EP4554955A1 - Dérivés de célastrol - Google Patents

Dérivés de célastrol

Info

Publication number
EP4554955A1
EP4554955A1 EP23751170.4A EP23751170A EP4554955A1 EP 4554955 A1 EP4554955 A1 EP 4554955A1 EP 23751170 A EP23751170 A EP 23751170A EP 4554955 A1 EP4554955 A1 EP 4554955A1
Authority
EP
European Patent Office
Prior art keywords
compound
administration
disease
disorder
celastrol
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
EP23751170.4A
Other languages
German (de)
English (en)
Inventor
Seunghwan LIM
Tej Kumar PAREEK
Liraz LEVI
Elizabeth MEYERS
William J. Greenlee
Seong-Jin Kim
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.)
Celloram Inc
Celloram Inc
Original Assignee
Celloram Inc
Celloram Inc
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 Celloram Inc, Celloram Inc filed Critical Celloram Inc
Publication of EP4554955A1 publication Critical patent/EP4554955A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present disclosure relates to compounds that are derivatives of celastrol, pharmaceutical compositions comprising these compounds, and uses thereof.
  • Celastrol also named tripterine, a naturally occurring compound derived from the plant species, Tripterygium wilfordii Hook F.
  • Celastrol has been found to exhibit significant antitumor activity in preclinical studies, including studies for the treatment of liver cancer, breast cancer, prostate cancer, lung cancer, leukemia, melanoma (see e.g., Kashyap et al., 2018; Yadav et al., 2018) and was shown to have radiosensitizing effect (see e.g., Dai et al., 2011 ; Lee et al., 2011).
  • celastrol can kill tumors via a range of mechanisms of action including: i) induced apoptosis and autophagy, ii) cell cycle arrest, iii) antimetastatic and anti-angiogenic actions, iv) anti-inflammatory effects, and v) antioxidant activities, (see e.g., Cascao et al., 2017; Kashyap et al., 2018).
  • celastrol acts by targeting multiple signaling pathways, including but not limited to, reactive oxygen species (ROS)ZJNK and Akt/mTOR (see e.g., Liu et al., 2019), NF-Kb (see, e.g., Chiang et al., 2014), STAT3/JAK2 (see, e.g., Rajendran et al., 2012), HSP90 (see, e.g., Sreeramulu et al., 2009; Zhang et al., 2009), Cdc37, p23, iKKb, p-Akt (see e.g., Kannaiyan et al., 2011), ERa (see e.g., Jang et al., 2011).
  • ROS reactive oxygen species
  • Akt/mTOR see e.g., Liu et al., 2019
  • NF-Kb see, e.g., Chiang et al., 2014
  • Celastrol has been shown to act as an inflammasome inhibitor (see e.g., Lee et al. ,2019; Yu et al., 2017), and has been proposed for the treatment of a range of inflammatory indications, autoimmune, and several chronic diseases including, but not limited to, rheumatoid arthritis (RA), multiple sclerosis (MS) (see e.g., Wang et al., 2015; Abdin and Hasby, 2014), ankylosing spondylitis, systemic lupus erythematosus (SLE), inflammatory bowel disease, osteoarthritis (OA), acute respiratory distress syndrome (ARDS) (see e.g., Wei and Wang, 2017), Guillain-Barre syndrome (GBS) (e.g.
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • SLE systemic lupus erythematosus
  • OA inflammatory bowel disease
  • OA osteoarthritis
  • Shao et al., 2023 Sickle cell disease (SCD) (see e.g., Kumar et al., 2016), allergy (e.g. Asthma), psoriasis and other inflammatory skin conditions (see e.g., Vankatesha and Moudgil, 2021 ; Song et al., 2023).
  • SCD Sickle cell disease
  • allergy e.g. Asthma
  • psoriasis e.g., Vankatesha and Moudgil, 2021 ; Song et al., 2023.
  • Celastrol has also been shown to exhibit neuroprotective activity (see e.g., Cascao et al., 2017; Cleren et al, 2005; Paris et al., 2010), and has been proposed for the treatment of a range of neurological disorders, including but not limited to, Parkinson’s disease, Huntington disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Gaucher disease (GD) (see e.g., Vankatesha and Moudgil, 2021).
  • Parkinson’s disease Huntington disease
  • Alzheimer’s disease amyotrophic lateral sclerosis
  • GD Gaucher disease
  • Celastrol, and celastrol analog compounds have also been proposed as a treatment for multiple metabolic and atherosclerotic diseases, liver diseases, and cardiac disorders, including but not limited to obesity (see e.g., Liu et al., 2015; Feng et al., 2019), atherosclerosis (see e.g., Coll et al., 2015; Voutyritsa et al., 2021), type 2 diabetes (T2D) (see e.g. Liu et al, 2015; Zhou et al., 2021), diabetic nephropathy (see e.g.
  • Celastrol was also shown to be useful in the treatment and prevention of multiple brain disorders and injuries due to its anti-inflammatory activities. These include but not limited to middle cerebral artery occlusion (MCAO)-induced brain injury, cerebral ischaemia/reperfusion (l/R) injury, Vascular dementia (VD), and acute ischemic stroke-induced brain injury (see e.g. Jiang et al., 2018).
  • MCAO middle cerebral artery occlusion
  • l/R cerebral ischaemia/reperfusion
  • VD Vascular dementia
  • acute ischemic stroke-induced brain injury see e.g. Jiang et al., 2018.
  • celastrol In recent years more and more application for celastrol were explored for treatment of ocular disorders, this includes but not limited to dry eye disease (see e.g. Siu Law, 2022), ocular inflammation, age-related macular degeneration (AMD) (see e.g., Zhang et al., 2019), subconjunctival fibrosis (see e.g., Li et al., 2023).
  • dry eye disease see e.g. Siu Law, 2022
  • AMD age-related macular degeneration
  • subconjunctival fibrosis see e.g., Li et al., 2023.
  • Celastrol was also shown to protect against the development of ocular hypertension-induced degeneration of retinal ganglion cells (see e.g., Gu et al., 2018), bright light-induced degeneration (see e.g., Bian et al., 2016), and macrophage-induced corneal neovascularization (see e.g., Li et al., 2016), and to support corneal allograft survival (see e.g., Li et al., 2016) and recovery from injuries caused by optic nerve crush (see e.g., Kyung et al., 2015).
  • celastrol interacts with many cellular targets and exhibits strong activities useful for many potential therapeutic indications
  • the compound exhibits poor ADME characteristics that have limited its further clinical development, including, water stability, low bioavailability, a narrow therapeutic window, and undesired side effects (see e.g., Cascao et al., 2017; Hou et al., 2020).
  • celastrol derivative or analog compounds that exhibit one or more improved ADME characteristics, while retaining some or all of functional activities of celastrol that are associated with its therapeutic efficacy.
  • the present disclosure relates generally to celastrol derivative compounds, compositions, formulations, and their use in medicaments and therapeutic methods. This summary is intended to introduce the subject matter of the present disclosure, but does not cover each and every embodiment, combination, or variation that is contemplated and described within the present disclosure. Further embodiments are contemplated and described by the disclosure of the detailed description, drawings, and claims. [0012] In at least one embodiment, the present disclosure provides a compound of structural formula (I)
  • the present disclosure provides a compound of structural formula (I) wherein
  • Ri is -NH-(CO) 2 -NR 2 R 3 , or -N(CH 3 )-(CO) 2 -NR 2 R 3 ;
  • R 2 and R 3 are independently selected from hydrogen, an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, amine, or heteroaryl, optionally substituted with substituents individually selected from alkyl, alkoxy, cycloalkyl, ether, amine optionally substituted with one or more alkyl, halogen, hydroxyl, ether, cyano, nitrile, CF 3 , ester, amide, cycloalkyl amide, sugar, heteroarylamide optionally substituted with alkyl and/or alkoxy, urea, carbamate, thioether, sulfate, sulfonyl, sulfonic acid carboxylic acid, and aryl; or
  • R 2 and R 3 taken together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally substituted with substituents individually selected from alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, heteroaryl, amine, halogen, hydroxyl, ether, nitrile, cyano, nitro, CF 3 , ester amide, urea, carbamate, thioether, or carboxylic acid group; or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, tautomer, or prodrug thereof.
  • the compound is selected from the group consisting of: compound 14, compound 15, compound 16, compound 17, compound 22, compound 22-1 , compound 42, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61 , compound 62, compound 63, compound 64, compound 65, compound 66, compound 67, compound 68, compound 69, compound 70, compound 71 , compound 72, compound 73, compound 74, compound 75, compound 76, compound 77, compound 78, compound 79, compound 80, compound 81 , compound 82, compound 83, compound 84, compound 85, compound 86, compound 87, compound 88, compound 89, compound 90, compound 91 , and compound 92.
  • the compound is characterized by having an IC50 in a NF-kB reporter assay of about 1200 nM or less, about 1000 nM or less, 750 nM or less, 500 nM or less, or 300 nM or less.
  • the present disclosure provides a pharmaceutical composition comprising a compound of structural formula (I) of the present disclosure, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating a celastrol-responsive disease or disorder in a subject suffering therefrom, the method comprising administering to the subject a therapeutically effective amount of a compound of structural formula (I) of the present disclosure, or a pharmaceutical composition of the present disclosure.
  • the celastrol-responsive disease or disorder is a cancer; optionally, wherein the cancer is selected from: gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung carcinoma, brain cancer, and glioblastoma multiforme (GBM).
  • the cancer is selected from: gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung carcinoma, brain cancer, and glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the celastrol-responsive disease or disorder is an inflammatory and/or autoimmune disorder; optionally, wherein the inflammatory and/or autoimmune disorder is selected from rheumatoid arthritis (RA), multiple sclerosis (MS), ankylosing spondylitis, systemic lupus erythematosus (SLE), inflammatory bowel disease, osteoarthritis (OA), acute respiratory distress syndrome (ARDS), Guillain-Barre syndrome (GBS), Sickle cell disease (SCD), allergy (e.g. Asthma), psoriasis and other inflammatory skin conditions.
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • SLE systemic lupus erythematosus
  • OA inflammatory bowel disease
  • OA acute respiratory distress syndrome
  • GBS Guillain-Barre syndrome
  • SCD Sickle cell disease
  • allergy e.g. Asthma
  • Asthma psoriasis and other inflammatory skin conditions
  • the celastrol-responsive disease or disorder is a neurological disorder; optionally, wherein the neurological disorder is selected from Parkinson’s disease, Huntington disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Gaucher disease (GD).
  • Parkinson’s disease Huntington disease
  • Alzheimer’s disease amyotrophic lateral sclerosis (ALS)
  • GD Gaucher disease
  • the celastrol-responsive disease or disorder is an obesity-related disease or disorder; optionally, wherein the obesity-related disease or disorder is selected from obesity, pre-obesity, morbid obesity, type 2 diabetes (T2D), atherosclerosis, diabetic nephropathy, gout, cardiac fibrosis, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, lipodystrophy, fatty liver, Bardet-Biedl Syndrome, Cohen Syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome, and MOMO (Macrosomia Obesity Macrocephaly Ocular abnormalities) Syndrome.
  • obesity-related disease or disorder is selected from obesity, pre-obesity, morbid obesity, type 2 diabetes (T2D), atherosclerosis, diabetic nephropathy, gout, cardiac fibrosis, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, non-alcoholic stea
  • the celastrol-responsive disease or disorder is a liver-related disease or disorder; optionally, wherein the liver-related disease or disorder is selected from acute-chronic liver failure (ACLF), alcoholic liver disease, cholestatic liver disease, drug-induced liver disease, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and viral liver disease.
  • ACLF acute-chronic liver failure
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • viral hepatitis and viral liver disease.
  • the celastrol-responsive disease or disorder is a brain injury or brain disorder optionally, wherein the brain-related injury or disorder is selected from middle cerebral artery occlusion (MCAO)-induced brain injury, cerebral ischemia/reperfusion (l/R) injury, Vascular dementia (VD), and acute ischemic stroke-induced brain injury.
  • MCAO middle cerebral artery occlusion
  • l/R cerebral ischemia/reperfusion
  • VD Vascular dementia
  • the celastrol-responsive disease or disorder is an ocular disorder or injury optionally, wherein the ocular-related injury or disorder is selected from dry eye disease, ocular inflammation, age-related macular degeneration (AMD), subconjunctival fibrosis, ocular hypertension-induced degeneration of the retina, bright light- induced degeneration, macrophage-induced corneal neovascularization, corneal allograft survival, and optic nerve crush.
  • AMD age-related macular degeneration
  • subconjunctival fibrosis ocular hypertension-induced degeneration of the retina
  • bright light- induced degeneration macrophage-induced corneal neovascularization
  • corneal allograft survival and optic nerve crush.
  • administering comprises oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intralesional administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhaled administration, or subcutaneous administration.
  • the pharmaceutical composition is administered in a form selected from the group comprising pills, capsules, tablets, granules, powders, salts, crystals, liquid, serums, syrups, suspensions, gels, creams, pastes, films, patches, and vapors.
  • the subject is a mammal. In at least one embodiment, the subject is a human.
  • the present disclosure provides a use of a compound of structural formula (I) of the present disclosure, or a pharmaceutical composition of the present disclosure for use in therapy, for use as a medicament, for use in treating a celastrol- responsive disease or disorder in a subject, or for the manufacture of a medicament for treating a celastrol-responsive disease or disorder in a subject.
  • FIG. 1A, FIG. 1B, and FIG. 1C show results illustrating that the celastrol derivative compound 22 (also referred to as “CLM-022”) robustly inhibits NF-kB inflammatory signaling as described in Example 14.
  • FIG. 1A depicts plots of relative NF-kB luciferase activity (RLU) for compound 22 and compound 1 (also referred to as “CLM-001”) assayed at 8-point concentrations (10 pM, 5 pM, 2.5 pM, 1.25 pM, 0.63 pM, 0.31 pM, 0.16 pM, 0.016 pM, and 0 pM).
  • RLU relative NF-kB luciferase activity
  • FIG. 1B depicts plots of the inhibitory concentrations (IC 50 ) for compounds 22 (CLM-022) and 1 (CLM-001).
  • FIG. 1C shows images of western blots of BMDCs pre-treated with the compounds 1 (CLM-001) or 22 (CLM-022) at the three different concentrations (10 nM, 25 nM, and 50 nM) followed by LPS (500 ng/mL) treatment and assay for the known NF-kB target proteins, iNOS, NLRP3, Cox-2, and IL-1/?.
  • FIG. 2A, FIG. 2B, and FIG. 2C show results illustrating that compound 22 (CLM-022) strongly inhibited IL-1/? secretion via suppression of NLRP3 inflammasome in bone marrow- derived dendritic cells (BMDCs) as described in Example 15.
  • FIG. 2A depicts western blot images showing the relative NLRP3 inflammasome activity of the compounds 22 (CLM-022) and 1 (CLM-001) by detecting the level of cellular ASC complex and the mature form of IL-1/?
  • FIG. 2B depict plots of results showing secreted IL-1 p levels measured by ELISA using conditioned media of BMDC treated with the compound 22 or compound 1 at 63 nM, 125nM, 250 nM, and 500 nM, under NLRP3 inflammasome activation induced either by LPS+ATP or LPS+Nigericin.
  • FIG. 3A, and FIG. 3B depict results showing compound 22 (CLM-022) inhibited NLRP3 inflammasome activity in THP1 and the cellular inflammasome complex as visualized by Amnis analysis as described in Example 16.
  • FIG. 3A, and FIG. 3B depict results showing compound 22 (CLM-022) inhibited NLRP3 inflammasome activity in THP1 and the cellular inflammasome complex as visualized by Amnis analysis as described in Example 16.
  • FIG. 3A shown images of western blot analysis of THP1 cells treated with LPS, and compound 1 (CLM-001) or compound 22, followed by Nigericin for NLRP3 inflammasome activation.
  • the inflammasome ASC complex in the control cells was compared with the treatment of compound 1 (CLM-001) (50 nM, 100 nM), compound 22 (CLM-022) (50 nM, 100 nM), and MCC950 (100 nM, 200 nM).
  • FLICA green
  • ASC red
  • ASC red
  • FIG. 4A depicts plot of data showing that the level of TNF-a decreased in the serum of compound 1 and compound 22 treated mice.
  • FIG. 4B depicts plots showing results of gene expression analysis performed by qPCR have shown that compound 22 pretreatment markedly inhibited for IL-/?, IL-6, TNF-a, and iNOS inflammatory cytokines and molecule in the colon.
  • FIG. 5A, FIG. 5B, FIG. 5C and FIG. 5D depict results showing that compound 22 (CLM- 022) outperforms the benchmark inflammasome inhibitor compound, MCC950, in inhibiting IL- 1 p secretion (but not TNF-a secretion) in BMDM cells and THP-1 cells activated for inflammasome activity and cytokine secretion by LPS and Nigericin treatment as described in Example 18.
  • CLM- 022 the benchmark inflammasome inhibitor compound
  • FIG. 6A, FIG. 6B, and FIG. 6C depict results of the DARTS assays described in Example 19 showing that the celastrol derivative, compound 22 (CLM-022), when compared to MCC950, exhibits markedly improved protection of NLRP3 protein, but not NEK7, from Pronase-induced degradation.
  • FIG. 7A, FIG. 7B, and FIG. 7C depict results of a study described in Example 20, which show that the celastrol derivative, compound 22 (CLM-022), when compared to MCC950, possesses a greater capacity to inhibit inflammasome-induced pyroptosis in human THP-1 macrophages.
  • Crolastrol refers to a compound having a chemical structure of compound (1):
  • “Celastrol-responsive disease or disorder” refers to any disease or disorder for which treatment with the compound, celastrol has been proposed or shown to provide a potentially therapeutic effect, based on clinical, pre-clinical, or in vitro studies.
  • Exemplary celastrol- responsive diseases or disorders of the present disclosure include, but are not limited to, cancer (e.g., gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung carcinoma, brain cancer, and glioblastoma multiforme), inflammatory and/or autoimmune disorders (e.g., rheumatoid arthritis (RA) multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), ankylosing spondylitis, systemic lupus erythematosus (SLE), Ulcerative colitis, inflammatory bowel disease, osteoarthritis (OA),
  • substituted includes embodiments in which a monoradical substituent is bound to a single atom of the substituted group (e.g. forming a branch), and also includes embodiments in which the substituent may be a diradical bridging group bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.
  • a given group (or “moiety”) is described herein as being attached to a second group and the site of attachment is not explicit, the given group may be attached at any available site of the given group to any available site of the second group.
  • a “lower alkyl-substituted phenyl,” where the attachment sites are not explicit, may have any available site of the lower alkyl group attached to any available site of the phenyl group.
  • an “available site” is a site of the group at which a hydrogen of the group may be replaced with a substituent.
  • the individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound by conventional means.
  • the individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present disclosure, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
  • isomers means different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.
  • stereoisomers means isomers that differ only in the way the atoms are arranged in space.
  • enantiomers means a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a “racemic” mixture.
  • ( ⁇ )” is used to designate a racemic mixture where appropriate.
  • diastereoisomers means stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Absolute stereochemistry is specified herein according to the Cahn Ingold Prelog R S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or levorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.
  • Certain compounds of the present disclosure include asymmetric atoms (optical or chiral centers) or double bonds.
  • the present disclosure is intended to encompass within the scope of the compounds described herein, even where those compounds described by chemical structures and formulas that do not explicitly show the various stereoisomeric or diastereomeric forms, including the racemic or optically pure forms of the compounds.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • “Tautomeric isomers” or “tautomers” are isomers that are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers.
  • Certain compounds of the present disclosure exist as ‘tautomeric isomers” or “tautomers.” Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers.
  • polymorph refers to different crystal structures of a crystalline compound. The different polymorphs may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the disclosure.
  • solvate refers to a complex formed by combining a compound and a solvent.
  • hydrate refers to the complex formed by combining a compound and water.
  • Certain compounds of the present disclosure can exist in unsolvated forms, solvated forms, which includes hydrated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are intended to be encompassed within the scope of the compounds described herein, even where those compounds are described by chemical structures and formulas that do not explicitly show the solvated form.
  • salt refers to ionic compounds that result from the neutralization reaction of an acid and a base. Salts are composed of related numbers of cations (positively charged ions) and anions (negative ions) so that the product is neutral (without a net charge).
  • component ions can be inorganic, such as chloride (Cl ⁇ ), or organic, such as acetate (C2H 3 O2 _ ); and can be monatomic, such as fluoride (F ⁇ ), or polyatomic, such as sulfate (SO 4 2 “).
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • the compounds of this disclosure are capable of forming pharmaceutically acceptable acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloal amines, substituted cycloalkyl amines, substituted
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • any formula or structure given herein, including Formula (I), is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 3S CI, and 125 l.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated.
  • isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection, or imaging techniques, such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT singlephoton emission computed tomography
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • deuterium in this context is regarded as a substituent in the compound of the Formula (I).
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the present disclosure provides a range of compounds having chemical structures that are derivatives of the structure of celastrol (compound (1)).
  • the celastrol derivative compounds of the present disclosure retain the 5-ring tripterine core structure of compound (1) and replace the carboxylic acid group with a range of different substituted amine and amide groups as described in greater detail below.
  • the celastrol derivative compounds of the present disclosure retain or improve upon the functional features of celastrol including NF-kB cell inhibition and ADME properties, thereby providing alternative molecules for use in treating celastrol-responsive diseases and disorders.
  • the celastrol derivative compounds of the present disclosure include those compounds of structural formula (I) wherein the Ri group (or moiety) of the derivative compound is the group that replaces the carboxylic acid group of compound 1.
  • the present disclosure contemplates a range of possible chemical groups for Ri including those listed in Table 2 (below).
  • the present disclosure also contemplates that the celastrol derivative compounds of structural formula (I) can include selected sub-genera of compounds.
  • the present disclosure provides celastrol derivative compounds of structural formula (I), where the group Ri can be -NH-(CO) 2 -NR 2 R 3 , or-N(CH 3 )-(CO) 2 -NR 2 R 3 .
  • the groups R 2 and R 3 of the structural formula can be independently selected from a hydrogen, an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, amine, or heteroaryl, optionally substituted with substituents individually selected from alkyl, alkoxy, cycloalkyl, ether, amine optionally substituted with one or more alkyl, halogen, hydroxyl, ether, cyano, nitrile, CF 3 , ester, amide, cycloalkyl amide, sugar, heteroarylamide optionally substituted with alkyl and/or alkoxy, urea, carbamate, thioether, sulfate, sulfonyl, sulfonic acid carboxylic acid, and aryl.
  • celastrol derivative compounds provided herein can exist in various well-known closely-related and/or equivalent forms not explicitly described by the chemical structures and formulae. It is intended that the celastrol derivative compounds of structural formula (I) of the present disclosure includes these closely-related forms of the compounds defined by the chemical structures and formulae including, but not limited to, pharmaceutically acceptable salts of the compounds, mixture of stereoisomers of the compounds, single stereoisomers of the compounds, tautomeric forms of the compounds, and/or prodrug forms of the compounds.
  • the celastrol derivative compounds of structural formula (I) can be prepared from readily available starting materials using methods and procedures known in the art.
  • the present disclosure provides general synthetic strategies for preparing compounds of structural Formula (I).
  • Schemes A-F presented below provide a series of six reactions starting from celastrol (compound 1) that can be used, adapted, and/or combined with well-known synthetic methods by the ordinary artisan to synthesize the celastrol derivative compounds of the present disclosure, e g., the compounds of Table 3 (above).
  • Examples 1-7 provide specific synthesis protocols that demonstrate the preparation of the celastrol derivative compounds 14, 15, 16, 17, and 22.
  • One of ordinary skill can use and/or adapt these synthesis protocols of Examples 1-7 for the preparation of additional celastrol derivative compounds of structural formula (I) described in the present disclosure.
  • process conditions /.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • a protecting group may be used to allow a functional group (such as O, S, or N) to be temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
  • a functional group such as O, S, or N
  • Protecting groups useful in syntheses of the present disclosure are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, Fourth Ed., Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 2007, the entire contents of which are hereby incorporated by reference, and references cited therein.
  • the starting materials and/or reagents used in the synthetic reaction Schemes A-F are commercially available, or generally known compounds that can be prepared by known procedures or obvious modifications thereof or are disclosed in the Examples herein.
  • many of the materials/reagents are available from commercial suppliers such as Sigma-Aldrich Chemical Co. (St. Louis, Missouri, USA).
  • celastrol has been proposed or shown to provide a potentially therapeutic effect, based on clinical, pre-clinical, or in vitro studies, in a number of diseases and disorders.
  • cancer e.g., gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung carcinoma, brain cancer, and glioblastoma multiforme
  • cancer e.g., gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung carcinoma, brain cancer, and glioblastoma multiforme
  • inflammatory and/or autoimmune disorders e.g., rheumatoid arthritis (RA), ankylosing spondylitis, systemic lupus erythematosus (SLE),
  • the present disclosure contemplates the use of a celastrol derivative compound of structural formula (I) of the present disclosure, or a pharmaceutical composition of such a compound, in a therapy, as a medicament, or in a method of treating a celastrol- responsive disease or disorder in a subject, or in the manufacture of a medicament for treating a celastrol-responsive disease or disorder in a subject.
  • the present disclosure contemplates that the celastrol derivative compounds of structural formula (I) disclosed herein can be used in methods of treating a celastrol-responsive disease or disorder in a subject suffering therefrom.
  • the method of treatment comprises administering to the subject in need thereof, a therapeutically effective amount of a compound of structural formula (I) as disclosed herein.
  • the administered compound of structure formula (I) can be a compound is selected from compound 14, compound 15, compound 16, compound 17, compound 22, compound 22-1 , compound 42, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61 , compound 62, compound 63, compound 64, compound 65, compound 66, compound 67, compound 68, compound 69, compound 70, compound 71, compound 72, compound 73, compound 74, compound 75, compound 76, compound 77, compound 78, compound 79, compound 80, compound 81 , compound 82, compound 83, compound 84, compound 85, compound 86, compound 87, compound 88, compound 89, compound 90, compound 91 , and compound 92, or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, tautomer, or prodrug of any one of these compounds.
  • the administered compound of structure formula (I) can be in the form of a pharmaceutical composition comprising the compound of structural formula (I) or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, as described elsewhere herein.
  • the administered pharmaceutical composition can comprise one or more pharmaceutically acceptable excipients and a compound is selected from compound 14, compound 15, compound 16, compound 17, compound 22, compound 22-1, compound 42, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61 , compound 62, compound 63, compound 64, compound 65, compound 66, compound 67, compound 68, compound 69, compound 70, compound 71 , compound 72, compound 73, compound 74, compound 75, compound 76, compound 77, compound 78, compound 79, compound 80, compound 81, compound 82, compound 83, compound 84, compound 85, compound 86, compound 87, compound 88, compound 89, compound 90, compound 91 , and compound 92, or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, tautomer, or prodrug of any one of these compounds.
  • the celastrol-responsive disease or disorder that the subject is suffering from can be a cancer.
  • the cancer treated by the method can include, but is not limited to, gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung carcinoma, brain cancer, and glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the celastrol-responsive disease or disorder that the subject is suffering from can be an inflammatory and/or autoimmune disorder.
  • the inflammatory and/or autoimmune disorder treated by the method can include, but is not limited to, rheumatoid arthritis (RA), ankylosing spondylitis, systemic lupus erythematosus (SLE), inflammatory bowel disease, osteoarthritis (OA), allergy, and skin inflammation.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • OA osteoarthritis
  • allergy and skin inflammation.
  • the celastrol-responsive disease or disorder that the subject is suffering from can be a neurological disorder.
  • the neurological disorder treated by the method can include, but is not limited to, Parkinson’s disease, Huntington disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
  • the celastrol-responsive disease or disorder that the subject is suffering from can be an obesity-related disease or disorder.
  • the obesity-related disease or disorder treated by the method can include, but is not limited to, obesity, pre-obesity, morbid obesity, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, lipodystrophy, fatty liver, Bardet-Biedl Syndrome, Cohen Syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome, and MOMO (Macrosomia Obesity Macrocephaly Ocular abnormalities) Syndrome.
  • the celastrol-responsive disease or disorder that the subject is suffering from can be a liver-related disease or disorder.
  • the liver- related disease or disorder treated by the method can include, but is not limited to, acutechronic liver failure (ACLF), acute hepatic porphyria, Alagille syndrome, alpha-1 antitrypsin deficiency, alcoholic liver disease, alcoholic hepatitis, amoebic liver, autoimmune hepatitis, benign liver tumors, biliary atresia, cardiac cirrhosis, cholestatic liver disease, congestive hepatopathy, cirrhosis, Crigler-Najjar syndrome, drug-induced liver disease, Dubin-Johnson syndrome, conjugated hyperbilirubinemia, galactosemia, Gilbert syndrome, glycogen storage disease, hemochromatosis, hepatic abscesses , hepatic cysts, he
  • the liver-related disease or disorder treated by the method is selected from acute-chronic liver failure (ACLF), alcoholic liver disease, cholestatic liver disease, drug- induced liver disease, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and viral liver disease.
  • ACLF acute-chronic liver failure
  • alcoholic liver disease cholestatic liver disease
  • drug- induced liver disease hepatocellular carcinoma
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • viral hepatitis and viral liver disease.
  • compositions and modes of Administering The present disclosure also provides uses and methods in which a celastrol derivative compound, such as a compound of structural formula (I), is administered to a subject in the form of a pharmaceutical composition, as described above.
  • the pharmaceutical composition includes a therapeutically effective amount of the celastrol derivative compound of structural formula (I) (e.g., a compound of Table 3), or a pharmaceutically acceptable salt or ester such a compound and one or more pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be prepared using methods well known in the pharmaceutical art (see, e g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed.
  • the pharmaceutical compositions can be prepared by diluting the active ingredient(s) with an excipient and/or enclosing it within a carrier in the form of a capsule, sachet, paper, or other container.
  • a carrier in the form of a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • the pharmaceutical composition(s) suitable for administering in the methods of the disclosure can be in the dosage form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • the carriers used in the preparation of the pharmaceutical compositions can include excipients such as inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • excipients such as inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Suitable excipients for use in the pharmaceutical compositions comprising a celastrol derivative of the present disclosure are well known in the art and include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propyl hydroxybenzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propyl hydroxybenzoates
  • sweetening agents such as methyl- and propyl hydroxybenzoates
  • flavoring agents such as talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition comprising the celastrol derivative compounds, such as a compound of structural Formula (I) (e.g., compounds of Table 3), can be administered either as single or multiple doses, and by any of the accepted modes of administration of active ingredients having similar utility.
  • a compound of structural Formula (I) e.g., compounds of Table 3
  • a pharmaceutical composition comprising an celastrol derivative can be administered using a variety of different modes including oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intralesional administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhaled administration, or subcutaneous administration.
  • oral administration intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intralesional administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration
  • the pharmaceutical compositions including the celastrol derivative compounds of the present disclosure can be used in a range of therapeutic methods of treatment and a range of dosages are contemplated for administration of a pharmaceutically effective amount.
  • the dosage and frequency (single or multiple doses) of administration of the pharmaceutical composition to a subject can vary depending upon a range of factors, such as, the route of administration; the subject’s size, age, sex, health, body mass, and/or diet; the state of the disease being treated; whether the subject is suffering from any other diseases, and any concurrent treatment being received.
  • adjustment of established dosages e.g., frequency and duration
  • to obtain the therapeutically effective amount may be required depending on the subject.
  • the amount of a pharmaceutical composition containing a celastrol derivative compound to be administered to a subject in a therapeutic method of treatment will be determined by a physician, in view of relevant circumstances of the subject being so treated, the chosen route of administration, and of course, the age, the weight, the severity of symptoms, the response of the individual subject to the treatment, and the like.
  • a therapeutically effective amount is the amount sufficient for the administered composition to accomplish a desired therapeutic purpose relative to the absence of the compound.
  • the therapeutically effective amount can be the amount determined to be sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease.
  • Methods for determining the dosage providing a therapeutically effective amount of a compound are well-known to those of ordinary skill in the art, and typically are based on analysis of amounts determined in cellular assays and/or animal models.
  • a dosage for administration to humans can be formulated to achieve a concentration that has been observed as therapeutically effective in an animal model. The dosage in the pharmaceutical composition for humans can further be adjusted by monitoring the effectiveness and adjusting upwards or downwards.
  • One of ordinary skill can used methods well known in the art to adjust the dosage in a pharmaceutical composition of the present disclosure (e.g., compounds of Table 3) to achieve maximal therapeutic efficacy for humans.
  • methods for therapeutic treatment are developed by starting with a pharmaceutical composition containing less than the optimal dose of the celastrol derivative compound. Thereafter, the dosage of the compound is increased incrementally until optimal efficacy is attained.
  • a key factor considered in developing the optimal dose is the ratio between the toxicity and the therapeutic efficacy of the active ingredient. This ratio, referred to as the compound’s therapeutic index, is typically described as the ratio of the active ingredient’s LD 50 (the amount of compound lethal in 50% of the population) to its ED 5 o (the amount of compound effective in 50% of the population).
  • Therapeutic index data can be obtained from cell culture assays and/or animal model studies and then used to determine a safe range of dosages of the active ingredient in a pharmaceutical composition for administration to humans. Ideally the dosage determined provides the active ingredient at its ED 5 o level in the subject with little or no toxicity.
  • the pharmaceutical composition contains a dosage of the celastrol derivative compound as the active ingredient in an amount of about 0.05 to about 100 mg/kg, about 0.1 to about 0.5 mg/kg, about 0.1 to about 1 mg/kg, about 0.1 to about 5 mg/kg, about 0.1 to about 10 mg/kg, about 0.1 to about 25 mg/kg, about 1 to about 5 mg/kg, about 1 to about 25 mg/kg, about 5 to about 25 mg/kg, about 10 to about 25 mg/kg, about 10 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 75 mg/kg, or about 50 to about 100 mg/kg.
  • the pharmaceutical composition comprises a dosage of the celastrol derivative compound of Formula (I) in an amount of about 0.05 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, or about 100 mg/kg.
  • the pharmaceutical compositions comprising celastrol derivative compounds of the present disclosure can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration.
  • controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in e.g., U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • the pharmaceutical compositions comprising a celastrol derivative compound of the present disclosure can also be formulated for administration via transdermal delivery devices (e.g., “patches”).
  • transdermal patches may be used to provide continuous or discontinuous infusion of the pharmaceutical compositions in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical compositions is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001 ,139.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of the pharmaceutical composition(s).
  • the pharmaceutical composition of the present disclosure can be prepared as a solid formulation, e.g., for oral administration.
  • Such solid formulations can be prepared by mixing the celastrol derivative compound active ingredient with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the active ingredient and the excipients.
  • Tablets or pills may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions of the present disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the active ingredients of the present disclosure (e.g., compounds of Table 3) in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the known methods of preparation include vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • compositions that can be administered by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein and as known in the art.
  • the pharmaceutical composition of the celastrol derivative e.g., compound of Table 3
  • the pharmaceutical compositions are prepared in pharmaceutically acceptable solvents which can be nebulized by use of inert gases.
  • nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine.
  • the pharmaceutical compositions useful in the methods can be in solution, suspension, or powder compositions and can be administered, orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • the crude product (50 mg, crude) was purified by silica gel chromatography (eluent of 0 ⁇ 20% methanol/dichloromethane) to give (6aS,6bS,8aS,11 R,12aR,14aR)-11- amino-3-hydroxy- 4, 6a, 6b, 8a, 11 , 14a-hexamethyl-7,8,9, 10, 12, 12a, 13, 14-octahydropicen-2-one (compound 4-2) (11.3 mg, 100% purity) as yellow solid.
  • Example 3 Synthesis of N-((2R,4aS,6aS, 12bR, 14aS)-10-hydroxy-2,4a,6a,9, 12b, 14a- hexamethyl-1 1-oxo- 1 , 2, 3, 4, 4a, 5, 6, 6a, 11 ,12b,13,14,14a,14b-tetradecahydropicen-2-yl)-2-(4- methylpiperazin-1-yl)- 2-oxoacetamide (compound 14).
  • Example 4 Synthesis of N-((2R,4aS,6aS, 12bR, 14aS)-10-hydroxy-2,4a,6a,9, 12b, 14a- hexamethyl-1 1-oxo-1 , 2, 3, 4, 4a, 5, 6, 6a, 1 1 ,12b,13,14,14a,14b-tetradecahydropicen-2-yl)-2-oxo-2- (2-oxa-6-azaspiro[3.3]heptan-6-yl)acetamide (compound 15).
  • the brown solid was purified by prep-TLC to give N-((2R,4aS,6aS,12bR,14aS)-10- hydroxy-2,4a,6a,9, 12b, 14a-hexamethyl-11-oxo- 1 , 2, 3, 4, 4a, 5, 6, 6a, 11 ,12b, 13, 14, 14a, 14b- tetradecahydropicen-2-yl)-2-oxo-2-(2-oxa-6- azaspiro[3.3]heptan-6-yl)acetamide (compound 15) (5.5 mg, 3.11% yield) as yellow solid.
  • Example s Synthesis of N-((2R,4aS,6aS,12bR,14aS)-10-hydroxy-2,4a,6a,9,12b,14a- hexamethyl-11 -oxo-1 ,2, 3, 4, 4a, 5, 6, 6a, 11 , 12b, 13, 14, 14a, 14b-tetradecahydropicen-2-yl)-N- methyl-2-(4-methylpiperazin-1-yl)-2-oxoacetamide (compound 16).
  • Example 6 Synthesis of N1-((2R,4aS,6aS,12bR,14aS)-10-hydroxy-2,4a,6a,9,12b,14a- hexamethyl-11- oxo-1 , 2, 3, 4, 4a, 5, 6, 6a, 11 ,12b,13,14,14a,14b-tetradecahydropicen-2-yl)-N2-(1- methylazetidin- 3-yl)oxalamide (compound 17)
  • Example 7 Synthesis of N'-[(2R,4aS,6aR,6aS,14aS,14bR)-10-methoxy- 2,4a,6a,6a,9,14a-hexamethyl-1 l-oxo-I .SA.S.e.lS.U.Ub-octahydropicen ⁇ -yll-N.N.N'- trimethyl-oxamide (compound
  • reaction mixture was poured into H 2 O (50 mL). The mixture was extracted with DCM (4x10 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuum.
  • Compound 14-4 can be prepared via a 6-step synthesis as summarized in Scheme 8 (below).
  • Compound 55 can be prepared from compound 14-4 via the synthesis summarized in
  • Compound 56 can be prepared from compound 14-4 via the synthesis summarized in
  • Example 13 Inhibition of NF-kB Signaling by Celastrol Derivative Compounds
  • Example 14 Anti-Inflammatory Potential of a Celastrol Derivative Compound
  • This example illustrates a study of the anti-inflammatory potential of an exemplary celastrol derivative of the present disclosure (compound 22) using an NF-kB luciferase promoter reporter gene assay in the human liver cancer cell line, HepG2.
  • NF-kB luciferase reporter assay The celastrol derivative, compound 22 (prepared as described in Example 13) and the parent molecule, compound 1 (celastrol), were freshly dissolved in DMSO. HepG2 NF-kB reporter cells were seeded (2.5 x 10 4 /well) in 96-well plate and then pre-treated with either compound 22 or compound 1 at the 8-point concentrations of 10, 5, 2.5, 1.25, 0.63, 0.31 , 0.16, 0.016, or 0 pM, respectively, and the NF-kB promoter was activated by adding IL-1/?(20ng/ml) to the cells.
  • the cells were harvested by adding the 1x passive cell lysis buffer (Promega) and followed by measurement of the relative NF-kB luciferase activity (RLU) using GloMax discover microplate reader (Promega). Inhibitory concentrations (IC 50 ) after normalization using Prizm 9.0 software.
  • LPS-induced NF-kB target protein expression Bone marrow-derived dendritic cells (BMDCs) were pre-treated with compound 22 or compound 1 at three concentrations (10 nM, 25 nM, 50 nM) for an hour and then treated overnight with LPS (500 ng/mL). The next day, the cells were subjected to western blotting for iNOS, COX2, NLRP3, and IL-1/?.
  • BMDCs Bone marrow-derived dendritic cells
  • Example 15 Anti-Inflammatory Potential of a Celastrol Derivative Compound
  • This example illustrates a study of the anti-inflammatory potential of an exemplary celastrol derivative of the present disclosure (compound 22) using specific NLRP3 inflammasome assays that employ bone marrow-derived dendritic cells (BMDCs) activated with LPS+ATP or LPS+Nigericin.
  • BMDCs bone marrow-derived dendritic cells
  • BMDCs were treated with LPS (100 ng/mL) for 3 hours (Signal 1) to prime NLRP3 inflammasome, and then treated with celastrol (compound 1) or the celastrol derivative compound, compound 22, at concentrations of 50 nM, 100 nM, and 500 nM. After 30 minutes Nigericin (10 pM) or ATP (5 mM) was added (Signal 2) and the level of NLRP3-dependent inflammasome activity was determined by western blotting the treated cells with ASC complex (>48 kDa). Also, the level of secreted IL-1/? in the conditioned media represents an active caspase-1 , a downstream molecule of NLRP3 inflammasome, which cleaves pro-IL1/? resulting in the secreted form of mature IL-1/?.
  • Compound 22 exhibited a robust inhibitory function on NLRP3 inflammasome activity that was better than that observed for the parental molecule celastrol (compound 1). As shown by the results depicted in FIG. 2A, compound 22 suppressed ASC complex formation more strongly than compound 1. Additionally, as shown by the plots depicted in FIG. 2B, compound 22 more strongly inhibited IL-1 ? secretion induced by both LPS+ATP and LPS+Nigericin. As shown in FIG. 2C, compound 22 (and compound 1) exhibited no significant suppressive effect on TNF-a inflammatory cytokine secretion under identical NLRP3 inflammasome activation.
  • Example 16 Inhibition of NLRP3 Inflammasome in Human THP-1 Cells by a Celastrol Derivative Compound
  • This example illustrates a study of the anti-inflammatory potential of an exemplary celastrol derivative of the present disclosure (compound 22) using an NLRP3 inflammasome assay in THP-1 , a human monocytic cell line, activated with LPS+Nigericin in the presence of compound 22 or the known NLRP3 inhibitor compound, MCC950 (CAS 256373-96-3), as a benchmark molecule.
  • Amnis Imaging flow cytometry is a high-throughput, single-cell, fluorescence-based image analysis method which can detect inflammasome by acquiring images of cellular distribution of ASC complex and active caspase-1.
  • the THP-1 cells were treated with LPS+Nigericin in the presence of inhibitors.
  • the treated cells were subjected to ASC staining and visualization of active caspase-1 using FLICA, a caspase-1 substrate exerting fluorescence upon cleavage.
  • the ASC+/FLICA+ cells were counted as THP-1 cells with active NLRP3 inflammasome complex.
  • THP-1 human monocytic cells form a strong ASC complex in response to LPS+Nigericin treatment.
  • the presence of compound 22 at 50 nM and 100 nM concentration strongly inhibited this ASC complex formation with an inhibitory capacity that was stronger than that observed for celastrol (compound 1) and MCC950, the benchmark molecule.
  • the strong inhibitory effect observed for compound 22 was verified further by counting of THP-1 cells carrying cellular ASC+ FLICA+ specks.
  • compound 22 was observed to exert a strong inhibitory function at concentrations as low as 25 nM, while the benchmark molecule, MCC950 displayed 5 ⁇ 10-fold lesser inhibitory potency at 100 nM concentration.
  • Example 17 Inhibition of Inflammation by a Celastrol Derivative Compound in an LPS- Induced Septic Shock Mouse Model
  • Cytokine expression was measured by conducting ELISA (Cat# 900-T54, PeproTech) for TNF-a on blood serum samples and qPCR for the cytokines, IL-1 (TaqMan, Mm00434228), IL-6 (TaqMan, Mm00446190), TNF-a (TaqMan, 00443258), iNOS (TaqMan, 00440502), on colonic mucosa samples.
  • the celastrol derivative compound, compound 22 successfully inhibited LPS-induced acute inflammation responses in the mouse septic-shock model which efficiently suppressed expression of an inflammatory mediator and the inflammatory cytokines including IL-1 , IL-6, TNF-a, and iNOS in the blood serum and colon mucosa to levels comparable to or lower than the levels observed in the group administered celastrol (compound 1).
  • Example 18 Comparative NLRP3 inflammasome inhibitory activity of CLM-022 and MCC950 in mouse and human macrophages
  • This example illustrates a comparative study of CLM-022 and MCC950 in inhibiting NLRP3 inflammasome activity in mouse and human macrophages.
  • BMDMs Bone marrow-derived macrophages
  • LPS 100 ng/mL
  • IL-1 p IL-1 p
  • CLM-022 or MCC950 CLM-022 or MCC950 in a dose range of 0-10 M for 30 minutes.
  • Nigericin (10pM) was added to the BMDMs for an additional 30 minutes.
  • THP-1 cell study To confirm the inhibitory effect of CLM-022 in human macrophages, THP-1 cells, a human leukemia monocytic cell line, were differentiated into macrophages using phorbol 12- myristate-13-acetate (PMA, 100 ng/ml) treatment for one day. The THP-1 macrophages were then treated with LPS (100 ng/mL) for 3 hours to induce the expression of inflammatory genes. Subsequently, the THP-1 cells were treated with CLM-022 or MCC950 in a dose range of 0-10 pM for 30 minutes. Then, to fully activate NLRP3-dependent inflammasome activity, Nigericin (10 pM) was added to the THP-1 cells for an additional 60 min.
  • PMA phorbol 12- myristate-13-acetate
  • CLM-022 robustly inhibited IL-1 p secretion but not TNF-a.
  • the NLRP3 inflammasome is composed of a multi-protein complex and the exact molecular mode of NLRP3 activation remains unclear.
  • This example illustrates a study of the ability of CLM-022 to protect the NLRP3 molecule as determined using a drug affinity responsive target stability (DARTS) assay.
  • DARTS assay is a robust method to identify small molecule target protein. In case of a drug-target interaction, the small molecule protects target protein from degradation by proteinase (Pronase) whereas free-proteins may be degraded very efficiently in the given condition.
  • the DARTS assay was performed using THP-1 lysates pretreated with LPS and Nigericin to induce activation of NLRP3 inflammasome.
  • THP-1 cells (1x10 5 /mL) were treated with LPS (100 ng/mL) for 3 hours, followed by 10 pM Nigericin for an additional 30 minutes.
  • Pronase 50-500 ng/pg of protein was added to the lysate with CLM-022 (10 pM) or MCC950 (10 pM) for the indicated time (10-15 min) at room temperature.
  • the protein components of NLRP3 inflammasome were visualized using antibody recognizing NLRP3-Natch domain (FIG. 6A), NLRP-PYD domain (FIG. 6B), or NEK7 protein (FIG. 6C).
  • the relative band intensities were normalized by GAPDH after densitometry scanning.
  • CLM-022 markedly protected NLRP3 protein from degradation which was obviously more efficient than that of MCC950.
  • CLM-022 did not protect NEK7 from Pronase-induced degradation. This result highlights that CLM-022 would directly interact with NLRP3 protein in a target-specific manner.
  • Example 20 Protection of THP-1 cells from inflammasome-induced pyroptosis
  • Pyroptosis a pro-inflammatory form of cell death, is triggered by the activation of NLRP3 inflammasome components (GSDMD and Caspase-1), leading to the release of pro- inflammatory cytokines IL-1 and IL-18, as well as damage-associated molecular patterns (DAMPs). This process elicits a cascade of inflammatory responses, which can persist if dysregulated in affected tissues.
  • DAMPs damage-associated molecular patterns
  • CLM-022 could effectively enhance cell viability by inhibiting pyroptosis in the context of inflammation and inflammasome activation.
  • This example illustrates a comparative study of the abilities of CLM-022 and MCC950 to protect THP-1 cells from inflammasome-induced pyroptosis.
  • THP-1 cells were treated with either CLM-022 or MCC950 over a dosage range of 0 pM to 10 pM and cell viability was determined by impermeant live/dead staining dye and flow cytometric analysis. Additionally, NLRP3 inflammasome-induced cytotoxicity was investigated by measuring the level of LDH in the conditioned media after the CLM-022 and MCC950 treatments. Further, Western blotting of samples from the THP-1 cell viability assays was carried out to determine levels of the pyroptosis-mediating molecules, GSDMD and Caspase-1.
  • CLM-022 possesses a greater capacity than the benchmark molecule, MCC950, to inhibit inflammasome-induced pyroptosis in human THP-1 macrophages.

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Abstract

La présente divulgation concerne des composés qui sont des dérivés du composé, du célastrol, de formule (I), R étant un groupe amide et des compositions pharmaceutiques qui comprennent ces composés dérivés de célastrol. La divulgation concerne également des utilisations des composés dérivés de célastrol divulgués, y compris des utilisations dans des médicaments, une thérapie et des méthodes de traitement d'une maladie ou de troubles sensibles au célastrol, tels que des cancers, des troubles inflammatoires et/ou auto-immuns, des troubles neurologiques, des lésions et des troubles cérébraux, des maladies et des troubles liés à l'obésité et/ou des maladies et des troubles liés au foie.
EP23751170.4A 2022-07-15 2023-07-12 Dérivés de célastrol Pending EP4554955A1 (fr)

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