- SULFONIMIDAMIDE COMPOUNDS AS NLRP3 MODULATORS
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Described herein are compounds of Formula (I), Formula (I-A), and Formula (I-B), solvates thereof, tautomers thereof, and pharmaceutically acceptable salts of the foregoing, Further described herein are methods of inhibiting NLRP3 using said compounds, and methods of and compositions useful in treating NLRP3-dependent disorders.
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Paragraph 0250
(2021/07/31)
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- MACROCYCLIC SULFONYLUREA DERIVATIVES USEFUL AS NLRP3 INHIBITORS
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The present invention relates to macrocyclic compounds, such as macrocyclic sulfonyl ureas. The present invention further relates to associated salts, solvates, prodrugs and pharmaceutical compositions and to the use of such compounds in the treatment and
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Page/Page column 190-191
(2021/02/26)
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- NOVEL PROCESSES
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The present invention relates to processes of preparing N- ((1,2,3,4,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-isopropyl-1H- pyrazole-3-sulfonamide and salts thereof. The present invention further relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.
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Page/Page column 26-27; 31-32
(2020/05/21)
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- AMINO HETEROCYCLIC COMPOUNDS AND USES THEREOF
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The present disclosure relates to compounds of Formula (I): and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inflammatory, autoinflammatory, and autoimmune diseases and cancers.
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Paragraph 01304
(2020/08/22)
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- NLRP3 INHIBITORS
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The present application relates to compounds with NLRP3inhibitory activity and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present application further relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3inhibition.
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Page/Page column 128-129
(2020/06/10)
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- Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors
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NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion in mice.
- Agarwal, Sameer,Sasane, Santosh,Shah, Hardik A.,Pethani, Jignesh P.,Deshmukh, Prashant,Vyas, Vismit,Iyer, Pravin,Bhavsar, Harsh,Viswanathan, Kasinath,Bandyopadhyay, Debdutta,Giri, Poonam,Mahapatra, Jogeswar,Chatterjee, Abhijit,Jain, Mukul R.,Sharma, Rajiv
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supporting information
p. 414 - 418
(2020/03/13)
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- NLRP MODULATORS
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein, useful to treat connected to the modulation of NRLP3.
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Page/Page column 346; 382-383
(2020/01/31)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula A, or a pharmaceutically acceptable salt thereof, are featured (Formula A) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
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Page/Page column 305
(2020/06/10)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
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Page/Page column 274; 280-281
(2020/06/05)
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- SULFONIMIDAMIDE COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: (Formula AA) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
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Page/Page column 472-473
(2020/08/13)
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- SELECTIVE INHIBITORS OF NLRP3 INFLAMMASOME
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The present disclosure relates to compounds of Formula (I): (I); and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as autoinflammatory and autoimmune diseases and cancers.
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Paragraph 0468
(2019/02/15)
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- NOVEL COMPOUNDS
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The present invention relates to substituted 5-membered nitrogen containing heteroaryl compounds, such as sulfonyl triazoles, where the heteroaryl ring is further substituted, optionally via a linking group such as -NH-, with a cyclic group which in turn is substituted at the α-position. The present invention further relates to associated salts, solvates, prodrugs and pharmaceutical compositions, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.
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Page/Page column 187
(2019/11/19)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured.The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
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Page/Page column 461-462
(2019/02/13)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured. The variables shown in Formula AA are as defined in the claims. The compounds of formula AA are NLRP3 activity modulators and, as such, can be used in the treatment of metabolic disorders (e.g. Type 2 diabetes, atherosclerosis, obesity or gout), a disease of the central nervous system (e.g. Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease), lung disease (e.g. asthma, COPD or pulmonary idiopathic fibrosis), liver disease (e.g. NASH syndrome, viral hepatitis or cirrhosis), pancreatic disease (e.g. acute pancreatitis or chronic pancreatitis), kidney disease (e.g. acute kidney injury or chronic kidney injury), intestinal disease (e.g. Crohn's disease or Ulcerative Colitis), skin disease (e.g. psoriasis), musculoskeletal disease (e.g. scleroderma), a vessel disorder (e.g. giant cell arteritis), a disorder of the bones (e.g. osteoarthritis, osteoporosis or osteopetrosis disorders), eye disease (e.g. glaucoma or macular degeneration), a disease caused by viral infection (e.g. HIV or AIDS), an autoimmune disease (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus or Autoimmune Thyroiditis), cancer or aging.
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Page/Page column 402; 403
(2019/02/13)
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- SULFONYL UREA DERIVATIVES AND THEIR USE IN THE CONTROL OF INTERLEUKIN-1 ACTIVITY
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The present invention relates to compounds of Formula (I) and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein inhibit the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inter alia autoinflammatory and autoimmune diseases.
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Page/Page column 65
(2018/02/17)
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- CHEMICAL COMPOUNDS
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The present disclosure relates to compounds of Formula (I): and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein inhibit the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inter alia autoinflammatory and autoimmune diseases and cancers.
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Page/Page column 45; 46
(2018/10/19)
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- COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY
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In one aspect, compounds of Formulae (I) and (II), or pharmaceutically acceptable salts thereof, are featured; Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formulae (I) and (II) can be as defined anywhere herein.
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Page/Page column 207; 208
(2017/11/15)
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- Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950
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MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite. Further synthesis of individual enantiomers and coelution studies using a chiral column in HPLC-MS/MS showed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (2a). Incubation of MCC950 with a panel of cytochrome P450 enzymes showed P450s 2A6, 2C9, 2C18, 2C19, 2J2, and 3A4 catalyze the formation of the major metabolite 2a, with a lower level of activity shown by P450s 1A2 and 2B6. All of the synthesized compounds were tested for inhibition of NLRP3-induced production of the pro-inflammatory cytokine IL-1β from human monocyte derived macrophages. The identified metabolite 2a was 170-fold less potent than MCC950, while one regioisomer had nanomolar inhibitory activity. These findings also give first insight into the SAR of the hexahydroindacene moiety.
- Salla, Manohar,Butler, Mark S.,Pelingon, Ruby,Kaeslin, Geraldine,Croker, Daniel E.,Reid, Janet C.,Baek, Jong Min,Bernhardt, Paul V.,Gillam, Elizabeth M. J.,Cooper, Matthew A.,Robertson, Avril A. B.
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supporting information
p. 1034 - 1038
(2016/12/16)
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- Regioselectivity of acid-catalyzed cyclization of 1-(3,4-dialkylaryl)-3- chloropropan-1-ones to indanones. Comparison of experimental data and results of computer simulation
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The acid-catalyzed cyclization of 1-(3,4-dialkylaryl)-3-chloropropan-1-ones to dialkyl-indanones via the intermediate formation of (3,4-dialkylaryl) propenones was studied. This reaction affords isomeric products: 5,6-dialkylindan-1-ones and 4,5-dialkylin
- Ivchenko,Nifant'Ev,Ustynyuk,Ezerskii
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experimental part
p. 929 - 935
(2010/10/04)
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- Novel synthesis of 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl) furan-2-sulfonyl]urea, An anti-inflammatory agent
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A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)- furan-2-sulfonyl]urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.
- Urban, Frank J.,Jasys, V. John,Raggon, Jeffrey W.,Buzon, Richard A.,Hill, Paul D.,Eggler, James F.,Weaver, John D.
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p. 2029 - 2043
(2007/10/03)
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- Electron Paramagnetic Resonance Spectra of the Radical Cations of Some Benzocyclobutenes, Benzocyclopentenes and Benzocyclohexenes
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1,2,4,5-Tetrahydrobenzodicyclobutene, 1,2,3,5,6,7-hexahydrobenzodicyclopentene and 1,2,3,4,6,7,8,9-octahydrobenzodicyclohexene, and their dimethyl derivatives, and tetramethylbenzocyclo-butene, -pentene and -hexene have been prepared.All except the first compound have been oxidised to their corresponding radical cations, and the EPR spectra have been analysed by assigning McConnell-type Q-values to the substituents in the benzene ring.It is suggested that the ordering of the orbital energy levels (ΨA above ΨS) in 3,6-dimethylbenzobiscyclobutene and -pentene is a manifestation of the Mills-Nixon effect, and results from rehybridisation of the strained molecular framework.In the radical cations of 5,10-dimethyl-1,2,3,4,6,7,8,9-octahydrobenzodicyclohexene and 5,6,7,8-tetramethyl-1,2,3,4-tetrahydrobenzocyclohexene the total unpaired electron density, as implied by the McConnell type of relationship, appears to be less than unity.Various possible causes of this are examined.
- Avila, David V.,Davies, Alwyn G.,Li, Elizabeth R.,Ng, Kai M.
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p. 355 - 362
(2007/10/02)
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- Aromatic Spiranes, XIV: Syntheses of 2,2'-Spirobi-(s-hydrindacene) and its precursors
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The title compound 35 was prepared by catalytic reduction of the diones 29a and 11a. 29a was synthesized by systematic anellation of fivemembered rings to the positions 5,6 and 5',6', resp., of 2,2'-spirobiindane.The preparation of 11a was achieved by Friedel-Crafts cyclisation of bis-(5-indanylmethyl)-malonic acid. s-Hydrindacene-1-one 5a was prepared as a precursor for the synthesis of 11a (see forthcoming publication) and its derivates as models for corresponding anellation and substitution reactions. - Keywords: s-Hydrindacene-1-one and derivates; Mono- and bisanellation; 2,2'-Spirobiindane; 1H-nmr spectra
- Neudeck, Horst K.
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p. 627 - 658
(2007/10/02)
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