WO2006075955A1 - Derives de pyrazolyl acylsulfonamide utilises en tant qu'inhibiteurs de l'enzyme de conversion de l'endotheline et particulierement utiles dans le traitement d'une maladie pulmonaire obstructive chronique - Google Patents

Derives de pyrazolyl acylsulfonamide utilises en tant qu'inhibiteurs de l'enzyme de conversion de l'endotheline et particulierement utiles dans le traitement d'une maladie pulmonaire obstructive chronique Download PDF

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WO2006075955A1
WO2006075955A1 PCT/SE2006/000042 SE2006000042W WO2006075955A1 WO 2006075955 A1 WO2006075955 A1 WO 2006075955A1 SE 2006000042 W SE2006000042 W SE 2006000042W WO 2006075955 A1 WO2006075955 A1 WO 2006075955A1
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alkyl
phenyl
methyl
pyrazol
acetamide
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PCT/SE2006/000042
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Andrew Baxter
Mark Furber
Sarah King
Christopher Luckhurst
Austen Pimm
James Reuberson
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention concerns pyrazolyl acylsulfonamide derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Endothelin converting enzyme (ECE-1) is a protease involved in the biosynthesis of endothelin.
  • Endothelin is a strong vasoconstrictor and inhibitors of endothelin have been investigated with a view to developing therapeutic agents of use in treating cardiovascular diseases.
  • EP-0885890 and JP-2000-053649 describe pyrazolyl sulphonyl ureas and suggest that such compounds may be active agents in treating or preventing cardiovascular disease.
  • COPD chronic obstructive pulmonary disease
  • Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible.
  • the airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • the most important contributory source of such particles and gases, at least in the western isorld, is tobacco smoke.
  • COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells.
  • the tiso most important conditions covered by COPD are chronic bronchitis and emphysema.
  • the suppression of the biosynthesis of endothelin, by hindering ECE-1 may be effective in the prevention and treatment of chronic obstructive pulmonary disease (for example by reducing mucus secretion).
  • the present invention provides a compound of formula (I): wherein:
  • R 1 is optionally substituted aryl or optionally substituted heteroaryl
  • R 2 and R 4 each independently represent hydrogen, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 3-7 cycloalkyl [optionally substituted by halogen or C 1-4 alkyl];
  • R 3 is optionally substituted aryl, optionally substituted heteroaryl or C 3-7 cycloalkyl [optionally substituted by halogen or C 1-4 alkyl]; aryl and heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, OC(O)NR 5 R 6 , NR 7 R 8 , NR 10 C(O)NR 11 R 12 , S(O) 2 NR 13 R 14 ,
  • R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 17 , R 18 , R 19 , R 20 , R 21 , R 25 , R 26 , R 27 , R 28 and R 29 are, independently, hydrogen, C 1-6 alkyl [optionally substituted by halogen, C 3-6 cycloalkyl or phenyl ⁇ optionally substituted by halogen or C 1-4 alkyl ⁇ ], CH 2 (C 2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N
  • R 16 , R 22 , R 23 and R 24 are, independently, C 1-6 alkyl [optionally substituted by halogen, C 3-6 cycloalkyl or phenyl ⁇ optionally substituted by halogen or C 1-4 alkyl ⁇ ], CH 2 (C 2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 ,
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers).
  • the present invention covers all such isomers and mixtures thereof in all proportions.
  • Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. Salts also include metal salts, such as an alkali metal salt (for example a sodium or potassium salt) or an alkaline earth metal salt (for example magnesium or calcium).
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example magnesium or calcium
  • the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • Halogen is, for example fluorine or chlorine or bromine.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
  • Alkylene groups may similarly be straight or branched chain.
  • Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • Haloalkyl is an alkyl group carrying one or more (such as 1 to 6) halogen (such as chloro or fluoro atoms) and is, for example, CF 3 , CH 2 CF 3 or C 2 F 5 .
  • Hydroxyalkyl is an alkyl group carrying one or more (such as 1 to 3) hydroxy, groups.
  • Aryl is, for example, phenyl or naphthyl.
  • Heteroaryl is an aromatic 5- or 6-membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
  • Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benzo[b]thienyl (also known as benz[b]thienyl, benzothienyl or benzo[b]thiophenyl), 2,3-dihydrobenz[b]thienyl (for example in a 1-dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl
  • R 1 is aryl or heteroaryl, which aryl or heteroaryl moiety is optionally substituted by one or more of halogen, cyano, nitro, MH 2 , NH(C 1-4 alkyl), N(C 1-4 atkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , CO 2 H, CO 2 ( C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), CF 3 or
  • R 1 is phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl, which phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl moiety is optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy,
  • R 1 is phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl which phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl moiety is optionally substituted by one or more of halogen, cyano, S(C 1-4 alkyl), C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, CF 3 or OCF 3 .
  • R 1 is aryl (such as phenyl or naphthyl) optionally substituted by one or more of halogen, cyano, S(C 1-4 alkyl), C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, CF 3 or OCF 3 .
  • R 1 is heteroaryl optionally substituted by one or more of halogen, cyano, S(C 1-4 alkyl), C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, CF 3 or OCF 3 .
  • Heteroaryl moieties according to this embodiment include, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl and benzothienyl.
  • R 1 is an optionally substituted thienyl, thiazolyl, benzothienyl or indolyl moiety.
  • R 1 is a group of formula (II)
  • X is O, S, S(O) 1 , S(O) 2 , or C 1-6 alkylene
  • Ar 1 and Ar 2 each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl),
  • R 1 is a group of formula (II), wherein Ar 1 and Ar 2 each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety is optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C )
  • R 1 is a group of formula (II) wherein Ar 1 and Ar 2 each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety is optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CF 3 or OCF 3 .
  • R 2 is hydrogen or C 1-4 alkyl or C 3-7 cycloalkyl [optionally substituted by halogen or C 1-4 alkyl]; and R 4 is hydrogen.
  • R 2 is hydrogen or C 1-4 alkyl; and R 4 is hydrogen.
  • R 3 is phenyl optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (
  • R 3 is heteroaryl (such as pyridinyl) optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), C(O
  • R 3 is C 3-6 cycloalkyl (such as cyclohexyl) optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O) 2 (C
  • the present invention provides a compound of formula (I) wherein: R 1 is aryl or heteroaryl, which aryl or heteroaryl moiety is optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 4 alkyl), C(O)N(C 1-4 alkyl) 2 , CO 2 H, CO 2 (C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)C 1-4 al
  • X is O, S, S(O) 1 , S(O) 2 , or C 1-6 alkylene and: Ar 1 and Ar 2 each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl),
  • R 2 is hydrogen or C 1-4 alkyl or C 3-7 cycloalkyl [optionally substituted by halogen or C 1-4 alkyl]; and R 4 is hydrogen, and
  • R 3 is phenyl optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , S(C 1-4 alkyl), S(O)( C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy,
  • the present invention provides a compound of formula (I) wherein: R 1 is phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl, which phenyl, naphthyl, thienyl, thiazolyl, benzothienyl or indolyl moiety is optionally substituted by one or more of halogen, cyano, S(C 1-4 alkyl), C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, CF 3 or OCF 3 ; or R 1 is a group of formula (II)
  • Ar 1 and Ar 2 each independently represent phenyl, pyridinyl, thienyl, or thiazolyl, which phenyl, pyridinyl, thienyl, or thiazolyl moieties are independently optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CF 3 or OCF 3 ;
  • R is hydrogen or C 1-4 alkyl
  • R 4 is hydrogen
  • R 3 is phenyl, optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CF 3 or OCF 3 ; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is selected from: N-[(4-chlorophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetamide N-[(4-cyanophenyl)sulfonyl]-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetamide N-[(4-chlorophenyl)sulfonyl]-2-[1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]acetamide
  • R 1 represents a group of formula (II) (Ar 2 -X-Ar 1 -) wherein X is C 2-6 alkylene, reacting a compound of formula (V), wherein Y is C 2-6 alkenylene or C 2-6 alkynylene, with a reducing agent
  • the reaction may be performed in a suitable solvent (such as dichloromethane), in the presence of a suitable coupling agent (such as EDCI) and in the presence of one or more suitable bases (such as N,N-dimethylaminopyridine, triethylamine or N,N-diisopropylethylamine) at a suitable temperature (for example 0-35 °C).
  • a suitable solvent such as dichloromethane
  • a suitable coupling agent such as EDCI
  • suitable bases such as N,N-dimethylaminopyridine, triethylamine or N,N-diisopropylethylamine
  • a suitable solvent such as ethanol
  • a suitable reducing agent such as hydrogen (2 bar) and Pd/C
  • a compound of the invention wherein R 4 is hydrogen may be converted into a compound of the invention wherein R 4 is bromine or iodine, by electrophilic substitution e.g. with. Br 2 , or a source of electrophilic iodine, e.g. an iodine/silver acetate mixture.
  • a compound of the invention wherein R 4 is bromine may be converted into a compound of the invention wherein R 4 is C 1-6 alkyl (e.g. methyl) by reaction with a suitable dialkyl metal (e.g dimethyl zinc and a to-phosphino nickel dichloride catalyst).
  • Compounds of formula (III) can be prepared by treatment of a ⁇ , ⁇ -diketoester
  • the compounds of the invention have activity as pharmaceuticals, in particular as inhibitors of ECE-1 converting enzyme.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in a method of treatment of a warm-blooded animal (such as man) by therapy (including prophylaxis).
  • a method for modulating ECE- 1 activity in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating ECE-1 activity), in a warmblooded animal, such as man).
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAlD-induced) and dust-induced asthma., both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vascul
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget's
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses ⁇ and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal, hepatitis including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HTV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, mdeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema. .
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof. may be effective in the prevention and treatment of chronic obstructive pulmonary disease (COPD). That modulators of ECE-1 activity may be used in treating COPD has not been disclosed previously. ...
  • the present invention provides a method of treating chronic obstructive pulmonary disease in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of an ECE-1 inhibitor.
  • the present invention also provides the use of an ECE-1 inhibitor in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention further provides a method of treating an ECE-1 mediated disease state (such as COPD) in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention further provides a method of treating chronic obstructive pulmonary disease in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of the invention or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a warm-blooded animal, such as man, in particular modulating ECE-1 activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80% w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1mg and 1g of active ingredient
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg -1 to 100 mgkg -1 of the compound, for example in the range of 0.1 mgkg -1 to 20 mgkg -1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramus
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-1ike growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B- Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl,
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886,
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof,, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochlor
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (M1, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • M1, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • the invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramus
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-1ike growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling
  • Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 -
  • a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially coUagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-Il) and MMP-9 andMMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, arid a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as ZenecaZD-2138; the compound SB-210661; a pyridinyi-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-8
  • The.present invention further relates to the combination of a compound of the invention, or a. pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochlor
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (M1, M2, and M3) antagonist such as. atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • M1, M2, and M3 antagonist such as. atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a compound of the invention or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • another systemic or topically- applied anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-1actam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptas
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a-comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase);
  • -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892
  • TNF-alpha-1 for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for .
  • suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fiuoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, initomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as
  • an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that isorks by another mechanism (for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354
  • a compound that isorks by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2; interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-d
  • INTERMEDIATE 2 This shows the preparation of (3-methyl-1-phenyl-1H-pyrazol-5-yl)acetic acid.
  • cupric chloride (1.76 g). To this was added the solution of the diazonium salt resulting in effervescence and an exotherm to 30 °C. The green solution was stirred for 40 rain, before being poured into saturated brine (300 mL) and this mixture was then stirred at RT for 2 h. The solution was extracted with ethyl acetate three times. The combined organic extracts were washed with saturated aqueous sodium bicarbonate then with saturated brine, and dried over magnesium sulfate, filtered, and concentrated in vacuo to leave an orange oil.
  • INTERMEDIATE 32 This shows the preparation of N-(tert-butyl)-5-(pyridin-4-ylthio)thiophene-2-sulfonamide.
  • INTERMEDIATE 34 This shows the preparation of N-(tert-butyl)-5-(pyridin-2-ylthio)thiophene-2-sulfonamide.
  • INTERMEDIATE 37 This shows the preparation of 4- ⁇ [5-(aminosulfonyl)-2-thienyl]thio ⁇ -N,N- dimethylbenzamide.
  • This Example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acetamide.
  • This Example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-[1-(4- fluorophenyl)-3-methyl-1H-pyrazol-5-yl]acetamide.
  • reaction mixture was concentrated in vacuo, methanol was added and this solution was purified by RP ⁇ PLC (Xterra, 5% to 50% acetonitrile in formic acid (0.2% aq.)) to leave, after diethyl ether trituration, the title compound N-[(4- chlorophenyl)sulfonyl]-2-[1-(3-methoxyphenyl)-3-methyl-1H-pyrazol-5-yl]acetamide (20 mg) as a solid.
  • RP ⁇ PLC Xterra, 5% to 50% acetonitrile in formic acid (0.2% aq.
  • EXAMPLE 5 This Example illustrates the preparation of N-[(4-tert-butylphenyl)sulfonyl]-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acet amide.
  • This Example illustrates the preparation of N-( ⁇ 5-[(4-chlorophenyl)thio]-2- thienyl ⁇ sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazoI-5-yl)acetamide.
  • This Example illustrates the preparation ofN- ⁇ [5-(butylthio)-2-thienyl]sulfonyl ⁇ -2-(3- methyl-1-phenyl- 1H-pyrazol-5-yl)acetamide.
  • EXAMPLE 8 This Example illustrates the preparation of N- ⁇ [5-(isopropylthio)-2-thienyl]sulfonyl ⁇ -2-(3- methyl-1-phenyl- 1H-pyrazol-5 -yl)acetamide.
  • This Example illustrates the preparation of N-( ⁇ 4-[(4-chlorophenyI)thio]phenyl ⁇ sulfonyl)- 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.
  • This Example illustrates the preparation ofN- ⁇ [5-(4-fluorobenzyl)-2-thienyl]sulfonyl ⁇ -2- (3-methyl-1-phenyl-1H-pyrazol-5- yl)acetamide.
  • Phosphorus pentachloride (1.95 g) was added in small portions to stirred chlorosulfonic acid (1.1 g) at RT. The dark solution was then cooled using an ice bath. Slowly, Intermediate 14 (0.9 g) was added dropwise. After complete addition the reaction was poured onto ice, and extracted with DCM. The organic phase was washed with water, dried over sodium sulfate, and filtered. Concentration in vacuo gave an oil, which was dissolved in THF (5 mL), and aqueous ammonia (1 mL) was added. The mixture was stirred for 20 min then concentrated in vacuo to give a brown gum (60 mg) that was dissolved in DCM (5 mL).
  • EXAMPLE 12 This Example illustrates the preparation of N-( ⁇ 5-[2-(4-methylphenyl)ethyl]-2- thienyl ⁇ sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.
  • This example illustrates the preparation of N-[(2,5-dichloro-3-thienyl)sulfonyl]-2-(3- methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.
  • This example illustrates the preparation of 2-(3-methyl-1 -phenyl- 1H-pyrazol-5-yl)-N- ⁇ [5- (2-phenylethyl)-2-thienyl] sulfonyl ⁇ acetamide.
  • EXAMPLE 16 This example illustrates the preparation of 2-(3 -methyl- 1 -phenyl- 1H-pyrazol-5-yl)-N- [(4- phenoxyphenyl)sulfonyl] acetamide.
  • EXAMPLE 17 This example illustrates the preparation of N-[(3,4-dichlorophenyl)sulfonyl]-2-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)acetamide.
  • This example illustrates the preparation of N-[(5-bromo-2-thienyl)sulfonyl]-2-(3-methyl- 1 -phenyl- 1H-pyrazol-5-yl)acetamide.
  • This example illustrates the preparation of N-( ⁇ 5-[(2-chlorophenyl)thio]-2- thienyl ⁇ sulfonyl)-2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acetamide.
  • the resultant oil was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)> to give a small amount of 5-[(2-chlorophenyl)thio]thiophene-2-sulfonamide (22 mg) that was dissolved in DCM (2 mL). To this solution was added Intermediate 2 (15 mg), EDCI (17 mg) and DMAP (3 mg).
  • This example illustrates the preparation of methyl 4- ⁇ [5-( ⁇ [(3-methyl-1-phenyl-1H- pyrazol-5-yl)acetyl]amino ⁇ sulfonyl)-2-thienyl]thio ⁇ benzoate.
  • EXAMPLE 21 This example illustrates the preparation of 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N- ⁇ [5- (pyridin-4-ylthio)-2-thienyl]sulfonyl ⁇ acetamide hydrochloride.
  • This example illustrates the preparation of 2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-N- ⁇ [5- (pyridin-2-y lthio)-2-thienyl]sulfonyl ⁇ acetamide.
  • This example illustrates the preparation of 2-(4-bromo-3 -methyl- 1 -phenyl- 1H-pyrazol-5- yl)-N-[(4-chlorophenyl)sulfonyl]acetamide.
  • Example 2 To a stirred solution of Example 1 (40 mg) in acetic acid (5 mL) at RT was added bromine (10 ⁇ L). The reaction was stirred for 1 h then concentrated in vacuo and triturated with diethyl ether to give the title compound 2-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)- N-[(4-chlorophenyl)sulfonyl]acetamide (10 mg).
  • EXAMPLE 24 This example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-(4-iodo-3- memyl-1-phenyl-1H-pyrazol-5-yl)acetamide.
  • This example illustrates the preparation of N-[(4-chlorophenyl)sulfonyl]-2-(3,4-dimethyl- 1 -phenyl-1H-pyrazol-5-yl)acetamide.
  • Example 23 To a stirred solution of Example 23 (100 mg) and [1,3-bis-(diphenylphosphino)- ⁇ ropane] nickel dichloride (2 mg) in THF (4 mL) was added dimethylzinc (2.0 M in toluene, 213 ⁇ L). The mixture was then heated at 80 °C for 3 h. Having been allowed to cool, the reaction mixture was poured into saturated aqueous ammonium chloride solution, and extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • This example illustrates the preparation of N- ⁇ [4-chloro-3- (bydroxymethyl)phenyl]sulfonyl ⁇ -2-(3-methyl-1-phenyl-1H-pyrazol-5-yl)acstamide.
  • This example illustrates the preparation of N-(1H-indol-2-ylsulfonyl)-2-(3-methyl-1- phenyl-1H-pyrazol-5-yl)acetamide.
  • Exemplified compounds were tested to determine inhibition of endothelin-converting enzyme-1 (ECE-1) using the method of Johnson and Ahn (Anal. Biochem. 2000, 286,112- 118): with analysis being conducted at either ambient temperature using 50 mM Tris Maleate pH6.0 assay buffer and samples prepared in a 384 wel1-plate format (Conditions A); or alternatively at 37 °C using 50 mM Tris Maleate pH6.0 assay buffer and samples prepared in a 96 wel1-plate format (Conditions B).
  • the compounds of the examples have a pIC 50 of least 4.0.
  • pIC 50 values for a representative selection of compounds are given in the Table below.

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Abstract

Cette invention concerne des composés représentés par la formule (I), dans cette formule R1,R2,R3 et R4 sont tels que définis dans la spécification. Cette invention concerne également des procédés permettant de préparer de tels composés, ainsi que des compositions pharmaceutiques comprenant de tels composés. L'invention concerne également l'utilisation de ces composés en tant qu'agents thérapeutiques actifs (F).
PCT/SE2006/000042 2005-01-13 2006-01-11 Derives de pyrazolyl acylsulfonamide utilises en tant qu'inhibiteurs de l'enzyme de conversion de l'endotheline et particulierement utiles dans le traitement d'une maladie pulmonaire obstructive chronique WO2006075955A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099794A1 (fr) * 2007-02-09 2008-08-21 Takeda Pharmaceutical Company Limited Composés à cycles fusionnés utiles en tant qu'agonistes partiels de ppar-gamma
WO2019166629A1 (fr) * 2018-03-02 2019-09-06 Inflazome Limited Nouveaux composés
US11530200B2 (en) 2018-03-02 2022-12-20 Inflazome Limited Compounds
US11834433B2 (en) 2018-03-02 2023-12-05 Inflazome Limited Compounds
US11884645B2 (en) 2018-03-02 2024-01-30 Inflazome Limited Sulfonyl acetamides as NLRP3 inhibitors
US12030879B2 (en) 2018-03-02 2024-07-09 Inflazome Limited Sulfonyl acetamides as NLRP3 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997004772A1 (fr) * 1995-08-02 1997-02-13 Smithkline Beecham Corporation Antagonistes des recepteurs a l'endotheline
EP0885890A1 (fr) * 1996-02-26 1998-12-23 Sumitomo Pharmaceuticals Company, Limited Derives de sulfonylureidopyrazole
US6573270B1 (en) * 1999-07-29 2003-06-03 Pfizer Inc. Pyrazoles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997004772A1 (fr) * 1995-08-02 1997-02-13 Smithkline Beecham Corporation Antagonistes des recepteurs a l'endotheline
EP0885890A1 (fr) * 1996-02-26 1998-12-23 Sumitomo Pharmaceuticals Company, Limited Derives de sulfonylureidopyrazole
US6573270B1 (en) * 1999-07-29 2003-06-03 Pfizer Inc. Pyrazoles

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099794A1 (fr) * 2007-02-09 2008-08-21 Takeda Pharmaceutical Company Limited Composés à cycles fusionnés utiles en tant qu'agonistes partiels de ppar-gamma
WO2019166629A1 (fr) * 2018-03-02 2019-09-06 Inflazome Limited Nouveaux composés
US11530200B2 (en) 2018-03-02 2022-12-20 Inflazome Limited Compounds
US11834433B2 (en) 2018-03-02 2023-12-05 Inflazome Limited Compounds
US11884645B2 (en) 2018-03-02 2024-01-30 Inflazome Limited Sulfonyl acetamides as NLRP3 inhibitors
US12030879B2 (en) 2018-03-02 2024-07-09 Inflazome Limited Sulfonyl acetamides as NLRP3 inhibitors

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AR052457A1 (es) 2007-03-21

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