Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington disease and other related forms of disorders preferably Parkinson’s disease.
• the present invention provides a method of treating neuroinflammatory disorders or neurodegenerative disorder diseases using pharmaceutical composition of compound of formula (11) or its pharmaceutically acceptable salts.
• a method of treating neuroinflammatory disorders or neurodegenerative disorder diseases using compound of formula (11) or its pharmaceutical composition 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.
• 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.
• 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 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.
• 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. The supernatants were collected and analyzed by IL-1b (Mabtech Cat # 3415-1H-20) or TNF-a (Mabtech; Cat # 3510-1H-20) detection kit.
• the suspension was then filtered through cell strainer, subjected to centrifugation at 365g for 5 minutes at room temperature.
• the pellet was resuspended in RPMI complete medium and layered over 30% stock isotonic percoll (SIP). This gradient mixture was centrifuged for 10 minutes at 700g at room temperature. Discard the interphase between PBS and 30% percoll containing myelin. Washed the pelleted cells containing microglia and seed 50000 cells/well in poly-L-lysine coated 96 well plate and incubate overnight at 37OC in 5% CO 2 incubator. After overnight incubation, test compounds were added and further incubated for 1hr. Following this, LPS (1 ⁇ g/mL) was added and incubated for 4h.
• In-vivo efficacy studies Demonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration.
• Animals All the animal experiments were carried out in female rats and mice, bred in-house. Animals were housed in groups of 6 animals per cage, for a week, in order to habituate them to vivarium conditions (25 ⁇ 4 °C, 60-65 % relative humidity, 12: 12 h light: dark cycle, with lights on at 7.30 am). All the animal experiments were carried out according to the internationally valid guidelines following approval by the 'Zydus Research Center animal ethical committee'.
• In-vivo LPS and ATP induced IL-1 ⁇ assay Female C57 mice (6-8 weeks) received intraperitoneal injection of 50 ⁇ g/mouse of lipopolysaccharide (LPS) in PBS. Animals were treated immediately with the test compounds or the vehicle. After 2h of LPS injection, animals were administered with ATP at 12.5 mg/mouse dissolved in PBS via intraperitoneal route. After 30 minutes of ATP injection, serum was collected for IL-1 ⁇ estimation by ELISA.
• the blood sampling was performed from retro-orbital plexus under mild isoflurane anesthesia in a tube containing Na-heparin ( ⁇ 20 IU/mL of blood) and placed on ice cold condition.
• the blood samples were centrifuged at 4000 rpm for 15 min to obtain plasma and stored at -70 ⁇ 20°C until analysis.
• the animal was perfused with 4 mL 1X PBS buffer solution under deep isoflurane anesthesia followed by collection of brain tissue.
• the collected brain samples were immediately placed on the ice and then stored at - 70 ⁇ 20°C until homogenization.
• Brain tissue samples were homogenized using a Polytron tissue homogenizer in phosphate buffer saline, the brain homogenate density was kept 0.2 g/mL.
• the plasma and brain tissue homogenate samples were analyzed for total and unbound test compounds concentration using a separately developed fit for research LC-MS/MS assays.
• the calibration range was linear over 5 to 2000 ng/mL for total and 0.2 to 200 ng/mL for unbound fraction for test compounds.
• Phase 2a POC study Phase 2a POC study of test compound (compound 11 of the present invention) in patients with Parkinson's disease.
• Clinically diagnosed patients with Parkinson's disease aged 45 to 75 years and with Modified Hoehn and Yahr Stage of less than 3 are included in the study.
• Approximately 15 patients with Parkinson's disease are enrolled in the study.
• Study are conducted with dose range around 25 to 75 mg twice daily for 14 days.
• Eligible patients are received 27 doses of test compound (compound 11 of the present invention) twice daily from Day 1 to Day 13 in the morning before breakfast and in the evening before dinner. On Day 14, single dose is administered in the morning before breakfast.
• eligible patients are admitted in the clinical unit on Day (- 1).
• Cerebrospinal Fluid are collected after 2 hours of post last dose to correlate concentration of test compound (Compound 11 of the present invention) in CSF and plasma. Exploratory parameters like ⁇ -Synuclein levels, NLRP3, Soluble LAG-3, Toll-interacting protein and hs C-Reactive Protein are measured in the blood at defined time points. Safety are evaluated by physical examination and neurological examination, vital signs, clinical laboratory tests and ECGs at various time points during the study and documentation of AEs/SAEs. 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.

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• 2022
  • 2022-08-25 CN CN202280057882.8A patent/CN117858871A/zh active Pending
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