CN117858871A - Treatment for neuroinflammatory disorders - Google Patents

Treatment for neuroinflammatory disorders Download PDF

Info

Publication number
CN117858871A
CN117858871A CN202280057882.8A CN202280057882A CN117858871A CN 117858871 A CN117858871 A CN 117858871A CN 202280057882 A CN202280057882 A CN 202280057882A CN 117858871 A CN117858871 A CN 117858871A
Authority
CN
China
Prior art keywords
disease
compound
formula
alkyl
indacen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280057882.8A
Other languages
Chinese (zh)
Inventor
萨米尔·阿加瓦尔
德文·V·帕尔马尔
穆库尔·贾因
拉吉夫·莎玛
比努·菲利普
哈利拉尔·帕特尔
阿比吉特·查特杰
卡西纳斯·维斯瓦纳坦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zdus Life Science Co ltd
Original Assignee
Zdus Life Science Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zdus Life Science Co ltd filed Critical Zdus Life Science Co ltd
Publication of CN117858871A publication Critical patent/CN117858871A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/335—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
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/40—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/14—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D307/64—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to the development of therapeutic compounds for the treatment of mental disorders of the brain. In particular, the invention provides NLRP3 inhibitors or pharmaceutically acceptable salts thereof or suitable compositions that can be used to treat neuroinflammatory disorders or neurodegenerative disorders diseases. These severe and persistent diseases include craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.

Description

Treatment for neuroinflammatory disorders
Technical Field
The present invention relates to the development of therapeutic compounds for the treatment of mental disorders of the brain. In particular, the invention provides NLRP3 inhibitors or pharmaceutically acceptable salts thereof or suitable compositions that can be used to treat neuroinflammatory disorders or neurodegenerative disorders diseases. These severe and persistent diseases include craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
Background
The nucleotide binding oligomerization domain (NOD) like receptor family, the pyrin domain 3 (NLRP 3 or NALP 3) -containing inflammatory bodies are the major source of mucosal Interleukin (IL) -1 beta and are mostly activated by aspects of inflammation-related stress. NLRP3 is a cytosolic Pattern Recognition Receptor (PRR) that senses both exogenous and endogenous danger signals. NLRP3 protein consists of three domains: leucine rich repeat domain (LRR), NOD (NACHT) containing a Caspase Activation and Recruitment Domain (CARD), and pyrin domain (PYD). Upon activation, NLRP3 oligomerizes via PYD-PYD interactions and triggers assembly of CARD-containing linker apoptosis-related spot-like proteins (ASCs). ASC fibrils assemble into large structures called ASC spots and recruit caspase-1 precursor, resulting in its autoproteolytic activation. Activated caspase-1 is capable of cleaving both IL-1 beta precursor and IL-18 precursor to produce the inflammatory cytokines IL-1 beta and IL-18 (Guo et al 2015; dinarello et al 2012).
The involvement of NLRP3 inflammatory bodies in different types of diseases provides a new approach for designing drugs targeting NLRP3 inflammatory bodies. To date, clinical treatments of NLRP 3-related diseases target IL-1 beta with IL-1 beta antibodies or recombinant IL-1 beta receptor antagonists, such as Canakinumab (Canakinumab) and anakinra (anakinra), respectively. In addition, some small molecule compounds have been shown to have anti-inflammatory effects on NLRP3 inflammatory body activation in vitro, including MCC950, β -hydroxybutyrate (BHB), bay 11-7082, dimethylsulfoxide (DMSO), and type I interferon. However, most of these inhibitors are relatively nonspecific and have low therapeutic effects. For inhibitors targeting IL-1β, it should be noted that IL-1β secretion is not the only product of NLRP3 inflammatory body activation; in contrast, other pro-inflammatory cytokines, including high mobility histone 1 (HMGB 1) and IL-18, may be involved in the pathogenesis of these diseases. In addition, IL-1β can be produced by inflammatory body independent pathways or other inflammatory bodies. Thus, inhibitors targeting IL-1β have unexpected immunosuppressive effects in addition to preventing activation of the NLRP3 inflammatory body itself. Pharmacological inhibitors specific for the NLRP3 inflammatory bodies may be the best choice for treating NLRP3 related diseases. (Yang et al, 2019).
Parkinson's Disease (PD) is the most common synucleinopathy worldwide and the second most common neurodegenerative disease affecting about 2% of the population over 60 years of age (nat. Rev. Dis. Primers 3,17013 (2017)).
Inflammatory corpuscles are polyprotein complexes that function as intracellular sensors of environmental and cellular stress (nat. Rev. Neurosci.15,84-97 (2014)). The NLR family of pyrin-containing domain 3 (NLRP 3) inflammatory bodies consists of NLRP3 sensor, signal adaptor apoptosis-related spot-like protein (ASC) containing caspase recruitment domain and caspase-1 protease. Upon cellular stress, assembly of the NLRP3 complex in immune cells triggers caspase-1 activation and caspase-1 mediated release of interleukin-1 beta (IL-1 beta) and IL-18, thereby triggering an inflammatory response. In neurodegenerative conditions such as Alzheimer's Disease (AD), the sustained accumulation of misfolded protein aggregates can trigger and sustain inflammatory body activation, driving Central Nervous System (CNS) inflammation and neuropathology (19). Recent findings in AD models have demonstrated that microglial-derived inflammatory small body components such as ASC spots can cross-vaccinate with pathogenic amyloid fibrils (20). In the brain of patients with PD, the inflammatory small body pathway may be activated by oxidative stress and insoluble α -synuclein aggregates (PLOS ONE 8, e55375 (2013)).
NLRP3 inflammatory corpuscles play a key role in the PD-like pathophysiology of rodents and may represent a viable therapeutic target for alleviating neurotoxic alpha-synuclein pathology in PD and the resulting loss of nigrostriatal dopaminergic neurons (Sci. Transl. Med.10, eaah4066 (2018)).
Nanomolar doses of the small molecule NLRP3 inhibitor MCC950 were previously demonstrated to eliminate fibril alpha-synuclein mediated activation of inflammatory bodies and extracellular ASC release in mouse microglia. Furthermore, oral administration of MCC950 in various rodent models of PD inhibited inflammatory small body activation and was effective in reducing motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α -synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that can drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease modifying treatment of PD (sci. Transl. Med.10, eaah4066 (2018)).
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 increase IL-1 β levels after activation of inflammatory bodies compared to healthy controls. Furthermore, the release of IL-1β has been shown to be NLRP3 dependent, as it is blocked by MCC950 (Schuh et al, 2019). The IL-1 receptor antagonist anakinra is commonly used to control the symptoms of the syndrome, but patients relapse when the treatment is stopped.
At different stages of stage 1 and stage 2 development, there are various agents targeting the NLRP3 inflammatory bodies. (Freeman et al 2020). Agents such as MCC950, CY-09, OLT1177, tranilast, oridonin, NT-0167 show good therapeutic properties because they target NLRP3 itself directly, rather than other components upstream/downstream of NLRP3 inflammatory body activation (NEK 7, ASC, caspase-1 or IL-1β). Furthermore, these inhibitors are being used in clinical practice or being studied in phase II clinical trials, have shown relatively high safety (Yang et al, 2019).
NLRP3 in innate immune cells is activated by pathogen-associated and death-associated molecular patterns. The resulting NLRP3 inflammatory body activates caspase-1 and in turn cleaves and releases IL-1 beta and IL-18.NLRP3 inflammatory corpuscle inhibitors have the potential to eliminate IL-1 mediated neurodegenerative disorders, including Parkinson's disease.
All current therapies are limited to injectable biological agents, which generally have limited Central Nervous System (CNS) penetration, which is particularly important in NOMID patients with severe CNS disease. Thus, as an alternative to targeting IL-1 biologicals, the clinical need for more targeted, preferably small molecule compounds remains unmet.
Disclosure of Invention
The present invention provides therapeutic compounds of formula (I) and pharmaceutically acceptable salts thereof for the prevention and treatment of neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
Embodiments of the invention
In embodiments, the present invention provides therapeutic compounds of formula (I) suitable for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorders
These severe and persistent diseases include craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In embodiments, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, suitable for treating neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In another embodiment, the invention provides therapeutic compounds of formula (I) and pharmaceutically acceptable salts thereof, suitable for administration alone or in combination for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In another embodiment, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorders diseases such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In another embodiment, the invention provides methods of treating neuroinflammatory disorders or neurodegenerative disorders diseases such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders using pharmaceutical compositions of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention provides suitable compositions comprising compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
Detailed description of the preferred embodiments
Definition:
the term "treatment" or "treatment" refers to slowing, halting or delaying the progression of a disease or clinical symptom in a patient, as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease, disorder or condition.
"patient" includes both humans and animals. "mammal" means humans and other mammals.
The term "preventing" refers to first preventing a subject from suffering from a disorder or disease.
The "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).
As used herein, "treating" includes achieving one or more of the following results, either partially or substantially: partially or completely reduces the extent of a disease, disorder or syndrome. Delaying, inhibiting, or preventing the progression of a disease, disorder, or syndrome includes, for example, delaying, inhibiting, or preventing the progression of a neuroinflammatory disorder or neurodegenerative disorder disease such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
The present invention describes methods of treating subjects suffering from neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In embodiments, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, which are suitable for treating or preventing neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In another embodiment, the invention provides the use of a compound of formula (I) or a suitable pharmaceutical composition thereof for the treatment or prophylaxis of neuroinflammatory disorders or neurodegenerative disorders diseases such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In a preferred embodiment, the neuroinflammatory disorder or neurodegenerative disorder disease is Parkinson's Disease (PD).
The method comprising administering to the subject an effective amount of a compound according to formula (I),
Its tautomeric forms, its stereoisomers, its enantiomers, its metabolites, its deuterium analogs, its pharmaceutically acceptable salts and pharmaceutical compositions containing them or mixtures thereof,
wherein the method comprises the steps of
X is O, NH or N-R 3 Wherein R is 3 Independently at each occurrence, represents hydrogen, hydroxy, halogen, nitro, cyano, haloalkyl, amino, 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 groups、(C 2 -C 10 ) Alkynyl, SO 2 (C 1 -C 6 ) Alkyl, thiol, thioalkyl, thioalkoxy, SO (C) 1 -C 6 ) Alkyl, benzyl, aryl, heteroaryl, heterocyclyl;
y is O, S;
R 1 independently at each occurrence, represents hydrogen, halogen, haloalkyl, cyano, optionally substituted, a group selected from: (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 1 -C 6 ) Alkoxy, (C) 3 -C 7 ) Cycloalkyl, (C) 1 -C 6 ) Alkyl SO 2 (C 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, t-butoxycarbonyl, NH (C) 1 -C 6 ) Alkyl, N ((C) 1 -C 6 ) Alkyl group 2 、NH(C 2 -C 6 ) Alkenyl, N ((C) 2 -C 6 ) Alkenyl group) 2 -N-heterocyclyl, N (C) 1 -C 6 ) Alkyl-heterocyclyl, NR' R ", thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ) Alkyl, SO 2 (C 3 -C 7 ) Cycloalkyl, SO 2 -aryl, SO 2 -heterocyclyl, (C) 1 -C 6 ) Thioalkyl (C) 1 -C 6 ) Thioalkoxy group, (C) 1 -C 6 ) Alkyl SO 2 NH 2 、-CONH 2 、-CO(C 1 -C 6 ) Alkyl, -CO (C) 1 -C 6 ) Haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4-to 7-membered heterocycle, 7-to 14-membered bicyclic heterocycle system, bridged ring or spiro ring system optionally having one or more heteroatoms;
in embodiments, R 1 The representation is:
n independently represents an integer of 0 to 3;
R’、R”、R 1 ’、R 1 ”、R 2 ' and R 2 "each independently at each occurrence represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from: (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 1 -C 6 ) Alkoxy, (C) 3 -C 7 ) Cycloalkyl, (C) 1 -C 6 ) Alkyl SO 2 (C 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, t-butoxycarbonyl, thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ) Alkyl, SO 2 (C 3 -C 7 ) Cycloalkyl, SO 2 -aryl, SO 2 -heterocyclyl, (C) 1 -C 6 ) Thioalkyl (C) 1 -C 6 ) Thioalkoxy group, (C) 1 -C 6 ) Alkyl SO 2 NH 2 、-CONH 2 、-CO(C 1 -C 6 ) Alkyl, -CO (C) 1 -C 6 ) Haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4-to 7-membered heterocycle, 7-to 14-membered bicyclic heterocycle system, bridged ring or spiro ring system optionally having one or more heteroatoms; in embodiments, R' and R "optionally form a 4 to 7 membered heterocyclic ring system;
R 2 Selected from the following ring systems
Wherein X, Y, Z, at each occurrence, independently represents C, N, S, SO 2 And O, which may be optionally substituted;
R 4 independently at each occurrence, represents hydrogen, halogen, haloalkyl, cyano, optionally substituted, a group selected from: (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (C) 1 -C 6 ) Alkoxy, (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, bicyclic heterocyclic system, substituted amine, thiol, mercaptoalkyl, (C) 1 -C 6 ) A thioalkoxy group;
R 7 、R 8 、R 9 、R 10 、R 11 and R is 12 Independently at each occurrence selected from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxy, optionally substituted groups selected from the group consisting of: (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, (C) 3 -C 6 ) Cycloalkyl, (C) 1 -C 6 ) Alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; in one embodiment, R 8 And R is 9 、R 9 And R is 10 、R 10 And R is 11 R is as follows 11 And R is 12 Each may, where possible, together form a chain containing 0 to 2 members selected from N, O and S (O) p A 4 to 7 membered saturated or partially saturated ring of further heteroatoms of (a); p=1 to 2.
R x And R is y Independently at each occurrence selected from hydrogen, halogen, optionally substituted (C) 1 -C 6 ) A group of an alkyl group; alternatively, R x And R is y May together form a 4 to 7 membered heterocyclic ring system;
'M' is selected from aryl, heteroaryl, heterocyclyl;
when any of the above defined groups is substituted, the substitution thereon may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkoxy, alkylthio, optionally substituted selected from the group consisting of: (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 3 -C 10 ) Cycloalkyl, C 1 -C 6 Alkoxy groupAryl, heterocyclyl, heteroaryl, -COR 11 、-CSR 11 、C(O)OR 11 、C(O)-R 11 、-C(O)-NR 11 R 12 、-C(S)-NR 11 R 12 、-SO 2 R 11 A group, wherein R is 11 And R is 12 Independently selected from hydrogen, optionally substituted groups selected from the group consisting of: (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl groups;
in a preferred embodiment, the groups, radicals described above may be chosen from:
"alkyl" and other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chains which may be further substituted with oxygen atoms, which may be further linear or branched, and combinations thereof, as is well known to the skilled artisan, unless the carbon chains are otherwise defined. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, where the indicated number of carbon atoms permits, e.g., C 3-10 The term alkyl also includes cycloalkyl groups, as well as combinations of straight or branched alkyl chains in combination with cycloalkyl structures. When the number of carbon atoms is not specified, meaning C 1-6 . Substituted alkyl groups include alkyl groups substituted with one or more moieties selected from the group consisting of: halo (e.g., cl, F, br, and I); haloalkyl (e.g., CF) 3 2-Br-ethyl, CH 2 F、CH 2 Cl、CH 2 CF 3 Or CF (CF) 2 CF 3 ) The method comprises the steps of carrying out a first treatment on the surface of the A hydroxyl group; an amino group; a carboxylic acid ester; an amide group; an alkylamino group; an arylamino group; an alkoxy group; an aryloxy group; a nitro group; an azido group; cyano group; thio; sulfonic acid; a sulfate; phosphonic acid; phosphate esters and phosphonate esters, as those described under the definition of "optionally substituted".
"alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and which may be linear or branched or a combination thereof, unless the carbon chain is otherwise defined. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, isopropenyl,Hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like, where the specified number of carbon atoms permits, e.g. C 5-10 The term alkenyl also includes cycloalkenyl groups as well as combinations of straight, branched and cyclic structures. When the number of carbon atoms is not specified, meaning C 2-6 )。
"alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, and which may be linear or branched or a combination thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, and the like. When the number of carbon atoms is not specified, it means.
"thioalkyl" groups, alone or in combination with other groups, represent alkyl groups as defined above, e.g., thiomethyl, methylthiomethyl, phenylthiomethyl, and the like, which may be optionally substituted, attached to a group of the formula-SR '(sulfur and oxidized forms thereof) (wherein R' represents hydrogen, an alkyl or aryl group).
As used herein, "carbocycle" or "carbocycle residue" is intended to mean any stable mono-or bi-or tri-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 sense, the term carbocycle is intended to include (where applicable) groups representing cycloalkyl, phenyl, and other saturated, partially saturated, or aromatic residues;
The terms "cycloalkyl" and "cycloalkenyl" refer to optionally substituted, saturated and unsaturated monocyclic, bicyclic or tricyclic carbon groups. Where appropriate, cycloalkyl or cycloalkenyl groups can have the indicated number of carbon atoms, e.g., C 3 -C 6 Cycloalkyl or cycloalkenyl includes within its scope carbocyclic groups having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexylA group, cyclohexenyl, cyclohexadienyl, and the like. Substituted cycloalkyl or cycloalkenyl includes substitution with one or more moieties selected from the group consisting of: halo (e.g., cl, F, br, and I); haloalkyl (e.g., CF) 3 2-Br-ethyl, CH 2 F、CH 2 Cl、CH 2 CF 3 Or CF (CF) 2 CF 3 ) The method comprises the steps of carrying out a first treatment on the surface of the A hydroxyl group; an amino group; a carboxylic acid ester; an amide group; an alkylamino group; an arylamino group; an alkoxy group; an aryloxy group; a nitro group; an azido group; cyano group; thio; sulfonic acid; a sulfate; phosphonic acid; phosphate esters and phosphonate esters, as those described under the definition of "optionally substituted".
"alkoxy" refers to a straight or branched chain alkoxide of the indicated number of carbon atoms.
"aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6 to 10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.
"heterocyclyl" means a saturated, partially saturated or unsaturated, aromatic or non-aromatic, mono-, bi-or tricyclic radical containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including oxidized forms of sulfur, i.e., SO&SO 2 . The heterocyclyl system may be attached to another moiety by any number of carbon atoms or heteroatoms of the group, and may be 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, dithiane, 1, 3-dioxane, 1, 3-dithiane, oxathiane, thiomorpholine and the like. The term "heterocycloalkyl" refers to a heterocyclic group as defined above attached to an alkyl group as defined above;
"heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Thus, heteroaryl groups include heteroaryl groups fused to other kinds of rings, such as aryl, cycloalkyl, and non-aromatic heterocyclic rings. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, azafuranyl, isobenzofuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolinyl, indolyl, isoquinolinyl, dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing 3 to 15 carbon atoms forming 1 to 3 rings are included.
The term "haloalkyl" means an alkyl structure in which at least one hydrogen is replaced by a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all identical to each other.
The "haloalkoxy" group is selected from suitable haloalkyl groups as defined above directly attached to oxygen atoms, more preferably from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;
in certain other embodiments, wherein two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all identical to each other.
"aryloxyalkyl" means an alkyl group substituted with an aryloxy group as defined herein.
"aryloxyaryl" means an aryl group substituted with an aryloxy group as defined herein.
"aryloxyheteroaryl" means a heteroaryl group substituted with an aryloxy group as defined herein.
"halo/halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
Suitable groups and substituents on these groups may be selected from those described anywhere in the specification.
The term "substituted" as used herein means that any one or more hydrogens on the designated atom are replaced with a selection of the designated group, provided that the designated atom's normal valence is not exceeded, and the substitution results in a stable compound. The term "substituted" as used herein means that any one or more hydrogens on the designated atom are replaced with a selection of the designated group, provided that the designated atom's normal valence is not exceeded, and the substitution results in a stable compound.
"pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 1, 2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, dicarbonic acid, carbonic acid, citric acid, ethylenediamine tetraacetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, ethanoarsonic acid (glycolyarsenici), hexylisophthalic acid (hexylesporic), hydrazinoacetic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, -lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, nitrilosulfonic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, optionally substituted alkyl refers to "alkyl" or "substituted alkyl". In addition, optionally substituted groups include unsubstituted groups.
Unless otherwise indicated in the specification, structures described herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms.
Particularly useful compounds may be selected from, but are not limited to, the following:
n' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -5- (2-hydroxyprop-2-yl) thiophene-2-sulfonylimido amide;
n' -cyano-4-fluoro-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -3- (2-hydroxypropan-2-yl) benzenesulfonimide amide;
n' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -4- (2-hydroxyprop-2-yl) furan-2-sulfonylimido amide;
(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) vinylsulfonamide;
(E) -2- (1-ethyl-4-methyl-1H-imidazol-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) vinylsulfonamide;
(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) ethylene-1-sulfonamide;
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (1-methylpyrrolidin-2-yl) ethylene-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) ethylene-1-sulfonamide;
(S, E) -2- (1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-S-indacen-4-yl) carbamoyl) ethylene-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) ethylene-1-sulfonylimido amide;
(E) -N' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- ((R) -1-methylpyrrolidin-2-yl) ethylene-1-sulfonylimido amide;
(E) -N' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- ((R) -1-methylpyrrolidin-2-yl) ethylene-1-sulfonylimido amide;
(E) -N' -cyano-2- ((R) -1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonylimido amide;
n- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((1S, 8 aR) -3, 8 a-trimethyloctahydropyrrolo [1,2-a ] pyrazin-1-yl) methanesulfonamide;
n- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((4S, 8 aS) -2,3, 8 a-tetramethyl octahydropyrrolo [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;
(E) - ((3- (dimethylamino) -3-methylbut-1-en-1-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) sodium 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) ethylene-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) ethylene-1-sulfonamide
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (1- (methyl-d) pyrrolidin-2-yl) ethylene-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, 8 aR) -3, 8 a-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) ethylene-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) ethylene-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) ethylene-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) ethylene-1-sulfonamide;
or a pharmaceutically acceptable salt of any of the above compounds.
The following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:
μg: micrograms of
1 H NMR: proton nuclear magnetic resonance
bs: broad single peak
CDC1 3 : deuterated chloroform
CHC1 3 : chloroform (chloroform)
d: bimodal
DAMPs: a damage related molecular pattern;
DBU:1, 8-diazabicyclo (5.4.0) undec-7-ene
DCM: dichloromethane (dichloromethane)
dd: dual bimodal
DMAC: n, N- (dimethylacetamide)
DMAP:4- (dimethylamino) pyridine
DMF: n, N-dimethylformamide
DMSO: dimethyl sulfoxide
dt: double trimodal
EDTA: ethylenediamine tetraacetic acid
EtOAc: acetic acid ethyl ester
EtOH-ethanol
HCl (g): hydrogen chloride (gas)
IL1 beta: interleukin 1 beta
K 2 CO 3 : potassium carbonate
m: multiple peaks
MeOH: methanol
mmol: millimoles (milli)
MS: mass spectrometry
N 2 : nitrogen gas
Na 2 CO 3 : sodium carbonate
ng: nake (Nake)
NIS: n-iodosuccinimide
PAMP: pathogen-associated molecular patterns;
PMA: phorbol 12-myristate 13-acetate
POCI 3 : phosphorus oxychloride
RM: reaction mixture
T., RT: room temperature
s: unimodal peak
t: three peaks
td: triple double peak
THF: tetrahydrofuran (THF)
TLC: thin layer chromatography
TLR: toll-like receptors.
Tnfα: tumor necrosis factor alpha
In one embodiment, the present invention provides suitable compositions comprising compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorders such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's 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 (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and/or thickening agents. The pharmaceutical compositions facilitate administration of the NLRP3 antagonist or other compound to an organism. There are a variety of techniques in the art for administering compounds including, but not limited to, rectal, oral and intravenous, aerosol and parenteral, ocular, pulmonary and topical.
In embodiments, the present invention provides an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may be selected from 1mg to 500mg, for the treatment and prevention of neuroinflammatory disorders or neurodegenerative disorders diseases; preferably 1mg to 250mg and more preferably 1mg to 150mg.
In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 150mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. For example, in certain embodiments, the compound is administered orally to a subject in an amount that provides about 1mg to about 25mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 25mg to about 50mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 50mg to about 75mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 75mg to about 100mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 100mg to about 125mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 125mg to about 150mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 150mg to about 175mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 175mg to about 200mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 200mg to about 225mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 225mg to about 250mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day.
In certain other embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 25mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 50mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 75mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 100mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 125mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 150mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 175mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 200mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 225mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 250mg of the compound of formula (I), or a pharmaceutically acceptable salt thereof, per day.
In embodiments, the present invention provides that an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered by oral, topical, parenteral, intravenous or intramuscular routes of administration. In a preferred embodiment, the present invention provides for the administration of an effective amount of formula (I) or a pharmaceutically acceptable salt thereof by the oral route.
The compound of formula (I), or a pharmaceutically acceptable salt thereof, may be provided to a subject daily, weekly, as prescribed by a physician to a person in need thereof.
In another embodiment, the invention provides a method of treating a subject suffering from a neuroinflammatory disorder or neurodegenerative disorder disease, such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders, preferably Parkinson's Disease (PD), comprising treating a patient in need of such treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a suitable pharmaceutical composition containing the same.
In embodiments, the present invention provides a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and other suitable agents as therapeutic agents for the treatment of neuroinflammatory disorders or neurodegenerative disorders diseases.
In embodiments, the additional therapeutic agent used is selected from inhibitors of interleukin-1 beta (e.g., li Luoxi pu, kanamab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, gasdermin D inhibitors (e.g., niacin Luo Huang amide); cox-2 specific inhibitors, TNF-alpha binding proteins (e.g., infliximab, etanercept), interferon-13, interferon, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergics, anticancer agents; antiviral drugs, for example: redexivir, lopinavir/ritonavir, fampicvir, mo Nuola, and darifenacin; antimalarial agents, for example: chloranil and hydroxychloroquinone; or a suitable pharmaceutically acceptable salt thereof. Other examples used in combination with the following: non-alcoholic steatohepatitis (NASH) and fibrotic drugs; anticancer drugs; antibiotics, such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL 6 drugs; antiparasitic agents; a vaccine; an interferon; a drug conjugate; drugs originally developed for SARS (ACE 2 protein baits); intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: bay 43-9006); syk inhibitors; an mTOR inhibitor; antibodies (rituximab (Rituxan)); and BCR/ABL antagonists.
The compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof, may further be used in combination with one or more suitable pharmaceutically active agents selected from the group of therapeutic agents of any combination. MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect), and sarfenamide (Xadago); catechol O-methyltransferase (COMT) inhibitors, entacapone (Comtan) and opiperidone (oncogenes); benztropine (togetin), benzhaline, amantadine; cholinesterase inhibitors, donepezil (aricet), galantamine (Razadyne) and rismin (Exelon), memantine (Namenda), adakamab (Aduhelm); riluzole (Riluzole), edaravone (Radicava); omeprazole (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austedo), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (sequel), levetiracetam (Keppra, elegsia XR, spritam) and clonazepam (Klonopin); citalopram (celex), escitalopram (Lexapro), fluoxetine (Prozac, sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex sodium (Depakote), carbamazepine (Carbatrol, epitol) and lamotrigine (lamotrl).
The compounds and compositions of the invention are also intended for use with general care provided for patients suffering from arenaviridae virus infections, including parenteral fluids (including dextrose brines and ringer's lactate) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, antipyretic analgesic drugs, antiemetics (such as metoclopramide) and/or antidiarrheal drugs, vitamins and mineral supplements (including vitamin C or/and K and zinc sulfate), anti-inflammatory drugs (such as ibuprofen), analgesic drugs, and drugs for other common diseases in the patient population, such as antimalarials (including artemether and artesunate-benzol combination therapy), typhoids (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone or aminopenicillines, such as ampicillin), or shigella.
In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition.
In embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease, such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of the disorder, preferably Parkinson's Disease (PD)
In embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (I) and a suitable pharmaceutically acceptable excipient for use in the treatment of neuroinflammatory disorders or neurodegenerative disorders diseases such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders, preferably Parkinson's Disease (PD).
The pharmaceutically acceptable excipient may be selected from at least one of diluents, carriers, binders, disintegrants, lubricants, surfactants, etc.
In embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be selected from 1mg to 500mg, for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease; preferably 1mg to 250mg and more preferably 1mg to 150mg.
In embodiments, the present invention provides that pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered by oral, topical, parenteral, intravenous or intramuscular routes of administration. In a preferred embodiment, the pharmaceutical composition may be administered by an oral route of administration.
In another embodiment of the present invention, a process for preparing a stable pharmaceutical composition of a compound of formula (1) or a pharmaceutically acceptable salt thereof is provided.
The stable pharmaceutical compositions may be prepared by dry mixing, wet granulation or dry granulation methods by techniques known to those skilled in the art. Thus, for example,
in the wet granulation process, the drug is mixed with one or more pharmaceutically acceptable excipients and granulated with a suitable binding solution as previously described to form wet granules, which are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients as described elsewhere and then compressed into tablets or filled into capsules.
In the dry mixing process, the drug is mixed with all of the pharmaceutically acceptable excipients required. The blend is mixed with one or more suitable excipients as described elsewhere, and the final blend is then compressed into tablets or filled into capsules.
In the dry granulation process, the drug is mixed with one or more pharmaceutically acceptable excipients and compressed into pellets and the pellets are passed through a desired screen. The sieved granules are mixed with one or more suitable excipients as described elsewhere and then compressed into tablets or filled into capsules.
The one or more solvents or vehicles used in the formulation are selected from the group consisting of water, acetone, chloroform, methylene chloride, ethanol, ethyl acetate, methanol, isopropanol, and combinations thereof and other such materials known to one of ordinary skill in the art.
The invention also discloses the use of a compound of formula (I) or a suitable pharmaceutical composition thereof for the treatment of a neuroinflammatory or neurodegenerative disorder, such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease and other related forms of disorders, preferably Parkinson's Disease (PD).
In another embodiment, the invention provides a method of treating a neuroinflammatory disorder or a neurodegenerative disorder disease using a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, methods of treating a neuroinflammatory disorder or a neurodegenerative disorder disease using a compound of formula (I) or a pharmaceutical composition thereof are provided.
In a preferred embodiment, the present invention provides a compound of formula (11) suitable for treating a neuroinflammatory disorder or a neurodegenerative disorder disease
Or a pharmaceutically acceptable salt thereof. These severe and persistent diseases include craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In a preferred embodiment, the neuroinflammatory disorder or neurodegenerative disorder disease is Parkinson's Disease (PD).
In another preferred embodiment, the present invention provides the use of a compound of formula (11) or a suitable pharmaceutical composition thereof for the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease, such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders, preferably Parkinson's Disease (PD).
In another preferred embodiment, the present invention provides an effective amount of a compound of formula (11), or a pharmaceutically acceptable salt thereof, for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease, which effective amount may be selected from 1mg to 500mg; preferably 1mg to 250mg and more preferably 1mg to 150mg.
In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 250mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. For example, in certain embodiments, the compound is administered orally to a subject in an amount that provides about 1mg to about 25mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 25mg to about 50mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 50mg to about 75mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 75mg to about 100mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 100mg to about 125mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 125mg to about 150mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 150mg to about 175mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 175mg to about 200mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 200mg to about 225mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 225mg to about 250mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day.
In certain other embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 25mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 50mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 75mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 100mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 125mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides from about 1mg to about 150mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 175mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 200mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 225mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day. In certain embodiments, the compound is administered orally to the subject in an amount that provides about 1mg to about 250mg of the compound of formula (11), or a pharmaceutically acceptable salt thereof, per day.
In another preferred embodiment, the present invention provides that an effective amount of a compound of formula (11), or a pharmaceutically acceptable salt thereof, may be administered by oral, topical, parenteral, intravenous or intramuscular routes of administration. In a preferred embodiment, the invention provides for the administration of an effective amount of formula (11) or a pharmaceutically acceptable salt thereof by the oral route.
The compound of formula (11), or a pharmaceutically acceptable salt thereof, may be provided to a subject daily, weekly, as prescribed by a physician to a person in need thereof.
In one of the preferred embodiments, the present invention provides a combination of a compound of formula (11) and pharmaceutically acceptable salts thereof, and other suitable agents as therapeutic agents for the treatment of neuroinflammatory disorders or neurodegenerative disorders diseases.
Wherein the other suitable therapeutic agent may be selected from inhibitors of interleukin-1 beta (e.g., li Luoxi pu, kanamazumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, gasdermin D inhibitors (e.g., niacin Luo Huang amide); cox-2 specific inhibitors, TNF-alpha binding proteins (e.g., infliximab, etanercept), interferon-13, interferon, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergics, anticancer agents; antiviral drugs, for example: redexivir, lopinavir/ritonavir, fampicvir, mo Nuola, and darifenacin; antimalarial agents, for example: chloranil and hydroxychloroquinone; or a suitable pharmaceutically acceptable salt thereof. Other examples used in combination with the following: non-alcoholic steatohepatitis (NASH) and fibrotic drugs; anticancer drugs; antibiotics, such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL 6 drugs; antiparasitic agents; a vaccine; an interferon; a drug conjugate; drugs originally developed for SARS (ACE 2 protein baits); intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: bay 43-9006); syk inhibitors; an mTOR inhibitor; antibodies (rituximab (Rituxan)); and BCR/ABL antagonists may also be combined with compounds of formula (11) for use in the treatment of neuroinflammatory disorders or neurodegenerative disorders.
The compounds of formula (11) of the present invention, or pharmaceutically acceptable salts thereof, may further be used in combination with one or more suitable pharmaceutically active agents selected from the group of therapeutic agents of any combination. MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect), and sarfenamide (Xadago); catechol O-methyltransferase (COMT) inhibitors, entacapone (Comtan) and opiperidone (oncogenes); benztropine (togetin), benzhaline, amantadine; cholinesterase inhibitors, donepezil (aricet), galantamine (Razadyne) and rismin (Exelon), memantine (Namenda), adakamab (Aduhelm); riluzole (Riluzole), edaravone (Radicava); omeprazole (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austedo), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (sequel), levetiracetam (Keppra, elegsia XR, spritam) and clonazepam (Klonopin); citalopram (celex), escitalopram (Lexapro), fluoxetine (Prozac, sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex sodium (Depakote), carbamazepine (Carbatrol, epitol) and lamotrigine (lamotrl).
The compounds of formula (11) and compositions thereof of the present invention are also intended for use with general care provided for patients suffering from arenaviridae virus infections, including parenteral fluids (including dextrose brines and ringer's lactate) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungals, antipyretic analgesic drugs, antiemetics (such as metoclopramide) and/or antidiarrheals, vitamins and mineral supplements (including vitamin C or/and K and zinc sulfate), anti-inflammatory drugs (such as ibuprofen), analgesic drugs and drugs for other common diseases in the patient population, such as antimalarials (including artemether and artesunate-benzyl alcohol combination therapy), typhoid drugs (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporins antibiotics, such as ceftriaxone or aminopenicillins, such as ampicillin), or shigella.
In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11), or a pharmaceutically acceptable salt thereof, for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease. These severe and persistent diseases include craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
In a preferred embodiment, the neuroinflammatory disorder or neurodegenerative disorder disease is parkinson's disease.
In another preferred embodiment, the present invention provides a pharmaceutical composition for treating a neuroinflammatory disorder or a neurodegenerative disorder disease comprising a compound of formula (11) and a suitable pharmaceutically acceptable excipient.
The pharmaceutically acceptable excipient may be selected from at least one of diluents, carriers, binders, disintegrants, lubricants, surfactants, etc.
In another embodiment, the invention also discloses the use of a compound of formula (11) or a suitable pharmaceutical composition thereof for the treatment of a neuroinflammatory or neurodegenerative disorder disease, such as craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders, preferably parkinson's disease.
In another preferred embodiment, the present invention provides a method of treating a neuroinflammatory disorder or a neurodegenerative disorder disease using a pharmaceutical composition of a compound of formula (11) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, methods of treating a neuroinflammatory disorder or neurodegenerative disorder disease using a compound of formula (11) or a pharmaceutical composition thereof are provided.
In another preferred embodiment of the present invention, a process for preparing a stable pharmaceutical composition of a compound of formula (11) is provided.
The stable pharmaceutical compositions may be prepared by dry mixing, wet granulation or dry granulation methods by techniques known to those skilled in the art. Thus, for example,
in the wet granulation process, the drug is mixed with one or more pharmaceutically acceptable excipients and granulated with a suitable binding solution as previously described to form wet granules, which are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients as described elsewhere and then compressed into tablets or filled into capsules.
In the dry mixing process, the drug is mixed with all of the pharmaceutically acceptable excipients required. The blend is mixed with one or more suitable excipients as described elsewhere, and the final blend is then compressed into tablets or filled into capsules.
In the dry granulation process, the drug is mixed with one or more pharmaceutically acceptable excipients and compressed into pellets and the pellets are passed through a desired screen. The sieved granules are mixed with one or more suitable excipients as described elsewhere and then compressed into tablets or filled into capsules.
The one or more solvents or vehicles used in the formulation are selected from the group consisting of water, acetone, chloroform, methylene chloride, ethanol, ethyl acetate, methanol, isopropanol, and combinations thereof and other such materials known to one of ordinary skill in the art.
In an embodiment, the pharmaceutically acceptable excipient described in the present invention is selected from at least one of diluents, carriers, binders, disintegrants, lubricants, surfactants, and the like.
Diluents include, but are not limited to, lactose monohydrate, polymethacrylates selected from among Eudragit (Eudragit), potassium chloride, sulfobutyl ether beta-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, dextrose, 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 (carbopol), gellan gum, gum arabic, hydrogenated vegetable oils, polymethacrylates selected from among ewing, xanthan gum, lactose and zein, combinations thereof, and other such materials known to one of ordinary skill in the art.
Disintegrants include, but are not limited to, bicarbonate, chitin, gellan gum, polacrilin potassium, and docusate sodium, combinations thereof, and other such materials known to those of ordinary skill in the art.
Lubricants used include, but are not limited to, glyceryl behenate, hydrogenated vegetable oils, sodium stearyl fumarate, and myristic acid, combinations thereof, and other such materials known to those of ordinary skill in the art.
Surfactants include, but are not limited to, nonionic surfactants selected from the group consisting of alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside, and octyl glucoside; an anionic surfactant selected from the group consisting of arachnidian acid and arachidonic acid; a cationic surfactant selected from cetyltrimethylammonium bromide and cetylpyridinium chloride; combinations thereof and other such materials known to those of ordinary skill in the art.
General procedure for preparation
The novel compounds of the present invention may be prepared using the reactions and techniques described below, as well as conventional techniques known to those skilled in the art of organic synthesis or variations thereof as understood by those skilled in the art.
The reaction may be carried out in a solvent suitable for the reagents and materials used and suitable for the transformation effected. Preferred methods include, but are not limited to, those described below, wherein all symbols are as defined above, unless otherwise defined below.
The compounds of formula (I) may be prepared as described in the schemes below, with appropriate modifications/variations within the scope of those skilled in the art.
Scheme 1
Wherein R is 1 、R 2 Each of X and Y is as previously defined. Compound 1 and compound 2 can be prepared by various methods familiar to those skilled in the art using the reported procedures. Under suitable conditions, in the presence of a base (e.g. sodium hydride) and a suitable solvent, using an isogenThe cyanate ester derivative (2) is used for treating the compound (1) to obtain the compound of the formula (I).
The specific reaction conditions, solvents and other parameters required to carry out the process steps as described above are within the ability of those skilled in the art.
The invention is further illustrated by the following non-limiting examples describing preferred modes of carrying out the invention. These are not intended to limit the scope of the invention in any way.
Given in the examples 1 H NMR spectroscopic data (see below) were recorded using a 400MHz spectrometer (Bruker AVANCE-400) and reported on the delta scale. Unless otherwise indicated, the solvent used for NMR is CDCl 3 TMS was used as an internal standard.
Example-1
N' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -5- (2-hydroxyprop-2-yl) thiophene-2-sulfonylimido amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.95(bs,1H),7.23(d,J＝4.0Hz,1H),6.82(d,J＝4.0Hz,1H),6.81(s,1H),5.63(s,2H),2.77(t,J＝7.2Hz,4H),2.68–2.65(m,4H),1.94(qui,J＝7.2Hz,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) benzenesulfonimide amide
1 H NMR(400MHz,DMSO):δ＝8.13(dd,J＝2.4Hz,J＝7.6Hz,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-hydroxyprop-2-yl) furan-2-sulfonylimido amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.10(bs,1H),7.55(s,1H),6.82(s,1H),6.79(s,1H),5.03(s,1H),2.77(t,J＝7.2Hz,4H),2.68(t,J＝7.2Hz,4H),1.94(qui,J＝7.2Hz,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
1 H NMR(400MHz,DMSO-d 6 ,D2O-X):δ＝10.7(br,s,1H),8.23(s,1H),8.05(d,J＝2.8Hz,1H),8.02(d,J＝2.8Hz,1H),7.74(d,J＝15.2Hz,1H),7.58(d,J＝15.2Hz,1H),6.96(s,1H),2.79(t,J＝7.2Hz,4H),2.66(t,J＝6.8Hz,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) vinylsulfonamide
1 H NMR(400MHz,DMSO):δ＝10.55(bs,1H),8.20(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) vinylsulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.55(s,1H),8.16(s,1H),7.36(d,J＝14.8Hz,1H),7.21(d,J＝14.8Hz,1H),7.17(s,1H),6.95(s,1H),4.08(q,J＝7.2Hz,2H),2.80(t,J＝7.2Hz,4H),2.66(t,J＝7.2Hz,4H),2.12(s,3H),1.98–1.91(m,4H),1.27(d,J＝7.2Hz,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
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.03(s,1H),6.92(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-8
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (pyrrolidin-2-yl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝9.71(brs,1H),7.49(s,1H),6.95(d,J＝15.2Hz,1H),6.80(s,1H),6.36(dd,J＝7.2Hz,J＝15.2Hz,1H),4.08–4.02(m,1H),3.18–3.03(m,2H),2.77(t,J＝7.2Hz,4H),2.70(t,J＝7.2Hz,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)。
Examples-9
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (1-methylpyrrolidin-2-yl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.53(brs,1H),7.97(s,1H),6.92(s,1H),6.84(d,J＝15.2Hz,1H),6.53(dd,J＝7.6Hz,J＝15.2Hz,1H),3.13–3.04(m,1H),3.05–2.92(m,1H),2.80(t,J＝7.2Hz,4H),2.67(t,J＝7.2Hz,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).
Examples-10
(S, E) -2- (1-ethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-S-indacen-4-yl) carbamoyl) -ethanesulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.03(s,1H),6.92(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) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.04(s,1H),6.93(s,1H),6.74(d,J＝15.6Hz,1H),6.65(d,J＝15.2Hz,1H),2.93–2.86(m,1H),2.80(t,J＝7.2Hz,4H),2.67(t,J＝7.2Hz,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) + .
Examples-12
(S, E) -2- (1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-S-indacen-4-yl) carbamoyl) ethylene-1-sulfonamide
1H NMR(400MHz,DMSO-d6):δ＝8.04(s,1H),6.93(s,1H),6.73(d,J＝15.2Hz,1H),6.65(d,J＝15.2Hz,1H),2.80(t,J＝7.2Hz,4H),2.68(t,J＝7.2Hz,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).
Examples-13
(S, E) - ((2- (1, 2-dimethylpyrrolidin-2-yl) vinyl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-S-indacen-4-yl) carbamoyl) sodium amide
1H NMR(400MHz,DMSO-d6):δ＝7.33(s,1H),6.77(s,1H),6.56(d,J＝15.2Hz,1H),6.16(d,J＝16Hz,1H),2.76(t,J＝7.2Hz,4H),2.69(t,J＝7.2Hz,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).
Examples-14
(R, E) - ((2- (1, 2-dimethylpyrrolidin-2-yl) vinyl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) potassium amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.33(s,1H),6.77(s,1H),6.58(d,J＝15.6Hz,1H),6.18(d,J＝15.6Hz,1H),2.77–2.72(m,5H),2.69(t,J＝7.2Hz,4H),2.64–2.58(m,1H),2.08(s,3H),1.90(quin,J＝7.6Hz,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) + .
Examples-15
(R, E) - ((2- (1, 2-dimethylpyrrolidin-2-yl) vinyl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) sodium amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.36(s,1H),6.77(s,1H),6.57(d,J＝15.6Hz,1H),6.19(d,J＝15.6Hz,1H),2.76(t,J＝7.2Hz,5H),2.69(t,J＝7.2Hz,4H),2.64–2.59(m,1H),2.08(s,3H),1.91(quin,J＝7.6Hz,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) + .
Examples-16
(E) -N' -cyano-2- ((S) -1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-S-indacen-4-yl) carbamoyl) ethylene-1-sulfonylimido amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝9.94(s,1H),8.06(s,1H),6.97(d,J＝16.0Hz,1H),6.83(s,1H),6.56–6.48(m,1H),3.58(br s,1H),3.24–3.12(m,1H),2.77(t,J＝7.2Hz,4H),2.69(t,J＝7.2Hz,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] + Calculated [ C22H30N5O2S] + 428.2120; actual measurement value: 428.2052Examples-17
(E) -N' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- ((R) -1-methylpyrrolidin-2-yl) ethylene-1-sulfonylimido amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝9.82(s,1H),8.06(s,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＝7.2Hz,7H),2.70(t,J＝7.2Hz,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) - .
Examples-18
(E) -N' -cyano-2- ((R) -1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonylimido amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝9.98(s,1H),8.03(s,1H),6.94–6.90(m,1H),6.83(s,1H),6.54–6.51(m,1H),2.77(t,J＝7.2Hz,5H),2.70(t,J＝7.2Hz,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) - .
Examples-19
N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((1S, 8 aR) -3, 8 a-trimethyloctahydropyrrolo [1,2-a ] pyrazin-1-yl) methanesulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.92(s,1H),6.87(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) + .
Examples-20
N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((4S, 8 aS) -2,3, 8 a-tetramethyl octahydropyrrolo [1,2-a ] pyrazin-4-yl) methanesulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.03(s,1H),6.93(s,1H),3.52–3.48(m,2H),3.18–3.09(m,1H),3.09–3.01(m,1H),3.00–2.88(m,1H),2.81(t,J＝7.2Hz,4H),2.70(t,J＝7.2Hz,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).
Examples-21
(E) -3- (dimethylamino) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) prop-1-ene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.22(brs,1H),7.94(s,1H),6.91(s,1H),6.86(d,J＝15.2Hz,1H),6.62–6.55(m,1H),3.27(t,J＝6.0Hz,2H),2.79(t,J＝7.2Hz,4H),2.67(t,J＝7.2Hz,4H),2.30(s,6H),1.99–1.91(m,4H)；MS(ESI):m/z(％)＝364.1513(100％)(M+H) + .
Examples-22
(E) - ((3- (dimethylamino) -3-methylbut-1-en-1-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) sodium amide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.36(s,1H),6.77(s,1H),6.51(d,J＝15.6Hz,1H),6.23(d,J＝15.6Hz,1H),2.76(t,J＝7.2Hz,4H),2.69(t,J＝7.2Hz,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).
Examples-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) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.93(s,1H),6.91(s,1H),6.71(d,J＝15.2Hz,1H),6.60(d,J＝15.6Hz,1H),2.85–2.83(m,1H),2.80(t,J＝7.2Hz,4H),2.73–2.71(m,1H),2.67(t,J＝7.2Hz,4H),2.15(s,2H),1.95(quin,J＝7.2Hz,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] - .
Examples-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) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.94(s,1H),6.91(s,1H),6.72(d,J＝15.2Hz,1H),6.61(d,J＝15.2Hz,1H),2.88–2.83(m,1H),2.80(t,J＝7.2Hz,4H),2.75–2.71(m,1H),2.67(t,J＝7.2Hz,4H),2.15(s,2H),1.95(quin,J＝7.2Hz,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] - .
Examples-25
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (1- (methyl-d) pyrrolidin-2-yl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.5(br s,1H),7.99(s,1H),6.92(s,1H),6.86(d,J＝15.2Hz,1H),6.56(dd,J 1 ＝7.6Hz,J 2 ＝15.2Hz,1H),3.12–3.06(m,2H),2.80(t,J＝7.2Hz,4H),2.67(t,J＝7.2Hz,4H),2.38–2.32(m,1H),2.25(s,2H),2.08–2.01(m,1H),1.95(quin,J＝7.2Hz,4H),1.80–1.73(m,2H),1.63–1.54(m,1H),ESI-Q-TOF-MS:m/z391.1956(100％)[M+H] + ,389.1756(100％)[M-H] -
Examples-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
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.87(s,1H),6.89(s,1H),6.73(d,J＝15.2Hz,1H),6.61(d,J＝15.2Hz,1H),2.79(t,J＝7.6Hz,4H),2.67(t,J＝7.2Hz,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] - .
Examples-27
(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 sodium
1 H NMR(400MHz,DMSO-d 6 ):δ＝7.35(s,1H),6.77(s,1H),6.55(d,J＝15.6Hz,1H),6.18(d,J＝15.6Hz,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).
Examples-28
N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((1S, 8 aR) -3, 8 a-trimethyl-2- (methyl-d) octahydropyrrolo [1,2-a ] pyrazin-1-yl) methanesulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.01(bs,1H),6.94(s,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) - .
Examples-29
(R, E) -2- (1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3, 5-tetrahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.27(bs,1H),7.18(s,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) + 。
Examples-30
(E) -2- ((R) -1, 2-dimethylpyrrolidin-2-yl) -N- ((2-hydroxy-1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.5(bs,1H),8.10(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) + .
Examples-31
(E) -2- ((R) -1, 2-dimethylpyrrolidin-2-yl) -N- ((3-hydroxy-1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.05(s,1H),6.90(s,1H),6.75(t,J＝15.2Hz,1H),6.60(t,J＝15.6Hz,1H),5.01(t,J＝3.2Hz,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).
Examples-32
(E) -2- ((R) -1, 2-dimethylpyrrolidin-2-yl) -N- ((1-hydroxy-1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonamide
1 H NMR(400MHz,DMSO-d 6 ):δ＝10.4(br s,1H),8.02(s,1H),7.02(s,1H),6.75(t,J＝15.2Hz,1H),6.65(t,J＝15.6Hz,1H),5.13(d,J＝4.4Hz,1H),4.98(d,J＝3.6Hz,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).
Biological activity:
in vitro assay:
THP1 monocytes were differentiated with PMA (100 ng/ml) and treated with 5% CO 2 Is incubated at 37℃for 20 hours. Plating 2X 10 plates in each well of a 96 well tissue culture plate 5 And differentiating the cells. Cells were primed with 500ng/ml lipopolysaccharide and incubated under the same conditions for 4 hours. The cells were then treated with various concentrations of the compound for 30 minutes, followed by treatment with 5mM ATP for 1 hour. Supernatants were collected and analyzed by IL-1b (Mabtech Cat#3415-1H-20) or TNF-a (Mabtech; cat#3510-1H-20) detection kit. Data were analyzed using GraphPad Prism V7.0. Dose Response Curves (DRCs) were constructed to determine IC by fitting cell percent survival data to GraphPad Prism using nonlinear regression analysis 50 Values. In vitro IL-1 beta inhibitory Activity of representative Compounds (IC 50 ) Listed in table 1.
Table 1:
NLRP 3-assay in vitro MPTP-induced microglia: the study was performed using adult mouse brains. The brain was washed with PBS and cut into pieces, and then mechanically homogenized. The homogenized suspension was then digested with 0.25% trypsin EDTA solution at 37 ℃ for 10 minutes. The suspension was then filtered through a cell screen and centrifuged at 365g for 5 minutes at room temperature. The pellet was resuspended in RPMI complete medium and layered on 30% isotonic Percoll Stock (SIP). The gradient mixture was centrifuged at 700g for 10 minutes at room temperature. The interphase between PBS and 30% percoll containing myelin was discarded. The precipitated cells containing microglia and seed 50000 cells/well were washed in poly-L-lysine coated 96-well plates and incubated at 37℃in 5% CO 2 Incubate overnight in incubator. After overnight incubation, test compounds were added and incubated for a further 1 hour. LPS (1. Mu.g/mL) was then added and incubated for 4 hours. Subsequently, 20 μm nigericin was added to each well and the plates were incubated again for 1 hour. After 1 hour, the supernatant was collected and passed through mouse R&The D-system ELISA kit (MLB 00C) measures IL-1. Beta. Secretion.
Mouse microglia IC 50 (nM)
Compound 11 43
MCC950 108
Results:
significant induction of NLRP3 was observed by an increase in secreted IL-1 beta when the microglial cells were primed with LPS and activated with nigericin. The test compounds (inventive compound 11 and MCC 950) both inhibited inflammatory body activation. Compound 11 of the present invention showed better activity compared to MCC950, which had a half maximal inhibitory concentration of 43nM compared to MCC950 of 108 nM.
In vivo efficacy study:
demonstration of in vivo efficacy of test compounds in rat mice, oral route of administration.
Animals: all animal experiments were performed in female rats and mice, fed internally. Animals were divided into groups of 6 animals per cage and kept for one week in order to adapt them to the conditions of the feeding facility (25.+ -. 4 ℃ C., 60-65% relative humidity, 12:12h light: dark cycle, beginning light at 7.30 am). All animal experiments were performed according to the international guidelines for effectiveness after approval of "Zydus Research Center animal ethical committee".
In vivo LPS and ATP-induced IL-1. Beta. Assay:
female C57 mice (6-8 weeks) received intraperitoneal injections of Lipopolysaccharide (LPS) in PBS at 50. Mu.g/mouse. Animals were immediately treated with test compound or vehicle. After 2 hours of LPS injection, 12.5 mg/mouse ATP in PBS was administered to the animals via the intraperitoneal route. After 30 minutes of ATP injection, serum was collected for IL-1β assessment by ELISA.
Pharmacokinetic analysis in plasma and brain tissue: the purpose of the study was to study the brain distribution of the test compound after a single oral administration of the test compound to C57 mice. Studies were performed in male or female C57 mice (n=4 per time point). Throughout the study period, animals were free to eat and drink water. 1% v/v in purified water80. Formulations were prepared in 99% v/v 0.5% methylcellulose. Animals received a 30mg/kg dose of the test compound suspension formulation by oral gavage at a dose volume of 10.0 mL/kg. The formulation strength was 3.0mg/mL. A total of 6 blood were collected at different time intervalsFluid and brain tissue samples. After dosing, blood samples were collected at specific time points and animals were then sacrificed for humanization of brain tissue. Blood and brain samples were collected at 0.25, 0.5, 1, 2, 4 and 8 hours (n=4/time point) post-dosing. Blood samples were taken from the retroorbital plexus under mild isoflurane anesthesia in tubes containing heparin sodium (-20 IU/mL blood) and placed under ice-cold conditions. Blood samples were centrifuged at 4000rpm for 15 minutes to obtain plasma and stored at-70.+ -. 20 ℃ until analysis. Immediately after blood sampling, animals were perfused with 4ml of 1x PBS buffer solution under deep isoflurane anesthesia, and then brain tissue was collected. The collected brain samples were immediately placed on ice and then stored at-70±20 ℃ until homogenized. Brain tissue samples were homogenized in phosphate buffered saline using a Polytron tissue homogenizer, maintaining a brain homogenate density of 0.2g/mL. The total test compound concentration and unbound test compound concentration of plasma and brain tissue homogenate samples were analyzed using a separately developed LC-MS/MS assay suitable for the study. The calibration range was linear in 5 to 2000ng/mL for the total test compound and 0.2 to 200ng/mL for the unbound test compound fraction.
POC study at stage 2 a:
POC study at stage 2a of test compound (Compound 11 of the invention) in Parkinson's disease patients. Clinically diagnosed patients with 45 to 75 years old parkinsonism and patients with improved barbus stage less than 3 are included in this study. About 15 patients with parkinson's disease were added to the study. The study was conducted at a dosage range of about 25 to 75mg twice daily for 14 days. A eligible patient who 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, a single dose was administered in the morning prior to breakfast.
During the 28 day screening period, eligible patients entered the clinical unit on day (-1). At 12 hours after the first dosing on day 1 and day 14, the patient continued to enter the clinical unit for safety assessment, as well as pharmacokinetic and pharmacodynamic sampling. The patient was again reported to the facility on day 2, day 4, day 7, day 10, day 14, day 15 and day 21 (follow-up) for safety assessment and pharmacokinetic and pharmacodynamic blood sampling.
The main objective of this study was to evaluate the safety and tolerability of the oral administration of the test compound (compound 11 of the invention) in parkinson's disease patients. Secondary and exploratory purposes included evaluating the pharmacokinetics and pharmacodynamics of the test compound (compound 11 of the present invention) for 14 days of oral administration twice daily. Blood samples were collected at various time points for pharmacokinetic and pharmacodynamic assessment. Cerebrospinal fluid (CSF) was collected 2 hours after the last dose to correlate CSF with the concentration of the test compound (compound 11 of the invention) in plasma. Exploratory parameters such as alpha-synuclein levels, NLRP3, soluble LAG-3, toll-interacting protein and hs C-reactive protein in blood were measured at defined time points.
Safety was assessed by physical and neurological examination, vital signs, clinical laboratory tests and ECG at various time points during the study and recording of AEs/SAEs.
While the 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 invention.

Claims (40)

1. A method for treating a neuroinflammatory disorder or a neurodegenerative disorder disease comprising administering a compound of formula (I)
Or a pharmaceutically acceptable salt thereof
Wherein the method comprises the steps of
X is O, NH or N-R 3 Wherein R is 3 Independently at each occurrence, selected from hydrogen, hydroxy, halogen, nitro, cyano, haloalkyl, 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 group (C) 2 -C 10 ) Alkynyl, SO 2 (C 1 -C 6 ) Alkyl, thiol, thioalkyl, thioalkoxy, SO (C) 1 -C 6 ) Alkyl, benzyl, aryl, heteroaryl, heterocyclyl;
y is O, S;
R 1 independently at each occurrence a group selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted selected from: (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 1 -C 6 ) Alkoxy, (C) 3 -C 7 ) Cycloalkyl, (C) 1 -C 6 ) Alkyl SO 2 (C 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, t-butoxycarbonyl, NH (C) 1 -C 6 ) Alkyl, N ((C) 1 -C 6 ) Alkyl group 2 、NH(C 2 -C 6 ) Alkenyl, N ((C) 2 -C 6 ) Alkenyl group) 2 -N-heterocyclyl, N (C) 1 -C 6 ) Alkyl-heterocyclyl, NR' R ", thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ) Alkyl, SO 2 (C 3 -C 7 ) Cycloalkyl, SO 2 -aryl, SO 2 -heterocyclyl, (C) 1 -C 6 ) Thioalkyl (C) 1 -C 6 ) Thioalkoxy group, (C) 1 -C 6 ) Alkyl SO 2 NH 2 、-CONH 2 、-CO(C 1 -C 6 ) Alkyl, -CO(C 1 -C 6 ) Haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4-to 7-membered heterocycle, 7-to 14-membered bicyclic heterocycle system, bridged ring or spiro ring system optionally having one or more heteroatoms;
alternatively, R 1 Selected from the group consisting of
n is independently selected from integers 0 to 3;
R’、R”、R 1 ’、R 1 ”、R 2 ' and R 2 "each of which is independently at each occurrence selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from: (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 1 -C 6 ) Alkoxy, (C) 3 -C 7 ) Cycloalkyl, (C) 1 -C 6 ) Alkyl SO 2 (C 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkyl N (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, t-butoxycarbonyl, thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ) Alkyl, SO 2 (C 3 -C 7 ) Cycloalkyl, SO 2 -aryl, SO 2 -heterocyclyl, (C) 1 -C 6 ) Thioalkyl (C) 1 -C 6 ) Thioalkoxy group, (C) 1 -C 6 ) Alkyl SO 2 NH 2 、-CONH 2 、-CO(C 1 -C 6 ) Alkyl, -CO (C) 1 -C 6 ) Haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4-to 7-membered heterocycle, 7-to 14-membered bicyclic heterocycle system, bridged ring or spiro ring system optionally having one or more heteroatoms; in embodiments, R 'and R' optionally form a 4 to 7 membered heterocyclic ring system,
R 2 selected from the following ring systems
Wherein X, Y, Z, at each occurrence, independently represents C, N, S, SO 2 And O, which may be optionally substituted;
R 7 、R 8 、R 9 、R 10 、R 11 and R is 12 Independently at each occurrence selected from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxy, optionally substituted groups selected from the group consisting of: (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Haloalkyl, (C) 3 -C 6 ) Cycloalkyl, (C) 1 -C 6 ) Alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; in one embodiment, R 8 And R is 9 、R 9 And R is 10 、R 10 And R is 11 R is as follows 11 And R is 12 Each may, where possible, together form a mixture containing 0 to 2 members selected from N, O and S (O) p 4 to 7 membered saturated or partially saturated ring of further heteroatoms of (a); p=1 to 2 and,
R x and R is y Independently at each occurrence selected from hydrogen, halogen, optionally substituted (C) 1 -C 6 ) A group of an alkyl group; alternatively, R x And R is y May together form a 4 to 7 membered heterocyclic ring system;
'M' is selected from aryl, heteroaryl, heterocyclyl; and wherein when any of the above defined groups is substituted, the substitution thereon is selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkoxy, alkylthio, optionally substituted selected from the group consisting of: (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (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)-R 11 、-C(O)-NR 11 R 12 、-C(S)-NR 11 R 12 、-SO 2 R 11 A group, wherein R is 11 And R is 12 Independently selected from hydrogen, optionally substituted groups selected from the group consisting of: (C) 1 -C 6 ) Alkyl, (C) 2 -C 6 ) Alkenyl group (C) 2 -C 6 ) Alkynyl, (C) 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl groups.
2. The method of claim 1, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is selected from the group consisting of craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
3. The method of claims 1 and 2, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is parkinson's disease.
4. The method of claim 1, wherein the compound of formula (I) is selected from:
N '-cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -5- (2-hydroxypropyl-2-N' -cyano-4-fluoro-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -3- (2-hydroxypropyl-2-yl) benzenesulfonimide amide;
n' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -4- (2-hydroxyprop-2-yl) furan-2-sulfonylimido amide;
(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) vinylsulfonamide;
(E) -2- (1-ethyl-4-methyl-1H-imidazol-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) vinylsulfonamide;
(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) ethylene-1-sulfonamide;
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (1-methylpyrrolidin-2-yl) ethylene-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) ethylene-1-sulfonamide;
(S, E) -2- (1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-S-indacen-4-yl) carbamoyl) ethylene-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) ethylene-1-sulfonylimido amide;
(E) -N' -cyano-N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- ((R) -1-methylpyrrolidin-2-yl) ethylene-1-sulfonylimido amide;
(E) -N' -cyano-2- ((R) -1, 2-dimethylpyrrolidin-2-yl) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) ethylene-1-sulfonylimido amide;
N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((1S, 8 aR) -3, 8 a-trimethyloctahydropyrrolo [1,2-a ] pyrazin-1-yl) methanesulfonamide
N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -1- ((4S, 8 aS) -2,3, 8 a-tetramethyl octahydropyrrolo [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;
(E) - ((3- (dimethylamino) -3-methylbut-1-en-1-yl) sulfonyl) ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) sodium 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) ethylene-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) ethylene-1-sulfonamide;
(R, E) -N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -2- (1- (methyl-d) pyrrolidin-2-yl) ethylene-1-sulfonamide;
or a pharmaceutically acceptable salt of any of the above compounds.
5. The method of claim 1, wherein the therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1mg to 500mg, preferably from 1mg to 250mg, more preferably from 1mg to 150mg.
6. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by an oral, topical or parenteral route of administration, preferably by an oral route of administration.
7. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.
8. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.
9. Use of a compound of formula (I) as defined in claim 1 or 4 in the manufacture of a medicament for the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease.
10. The use of a compound of formula (I) as claimed in claim 1 or 4, wherein the compound is administered in a daily dosage range selected from 1mg to 500mg, preferably from 1mg to 250mg, more preferably from 1mg to 150 mg.
11. Pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease
12. The pharmaceutical composition of claim 11, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is selected from the group consisting of craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
13. The pharmaceutical composition of claim 11 or 12, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is parkinson's disease.
14. The pharmaceutical composition according to claim 11, wherein the therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1mg to 500mg, preferably from 1mg to 250mg, more preferably from 1mg to 150mg.
15. The pharmaceutical composition of claim 11 comprising a compound of formula (I) and other pharmaceutically acceptable excipients and is useful for the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease.
16. The pharmaceutical composition of claim 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.
17. Use of a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease.
18. A method for treating a neuroinflammatory disorder or a neurodegenerative disorder disease comprising administering a compound of formula (11)
Or a pharmaceutically acceptable salt thereof.
19. The method of claim 18, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is selected from the group consisting of craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
20. The method of claim 18 or 19, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is parkinson's disease.
21. The method of claim 18, wherein the therapeutically effective amount of the compound of formula (11) or a pharmaceutically acceptable salt thereof is selected from 1mg to 500mg, preferably from 1mg to 250mg, more preferably from 1mg to 150mg.
22. The method of claim 18, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered by an oral, topical or parenteral route of administration, preferably by an oral route of administration.
23. The method of claim 18, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.
24. The method of claim 13, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.
25. Use of a compound of formula (11) as claimed in any one of the preceding claims in the manufacture of a medicament for the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease.
26. Use of a compound of formula (11) according to any one of the preceding claims, wherein the compound is administered in a daily dosage range selected from 1mg to 500mg, preferably from 1mg to 250mg, more preferably from 1mg to 150mg.
27. Pharmaceutical composition comprising a compound of formula (11) or a pharmaceutically acceptable salt thereof for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease, wherein the compound of formula (11) is
28. The pharmaceutical composition of claim 27, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is selected from the group consisting of craniocerebral injury (TBI), amyotrophic Lateral Sclerosis (ALS), alzheimer's Disease (AD), parkinson's Disease (PD), multiple Sclerosis (MS), huntington's disease, and other related forms of disorders.
29. The pharmaceutical composition of claim 27 or 28, wherein the neuroinflammatory disorder or neurodegenerative disorder disease is parkinson's disease.
30. The pharmaceutical composition of claim 27, wherein the therapeutically effective amount of the compound of formula (11) or a pharmaceutically acceptable salt thereof is selected from 1mg to 500mg, preferably from 1mg to 250mg, more preferably from 1mg to 150mg.
31. The pharmaceutical composition of claim 27, comprising a compound of formula (11) and other pharmaceutically acceptable excipients, for use in the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease.
32. The pharmaceutical composition of claim 27, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.
33. Use of a pharmaceutical composition according to claim 27 in the manufacture of a medicament for the treatment of a neuroinflammatory disorder or a neurodegenerative disorder disease.
34. The pharmaceutical composition of claim 31, wherein the additional pharmaceutically acceptable excipient is selected from the group consisting of diluents, carriers, binders, disintegrants, lubricants, and surfactants.
35. The pharmaceutical composition of any one of the preceding claims, wherein the diluent is selected from lactose monohydrate, selected from among ewing's polymethacrylate, potassium chloride, sulfobutyl ether β -cyclodextrin, sodium chloride, and spray dried lactose, and suitable combinations thereof.
36. The pharmaceutical composition of any one of the preceding claims, wherein the carrier is selected from lactose, white sugar, sodium chloride, dextrose, urea, starch, calcium carbonate and kaolin, crystalline cellulose, silicic acid and suitable combinations thereof.
37. The pharmaceutical composition of any one of the preceding claims, wherein the binder is a carbomer selected from carbopol (carbopol), gellan gum, gum arabic, hydrogenated vegetable oil, polymethacrylate selected from among ewing, xanthan gum, lactose and zein, and suitable combinations thereof.
38. The pharmaceutical composition of any one of the preceding claims, wherein the disintegrant is selected from bicarbonate, chitin, gellan gum, polacrilin potassium, docusate sodium, and suitable combinations thereof.
39. A pharmaceutical composition according to any one of the preceding claims wherein the lubricant is selected from glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, myristic acid and suitable combinations thereof.
40. The pharmaceutical composition according to any one of the preceding claims, wherein the surfactant is a nonionic surfactant selected from the group consisting of alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside; an anionic surfactant selected from the group consisting of eicosanoids and arachidonic acid; cationic surfactants selected from cetyl trimethylammonium bromide and cetyl pyridinium chloride, and suitable combinations thereof.
CN202280057882.8A 2021-08-25 2022-08-25 Treatment for neuroinflammatory disorders Pending CN117858871A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN202121038491 2021-08-25
IN202121038491 2021-08-25
PCT/IB2022/057951 WO2023026222A1 (en) 2021-08-25 2022-08-25 Treatment for neuroinflammatory disorders

Publications (1)

Publication Number Publication Date
CN117858871A true CN117858871A (en) 2024-04-09

Family

ID=85322831

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202280057882.8A Pending CN117858871A (en) 2021-08-25 2022-08-25 Treatment for neuroinflammatory disorders

Country Status (6)

Country Link
EP (1) EP4392413A1 (en)
JP (1) JP2024532303A (en)
KR (1) KR20240052009A (en)
CN (1) CN117858871A (en)
CA (1) CA3226855A1 (en)
WO (1) WO2023026222A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20220195T1 (en) * 2017-07-07 2022-04-15 Inflazome Limited Novel sulfonamide carboxamide compounds
JP7488267B2 (en) * 2019-01-14 2024-05-21 ザイダス・ライフサイエンシーズ・リミテッド Novel substituted sulfonylurea derivatives

Also Published As

Publication number Publication date
JP2024532303A (en) 2024-09-05
WO2023026222A1 (en) 2023-03-02
CA3226855A1 (en) 2023-03-02
EP4392413A1 (en) 2024-07-03
KR20240052009A (en) 2024-04-22

Similar Documents

Publication Publication Date Title
AU2017258909B2 (en) Pyrazol-1-yl benzene sulfonamides as CCR9 antagonists
KR102547834B1 (en) Substituted indazoles useful for the treatment and prevention of allergic and/or inflammatory diseases in animals
BR112021002327A2 (en) 6-(4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decan-8-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3h) derivatives -one and related compounds as ptpn11(shp2) inhibitors for cancer treatment
JP2019512009A (en) Sulfonylurea and related compounds and uses thereof
EP3674298A1 (en) Substituted indazoles, process for their preparation, pharmaceutical formulations containing them, and their use for the preparation of medicaments
KR102312294B1 (en) Pharmaceutical composition comprising glutarimide derivatives and use thereof in the treatment of eosinophilic diseases
US20210393759A1 (en) Methods of treating cancer using heteroaryl-biphenyl amide derivatives
KR20190104389A (en) Bicyclic Inhibitors of Histone Deacetylase
US20210163406A1 (en) Bumetanide Derivatives for the Therapy of Stroke and Other Neurological Diseases/Disorders Involving NKCCs
JP7518900B2 (en) Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and lichen planus (LP) - Patent Application 20070233334
JP2023515209A (en) Novel substituted sulfonylurea and sulfoximine urea derivatives
JP2020505437A (en) Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) for the treatment of neurodegenerative diseases
CN117858871A (en) Treatment for neuroinflammatory disorders
JP7329509B2 (en) Kinase inhibitors for the treatment of central and peripheral nervous system disorders
TWI768781B (en) TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITOR
AU2021293907A1 (en) Targeted aberrant alpha-synuclein species and induced ubiquitination and proteosomal clearance via co-recruitment of an E3-ligase system
CN117940126A (en) Treatment for cold-related periodic syndromes (CAPS)
CN114746087A (en) Novel substituted sulfoximine derivatives
WO2024180521A1 (en) Treatment for inflammatory bowel disease
KR20080106226A (en) Use of pyrazolo[1,5a]pyrimidin-7-yl amine derivatives in the treatment of neurological disorders
WO2024178425A1 (en) Hydroxyalkyl and methoxyalkyl tryptamines
WO2024023696A1 (en) Dosing regimen for a nlrp3 inhibitor
BR112018009880B1 (en) PHARMACEUTICAL COMPOUNDS AND COMPOSITIONS MODULATING CHEMOKIN RECEPTORS AND THEIR USES

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination