WO2006085815A1 - Thiazole derivatives, their process for their preparation and their use in therapy - Google Patents

Thiazole derivatives, their process for their preparation and their use in therapy Download PDF

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Publication number
WO2006085815A1
WO2006085815A1 PCT/SE2006/000168 SE2006000168W WO2006085815A1 WO 2006085815 A1 WO2006085815 A1 WO 2006085815A1 SE 2006000168 W SE2006000168 W SE 2006000168W WO 2006085815 A1 WO2006085815 A1 WO 2006085815A1
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alkyl
phenyl
thiazol
optionally substituted
carbonyl
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PCT/SE2006/000168
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French (fr)
Inventor
Andrew Baxter
Mark Furber
Sarah King
Christopher Luckhurst
Ian Millichip
Austen Pimm
James Reuberson
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Astrazeneca Ab
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Publication of WO2006085815A1 publication Critical patent/WO2006085815A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to thiazole 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 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 and renal failure.
  • EP-0885890 describes how certain pyrazolyl sulphonyl ureas may inhibit ECE-I and suggests that such compounds may be active agents in treating or preventing, in particular, 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 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 two most important conditions covered by COPD are chronic bronchitis and emphysema.
  • R 1 is optionally substituted aryl or optionally substituted heteroaryl;
  • R is cyano, CF 3 , halogen or XR ;
  • R 3 is optionally substituted aryl, optionally substituted heteroaryl or C 3-7 cycloalkyl [optionally substituted by halogen or C 1-4 alkyl];
  • A is NR 4 or CR 5 R 6 ;
  • R 4 , R 5 and R 6 each independently represent hydrogen or Q. 4 alkyl or C 3-7 cycloalkyl [optionally substituted by halogen or C 1-4 alkyl];
  • X is a single bond, Cr 6 alkylene [optionally substituted by halogen], C 2 - 6 alkenylene [optionally substituted by halogen], C 2 - 6 alkynylene, [optionally substituted by halogen], S(O)n, NR 8 C(O), C(O)NR 9 , NR 10 , C(O), OC(O), C(O)O, O(C 1-4 )alkylene, S(OKC 1- 4 )alkylene, NR ⁇ C(O)(C 1-4 )alkylene, C(O)NR 12 (C 1-4 )alkylene, NR 13 (C 1-4 )alkylene, C(O)(C 1-4 )alkylene, OC(O)(C 1-4 )alkylene, C
  • R 28 , R 29 , R 30 , R 32 , R 33 , R 34 and R 35 are, independently, hydrogen or C r6 alkyl [optionally substituted by halogen]; aryl and heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, OC(O)NR 36 R 37 , NR 38 R 39 , NR 40 C(O)R 41 , NR 42 C(O)NR 43 R 44 , S(O) 2 NR 45 R 46 , NR 47 S(O) 2 R 48 , C(O)NR 49 R 50 , CO 2 R 51 , NR 52 CO 2 R 53 , S(O) n R 54 , OS(O) 2 R 55 , Ci -6 alkyl [optionally mono-substituted by S(O) 2 R 56 , C(O)NR 57 R 58 OrNR 31 R 62 ], C(O)R 59 , NR 60 C(O)R 61
  • JK. , JK. , K. , Jx is. , SS. , XS. , IS. , XS. , IS. , JK. , K. , K. , JK. , K. , JK. , K. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK. , JK
  • R 59 , R 60 , R 61 and R 62 are, independently, hydrogen, Ci -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(Ci -4 alkyl) 2 , S(Ci -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(Cj -4 alkyl) 2> cyano, Ci -4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or/>-toluenesulfonate.
  • Suitable 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).
  • 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).
  • 'Cycloalkyl denotes monocyclic aliphatic carbon rings, for example cyclopropyl, cyclopentyl or cyclohexyl.
  • 'Aryl' denotes aromatic carbon rings, for example phenyl or naphthyl.
  • heteroaryl denotes aromatic rings comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an iV-oxide thereof, or an S-oxide or S-dioxide thereof:
  • heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benzo[£]thienyl (also known as benz[b]thienyl, benzothienyl or benzo[ ⁇ ]thiophenyl), 2,3-dihydrobenz[6]thienyl (for example in a l-dioxo-2,3- dihydrobenz[ ⁇ ]thienyl moiety), ind
  • An 'aliphatic heterocyclic ring' is a saturated or partially saturated monocyclic ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur: or an N-oxide thereof, or an iS-oxide or S-dioxide thereof: for example pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl and morpholinyl.
  • Halogen is, for example, fluorine or chlorine or bromine.
  • alkyl groups and moieties are straight or branched chain and include, for example, methyl, ethyl, n-propyl, zso-propyl and tert-butyl.
  • Alkylene, alkenylene and alkynylene groups may similarly be straight or branched chain; examples of (C 1-4 )alkylene moieties include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - and -CH 2 CH 2 CH 2 CH 2 -.
  • A is NR 4 . In another embodiment of the invention A is CR 5 R 6 . In another embodiment of the invention A is NH, NMe or CH 2 .
  • R 1 is aryl or heteroaryl, which aryl or heteroaryl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH 2 , NH(Ci -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 , Ci -4 alkyl, C ⁇ 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
  • R 1 is phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl, which phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl moiety may be 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), S(O
  • R 1 is phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl, which phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl moiety may be 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), C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, CF 3 , OCF 3 or morpholinyl.
  • R 1 is aryl (such as phenyl) optionally substituted by halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy.
  • R 1 is a group of formula (II):
  • Y is a bond, O, S, S(O), S(O) 2 , Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • 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(Ci -4 alkyl) 2 , S(C 1-4 alkyl), S(O)(Ci -4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Ci -4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, Ci -4 hydroxyalkyl, Cj -4 alkoxy, C(O)NH 2 , C(O)NH(Ci -4 alkyl), 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 may be 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)(Cj -4 alkyl), S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Ci -4 alkyl), S(O) 2 N(Ci -4 alkyl) 2 , Ci -4 alkyl, Cj -4 hydroxyalkyl, Ci -4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(II)
  • 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 may be optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CO 2 (C 1-4 alkyl), CF 3 or OCF 3 .
  • R 1 is a group of formula (II) wherein Ar 1 is thienyl or thiazolyl, which thienyl or thiazolyl moiety may be optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CO 2 (C 1-4 alkyl), CF 3 or OCF 3 ; Ar 2 is phenyl or thiazolyl or pyridinyl, which phenyl, thiazolyl or pyridinyl moiety may be optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CO 2 (C 1-4 alkyl), CF 3 or OCF 3 ; and Y is O, S, C 1-4 alkylene, C 1-4 alkenylene or C 1-4 alkynylene.
  • R 2 is hydrogen, halogen, C 1-4 alkyl [optionally substituted by one or more of halogen, hydroxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , NHC(O)O(Cj -4 alkyl), N(C 1-4 alkyl)C(O)O(C 1-4 alkyl) or CO 2 H], C 1-4 alkoxy [optionally substituted by one or more of halogen, hydroxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , NHC(O)O(C 1-4 alkyl) or
  • R is hydrogen, halogen, C 1-4 alkyl [optionally substituted by one or more of halogen, hydroxy, NH 2 , NH(Ci -4 alkyl), N(Cj -4 alky I) 2 , NHC(O)O(Ci -4 alkyl) or N(Cj -4 alkyl)C(O)O(Ci -4 alkyl)], Ci -4 alkoxy [optionally substituted by one or more of halogen, hydroxy or NH 2 ], S(Ci -4 alkyl) [optionally substituted by one or more of halogen, hydroxy, NH 2 , C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1- 4 alkyl) or C(O)N(C 1-4 alkyl)2], phenoxy, pyridinyloxy or C 2-4 alkynyl.
  • R 2 is hydrogen, halogen, C 1-4 alkyl, NR 21 R 22 , (C 1- 4 ) alkyleneNR 14 C(O)OR 20 , (C 1-4 )alkylene0(C 1-4 )alkyleneNR 21 R 22 , S(C 1-4 )alkyleneOR 20 , S(C 1-4 )alkyleneC(O)NR 26 R 27 , phenoxy, heteroaryloxy or C 2-4 alkynyl; and R 14 , R 20 , R 21 , R 22 , R 26 and R 27 are independently, hydrogen or Q- 4 alkyl.
  • R 2 is hydrogen, C 1-4 alkyl, (C 1- 4 )alkyleneNR 14 C(O)OR 20 or (C 1-4 )alkylene0(C 1-4 )alkyleneNR 21 R 22 .
  • R 2 is C 1-4 alkyl (e.g. methyl).
  • R 3 is phenyl optionally substituted by one or more s 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 (Ci -4 alkyl), C(O)(C 1-4 alkyl), CF 3
  • R 3 is heteroaryl (such as pyridinyl or thienyl) 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 s 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
  • 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(Ci -4 0 alkyl) 2 , S(Ci -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, Ci hydroxyalkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C(O)N(Ci -4 alkyl) 2 , CO 2 H, CO 2 (Ci -4 alkyl), NHC(O)(Ci -4 alkyl), NHS(O) 2 (Ci
  • R 3 is optionally substituted by one or more of halogen, C 1-4 alkyl, C 1-4 alkoxy, CF 3 or OCF 3 . 5
  • the present invention provides a compound of formula (I),
  • A is NH, NMe or CH 2 ;
  • R 1 is aryl or heteroaryl, which aryl or heteroaryl moiety may be 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 (Cj -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(Ci -4 alkyl) 2 , CO 2 H, CO 2 (C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)
  • Y is a bond, O, S, S(O), S(O) 2 , Ci -6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;
  • 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(Ci -4 alkyl) 2 , S(Ci -4 alkyl), S(O)(C 1-4 alkyl), S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Cj -4 alkyl), S(O) 2 N(Cj -4 alkyl) 2 , C 1-4 alkyl, C M hydroxyalkyl, Ci -4 alkoxy, C(O)NH 2 , C(O)NH(Ci -4 alkyl), C(O)
  • the present invention provides a compound of formula (I)
  • A is NH, NMe or CH 2 ;
  • R 1 is phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl, which phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl moiety may be 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), Ci -4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, CF 3 , OCF 3 or mo ⁇ holinyl, or R 1 is a group of formula (II)
  • Y is O, S, C 1-4 alkylene, C 1-4 alkenylene or Ci -4 alkynylene;
  • Ar 1 and Ar 2 each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety may be 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,
  • R is hydrogen, halogen or C 1-4 alkyl
  • 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: 4-chloro-N- ⁇ [(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl ⁇ benzenesulfonamide,
  • 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,iV-dimethylaminopyridine, triethylamine or ⁇ iV-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,iV-dimethylaminopyridine, triethylamine or ⁇ iV-diisopropylethylamine
  • the reaction may be performed in a suitable solvent (such as benzene or toluene) and at a suitable temperature (such as 50 to 100 °C, e.g. 8O 0 C).
  • suitable phosphoryl azides include diphenyl phosphoryl azide and the reaction may further include a suitable base (such as triethylamine or diisopropylamine).
  • the reaction may be performed in a suitable solvent (such as benzene or toluene) and at a suitable temperature (such as 50 to 100 0 C, e.g. 80°C ).
  • a suitable solvent such as benzene or toluene
  • a suitable temperature such as 50 to 100 0 C, e.g. 80°C .
  • the reaction may be performed in a suitable solvent such as dichloromethane at a suitable temperature (such as 0 to 30 °C, e.g. 20 °C).
  • a suitable solvent such as dichloromethane
  • a suitable temperature such as 0 to 30 °C, e.g. 20 °C.
  • compounds of formula (IV) may be prepared using known techniques e.g. see US 2002/0143176; J. Med. Chem. 1981, 24, 959; WO95/29904; Tet. Lett. 2002, 43, 8479; J. Med. Chem. 1990, 33, 749; Tet. Lett. 1985, 26, 5935; European Patent 602878A1; European Patent 0238070A2; US 1988/4731368; European Patent
  • Compounds of formula (V) may be prepared using known techniques e.g. see J. Chem Soc. 1947, 1656; Acta. Polaniae Pharmaceutica 1984, 41, (6) 633).
  • Compounds of formula (VI) may be prepared, for example, from the corresponding thiazole methyl ester by reaction with a suitable reagent such as diethylaluminium azide.
  • Compounds of formula (VII) may be prepared using known techniques, for example Khimiya Geterotsiklicheskikh Soedinenii 1974, 7, 928, Acta Chimica Academiae Scientiarum Hungaricae 1972, 73(1), 43.
  • the compounds of the invention have activity as pharmaceuticals, in particular as inhibitors of ECE-I 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-I 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 in therapy
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy, for example in the manufacture of a medicament for use in treating an ECE-I mediated disease.
  • obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-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
  • 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 tissue
  • musculoskeletal disorders due to injury [for example sports injury] or disease: 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, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);
  • 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 scleroderma
  • mixed connective tissue disorder spondylo
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis he ⁇ etiformis, 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-mel
  • 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; 5 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 I 0 diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; 20 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, indeterminant 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-I activity may be used in treating COPD has not been disclosed previously.
  • COPD chronic obstructive pulmonary disease
  • 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-I inhibitor.
  • the present invention also provides the use of an ECE-I 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-I 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.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • 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-I 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 0.1 mg and Ig 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. Alternatively 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-I / 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, intravepiroxicam, rt
  • 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-like growth factor type I (IGF-I); interleukins (IL) including ILl 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 signal
  • 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 CCRI l (for the C-C family); CXCRl, 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 CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-
  • 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-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-Il) 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 iV-(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, M
  • 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-ls 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 (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, 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.
  • 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).
  • 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-I / 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, intravepiroxicam, rt
  • 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-like growth factor type I (IGF-I); interleukins (IL) including ILl 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 signal
  • 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 CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 - C family.
  • a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X
  • 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-IO), and stromelysin-3 (MMP-Il) 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-li ⁇ oxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a iV-(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, M
  • 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-ls 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 ethyinorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride
  • 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 (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, 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 fmnisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as fmnisolide, 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-lactam, 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, nelf ⁇ navir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcript
  • 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, INK, 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
  • suitable agents include: (i) 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 fluoropyrimidine 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,
  • 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 works 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 works 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 BRCA2, 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
  • Phenyl carbamic acid methyl ester (11.5 g) was added to a stirred solution of ⁇ -oxo- benzeneacetaldehyde monohydrate (1.5 g) in toluene (50 mL), and the reaction mixture was heated at reflux under Dean-Stark conditions for 6 h. The reaction mixture was cooled and filtered to give the title compound (2.2 g).
  • INTERMEDIATE 5 This illustrates the preparation of benzyl methyl(2-methyl-4-phenyl-l,3-thiazol-5- yl)carbamate.
  • INTERMEDIATE 7 This illustrates the preparation of fert-Butyl (2-amino-2-thioxoethyl)methylcarbamate.
  • aqueous layer was acidified by the addition of 2 M aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give the title compound (480 mg).
  • APCI+MS m/z 234 [M+H] + .
  • INTERMEDIATE 13 This shows the preparation of iV-[(l-5)-(Dimethylamino)methylene]-5-(phenylethynyl)- thiophene-2-sulfonamide.
  • INTERMEDIATE 20 This shows the preparation of 5-(pyridin-4-ylthio)thiophene-2-sulfonamide.
  • INTERMEDIATE 22 is This illustrates the preparation of N-[4-(aminosulfonyl)phenyl]-JV-ethyl-2,2,2- trifluoroacetamide .
  • INTERMEDIATE 23 This illustrates the preparation of iV-ethyl-2,2,2-trifluoro-iV- ⁇ 4-[( ⁇ [(2-methyl-4-phenyl-l,3- thiazol-5-yl)ammo]carbonyl ⁇ amino)sulfonyl]phenyl ⁇ acetamide.
  • INTERMEDIATE 29 This illustrates the preparation of ethyl 2- ⁇ [2-(methylammo)-2-oxoethyl]thio ⁇ -4-phenyl- 1 ,3-thiazole-5-carboxylate.
  • INTERMEDIATE 32 This illustrates the preparation of 2-phenoxy-4- ⁇ henyl- 1 ,3-thiazole-5-carboxylic acid.
  • INTERMEDIATE 36 This illustrates the preparation of 2-(2-methoxyethoxy)-4-phenyl-l,3-thiazole ⁇ 5- carboxylic acid.
  • EXAMPLE 8 This shows the preparation of 2-methoxy-4-methyl-N- ⁇ [(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl ⁇ benzenesulfonamide.
  • EXAMPLE 15 This shows the preparation of iV- ⁇ [(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl ⁇ - 5-(2-phenylethyl)thiophene-2-sulfonamide.
  • EXAMPLE 19 This shows the preparation of N- ⁇ [(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl ⁇ - 1 -benzothiophene-2-sulfonamide.
  • the isolated material from the column (1.2 g) was dissolved in a mixture of 1 : 1 DMSO / acetonitrile (6 mL). Water (50 mL) was added, and the mixture was acidified with trifluoroacetic acid. The precipitated solid was collected by filtration, dried in vacuo at 40 °C, and then recrystallised from acetonitrile to afford the title compound as a mono hydrate (400 mg).
  • Example 25 A stirred mixture of Example 25 (350 mg), copper. (I) bromide dimethylsulfide complex (7 mg), dry DMF (3 mL), ethynyl(trimethyl)silane (300 ⁇ L), and tetrakis(triphenylphosphine)-palladium(0) (17 mg) in triethylamine (10 mL) was heated at 90 °C for 15 min. Water (50 mL) was added, and the mixture was acidified to pH2 with 2 N aqueous hydrochloric acid. The crude product was extracted into ethyl acetate and the solution dried over magnesium sulfate, filtered then concentrated in vacuo to dryness. At this stage the crude product had almost completely desilylated and was purified by both RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) and normal phase column
  • the acetonitrile solution was concentrated in vacuo and the residue purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) followed by RPHPLC (Xterra, 5% to 95% acetonitrile in ammonia (0.2% aq.)).
  • the title compound was isolated as a pale yellow solid (35 mg).
  • the residue was initially purified on a 10 g isolute flash silica cartridge which was eluted with 5% triethylamine in ethyl acetate to remove non-polar impurities.
  • the silica cartridge was then o eluted with acetonitrile and the solution concentrated to dryness.
  • the crude product was purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) to afford the title compound as a colourless solid (580 mg).
  • EXAMPLE 35 o This shows the preparation of 4-chloro-JV- ⁇ [(2-methoxy-4-phenyl-l ,3-thiazol-5- yl)amino]carbonyl ⁇ benzenesulfonamide.
  • Exemplified compounds were tested to determine inhibition of endothelin- converting enzyme-1 (ECE-I) 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 pH 6.0 assay buffer and samples prepared in a 384 well-plate format (Conditions A); or alternatively at 37 °C using 50 mM Tris Maleate pH6.0 assay buffer and samples prepared in a 96 well-plate format (Conditions B).
  • ECE-I endothelin- converting enzyme-1
  • the compounds of the examples have a PlC 50 of at least 4.0.
  • pICso values for a representative selection of compounds are given in Table 2 below.

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Abstract

The invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein A, R1, R2 and R3 are as defined in the specification; a process for their preparation; pharmaceutical compositions containing them; and their use in therapy.

Description

THIAZOLE DERIVATIVES, THEIR PROCESS FOR THEIR PREPARATION AND THEIR USE IN THERAPY.
The present invention relates to thiazole 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-I) 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 and renal failure. For example, EP-0885890 describes how certain pyrazolyl sulphonyl ureas may inhibit ECE-I and suggests that such compounds may be active agents in treating or preventing, in particular, cardiovascular disease.
Chronic obstructive pulmonary disease (COPD) is a term that refers to a group of lung diseases that can interfere with normal breathing. 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 world, 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 two most important conditions covered by COPD are chronic bronchitis and emphysema.
There is a pressing medical need for new therapies against COPD, in particular for therapies with disease modifying potential. Moreover, there is a need for compounds having improved pharmacological properties. Suppressing the biosynthesis of endothelin by hindering ECE-I may be effective in the prevention and treatment of chronic obstructive pulmonary disease (for example by reducing mucus secretion). The present invention provides a novel class of thiazole derivative capable of inhibiting ECE-I.
Accordingly, the present invention provides a compound of formula (I):
Figure imgf000003_0001
wherein:
R1 is optionally substituted aryl or optionally substituted heteroaryl; R is cyano, CF3, halogen or XR ; R3 is optionally substituted aryl, optionally substituted heteroaryl or C3-7 cycloalkyl [optionally substituted by halogen or C1-4 alkyl]; A is NR4 or CR5R6;
R4, R5 and R6 each independently represent hydrogen or Q.4 alkyl or C3-7 cycloalkyl [optionally substituted by halogen or C1-4 alkyl]; X is a single bond, Cr6 alkylene [optionally substituted by halogen], C2-6 alkenylene [optionally substituted by halogen], C2-6 alkynylene, [optionally substituted by halogen], S(O)n, NR8C(O), C(O)NR9, NR10, C(O), OC(O), C(O)O, O(C1-4)alkylene, S(OKC1- 4)alkylene, NRπC(O)(C1-4)alkylene, C(O)NR12(C1-4)alkylene, NR13(C1-4)alkylene, C(O)(C1-4)alkylene, OC(O)(C1-4)alkylene, C(O)O(C1-4)alkylene, (C1-4)alkylene0, (C1-4) alkyleneS(O)n, (C1-4)alkyleneNR14C(O), (C1-4)alkyleneC(O)NR15, (C1-4)alkyleneNR16, (C1- 4)alkyleneC(O), (C1-4)alkyleneOC(O), (CM)alkylene0(C1-4)alkylene, (C1-4) alkyleneS(O)n(C1-4)alkylene, (C1-4)alkyleneNR17C(O)(C1-4)alkylene, (C1- 4)alkyleneC(O)NR18(C1-4)alkylene, (C1-4)alkyleneNR19(C1-4)allcylene, (C1-4)allcyleneC(O) (C1-4)alkylene, (C1-4)alkyleneOC(O)(C1-4)alkylene or (C1-4)alkyleneC(O)O(C1-4)alkylene; R7 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, C3-7 cycloalkyl [optionally substituted by halogen or C1-4 alkyl], a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 alkyl], OR , NR R , C(O)R23, CO2R24, OC(O)R25, C(O)NR26R27, S(O)nR28, SO2NR29R30, NR32C(O)R33, NR34C(O)OR35, phenoxy [optionally substituted by halogen, cyano, CF3 or C1-4 alkyl] or heteroaryloxy [optionally substituted by halogen, cyano, CF3 or C1-4 alkyl];
P K.8 , P JK.9 , T K?.10 , PJK.11 , PJK.12 , P is.13 , PJK.14 , PJK.15 , PJK.16 , PJK.17 , P is.18 , PJK.19 , PK.20 , PJK.21 , PJK.22 , PJtV23 , PJK.24 , PJK.25 , P K.26 , P is.27 ,
R28, R29, R30, R32, R33, R34 and R35 are, independently, hydrogen or Cr6 alkyl [optionally substituted by halogen]; aryl and heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, OC(O)NR36R37, NR38R39, NR40C(O)R41, NR42C(O)NR43R44, S(O)2NR45R46, NR47S(O)2R48, C(O)NR49R50, CO2R51, NR52CO2R53, S(O)nR54, OS(O)2R55, Ci-6 alkyl [optionally mono-substituted by S(O)2R56, C(O)NR57R58 OrNR31R62], C(O)R59, NR60C(O)R61, C2-6 alkenylene [optionally substituted by phenyl or heteroaryl], C2-6 alkynylene [optionally substituted by phenyl or heteroaryl], C3-7 cycloalkyl, Ci-6 haloalkyl, C1-6 alkoxy(C1-6)alkylene, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkylene, phenoxy, phenylthio, phenylS(O), phenylS(O)2, phenyl(Ci-4)alkoxy, heteroaryl, heteroaryl(Ci-4)alkyl, heteroaryloxy, heteroaryl(Ci-4)alkoxy or a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or Ci-4 alkyl]; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, nitro, NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, S(Ci-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Cj-4 alkyl), S(O)2N(Ci-4 alkyl)2, cyano, Ci-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3;
-p31 p36 p37 τ>38 p39 -p40 p41 p42 -p43 p44 -p45 p46 -p47 p49 p50 p51 p52 p53 p57 -p58 JK. , JK. , K. , Jx , is. , SS. , XS. , IS. , XS. , IS. , JK. , K. , K. , JK. , K. , JK. , K. , JK. , JK. , JK. ,
R59, R60, R61 and R62 are, independently, hydrogen, Ci-6 alkyl [optionally substituted by halogen, C3-6 cycloalkyl or phenyl {optionally substituted by halogen or C1-4 alkyl}], CH2(C2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH2, NH(C1-4 alkyl), N(Ci-4 alkyl)2, S(Ci-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Cj-4 alkyl)2> cyano, Ci-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3] or heteroaryl [itself optionally substituted by halogen, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, Ci-4 alkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(Ci-4 alkyl), CF3 or OCF3]; R48, R54, R55 and R56 are, independently, C1-6 alkyl [optionally substituted by halogen, C3-6 cycloalkyl or phenyl {optionally substituted by halogen or Ci-4 alkyl}], CH2(C2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(Ci-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Cj-4 alkyl), S(O)2N(Cj-4 alkyl)2, cyano, Ci-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3] or heteroaryl [itself optionally substituted by halogen, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H5 CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3]; and, n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Suitable pharmaceutically acceptable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or/>-toluenesulfonate.
Suitable 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).
It will be understood that certain compounds of the present invention and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms.
In the context of the present specification the term 'Cycloalkyl' denotes monocyclic aliphatic carbon rings, for example cyclopropyl, cyclopentyl or cyclohexyl. 'Aryl' denotes aromatic carbon rings, for example phenyl or naphthyl. 'Heteroaryl' denotes aromatic rings comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an iV-oxide thereof, or an S-oxide or S-dioxide thereof: examples of heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benzo[£]thienyl (also known as benz[b]thienyl, benzothienyl or benzo[ό]thiophenyl), 2,3-dihydrobenz[6]thienyl (for example in a l-dioxo-2,3- dihydrobenz[δ]thienyl moiety), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2- α]pyridinyl), a thienopyridinyl (for example thieno[3,2-δ]pyridin-6-yl, thieno[2,3- c]pyridin-2-yl or thieno[3,2-c]pyridin-2-yl), mieno[3,2-^pyrimidin-6-yl, 1,2,3- benzoxadiazolyl, benzo[l,2,3]thiadiazolyl, 2,1,3-benzothiadiazolyl, benzofurazan (also Known as 2,1,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyridine (for example IH- pyrazolo[3,4-&]pyridinyl), quinolinyl, isoquinolinyl, a naphthyridinyl (for example
[l,6]naphthyridinyl or [l,8]naphthyridinyl) or a benzothiazinyl; or anN-oxide thereof, or an £-oxide or S-dioxide thereof. An 'aliphatic heterocyclic ring' is a saturated or partially saturated monocyclic ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur: or an N-oxide thereof, or an iS-oxide or S-dioxide thereof: for example pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl and morpholinyl.
Halogen is, for example, fluorine or chlorine or bromine.
Unless otherwise stated alkyl groups and moieties are straight or branched chain and include, for example, methyl, ethyl, n-propyl, zso-propyl and tert-butyl. Alkylene, alkenylene and alkynylene groups may similarly be straight or branched chain; examples of (C1-4)alkylene moieties include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2- and -CH2CH2CH2CH2-.
In an embodiment of the invention A is NR4. In another embodiment of the invention A is CR5R6. In another embodiment of the invention A is NH, NMe or CH2.
In an embodiment of the invention R1 is aryl or heteroaryl, which aryl or heteroaryl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(Ci-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, Ci-4 alkyl, Cμ4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, OCF3 or a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 alkyl].
In an embodiment of the invention R1 is phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl, which phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 allcoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H5 CO2(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, OCF3 or a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 alkyl]. In an embodiment of the invention R1 is phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl, which phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, CF3, OCF3 or morpholinyl.
In an embodiment of the invention R1 is aryl (such as phenyl) optionally substituted by halogen, cyano, C1-4 alkyl or C1-4 alkoxy.
In an embodiment of the invention, R1 is a group of formula (II):
Figure imgf000007_0001
wherein:
Y is a bond, O, S, S(O), S(O)2, Ci-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; Ar1 and Ar2 each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(Ci-4 alkyl)2, S(C1-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl, Ci-4 hydroxyalkyl, Cj-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3.
In an embodiment of the invention, R1 is a group of formula (II) wherein Ar1 and Ar2 each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(Cj-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, Ci-4 alkyl, Cj-4 hydroxyalkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3. In an embodiment of the invention, R1 is a group of formula (II) wherein Y is O, S, C1- 4 alkylene, C1-4 alkenylene or C1-4 alkynylene.
In an embodiment of the invention, R1 is a group of formula (II) wherein Ar1 and Ar2 each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety may be optionally substituted by one or more of halogen, C1-4 alkyl, C1-4 alkoxy, CO2(C1-4 alkyl), CF3 or OCF3.
In an embodiment of the invention, R1 is a group of formula (II) wherein Ar1 is thienyl or thiazolyl, which thienyl or thiazolyl moiety may be optionally substituted by one or more of halogen, C1-4 alkyl, C1-4 alkoxy, CO2(C1-4 alkyl), CF3 or OCF3; Ar2 is phenyl or thiazolyl or pyridinyl, which phenyl, thiazolyl or pyridinyl moiety may be optionally substituted by one or more of halogen, C1-4 alkyl, C1-4 alkoxy, CO2(C1-4 alkyl), CF3 or OCF3; and Y is O, S, C1-4 alkylene, C1-4 alkenylene or C1-4 alkynylene.
In an embodiment of the invention, R2 is hydrogen, halogen, C1-4 alkyl [optionally substituted by one or more of halogen, hydroxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)O(Cj-4 alkyl), N(C1-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], C1-4 alkoxy [optionally substituted by one or more of halogen, hydroxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)O(C1-4 alkyl), N(C1-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], S(C1-4alkyl) [optionally substituted by one or more of halogen, hydroxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)O(C1-4 alkyl), N(Cj-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], phenoxy, heteroaryloxy or C2-4 alkynyl.
In an embodiment of the invention, R is hydrogen, halogen, C1-4 alkyl [optionally substituted by one or more of halogen, hydroxy, NH2, NH(Ci-4 alkyl), N(Cj-4 alky I)2, NHC(O)O(Ci-4 alkyl) or N(Cj-4 alkyl)C(O)O(Ci-4 alkyl)], Ci-4 alkoxy [optionally substituted by one or more of halogen, hydroxy or NH2], S(Ci-4alkyl) [optionally substituted by one or more of halogen, hydroxy, NH2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1- 4 alkyl) or C(O)N(C1-4 alkyl)2], phenoxy, pyridinyloxy or C2-4 alkynyl.
In an embodiment of the invention, R2 is hydrogen, halogen, C1-4 alkyl, NR21R22, (C1- 4) alkyleneNR14C(O)OR20 , (C1-4)alkylene0(C1-4)alkyleneNR21R22, S(C1-4)alkyleneOR20, S(C1-4)alkyleneC(O)NR26R27, phenoxy, heteroaryloxy or C2-4 alkynyl; and R14, R20, R21, R22, R26 and R27are independently, hydrogen or Q-4 alkyl. In an embodiment of the invention, R2 is hydrogen, C1-4 alkyl, (C1- 4)alkyleneNR14C(O)OR20 or (C1-4)alkylene0(C1-4)alkyleneNR21R22.
In an embodiment of the invention, R2 is C1-4 alkyl (e.g. methyl).
In an embodiment of the invention, R3 is phenyl optionally substituted by one or more s of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3. In an aspect of this embodiment, R3 is phenyl optionally substituted by one or more of o halogen, C1-4 alkyl, C1-4 alkoxy, CF3 or OCF3.
In an embodiment of the invention, R3 is heteroaryl (such as pyridinyl or thienyl) optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 s alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3. In an aspect of this embodiment, R3 is optionally substituted by one or more of halogen, C1-4 alkyl, C1-4 alkoxy, CF3 or OCF3.
In an embodiment of the invention, R3 is C3-6 cycloalkyl (such as cyclohexyl) optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(Ci-4 0 alkyl)2, S(Ci-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl, Ci-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3. In an aspect of this embodiment, R3 is optionally substituted by one or more of halogen, C1-4 alkyl, C1-4 alkoxy, CF3 or OCF3. 5 In a further aspect, the present invention provides a compound of formula (I),
Figure imgf000009_0001
wherein:
A is NH, NMe or CH2; R1 is aryl or heteroaryl, which aryl or heteroaryl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(Cj-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(Cj-4 alkyl), CF3, OCF3 or a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 alkyl], or R1 is a group of formula (II):
Ar .2/ Y.
^Ar1
(H) wherein:
Y is a bond, O, S, S(O), S(O)2, Ci-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; Ar1 and Ar2 each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(Ci-4 alkyl)2, S(Ci-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Cj-4 alkyl), S(O)2N(Cj-4 alkyl)2, C1-4 alkyl, CM hydroxyalkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; R2 is hydrogen, halogen, C1-4 alkyl [optionally substituted by one or more of halogen, hydroxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)O(Ci-4 alkyl), N(Ci-4 alkyl)C(O)O(CM alkyl) or CO2H], Ci-4 alkoxy [optionally substituted by one or more of halogen, hydroxy, NH2, NH(Ci-4 alkyl), N(C-4 alkyl)2, Ci-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Ci-4 alkyl)2, NHC(O)O(Ci-4 alkyl), N(C1-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], S(Q-4alkyl) [optionally substituted by one or more of halogen, hydroxy, NH2, NH(Cj-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)O(C1-4 alkyl), N(C1-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], phenoxy, heteroaryloxy or C2-4 alkynyl; and R3 is phenyl optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(Cj-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(Cj-4 alkyl), S(O)2NH2, S(O)2NH(Cj-4 alkyl), S(O)2N(Cj-4 alkyl)2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Ci-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; or a pharmaceutically acceptable salt thereof.
In a still further aspect, the present invention provides a compound of formula (I)
Figure imgf000011_0001
wherein: A is NH, NMe or CH2;
R1 is phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl, which phenyl, thienyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, imidazolyl, imidazopyridinyl or thienopyridinyl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), Ci-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, CF3, OCF3 or moφholinyl, or R1 is a group of formula (II)
Ar2^Ar1
(H) wherein
Y is O, S, C1-4alkylene, C1-4alkenylene or Ci-4alkynylene; Ar1 and Ar2 each independently represent phenyl, pyridinyl, thienyl or thiazolyl, which phenyl, pyridinyl, thienyl or thiazolyl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, C1-4 alkyl,
C1-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3;
R is hydrogen, halogen or C1-4 alkyl; and
R3 is phenyl optionally substituted by one or more of halogen, C1-4 alkyl, C1-4 alkoxy, CF3 or OCF3; or a pharmaceutically acceptable salt thereof.
In an embodiment of the invention, the compound of formula (I) is selected from: 4-chloro-N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}benzenesulfonamide,
4-chloro-N-{[methyl(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- benzenesulfonamide, tert-butyl ({5-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]-4-phenyl-l,3-thiazol-
2-yl}methyl)methylcarbamate,
N-[(4-Chlorophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3-thiazol-5-yl)acetamide,
N-[(4-fluorophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3-thiazol-5-yl)acetamide, N-[(4-cyanophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3-thiazol-5-yl)acetamide,
2-[4-(4-chlorophenyl)-2-methyl-l,3-thiazol-5-yl]-N-[(4-chlorophenyl)sulfonyl]acetamide,
2-methoxy-4-methyl-N- { [(2-methyl-4-phenyl- 1 ,3-thiazol-5-yl)amino]carbonyl} - benzenesulfonamide,
4-(ethylamino)-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)ammo]carbonyl}- benzenesulfonamide,
5-[(4-chlorophenyl)thio]-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}thiophene-2-sulfonamide,
5-chloro-3-methyl-N- { [(2-methyl-4-phenyl- 1 ,3 -thiazol-5-yl)amino]carbonyl} - 1 - benzothiophene-2-sulfonamide, 6-ethoxy-N- {[(2-methyl-4-phenyl- 1 ,3-thiazol-5-yl)amino]carbonyl} - 1 ,3-benzothiazole-2- sulfonamide,
N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-(phenylethynyl)thiophene-2- sulfonamide,
N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-(phenylthio)thiophene-2- sulfonamide,
N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-(2-phenylethyl)thiophene-2- sulfonamide,
N- {[(2-methyl-4-phenyl- 1 ,3-thiazol-5-yl)amino]carbonyl} -5-morpholin-4-yl-4- nitrothiophene-2-sulfonamide, N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-(phenylthio)-l,3-thiazole-2- sulfonamide,
N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-(pyridm-4-ylthio)thiopliene-
2-sulfonamide,
N- { [(2-methyl-4-phenyl- 1 ,3 -thiazol-5-yl)amino]carbonyl} - 1 -benzothiophene-2- sulfonamide,
N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-2-(phenylthio)-l,3-thiazole-5- sulfonamide, methyl 4-( {5-[( { [(2-methyl-4-phenyl-l ,3-thiazol-5-yl)amino]carbonyl} ammo)sulfonyi]-2- thienyl } thio)benzoate,
N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-[(4-methyl-l,3-thiazol-2- yl)thio]thiophene-2-sulfonamide, N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-3-[(4-methyl-l,3-thiazol-2- yl)thio]thiophene-2-sulfonamide,
N- { [(2-methyl-4-phenyl- 1 ,3 -thiazol-5-yl)amino]carbonyl} - lff-indole-2-sulfonamide, iV-{[(2-bromo-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-4-chlorobenzenesulfonamide,
4-chloro-iV-{[(2-ethynyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}benzenesulfonamide, 4-chloro-N-[({2-[(2-hydroxyethyl)thio]-4-phenyl-l,3-thiazol-5- yl}amino)carbonyl]benzenesulfonamide,
4-chloro-N-{[(2-ethoxy-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}benzenesulfonamide,
4-chloro-iV-({[4-phenyl-2-(pyridin-3-yloxy)-l,3-thiazol-5-yl]amino}carbonyl)- benzenesulfonamide, 4-chloro-iV- { [(2-phenoxy-4-phenyl- 1 ,3 -thiazol-5-y l)amino] carbonyl } benzenesulfonamide,
2-({5-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]-4-phenyl-l,3-thiazol-2- yl } thio)-iV-methylacetamide,
4-chloro-N-( { [2-(2-methoxyethoxy)-4-phenyl- 1 ,3 -thiazol-5- yl] amino } carbony l)benzenesulfonamide, 4-chloro-iV-({[2-(dimethylammo)-4-phenyl-l,3-thiazol-5- yl]amino}carbonyl)benzenesulfonamide,
4-chloro-iV-({[2-(methylthio)-4-ρhenyl-l,3-thiazol-5- yl] amino } carbony l)benzenesulfonamide,
4-chloro-iV- { [(2-methoxy-4-phenyl- 1 ,3 -thiazol-5 -yl)amino] carbony 1} benzenesulfonamide, N" { [(2-methy 1-4-phenyl- 1 ,3 -thiazol-5 -y l)amino] carbonyl} imidazo [ 1 ,2-α]pyridine-3 - sulfonamide, iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}thieno[2,3-c]pyridine-2- sulfonamide,
N-[({2-[(2-hydroxyethyl)thio]-4-phenyl-l,3-thiazol-5-yl}amino)carbonyl]-l- benzothiophene-2-sulfonamide, or a pharmaceutically acceptable salt thereof. Compounds of the present invention can be prepared by methods analogous to those described in the literature. In a further aspect of the present invention there is provided a process for preparing a compound of formula (I), which comprises (a) when A is CR5R6 coupling a compound of formula (III):
Figure imgf000014_0001
with a compound of formula (IV):
(O)2
R 1/ S
"NK
(IV), or
(b) when A is NH reacting a compound of formula (V):
Figure imgf000014_0002
with a compound of formula (IV) as defined in (a) in the presence of a phosphoryl azide; or
(c) when A is NH reacting a compound of formula (VI):
Figure imgf000014_0003
with a compound of formula (IV) as defined in (a); or
(d) when A is NR4 reacting a compound of formula (VII):
Figure imgf000015_0001
with a compound of formula (VIII):
Figure imgf000015_0002
and optionally after (a), (b), (c) or (d) carrying out one or more of the following:
• converting the compound to a further compound of the invention or
• forming a pharmaceutically acceptable salt of the compound.
In process (a), 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,iV-dimethylaminopyridine, triethylamine or ΛζiV-diisopropylethylamine) at a suitable temperature (for example 0-35 °C).
In process (b), the reaction may be performed in a suitable solvent (such as benzene or toluene) and at a suitable temperature (such as 50 to 100 °C, e.g. 8O0C). Suitable phosphoryl azides include diphenyl phosphoryl azide and the reaction may further include a suitable base (such as triethylamine or diisopropylamine).
In process (c), the reaction may be performed in a suitable solvent (such as benzene or toluene) and at a suitable temperature (such as 50 to 100 0C, e.g. 80°C ).
In process (d), the reaction may be performed in a suitable solvent such as dichloromethane at a suitable temperature (such as 0 to 30 °C, e.g. 20 °C). Compounds of formula (III), (IV), (V), (VI), (VII) and (VIII) can be obtained commercially or can be prepared using methods according or analogous to those described in the literature. For example, compounds of formula (IV) may be prepared using known techniques e.g. see US 2002/0143176; J. Med. Chem. 1981, 24, 959; WO95/29904; Tet. Lett. 2002, 43, 8479; J. Med. Chem. 1990, 33, 749; Tet. Lett. 1985, 26, 5935; European Patent 602878A1; European Patent 0238070A2; US 1988/4731368; European Patent
0271273 A2. Compounds of formula (V) may be prepared using known techniques e.g. see J. Chem Soc. 1947, 1656; Acta. Polaniae Pharmaceutica 1984, 41, (6) 633). Compounds of formula (VI) may be prepared, for example, from the corresponding thiazole methyl ester by reaction with a suitable reagent such as diethylaluminium azide. Compounds of formula (VII) may be prepared using known techniques, for example Khimiya Geterotsiklicheskikh Soedinenii 1974, 7, 928, Acta Chimica Academiae Scientiarum Hungaricae 1972, 73(1), 43.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl, carboxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve at a certain stage the removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991) and 'Protecting Groups', PJ. Kocienski, Georg Thieme Verlag (1994).
The compounds of the invention, or pharmaceutically acceptable salts thereof, have activity as pharmaceuticals, in particular as inhibitors of ECE-I converting enzyme.
According to a further feature of the invention there is provided 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).
According to a further feature of the present invention there is provided a method for modulating ECE-I 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 in therapy In another aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy, for example in the manufacture of a medicament for use in treating an ECE-I mediated disease.
Diseases and conditions which may be treated with the compounds include: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-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 vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2. bone and joints: arthritides 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 tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies; 3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: 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, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);
4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis heφetiformis, 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 skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
6. 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);
7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
8. genitourinary: 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;
10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; 5 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 I0 diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, is eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;
13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; 20 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;
25 14. 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,
30 15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant 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.
In particular, 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-I activity may be used in treating COPD has not been disclosed previously.
Accordingly, in a further aspect 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-I inhibitor.
The present invention also provides the use of an ECE-I inhibitor in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
In a further aspect, 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).
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). The present invention further provides a method of treating an ECE-I 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.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition. In order to use 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-I activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect 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. In a further aspect 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. Depending on the mode of administration, 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.
The pharmaceutical 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. For these purposes 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 0.1 mg and Ig of active ingredient. In another aspect 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. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively 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.
In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below.
Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-I / 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, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. 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-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) 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.
In addition 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).
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 CCRI l (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CRl for the C-X3-
C family.
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-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-Il) and MMP-9 and MMP-12, including agents such as doxycycline.
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 iV-(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, and BAY x 1005. 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-ls 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.
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.
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.
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 (Ml, 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.
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.
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.
In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-I / 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, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofϊn or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.
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-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) 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.
In addition 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).
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 CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CRl for the C-X3- C family. 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-IO), and stromelysin-3 (MMP-Il) and MMP-9 and MMP-12, including agents such as doxycycline.
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-liρoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a iV-(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, and BAY x 1005.
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-ls 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.
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.
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 ethyinorepinephrine hydrochloride.
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 (Ml, 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.
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 fmnisolide, 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 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.
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.
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-lactam, 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, nelfϊnavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.
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. 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.
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, or a pharmaceutically acceptable salt thereof, can also be used in combination with 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, INK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-Bl. - or B2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.
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 example suitable agents include: (i) 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 fluoropyrimidine 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, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-moφholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
(v) 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 works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);
(vi) a 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; (vii) 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;
(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, 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. The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise:
(i) when given, 1H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300MHz or 400MHz using perdeuterio DMSO-D6 (CD3SOCD3) or CDCl3 as the solvent unless otherwise stated; (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe. Where indicated ionisation was effected by electrospray ionisation (ES), or atmospheric pressure chemical ionisation (APCI), or multimode ionisation, a combination of ES ionisation and APCI. Where values for m/z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive or negative mass ions - [M+H]+ or [M-H]"; (iii) the title and sub-title compounds of the examples and preparations were named using the IUPAC name program version 8.00 from Advanced Chemistry Development Inc. Labs; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry™, NovaPak™ or Xterra™ reverse phase silica column, all available from Waters Corp.; and (vi) the following abbreviations are used:
Figure imgf000033_0001
Figure imgf000034_0002
INTERMEDIATE 1
This illustrates the preparation of benzyl (l-hydroxy-2-oxo-2-ρhenylethyl)carbamate.
Figure imgf000034_0001
Phenyl carbamic acid methyl ester (11.5 g) was added to a stirred solution of α-oxo- benzeneacetaldehyde monohydrate (1.5 g) in toluene (50 mL), and the reaction mixture was heated at reflux under Dean-Stark conditions for 6 h. The reaction mixture was cooled and filtered to give the title compound (2.2 g).
1H NMR (300 MHz, DMSO) δ 8.23 (d, IH), 7.93 (d, 2H), 7.62-7.68 (m, IH), 7.52 (dd, 2H), 7.27-7.39 (m, 5H), 6.45 (d, IH), 6.14 (dd, IH), 5.07 (s, 2H).
INTERMEDIATE 2
This illustrates the preparation of benzyl (l-chloro-2-oxo-2-phenylethyl)carbamate.
Figure imgf000035_0001
Thionyl chloride (0.8 mL) was added to a suspension of Intermediate 1 (1.3 g) in anhydrous THF (10 mL), and the reaction mixture was stirred at RT for 1 h. The mixture was evaporated in vacuo and azeotroped twice with toluene to give the title compound in quantitative yield.
1H NMR (300 MHz3 DMSO) δ 8.14-8.29 (m, IH), 7.87-8.03 (m, 2H), 7.60-7.71 (m, IH), 7.45-7.60 (m, 2H), 7.21-7.42 (m, 5H), 6.14 (d, IH), 5.07 (s, 2H).
INTERMEDIATE 3 This illustrates the preparation of benzyl (2-methyl-4-phenyl-l,3-thiazol-5-yl)carbamate.
Figure imgf000035_0002
A solution of thioacetamide (0.5 g) in anhydrous THF (3 mL) was added to a solution of Intermediate 2 (2 g) in anhydrous THF (15 mL), and the reaction mixture was stirred at RT for 24 h. The mixture was evaporated to dryness, and the residue was dissolved in methanol. The solution was heated at reflux for 1 h, and then evaporated to dryness. The residue was dissolved in DCM and washed with a saturated aqueous solution of sodium bicarbonate, the organic phases were dried over magnesium sulfate and concentrated in vacuo to give the title compound (2.1 g). 1H NMR (400 MHz, DMSO) δ 9.89 (br s, IH), 7.74 (d, 2H), 7.44 - 7.31 (m, 8H), 5.15 (s, 2H), 2.62 (s, 3H); APCI+MS: m/z 325 [M+H]+. INTERMEDIATE 4
This illustrates the preparation of 2-methyl-4-phenyl- 1,3 -thiazol-5 -amine.
Figure imgf000036_0001
A solution of Intermediate 3 (1.2 g) in concentrated hydrochloric acid (10 mL) was heated at 60 °C for 18 h. The reaction mixture was cooled, diluted with water (20 mL) and then basified with concentrated aqueous sodium hydroxide, maintaining the temperature below 25 °C. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow gum. Trituration with a drop of methanol in diethyl ether gave the title compound (400 mg) as an off-white powder.
1H NMR (400 MHz, DMSO) δ 7.75 (dm, 2H), 7.35 (tm, 2H), 7.16 (tt, IH), 5.56 (s, 2H), 2.45 (s, 3H); APCI+MS: m/z 191 [M+Hf .
INTERMEDIATE 5 This illustrates the preparation of benzyl methyl(2-methyl-4-phenyl-l,3-thiazol-5- yl)carbamate.
Figure imgf000036_0002
Sodium hydride (53 mg, 60% dispersion in mineral oil) was added to an ice-cooled solution of Intermediate 3 (390 mg) in anhydrous THF (10 mL). After 15 min, iodomethane (123 μl) was added and the reaction was stirred at RT for 24 h. The mixture was concentrated in vacuo to near dryness and then diluted with ethyl acetate and 2 M aqueous sodium hydroxide solution. The two phases were separated, and the organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by RPHPLC (Xterra, 25% to 75% acetonitrile in aqueous TFA (0.2%)) gave the title compound (335 mg). APCI+MS: m/z 339 [M+H]+.
INTERMEDIATE 6
This illustrates the preparation of iV,2-dimethyl-4-ρhenyl-l,3-thiazol-5-amine.
Figure imgf000037_0001
A solution of Intermediate 5 (300 mg) in concentrated hydrochloric acid (10 mL) was heated at 40 °C for 2 h. The reaction mixture was cooled and then neutralised with concentrated aqueous sodium hydroxide, maintaining the temperature below 25 0C. The mixture was extracted three times with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the title compound (127 mg). APCI+MS: m/z 205 [M+H]+.
INTERMEDIATE 7 This illustrates the preparation of fert-Butyl (2-amino-2-thioxoethyl)methylcarbamate.
Figure imgf000037_0002
A mixture of iV-[(l,l-dimethylethoxy)carbonyl]-N-methyl-glycine (2 g), EDCI (2 g) and HOBT (1.43 g) in DCM (40 mL) was stirred at RT for 16 h. A solution of 0.5 M NH3 in 1,4-dioxane (25 mL) was then added and the reaction was stirred at RT for 30 min. The mixture was evaporated to dryness and the residue was suspended between ethyl acetate and 2 M aqueous sodium hydroxide solution. The resulting phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in a 2 : 1 toluene / THF mixture (30 mL) and Lawesson's reagent (2.5 g) was added. The suspension was stirred at RT for 3 d. The reaction was evaporated to dryness and ethyl acetate was added to the residue. The suspension was filtered and the filtrate was concentrated in vacuo. Purification by silica gel column chromatography, eluting with 25% ethyl acetate in DCM, gave the title compound (380 mg). APCI-MS: m/z 203 [M-H]".
INTERMEDIATE 8
This illustrates the preparation of benzyl (2-{[(tert- butoxycarbonyl)(methyl)amino]methyl} -4-phenyl- 1 ,3 -thiazol-5-yl)carbamate.
Figure imgf000038_0001
A stirred mixture of Intermediate 7 (330 mg) and Intermediate 2 (490 mg) in anhydrous THF (10 mL) was heated at reflux for 16 h. The reaction mixture was evaporated to dryness, and the residue was dissolved in DCM and washed with an aqueous saturated sodium bicarbonate solution. The two phases were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel column chromatography, eluting with 25% ethyl acetate in iso-hexane, gave the title compound (640 mg). APCI-MS: m/z 452 [M-H]'.
INTERMEDIATE 9
This illustrates the preparation of fert-Butyl [(5-amino-4-phenyl-l,3-thiazol-2- yl)methyl]methylcarbamate.
Figure imgf000039_0001
A mixture of Intermediate 8 (490 mg) and 10% Pd/C (500 mg) in ethanol (15 mL) was stirred at RT in the presence of hydrogen (3 bar). Portions of 10% Pd/C were added until the reaction was complete. The suspension was filtered, and the filtrate was concentrated in vacuo to give the title compound (320 mg). APCI-MS: m/z 318 [M-H]-.
INTERMEDIATE 10
This illustrates the preparation of (2-Methyl-4-phenyl-l,3-miazol-5-yl)acetic acid.
Figure imgf000039_0002
A solution of 3-bromo-4-oxo-4-phenylbutanoic acid (920 mg) and thioacetamide (270 mg) in isopropanol (20 mL) was heated at 80 °C for 3 h. The mixture was evaporated to dryness and the residue was dissolved in a mixture of 4 : 1 : 1 isopropanol / THF / water (20 mL). Sodium hydroxide (1 g) was added portionwise and the mixture was stirred for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in water and extracted with ethyl acetate. The aqueous layer was acidified by the addition of 2 M aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give the title compound (480 mg). APCI+MS : m/z 234 [M+H]+.
INTERMEDIATE 11
[4-(4-Chlorophenyl)-2-methyl-l,3-thiazol-5-yl]acetic acid was prepared in an analogous manner to Intermediate 10, using 3-bromo-4-(4-chlorophenyl)-4-oxobutanoic acid.
Figure imgf000040_0001
APCI-MS: m/z 266 [M-H]".
INTERMEDIATE 12
This shows the preparation of 5-bromo-Λ/-[(lE)-(dimethylamino)methylene]-thiophene-2- sulfonamide.
Figure imgf000040_0002
To a stirred solution of 5-bromothiophene-2-sulfonamide (2 g) in acetonitrile (20 mL) was added DMF-DMA (2.24 mL) dropwise. After 20 h the mixture was concentrated in vacuo, and the waxy solid slurried in water and collected by filtration. The solid was washed with water and air dried to give the title compound 5-bromo-iV-[(lE)-(dimethylamino) methylene]thiophene-2-sulfonamide (2.3 g).
1H NMR (400 MHz, DMSO) δ 8.21 (s, IH), 7.35 (d, IH), 7.26 (d, IH), 3.16 (s, 3H), 2.93 (s, 3H).
INTERMEDIATE 13 This shows the preparation of iV-[(l-5)-(Dimethylamino)methylene]-5-(phenylethynyl)- thiophene-2-sulfonamide.
Figure imgf000041_0001
To a stirred solution of Intermediate 12 (890 mg) in triethylamine (4 mL) and DMF (2 mL) was added ethynylbenzene (300 mg), tetrakis(triphenylphosphine)palladium(0) (5 mg) and copper (I) bromide.dimethylsulfide complex (5 mg). The reaction mixture was heated at 90 0C for 20 h, then water was added to the cooled mixture. The resulting solid was filtered and washed with water, isopropanol and diethyl ether to provide the title compound as a pale brown solid (850 mg). 1H NMR (300 MHz, DMSO) δ 8.25 (s, IH), 7.62 - 7.54 (m, 2H), 7.52 - 7.41 (m, 4H), 7.39 (d, IH), 3.18 (s, 3H), 2.96 (s, 3H).
INTERMEDIATE 14
This shows the preparation of 5-(phenylethynyl)-thiophene-2-sulfonamide.
Figure imgf000041_0002
To a stirred solution of Intermediate 13 (400 mg) in methanol (5 mL) was added 10% w/v aqueous sodium hydroxide (3 mL). The mixture was heated at reflux for 2 h, allowed to cool, and concentrated in vacuo. The residue was slurried in water, and acidified with aqueous 2 N hydrochloric acid. The resulting solid was extracted with ethyl acetate, and the organic phase separated and dried over sodium sulfate. This was filtered and concentrated in vacuo to give the title compound (310 mg) as a brown solid. 1H NMR (300 MHz, DMSO) δ 7.86 (s, 2H), 7.64 - 7.41 (m, 7H).
INTERMEDIATE 15
This shows the preparation of JV-[(lE)-(dimethylamino)methylene]-5-(2- phenylethyl)thiophene-2-sulfonamide.
Figure imgf000042_0001
To a solution of Intermediate 13 (350 mg) in ethanol (10 mL) was added platinum oxide (20 mg). The reaction was stirred under 2 bar of hydrogen pressure for 1 h. The reaction mixture was filtered through Celite, and concentrated in vacuo to give the title compound iV-[(ljE)-(dimethylamino)methylene]-5-(2-phenylethyl)thiophene-2-sulfonamide (320 mg). 1B. NMR (300 MHz, DMSO) δ 8.17 (s, IH), 7.33 - 7.15 (m, 6H), 6.84 (dd, IH)5 3.18 - 3.09 (m, 5H), 2.97-2.90 (m, 5H).
INTERMEDIATE 16
This shows the preparation of 5-(2-phenylethyl)thiophene-2-sulfonamide.
Figure imgf000042_0002
To a stirred solution of Intermediate 15 (320 mg) in methanol (5 mL) was added 10% w/v aqueous sodium hydroxide (3 mL). The reaction mixture was heated at reflux for 1 h then concentrated in vacuo, and water added. The aqueous solution was acidified to neutral pH, and the precipitate extracted into ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (240 mg). 1HNMR (300 MHz5 DMSO) δ 7.59 - 7.53 (m, 2H), 7.38 - 7.16 (m, 6H), 6.90 - 6.85 (m, IH), 3.22 - 3.10 (m, 2H), 3.01 - 2.90 (m, 2H).
5
INTERMEDIATE 17
This shows the preparation of 4-{[5-(aminosulfonyl)-2-thienyl]thio}benzoic acid.
Figure imgf000043_0001
I0 To a solution of 5-bromothiophene-2-sulfonamide (242 mg) and 4-mercaptobenzoic acid (154 mg) in DMF (1 mL) was added aqueous 2 N sodium.hydroxide solution (1 mL). The reaction mixture was heated in a CEM Discover microwave at 1500C for 25 min. After this time it was allowed to cool, then it was diluted with water (20 mL) and acidified with 10% v/v aqueous hydrochloric acid. The fine precipitate that formed was difficult to filter is so the majority of the liquid was decanted from the solid, and the gelatinous residue concentrated to dryness in vacuo to give the title compound 4-{[5-(aminosulfonyl)-2- thienyl]thio}benzoic acid (280 mg).
1HNMR (300 MHz, DMSO) δ 13.03 (s, IH), 7.91 (d, 2H), 7.85 (s, 2H), 7.59 (d, IH), 7.50 (d, IH), 7.34 (d, 2H). 0
INTERMEDIATE 18
This shows the preparation of methyl 4-{[5-(aminosulfonyl)-2-thienyl]thio}benzoate.
Figure imgf000043_0002
To a solution of Intermediate 17 (280 mg) in methanol (10 mL) was added chloro- 5 trimethylsilane (1 mL). The solution was stirred for 24 h then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound 4-{[5-(aminosulfonyl)-2-thienyl]thio}benzoate (120 mg) as a gum that solidified on standing.
1H NMR (300 MHz, DMSO) δ 7.93 (d, 2H), 7.86 (s, 2H), 7.60 (d, IH), 7.51 (d, IH), 7.35 (d, 2H), 3.84 (s, 3H).
INTERMEDIATE 19
This shows the preparation of N-(tert-butyl)-5-(pyridin-4-ylthio)thiophene-2-sulfonamide.
Figure imgf000044_0001
To a solution of 72-BuLi in hexanes (2.5 M, 2.4 rnL) in THF (20 mL) at -78 0C was added 5-bromo-iV-(terf-butyl)thiophene-2-sulfonamide (895 mg) in THF (3 mL) dropwise. The reaction mixture was stirred at this temperature for 30 min then 4,4'-dithiodipyridine (661 mg) in THF (3 mL) was added which caused the formation of a precipitate. The mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was then partitioned between ethyl acetate and water, and the organic phase washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography, eluting impurities with 2 : 1 zso-hexane / ethyl acetate, and then with 1 : 1 /so-hexane / ethyl acetate to give the title compound N-(tert- butyl)-5-(pyridin-4-ylthio)thiophene-2-sulfonamide (297 mg).
1H NMR (400 MHz, DMSO) δ 8.43 (s, 2H), 7.61 (d, IH), 7.27 - 7.26 (m, IH), 7.00 (d, 2H)5 4.62 (s, IH), 1.34 (s, 9H).
INTERMEDIATE 20 This shows the preparation of 5-(pyridin-4-ylthio)thiophene-2-sulfonamide.
Figure imgf000045_0001
To a stirred solution of Intermediate 19 (290 mg) in DCE (4 mL) was added methanesulfonic acid (255 mg). The reaction mixture was heated at 80 0C for 3 h. After cooling, saturated aqueous sodium bicarbonate solution was added slowly until a neutral pH was observed, and the reaction mixture was partitioned between water and DCM. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound 5-(pyridin-4-ylthio)thiophene-2 -sulfonamide (159 mg). 1H NMR (300 MHz, DMSO) δ 8.46 (dd, 2H), 7.90 (s, 2H), 7.65 (d, IH), 7.56 (d, IH), 7.14 (dd, 2H).
INTERMEDIATE 21
This shows the preparation of a mixture of 5-[(4-methyl~l,3-thiazol-2-yl)thio]thiophene-2- sulfonamide and 3-[(4-methyl- 1 ,3-thiazol-2-yl)thio]thiophene-2-sulfonamide.
To a stirred solution of ra-BuLi in hexanes (2.5 M, 3.1 mL) in THF (25 mL) at -78 0C was added a solution of iV-(ter/-butyl)thiophene-2-sulfonamide (842 mg) in THF (5 mL) dropwise. The reaction mixture was stirred at this temperature for 1 h prior to the addition of 2,2!-dithiobis(4-methyl-l,3-thiazole) (1.0 g) in THF (5 mL). After 30 min, the reaction mixture was allowed to warm to -50 °C and stirred thereafter for 30 min. It was then poured into dilute aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, before being filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a gradient from 1 : 9 to 1 : 4 ethyl acetate / zso-hexane to leave a yellow oil. This was dissolved in DCE (15 mL) and treated with methanesulfonic acid (1 mL) and heated at reflux for 4 h. Further methanesulfonic acid (1 mL) was added and the reaction mixture heated at reflux for a further 2 h. The cooled reaction mixture was partitioned between DCM and aqueous saturated sodium bicarbonate, and the aqueous phase extracted three more times with DCM. The combined organics were dried over sodium sulfate, before being filtered and concentrated in vacuo. The residue was chromatographed on silica gel
5 eluting with 1 : 5 to 1 : 3 ethyl acetate / iso-hexzne then 3 : 97 methanol / ethyl acetate to leave a yellow gum (470 mg) as a 0.63 to 0.37 mixture of the two isomers 5-[(4-methyl- l,3-thiazol-2-yl)thio]thiophene-2-sulfonamide and 3-[(4-methyl-l,3-thiazol-2- yl)thio]thiophene-2-sulfonarnide respectively. 1HNMR (400 MHz, DMSO) δ 7.91 (0.74H, s), 7.88 (1.26H, s), 7.85 (0.63H, d), 7.58 -
I0 7.55 (IH, m), 7.36 - 7.35 (0.37H, m), 7.31 - 7.30 (0.63H, m), 7.04 (0.37H, d), 2.36 (UlH, d), 2.33 (1.89H, d) as a 0.63 : 0.37 mixture of isomers; ES+ and ES-MS: m/z 293 [M+H]+ and 291 [M-H]-.
INTERMEDIATE 22 is This illustrates the preparation of N-[4-(aminosulfonyl)phenyl]-JV-ethyl-2,2,2- trifluoroacetamide .
Figure imgf000046_0001
To a stirred solution of 4-(ethylamino)benzenesulfonamide (European Patent 602878 Al) (1.5 g) and triethylamine (1.26 mL) in DCM (10 mL) was added trifluoroacetic acid 0 anhydride (1.17 mL). After 16 h, the mixture was partitioned between saturated aqueous sodium bicarbonate solution and DCM, and the aqueous phase further extracted twice with DCM. The combined organic phases were dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography, eluting with a gradient from 1 : 6 to 1 : 1 ethyl acetate / zso-hexane to give the title 5 compound (740 mg).
1H NMR (400 MHz, DMSO) δ, 7.93 (dm, 2H), 7.62 (dm, 2H), 7.51 (s, 2H), 3.75 (q, 2H), 1.08 (t, 3H); ES+ and ES-MS: m/z 297 [M+H]+ and 295 [M-H]'.
INTERMEDIATE 23 This illustrates the preparation of iV-ethyl-2,2,2-trifluoro-iV-{4-[({[(2-methyl-4-phenyl-l,3- thiazol-5-yl)ammo]carbonyl}amino)sulfonyl]phenyl}acetamide.
Figure imgf000047_0001
5 To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (J. Chem Soc. 1947, 1656) (220 mg), Intermediate 22(300 mg) and triethylamine (170 μL) in benzene (3 mL) was added diphenylphosphoryl azide (260 μL). The mixture was then heated at 80 0C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetom'trile with a few drops of acetic acid. This was subjected to RPHPLC (Xterra, 5% to 95%
I0 acetonitrile in TFA (0.2% aq.)) to give the title compound as a white solid (80 mg). A small amount of this solid was subjected to RPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) to provide clean title compound for analytical purposes. 1H NMR (400 MHz, DMSO) δ 8.94 (br s, IH)5 7.99 (d, 2H), 7.66 (dm, 2H), 7.60 (dm, 2H), 7.42 (to, 2H), 7.32 (to, IH), 3.75 (q, 2H), 2.54 (s, 3H), 1.07 (t, 3H); ES+MS and is ES-MS: m/z 513 [M+H]+ and 511 [M-H]'.
INTERMEDIATE 24
This illustrates the preparation of ethyl 2-bromo-4-phenyl-l,3-thiazole-5-carboxylate.
Figure imgf000047_0002
0 To a stirred solution of ethyl 2-amino-4-phenyl-l,3-thiazole-5-carboxylate (4.5 g) in acetonitrile (40 mL) was added copper (II) bromide (4.5 g) and tert-butyl nitrite (2.1 g, 2.3 mL). The mixture was heated at 800C for 4 h, then cooled to RT and poured into water. The products were extracted into diethyl ether, and the ethereal extract washed twice with a dilute aqueous solution of pyridine followed by a wash with 2 N aqueous hydrochloric acid. The organic extract was dried over magnesium sulfate and concentrated to dryness to afford the title compound as a yellow- solid (5 g). 1U NMR (400 MHz, DMSO) δ 7.73 - 7.69 (m, 2H), 7.49 - 7.42 (m, 3H), 4.23 (q, 2H), 1.20 (t, 3H).
INTERMEDIATE 25
This illustrates the preparation of 2-bromo-4-phenyl-l,3-thiazole-5-carboxylic acid.
Figure imgf000048_0001
Intermediate 24 (1.9 g) in THF (80 mL) was treated with potassium hydroxide (0.5 g) in water (20 mL), and the mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo, and the residue treated with aqueous 2 N hydrochloric acid. The solid was collected by filtration, and dried in vacuo to afford the title compound as a beige solid (1.7 g).
1H NMR (300 MHz, CDCl3) δ 7.77 - 7.70 (m, 2H), 7.46 - 7.38 (m, 3H).
INTERMEDIATE 26
This illustrates the preparation of 2-(dimethylamino)-4-phenyl-l,3-thiazole-5-carboxylic acid.
Figure imgf000048_0002
A solution of Intermediate 24 (1.6 g) in acetonitrile (30 mL) was treated with a 40% w/v aqueous solution of dimethylamine (10 mL), and the mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo, and the residue dissolved in methanol. The solution was treated with lithium hydroxide monohydrate (860 mg) in water (20 mL), and the mixture stirred at 90 °C for 2 h. The mixture was cooled to RT and diluted with water (100 mL). The solution was acidified to approximately pH 2 with 2N aqueous hydrochloric acid and the solid was collected by filtration. The title compound was obtained as a colourless solid (1.05 g).
1H NMR (300 MHz, DMSO) δ 7.72 - 7.64 (m, 2H), 7.43 - 7.35 (m, 3H), 3.11 (s, 3H), 3.11 (s, 3H).
INTERMEDIATE 27
This illustrates the preparation of ethyl 2-[(2-hydroxyethyl)thio]-4-phenyl-l,3-thiazole-5- carboxylate.
Figure imgf000049_0001
A mixture of Intermediate 24 (2 g), 2-mercaptoethanol (1.1 mL), and DIPEA (2.5 mL) in acetonitrile (20 mL) was stirred at RT for 5 d. The solution was concentrated in vacuo, and the residue purified by flash column chromatography on silica gel using 40% ethyl acetate / zsø-hexane. The title compound was isolated as a yellow oil (1.4 g). 1H NMR (300 MHz, CDCl3) δ 7.79 - 7.65 (m, 2H)5 7.48 - 7.36 (m, 3H), 4.26 (q, 2H), 4.02 (q, 2H), 3.60 (t, IH), 3.45 (t, 2H), 1.27 (t, 3H).
INTERMEDIATE 28
This illustrates the preparation of 2-[(2-hydroxyethyl)thio]-4-phenyl-l,3-thiazole-5- carboxylic acid.
Figure imgf000050_0001
A solution of Intermediate 27 (280 mg) in THF (5 mL) was treated with sodium hydroxide (72 mg) in water (20 mL) and the mixture stirred at RT for 3 h. The solution was acidified with 2 N aqueous hydrochloric acid and the mixture extracted into ethyl acetate. The organic phase was dried over magnesium sulfate, and concentrated in vacuo to dryness. The crude title compound (200 mg) was used without further purification . ES+MS: m/z 282 [M+H]+.
INTERMEDIATE 29 This illustrates the preparation of ethyl 2-{[2-(methylammo)-2-oxoethyl]thio}-4-phenyl- 1 ,3-thiazole-5-carboxylate.
Figure imgf000050_0002
A solution of Intermediate 24 (500 mg) in acetone (5 mL) was treated with caesium carbonate (650 mg) and 2-mercaρto-JV-methylacetamide (200 mg). The mixture was stirred at 50 °C for 4 h and then it was poured into water (50 mL). The mixture was acidified to pH2 with 2 N aqueous hydrochloric acid, and it was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (390 mg).
1H NMR (300 MHz5 CDCl3) δ 7.75 - 7.67 (m, 2H), 7.47 - 7.41 (m, 3H), 7.13 (s, IH)3 4.26 (q, 2H), 3.90 (s, 2H), 2.80 (d, 3H), 1.28 (t, 3H). INTERMEDIATE 30
This illustrates the preparation of 2-{[2-(methylamino)-2-oxoethyi]thio}-4-phenyl-l33- thiazole-5-carboxylic acid.
Figure imgf000051_0001
Intermediate 29 (370 mg) in methanol (10 mL) was treated with sodium hydroxide (22 mg) in water (10 mL), and the mixture was stirred at RT for 3 h. Further sodium hydroxide (22 mg) was added and stirring was allowed to continue until no starting material remained. The mixture was diluted with water (50 mL) and it was acidified to pH 2 with 2 N aqueous hydrochloric acid . The mixture was extracted into ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude title compound (160 mg) . ES+MS: m/z 309 [M+H]+.
INTERMEDIATE 31
This illustrates the preparation of ethyl 2-phenoxy-4-phenyl-l,3-thiazole-5-carboxylate.
Figure imgf000051_0002
A stirred mixture of Intermediate 24 (500 mg) and sodium phenoxide trihydrate (1.63 g) in acetone (25 mL) was heated at reflux for 24 h. The mixture was then cooled to RT and diluted with water. The mixture was extracted into ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated to dryness in vacuo to yield the title compound as a cream solid (380 mg). 1H NMR (400 MHz, CDCl3) δ 7.77 - 7.72 (m, 2H), 7.49 - 7.43 (m, 2H), 7.42 - 7.37 (m, 3H), 7.37 - 7.30 (m, 3H)5 4.22 (q, 2H), 1.24 (t, 3H).
INTERMEDIATE 32 This illustrates the preparation of 2-phenoxy-4-ρhenyl- 1 ,3-thiazole-5-carboxylic acid.
Figure imgf000052_0001
The title compound was prepared in the manner described for Intermediate 28 and afforded a beige solid (310 mg).
1H NMR (400 MHz, CDCl3) δ 7.77 - 7.29 (m, 10H).
INTERMEDIATE 33
This illustrates the preparation of ethyl 4-phenyl-2-(ρyridin-3-yloxy)-l,3-thiazole-5- carboxylate.
Figure imgf000052_0002
A stirred mixture of Intermediate 24 (500 mg), pyridin-3-ol (900 mg), and caesium carbonate (3.2 g) in acetone (25 mL) was heated at reflux for 24 h. The mixture was then cooled to RT and diluted with water. The mixture was extracted into ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a cream solid (350 mg).
1H NMR (300 MHz, CDCl3) δ 8.87 (s, IH), 8.61 (s, IH), 8.11 - 8.05 (m, IH), 7.75 - 7.67 (m, 2H), 7.65 - 7.56 (m, IH), 7.45 - 7.36 (m, 3H), 4.28 (q, 2H), 1.29 (t, 3H). INTERMEDIATE 34
This illustrates the preparation of 4-phenyl-2-(pyridin-3-yloxy)-l,3-thiazole-5-carboxylic acid.
Figure imgf000053_0001
The title compound was prepared in the manner described for Intermediate 28 and afforded a beige solid (100 mg). ES+MS: m/z 299 [M+H]+.
INTERMEDIATE 35
This illustrates the preparation of 2-ethoxy-4-phenyl-l,3-thiazole-5-carboxylic acid.
Figure imgf000053_0002
Under an atmosphere of nitrogen, sodium hydride (190 mg, 60% dispersion in mineral oil) was added to ethanol (5 mL) . After 5 min, Intermediate 24 (500 mg) was added, and the mixture stirred at 50 °C for 4 h. Water (5 mL) was added to the mixture, and the reaction mixture was heated for 6 h. The mixture was diluted with water (20 ml) and acidified to pH 2 with dilute aqueous hydrochloric acid. The solid was collected by filtration to afford the title compound (300 mg). 1H NMR (300 MHz, CDCl3) δ 7.77 - 7.66 (m, 2H), 7.48 - 7.32 (m5 3H)5 4.55 (q, 2H), 1.46 (t, 3H).
INTERMEDIATE 36 This illustrates the preparation of 2-(2-methoxyethoxy)-4-phenyl-l,3-thiazole~5- carboxylic acid.
Figure imgf000054_0001
The title compound was prepared in the manner described for Intermediate 35 and afforded a colourless solid (220 mg).
1H NMR (300 MHz, CDCl3) δ 7.77 - 7.65 (m, 2H), 7.47 - 7.35 (m, 3H), 4.69 - 4.64 (m, 2H), 3.80 - 3.75 (m, 2H), 3.45 (s, 3H).
INTERMEDIATE 37
This illustrates the preparation of tert-butyl (2~methoxy-4-phenyl-l,3-thiazol-5- yl)carbamate.
Figure imgf000054_0002
A stirred solution of 2-methoxy-4-phenyl-l,3-thiazole-5-carboxylic acid (Acta. Polaniae Pharmaceutic** 1984, 41, (6) 633-40) (700 mg) in t-butanol (20 mL) was treated with DIPEA (650 μL), and diphenylphosphoryl azide (800 μL). The mixture was stirred and heated under reflux for 3 h. The reaction mixture was cooled to RT, and poured into water (100 mL). The mixture was extracted into diethyl ether and the ethereal solution washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. This was filtered and concentrated in vacuo to give an oil which was purified by normal phase column chromatography on silica gel eluting with 30% ethyl acetate in zso-hexane to afford the title compound (800 mg) as a brown oil. ES+MS: m/z 307 [M+H]+.
EXAMPLE 1
This illustrates the preparation of 4-chloro-iV-{[(2-methyl-4-phenyH,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000055_0001
4-Chlorobenzenesulfonyl isocyanate (80 μl) was added to an ice-cooled solution of Intermediate 4 (100 mg) in DCM (3 mL). The reaction was stirred at RT for 1 h. Concentration in vacuo and trituration with methanol gave the title compound (95 mg). 1H NMR (300 MHz, DMSO) δ 9.21 (s, IH), 7.95 (d, 2H), 7.72 (d, 2H), 7.64 (d, 2H), 7.41- 7.44 (m, 2H), 7.33-7.37 (m, IH), 2.57 (s, 3H); APCI+MS: m/z 408 [M+H]+.
EXAMPLE 2
This illustrates the preparation of 4-chloro-JV-{[memyl(2~memyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000055_0002
4-Chlorobenzenesulfonyl isocyanate (90 μL) was added to an ice-cooled solution of Intermediate 6 (127 nag) in DCM (4 mL). The reaction mixture was stirred at RT for 20 h and then concentrated in vacuo. Purification by RPHPLC (Xterra, 25% to 75% acetonitrile in aqueous ammonia (0.2%)) followed by trituration with DCM gave the title compound (80 mg).
1H NMR (300 MHz, DMSO) δ 7.69 (d, 2H), 7.64 (d, 2H), 7.47 (d, 2H), 7.32-7.37 (m, 3H), 2.85 (s, 3H), 2.61 (s, 3H); APCI+MS: m/z 422 [M+H]+.
EXAMPLE 3
See Table 1.
EXAMPLE 4
This illustrates the preparation of iV-[(4-Chlorophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3- thiazol-5-yl)acetamide.
Figure imgf000056_0001
A solution of Intermediate 10 (100 mg), 4-chlorobenzene sulfonamide (86 mg), EDCI (86 mg), and DMAP (55 mg) in DCM (3 mL) was stirred at RT for 20 h. The reaction mixture was diluted with DCM and washed with 2 M aqueous hydrochloric acid. The two phases were separated and the aqueous layer was extracted twice with DCM. The combined organic phases were washed with brine and the solid that had precipitated out of the organic layer was filtered to give the title compound (86 mg). 1H NMR (400 MHz5 DMSO) δ 12.66 (br s, IH), 7.92 (d, 2H)5 7.73 (d, 2H)5 7.37-7.41 (m, 5H), 3.94 (s, 2H), 2.63 (s, 3H); APCI-MS: m/z 405 [M-H]". EXAMPLES 5, 6, 7
See Table 1.
EXAMPLE 8 This shows the preparation of 2-methoxy-4-methyl-N-{[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000057_0001
To a stiixed mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (J. Chem Soc. 1947, 1656) (150 mg), 2-methoxy-4-methylbenzenesulfonamide (152 mg) and triethylamine (116 μL) in toluene (3 rnL) was added diphenylphosphoryl azide (180 μL). The mixture was then heated at 80 °C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. This was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound as a white solid (70 mg).
1H NMR (300 MHz, DMSO) δ 10.96 (s, IH), 9.07 (s, IH), 7.70 (d, IH), 7.63 (dm, 2H), 7.48 (tm, 2H), 7.41 - 7.34 (m, IH), 7.09 (s, IH), 6.94 (d, IH), 3.87 (s, 3H), 2.55 (s, 3H), 2.38 (s, 3H); ES+MS: m/z 418 [M+H]+.
EXAMPLE 9
This shows the preparation of 4-(ethylamino)-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000058_0001
A mixture of Intermediate 23 (75 mg) and potassium carbonate (40 mg) was stirred in methanol (2 mL) for 16 h at RT. Further potassium carbonate (40 mg) was added and the reaction was complete after 1 h. The mixture was concentrated in vacuo and to the residue was added acetic acid (500 μL), before being concentrated in vacuo and re-dissolving in 10 : 1 acetonitrile / water (5 mL) with a few drops of acetic acid. This was subjected to RPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) to give the title compound as a white solid (20 mg). 1H NMR (400 MHz, DMSO) δ 8.89 (br s, IH), 7.62 (dm, 2H), 7.57 (dm, 2H), 7.43 (tm, 2H), 7.33 (tt, IH), 6.59 (dm, 2H)3 6.55 (br s, IH), 3.09 (dt, 2H), 2.54 (s, 3H), 1.15 (t, 3H); ES+MS: m/z 417 [M+H]+.
EXAMPLE 10
This shows the preparation of 5-[(4-chlorophenyl)thio]-N-{[(2-methyl-4-phenyl-l,3- thiazol-5-yl)amino]carbonyl}thiophene-2-sulfonamide.
Figure imgf000058_0002
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (150 mg), 5-[(4- chlorophenyl)thio]thiophene-2-sulfonamide (209 mg) and triethylamine (115 μL) in benzene (5 mL) was added diphenylphosphoryl azide (180 μL). The mixture was then heated at 80 °C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. A small amount of this solution was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound (80 mg) as a colourless solid. The remainder of the solution was concentrated in vacuo, and acetonitrile (3 mL) and water (3 mL) added along with trifluoroacetic acid (12 drops). The resulting white solid was collected by filtration to give further title compound (140 mg) as a colourless solid.
1H NMR (400 MHz, DMSO) δ 9.17 (s, IH), 7.74 (d, IH), 7.66 (dm, 2H), 7.48 - 7.39 (m, 7H), 7.36 - 7.31 (m, IH), 2.59 (s, 3H); ES+MS and ES-MS: m/z 522, 524 [M+H]+ and 520, 522 [M-H]-.
EXAMPLE 11
This shows the preparation of 5-chloro-3-methyl-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl} - 1 -benzothiophene-2-sulfonamide.
Figure imgf000059_0001
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (75 mg), 5- chloro-3-methyl-l-benzothioρhene-2-sulfonamide (95 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated at 80 °C for 2 h. The cooled mixture was concentrated in vacuo and suspended in acetonitrile. The supernatant was removed, and the solid was then triturated with methanol, then 1 : 1 methanol / acetonitrile to give the title compound (26 mg) as a colourless solid. 1H NMR (400 MHz, DMSO) δ 9.05 (br s, IH), 8.12 (d, IH), 8.07 (d, IH), 7.65 (dm, 2H), 7.61 (dd, IH), 7.41 (tm, 2H), 7.32 (tm, IH), 2.66 (s, 3H), 2.54 (s, 3H); ES+MS and ES- MS: m/z 478, 480 [MH-H]+ and 476, 478 [M-H]-.
EXAMPLE 12
This shows the preparation of 6-ethoxy-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl} - 1 ,3-benzothiazole-2-sulfonamide.
Figure imgf000060_0001
To a stirred mixture of 2-methyl-4-pheny 1-1,3 -thiazole-5-carboxy lie acid (75 mg), 6- ethoxy-l,3-benzothiazole-2-sulfonamide (95 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated at 80 0C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. This solution was subjected to RPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) twice to give the title compound (55 mg) as a colourless solid.
1H NMR (400 MHz, DMSO) δ 8.64 (br s, IH), 7.87 (d, IH), 7.74 (d, 2H), 7.65 (d, IH), 7.39 (t, 2H), 7.26 (t, IH), 7.11 (dd, IH), 4.11 (q, 2H), 1.36 (t, 3H), CH3 resonance obscured by residual DMSO in NMR solvent; ES+MS: m/z 475 [M+H]+.
EXAMPLE 13
This shows the preparation ofiV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- 5-(phenylethynyl)thiophene-2-sulfonamide.
Figure imgf000060_0002
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (75 mg), Intermediate 14 (95 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated at 80 °C for 2 h. The cooled mixture was concentrated in vacuo and suspended in 2 : 1 water / acetonitrile (3 mL) with a few drops of acetic acid . The resulting white solid was collected by filtration and redissolved in 1 : 1 methanol / acetonitrile. This solution was subjected to RPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) to give the title compound (55 mg) as a colourless solid.
1HNMR (300 MHz, DMSO) δ 8.97 (br s, IH), 7.70 (dm, 2H), 7.64 - 7.59 (m, 3H), 7.51 - 7.45 (m, 3H), 7.45 - 7.40 (m, 3H), 7.34 (tin, IH), 2.59 (s, 3H); ES+MS: m/z 480 [M+H]+.
EXAMPLE 14
This shows the preparation of ΛT-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- 5-(phenylthio)thiophene-2-sulfonamide.
Figure imgf000061_0001
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (75 mg), 5- (phenylthio)thiophene-2-sulfonamide (100 mg) and triethylamine (60 μL) in benzene (3 niL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated to 80 0C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. This was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) and RPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) to give the title compound (30 mg) as a colourless gum. To this was added 6 : 1 water / acetonitrile, and the suspension sonicated for 1 min to produce a colourless solid that was filtered, air dried, and collected (23 mg).
1H NMR (400 MHz, DMSO) δ 9.05 (br s, IH)5 7.68 - 7.63 (m, 3H), 7.43 - 7.30 (m, 10H), 2.57 (s, 3H); ES+MS: m/z 488 [M+H]+.
EXAMPLE 15 This shows the preparation of iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- 5-(2-phenylethyl)thiophene-2-sulfonamide.
Figure imgf000062_0001
To a stirred mixture of 2-methyl-4-phenyl-l,3-tliiazole-5-carboxylic acid (75 mg), Intermediate 16 (90 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated to 80 °C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. This was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) and PvPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) to give the title compound (36 mg) as a colourless solid. 1H NMR (300 MHz, DMSO) δ 8.45 (br s, IH)3 7.69 (dm, 2H), 7.41 (tm, 2H), 7.32 - 7.23 (m, 5H), 7.21 (app dd, IH), 7.17 (d, IH), 6.87 (v br s, IH), 6.71 (d, IH), 3.08 (t, 2H), 2.92 (t, 2H), CH3 resonance obscured by residual DMSO δ 2.50-2.55; ES+MS: m/z 484 [M+H]+.
EXAMPLE 16 See Table 1.
EXAMPLE 17
This shows the preparation of iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- 5-(phenylthio)- 1 ,3-thiazole-2-sulfonamide.
Figure imgf000062_0002
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (75 mg), 5- (phenylthio)-l,3-thiazole-2-sulfonamide (Patent WO95/29904) (93 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated at 80 °C for 3 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. This was subjected to RPHPLC (Novapak, 5% to 50% acetonitrile in NH4OAc (0.1% aq.)) and RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) and the isolated solid was triturated with methanol to give the title compound as a colourless solid (28 mg). 1H NMR (400 MHz, DMSO) δ 9.25 (br s, IH), 8.19 (s, IH), 7.67 (dm, 2H), 7.45 - 7.31 (m, 8H), 2.58 (s, 3H); ES+MS: m/z 489 [M+H]+.
EXAMPLE 18
This shows the preparation of N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- 5-(pyridin-4-ylthio)thiophene-2-sulfonamide.
Figure imgf000063_0001
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (75 mg), Intermediate 20 (93 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphenylphosphoryl azide (90 μL). The mixture was then heated at 80 0C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile and water with a few drops of acetic acid. This was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) and the isolated solid was triturated with methanol to give the title compound as a colourless solid (28 mg). 1H NMR (400 MHz, DMSO) δ 9.28 (s, IH), 8.54 (d, 2H), 7.89 (d, IH), 7.68 (dm, 2H), 7.64 (d, IH), 7.45 - 7.38 (m, 4H), 7.36 - 7.31 (m, IH), 2.59 (s, 3H); ES+MS: m/z 489 [MH-H]+.
EXAMPLE 19 This shows the preparation of N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- 1 -benzothiophene-2-sulfonamide.
Figure imgf000064_0001
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (75 mg), 1- benzothiophene-2-sulfonamide (Patent WO2004/048329A1) (73 mg) and triethylamine (60 μL) in benzene (3 mL) was added diphienylphosphoryl azide (90 μL). The mixture was then heated at 80 °C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid. This was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound as a colourless solid (28 mg).
1H NMR (400 MHz, DMSO) δ 9.17 (s, IH), 8.20 (s, IH), 8.12 (d, IH), 8.08 (d, IH), 7.65 (d, 2H), 7.59 (dd, IH), 7.55 (dd, IH), 7.51 (dd, IH), 7.39 (t, 2H), 7.31 (t, IH)5 2.56 (s, 3H); ES+MS: m/z 430 [M+H]+.
EXAMPLE 20
See Table 1.
EXAMPLE 21
This shows the preparation of methyl 4-({5-[({[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}amino)sulfonyl]-2-thienyl}thio)benzoate.
Figure imgf000064_0002
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (57 mg), Intermediate 18 (85 mg) and triethylamine (45 μL) in benzene (3 mL) was added diphenylphosphoryl azide (70 μL). The mixture was then heated at 80 °C for 2 h. The cooled mixture was concentrated in vacuo and redissolved in acetonitrile with a few drops of acetic acid, again concentrated in vacuo and passed through a plug of silica gel, eluting with ethyl acetate. The appropriate fractions were concentrated in vacuo and the solid was dissolved in hot acetonitrile. On cooling slightly, a few drops of water were added causing the formation of a precipitate. The solid was collected by filtration and washed with wet acetonitrile to give the title compound as a colourless solid (30 mg). 1H NMR (400 MHz, DMSO) δ 9.16 (s, IH), 7.90 (d, 2H), 7.79 (d, IH), 7.66 (d, 2H), 7.51 (d, IH), 7.43 - 7.30 (m, 5H), 3.83 (s, 3H), 2.58 (s, 3H); ES+MS: m/z 546 [M+H]+.
EXAMPLES 22, 23
See Table 1.
EXAMPLE 24
This shows the preparation of N-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- lH-indole-2-sulfonamide.
Figure imgf000065_0001
To a stirred mixture of 2-methyl-4-phenyl-l,3-thiazole-5-carboxylic acid (110 mg), IH- indole-2-sulfonamide (J. Med. Chem. 1990, 33, 749) (100 mg) and triethylamine (85 μL) in benzene (4 mL) was added diphenylphosphoryl azide (130 μL). The mixture was then heated at 80 °C for 2 h. As there had been appreciable urea formation, further 2-methyl-4- phenyl-l,3-thiazole-5-carboxylic acid (50 mg), triethylamine (40 μL) and diphenylphosphoryl azide (65 μL) were added and the mixture heated to 80 °C for a further 2 h. The cooled mixture was concentrated in vacuo and part dissolved in 1 : 4 methanol / acetonitrile, then filtered to remove the urea by-product. The filtrate was subjected to RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)) to give the title compound as a colourless solid (25 mg). 1H NMR (400 MHz5 DMSO) δ 12.15 (s, IH), 9.12 (s, IH), 7.69 (d, IH), 7.63 (dm, 2H), 7.51 (dm, IH), 7.40 (tm, 2H), 7.35 - 7.29 (m, 2H), 7.16 - 7.10 (m, 2H), 2.55 (s, 3H); ES+ and ES-MS: m/z 413 [M+H]+ and 411 [M-H]". EXAMPLE 25
This shows the preparation of iV-{[(2-bromo-4-phenyl-l,3-thiazol-5-yl)ammo]carbonyl}-4- chlorobenzenesulfonamide.
Figure imgf000066_0001
A stirred mixture of Intermediate 25 (1.6 g), 4-chlorobenzenesulfonamide (1.1 g), diphenylphosphoryl azide (1.7 g) and DIPEA (1.2 niL) in dry benzene (30 niL) was heated under reflux for 2 h. The mixture was cooled to RT, diluted with ethyl acetate (100 mL), and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to dryness. The crude product was purified on silica gel eluting with ethyl acetate. The isolated material from the column (1.2 g) was dissolved in a mixture of 1 : 1 DMSO / acetonitrile (6 mL). Water (50 mL) was added, and the mixture was acidified with trifluoroacetic acid. The precipitated solid was collected by filtration, dried in vacuo at 40 °C, and then recrystallised from acetonitrile to afford the title compound as a mono hydrate (400 mg).
1H NMR (400 MHz, DMSO) δ 9.61 (s, IH), 7.98 - 7.94 (m, 2H), 7.75 - 7.71 (m, 2H)3 7.66 - 7.61 (m, 2H), 7.51 - 7.45 (m, 2H), 7.43 - 7.37 (m, IH); APCI+MS: m/z 472, 474, 476 [M+H]+.
EXAMPLE 26
This shows the preparation of 4-chloro-7V-{[(2-ethynyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000067_0001
A stirred mixture of Example 25 (350 mg), copper. (I) bromide dimethylsulfide complex (7 mg), dry DMF (3 mL), ethynyl(trimethyl)silane (300 μL), and tetrakis(triphenylphosphine)-palladium(0) (17 mg) in triethylamine (10 mL) was heated at 90 °C for 15 min. Water (50 mL) was added, and the mixture was acidified to pH2 with 2 N aqueous hydrochloric acid. The crude product was extracted into ethyl acetate and the solution dried over magnesium sulfate, filtered then concentrated in vacuo to dryness. At this stage the crude product had almost completely desilylated and was purified by both RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) and normal phase column
10 chromatography on silica gel using ethyl acetate as eluent. The title compound was isolated as a brown powder (45 mg).
1H NMR (400 MHz, DMSO) δ 9.59 (s, IH), 7.99 - 7.94 (m, 2H), 7.75 - 7.70 (m, 2H), 7.66 - 7.62 (m, 2H), 7.52 - 7.46 (m, 2H), 7.44 - 7.39 (m, IH), 4.83 (s, IH); APCI-MS: m/z 416, 418 [M-H]".
I5
EXAMPLE 27
This shows the preparation of 4-chloro-iV-[({2-[(2-hydroxyethyl)thio]-4-ρhenyl-l,3- thiazol-5-yl}amino)carbonyl]benzenesulfonamide.
Figure imgf000067_0002
0 A stirred suspension of Intermediate 28 (200 mg) in dry benzene (20 mL) was treated with DIPEA (220 μL), 4-chlorobenzenesulfonamide (135 mg), and diphenyl phosphoryl azide (240 mg). The mixture was heated at reflux for 1 h, then ethyl acetate (15 mL) was added to aid solubilisation and heating continued for a further 3 h. The solution was cooled to RT and was applied to a 10 g isolute flash silica cartridge, which was eluted with ethyl acetate (300 mL) followed by acetonitrile (300 mL). The acetonitrile solution was concentrated in vacuo and the residue purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)). This afforded the title compound as an off-white solid (95 mg). 1H NMR (400 MHz, DMSO) δ 9.33 (s, IH), 7.98 - 7.91 (m, 2H), 7.75 - 7.69 (m, 2H), 7.68 - 7.62 (m, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.34 (m, IH), 3.67 (t, 2H), 3.24 (t, 2H); APCI- MS: m/z 468, 470 [M-H]".
EXAMPLE 28
This shows the preparation of 4-chloro-iV-{[(2-ethoxy-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000068_0001
A stirred mixture of Intermediate 35 (500 mg), 4-chlorobenzenesulfonamide (380 mg), diphenylphosphoryl azide (600 mg), and DIPEA (700 μL) in dry benzene (30 mL) was heated at reflux for 2 h. The reaction mixture was cooled to RT, and concentrated in vacuo. The residue was purified by three successive RPHPLC systems: (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)), (Xterra, 5% to 95% acetonitrile in ammonia (0.2% aq.)), and (Symmetry, 25% to 95% acetonitrile in ammonium acetate (0.1% aq.)). Finally flash column chromatography on silica gel using 10% methanol/DCM afforded the title compound as a colourless solid (68 mg).
1H NMR (400 MHz, DMSO) δ 8.27 (s, IH), 7.78 - 7.72 (m, 2H), 7.66 (d, 2H), 7.49-7.42 (m, 2H), 7.36 (t, 2H), 7.23 (t, IH), 4.35 (q, 2H), 1.34 (t, 3H); APCI-MS: m/z 436, 438 [M- H]-.
EXAMPLE 29
This shows the preparation of 4-chloro-N-({[4-phenyl-2-(pyridin-3-yloxy)-l,3-thiazol-5- yl]amino}carbonyl)benzenesulfonamide.
Figure imgf000069_0001
A stirred mixture of Intermediate 34 (100 mg), 4-chlorobenzenesulfonamide (64 mg), diphenylphosphoryl azide (110 mg), and DIPEA (200 μL) in dry benzene (10 mL) was heated at reflux for 3 h. The reaction mixture was cooled to RT, and concentrated in vacuo.
The residue was purified by RPHPLC (Xterra, 5% to 95% acetonitrile in TFA (0.2% aq.)), followed by normal phase column chromatography on silica gel eluting with 9 : 1 ethyl acetate / acetonitrile to afford the title compound (30 mg) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.63 (d, 2H), 8.47 (dd, IH), 7.84 (ddd, IH), 7.78 - 7.73 (m,
2H), 7.62 - 7.57 (m, 2H), 7.51 - 7.44 (m, 3H), 7.33 (t, 2H), 7.20 (t, IH); APCI-MS: m/z
485, 487 [M-H]'.
EXAMPLE 30 See Table 1. EXAMPLE 31
This shows the preparation of 2-({5-[({[(4-chloroρhenyl)sulfonyl]amino}carbonyl)amino]- 4-phenyl-l,3-thiazol-2-yl}thio)-iV-niethylacetamide.
Figure imgf000070_0001
A stirred suspension of Intermediate 29 (166 mg) in dry benzene (20 mL) was treated with DIPEA (170 μL), 4-chlorobenzenesulfonamide (103 mg), and diphenyl phosphoryl azide (150 mg). The mixture was heated at reflux for 1 h, before ethyl acetate (15 mL) was added to aid solubilisation and heating was continued for a further 3 h. The mixture was cooled to RT and the solution applied to a 10 g isolute flash silica cartridge. The cartridge was eluted with ethyl acetate (300 mL) followed by acetonitrile (300 mL). The acetonitrile solution was concentrated in vacuo and the residue purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) followed by RPHPLC (Xterra, 5% to 95% acetonitrile in ammonia (0.2% aq.)). The title compound was isolated as a pale yellow solid (35 mg). 1H NMR (400 MHz, DMSO) δ 9.35 (s, IH), 8.14 (br s, IH), 7.95 (d, 2H), 7.72 (d, 2H), 7.65 (d, 2H), 7.45 (t, 2H), 7.4-7.34 (m, IH), 3.88 (s, 2H), 2.60 (s, 3H); APCI-MS: m/z 495, 497 [M-H]-.
EXAMPLE 32 See Table 1.
EXAMPLE 33
This shows the preparation of 4-chloro-iV-({[2-(dimethylamino)-4-phenyl-l,3-thiazol-5- yl]amino}carbonyl)benzenesulfonamide mono trifluoroacetate salt.
Figure imgf000071_0001
A stirred mixture of Intermediate 26 (1 g), 4-chlorobenzenesulfonamide (924 mg), diphenylphosphoryl azide (1.35 g) and DIPEA (800 μL) in dry benzene (50 mL) was 5 heated at reflux for 2 h. The mixture was cooled to RT, diluted with ethyl acetate (100 mL), and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was initially purified on a 10 g isolute flash silica cartridge which was eluted with 5% triethylamine in ethyl acetate to remove non-polar impurities. The silica cartridge was then o eluted with acetonitrile and the solution concentrated to dryness. The crude product was purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) to afford the title compound as a colourless solid (580 mg).
1H NMR (400 MHz, DMSO) δ 8.89 (s, IH), 7.93 (d, 2H), 7.72 (d, 2H)3 7.61-7.57 (m, 2H), 7.50-7.10 (3H, m), 3.03 (6H, s); APCI+MS: m/z 437, 439 [M+H]+ . 5
EXAMPLE 34
See Table 1.
EXAMPLE 35 o This shows the preparation of 4-chloro-JV- {[(2-methoxy-4-phenyl-l ,3-thiazol-5- yl)amino]carbonyl}benzenesulfonamide.
Figure imgf000072_0001
Intermediate 37 (800 mg) was stirred in tiifluoroacetic acid (10 niL) until deprotection was complete, as determined by LC/MS. The trifluoroacetic acid was removed in vacuo and the residue dissolved in DCM (30 mL). DIPEA (10 mL) was added quickly followed by 4-chlorobenzenesulfonyl isocyanate (530 μL). After 5 min the reaction mixture was diluted with more DCM and partitioned with aqueous 2 N hydrochloric acid. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to a dark green oil. The crude product was purified by RPHPLC (Xterra, 25% to 95% acetonitrile in TFA (0.2% aq.)) to afford the title compound (80 mg).
1H NMR (400 MHz, DMSO) δ 8.82 (s, IH), 7.87 (d, 2H)5 7.68 - 7.59 (m, 4H), 7.41 - 7.36 (m, 2H), 7.32 - 7.27 (m, IH), 3.98 (s, 3H); APCI-MS: m/z 422, 424 [M-H]".
EXAMPLES 36, 37, 38 See Table 1.
The examples in Table 1 were prepared using methods analogous to those described herein above.
Table 1
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Pharmacological Analysis
Exemplified compounds were tested to determine inhibition of endothelin- converting enzyme-1 (ECE-I) 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 pH 6.0 assay buffer and samples prepared in a 384 well-plate format (Conditions A); or alternatively at 37 °C using 50 mM Tris Maleate pH6.0 assay buffer and samples prepared in a 96 well-plate format (Conditions B).
The compounds of the examples have a PlC50 of at least 4.0. pICso values for a representative selection of compounds are given in Table 2 below.
Table 2
Figure imgf000078_0001

Claims

1. A compound of formula (I) :
Ri/
Figure imgf000079_0001
wherein:
R1 is optionally substituted aryl or optionally substituted heteroaryl;
R2 is cyano, CF3, halogen or XR7;
R3 is optionally substituted aryl, optionally substituted heteroaryl or C3-7 cycloalkyl
[optionally substituted by halogen or C1-4 alkyl]; A is NR4 or CR5R6;
R4, R5 and R6 each independently represent hydrogen or C1-4 alkyl or C3-7 cycloalkyl [optionally substituted by halogen or Cj-4 alkyl];
X is a single bond, C1-O alkylene [optionally substituted by halogen], C2-6 alkenylene [optionally substituted by halogen], C2-6 alkynylene, [optionally substituted by halogen], S(O)n, NR8C(O), C(O)NR9, NR10, C(O)5 OC(O), C(O)O, O(Ci-4)alkylene, S(O)n(Q. 4)alkylene, NRuC(O)(C1-4)alkylene, C(O)NR12(C1-4)alkylene, NR13(Ci-4)alkylene, C(O)(C1-4)alkylene, OC(O)(C M)alkylene, C(O)O(C1-4)alkylene, (C1-4)alkyleneO, (Ci-4) alkyleneS(O)n, (CM)alkyleneNR14C(O), (C1-4)alkyleneC(O)NR15, (CM)alkyleneNR16, (Q- 4)alkyleneC(O), (C1-4)allcyleneOC(O), (C1-4)alkylene0(C1-4)alkylene, (C1-4) alkyleneS(O)n(C1-4)alkylene, (Ci-4)alkyleneNR17C(O)(C1-4)alkylene, (Ci-
4)alkyleneC(O)NR18(C1-4)allcylene, (C1-4)allcyleneNR19(C1-4)alkylene, (Ci-4)allcyleneC(O) (Ci-4)alkylene, (Ci_4)alkyleneOC(O)(Ci-4)allcylene or (Ci-4)alkyleneC(O)O(C1-4)alkylene; R7 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, C3-7 cycloalkyl [optionally substituted by halogen or C1-4 alkyl], a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 allcyl], OR20, NR21R22, C(O)R23, CO2R24, OC(O)R25, C(O)NR26R27, S(O)nR28, SO2NR29R30, NR32C(O)R33, NR34C(O)OR35, phenoxy [optionally substituted by halogen, cyano, CF3 or Ci-4 alkyl] or heteroaryloxy [optionally substituted by halogen, cyano, CF3 or Ci-4 alkyl]; R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R32, R33, R34 and R35 are, independently, hydrogen or Cr6 alkyl [optionally substituted by halogen]; aryl and heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, OC(O)NR36R37, NR38R39, NR40C(O)R41, NR42C(O)NR43R44,
S(O)2NR45R46, NR47S(O)2R48, C(O)NR49R50, CO2R51, NR52CO2R53, S(O)nR54, OS(O)2R55, C1-6 alkyl [optionally mono-substituted by S(O)2R56 , C(O)NR57R58 OrNR31R62], C(O)R59, NR60C(O)R61, C2-6 alkenylene [optionally substituted by phenyl or heteroaryl], C2-6 alkynylene [optionally substituted by phenyl or heteroaryl], C3-7 cycloalkyl, C1-6 haloalkyl, Ci-6 alkoxy(Ci-6)alkylene, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkylene, phenoxy, phenylthio, phenylS(O), phenylS(O)2, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy, heteroaryl(C1-4)alkoxy or a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 alkyl]; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl),
S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; p31 p36 τ>37 p38 -p39 p40 Ώ 4X π42 p43 p 44 ^45 ^46 TJ47 -p49 p50 τ>51 p52 p53 π 57 ^58 Jx , Jtv , xv , JK. , jtv , JK. , Jtv , Jtv , is. , is. , is. , JCv , Jtv , Jtv , iv , 1V , ix , JΛ. , iv , is. , R59, R60, R61 and R62 are, independently, hydrogen, Ci-6 alkyl [optionally substituted by halogen, C3-6 cycloalkyl or phenyl {optionally substituted by halogen or Ci-4 alkyl}], CH2(C2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(Ci-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Cj-4 alkyl)2; cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3] or heteroaryl [itself optionally substituted by halogen, nitro, NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(Cj-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(Ci-4 alkyl), C(O)N(Cj-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(Cj-4 alkyl), CF3 or OCF3];
R48, R54, R55 and R56 are, independently, C1-6 alkyl [optionally substituted by halogen, C3-6 cycloalkyl or phenyl {optionally substituted by halogen or Ci-4 alkyl}], CH2(C2-6 alkenyl), phenyl [itself optionally substituted by halogen, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(Ci-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(Ci-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3] or heteroaryl [itself optionally substituted by halogen, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, CM alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3]; and, n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein A is NH, NMe or CH2.
3. A compound according to claim 1 or claim 2, wherein R1 is aryl or heteroaryl, which aryl or heteroaryl moiety may be optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(Ci-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(Ci-4 alkyl)2, C1-4 alkyl, C1-4 hydroxyalkyl, Ci-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, OCF3 or a 4- to 8-membered aliphatic heterocyclic ring [optionally substituted by halogen or C1-4 alkyl].
4. A compound according to claim 1 or claim 2, wherein R1 is a group of formula (II):
Af z/ Y>
TVr' V (II) wherein:
Y is a bond, O, S, S(O), S(O)2, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; Ar1 and Ar2 each independently represent phenyl or heteroaryl, which phenyl or heteroaryl moieties are independently optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(Cj-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(C1-4 alkyl)2, Ci-4 alkyl, Q-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(Ci-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3.
5. A compound according to any one of claims 1 to 4, wherein R2 is hydrogen, halogen, Ci-4 alkyl [optionally substituted by one or more of halogen, hydroxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)O(C1-4 alkyl), N(Ci-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], C1-4 alkoxy [optionally substituted by one or more of halogen, hydroxyl, NH2, NH(Ci-4 alkyl), N(Ci-4 alkyl)2, Ci-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(Cj-4 alkyl)2, NHC(O)O(C1-4 alkyl), N(CL4 alkyl)C(O)O(Ci-4 alkyl) or CO2H], S(Ci-4alkyl) [optionally substituted by one or more of halogen, hydroxy, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NHC(O)O(C1-4 alkyl), N(C1-4 alkyl)C(O)O(C1-4 alkyl) or CO2H], phenoxy, heteroaryloxy or C2-4 alkynyl.
6. A compound according to any one of claims 1 to 5 wherein R3 is phenyl optionally substituted by one or more of halogen, cyano, nitro, NH2, NH(C1-4 alkyl), N(Ci-4 alkyl)2, S(C1-4 alkyl), S(O)(Cj-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(Ci-4 alkyl), S(O)2N(Ci-4 alkyl)2, C1-4 alkyl, Ci-4 hydroxyalkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(Ci-4 alkyl), C(O)(Ci-4 alkyl), CF3 or OCF3.
7. A compound according to claim 1, which is selected from:
4-chloro-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}benzenesulfonamide,
4-chloro-iV-{[methyl(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- benzenesulfonamide, tert-butyl ({5-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]-4-phenyl-l,3-thiazol-
2-yl} methyl)methylcarbamate, iV-[(4-Chlorophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3-thiazol-5-yl)acetamide,
N-[(4-fluorophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3-miazol-5-yl)acetamide, N-[(4-cyanophenyl)sulfonyl]-2-(2-methyl-4-phenyl-l,3-tliiazol-5-yl)acetamide,
2-[4-(4-chlorophenyl)-2-methyl-l,3-thiazol-5-yl]-JV-[(4-chlorophenyl)sulfonyl]acetamide, 2-methoxy-4-methyl-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)ammo]carbonyl}- benzenesulfonamide,
4-(ethylamino)-7V-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}- benzenesulfonamide, 5-[(4-chlorophenyl)thio]-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5- yl)amino]carbonyl}thiophene-2-sulfonamide,
5-chloro-3-methyl-iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)ainino]carbonyl}-l- benzothiophene-2-sulfonamide,
6-ethoxy-N- { [(2-methyl-4-phenyl- 1 ,3-thiazol-5-yl)amino]carbonyl} -1 ,3-benzothiazole-2- sulfonamide,
N- {[(2-methyl-4-phenyl- 1 ,3-thiazol-5-yl)amino]carbonyl} -5-(phenylethynyl)thiophene-2- sulfonamide,
N- { [(2-methyl-4-phenyl- 1 ,3 -thiazol-5-yl)amino]carbonyl} -5-(phenylthio)thiophene-2- sulfonamide, iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)ainino]carbonyl}-5-(2-phenyletb.yl)thiophene-2- sulfonamide,
ΛL{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-morpholin-4-yl-4- nitrothioρhene-2-sulfonamide,
N- {[(2-methyl-4-phenyl- 1 ,3-thiazol-5-yl)amino]carbonyl} -5-(phenylthio)- l,3-thiazole-2- sulfonamide, iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-5-(pyridin-4-ylthio)thiophene-
2-sulfonamide, iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-l-benzothiophene-2- sulfonamide, iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-2-(phenylthio)-l,3-thiazole-5- sulfonamide, methyl 4-({5-[({[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}amino)sulfonyl]-2- thienyl } thio)benzoate,
N- { [(2-methyl-4-phenyl- 1 ,3 -thiazol-5-yl)amino]carbonyl} -5-[(4-methyl- 1 ,3-thiazol-2- yl)thio]thiophene-2-sulfonamide, iV-{[(2-methyl-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-3-[(4-methyl-l,3-thiazol-2- yl)thio]thiophene-2-sulfonamide, N- { [(2-methyl-4-phenyl- 1 ,3 -thiazol-5-yl)amino]carbonyl} - lif-indole-2-sulfonamide, iV-{[(2-bromo-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}-4-chlorobenzenesulfonamide,
4-chloro-iV-{[(2-ethynyl-4-ρhenyl-l,3-thiazol-5-yl)amino]carbonyl}benzenesulfonamide,
4-chloro-iV-[({2-[(2-hydroxyethyl)thio]-4-ρhenyl-l,3-thiazol-5- 5 yl} amino)carbonyl]benzenesulfonamide,
4-chloro-iV- { [(2-ethoxy-4-phenyl- 1 ,3 -thiazol-5-yl)amino] carbonyl} benzenesulfonamide,
4-chloro-7V-( {[4-phenyl-2-(pyridin-3-yloxy)-l ,3-thiazol-5-yl]amino} carbonyl)- benzenesulfonamide,
4-chloro-iV-{[(2-phenoxy-4-phenyl-l,3-thiazol-5-yl)ammo]carbonyl} benzenesulfonamide, I0 2-({5-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]-4-phenyl-l,3-thiazol-2- yl} thio)-7V-methylacetamide,
4-chloro-JV-({[2-(2-methoxyemoxy)-4-phenyl-l,3-thiazol-5- yl]amino}carbonyl)benzenesulfonamide,
4-chloro-iV-( { [2-(dimethylamino)-4-phenyl- 1 ,3-thiazol-5- i5 yl]amino}carbonyl)benzenesulfonarnide,
4-chloro-iV-( { [2-(methylthio)-4-ρhenyl- 1 ,3-thiazol-5- yl]amino}carbonyl)benzenesulfonamide,
4-chloro-iV-{[(2-methoxy-4-phenyl-l,3-thiazol-5-yl)amino]carbonyl}benzenesulfonamide,
7V- { [(2-methy 1-4-pheny 1- 1 ,3 -thiazol-5 -yl)amino]carbonyl} imidazo [ 1 ,2-α]pyridine-3 - 0 sulfonamide,
TV- {[(2-methy 1-4-pheny 1- 1 ,3 -thiazol-5 -yl)amino] carbonyl} thieno [2,3 -c]pyridine-2- sulfonamide,
7V-[({2-[(2-hydroxyethyl)thio]-4-phenyl-l,3-thiazol-5-yl}amino)carbonyl]-l- benzothiophene-2-sulfonamide, 5 or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and a pharmaceutically acceptable adjuvant, diluent or carrier therefor. 0
9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in therapy.
10. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an ECE-I mediated disease.
11. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease.
12. A process for the preparation of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, which comprises: (a) when A is CR5R coupling a compound of formula (III):
Figure imgf000085_0001
with a compound of formula (IV):
S(O);
R" "2 (IV), or
(b) when A is NH reacting a compound of formula (V):
Figure imgf000085_0002
with a compound of formula (IV) as defined in (a) in the presence of a phosphoryl azide; or (c) when A is NH reacting a compound of formula (VI):
Figure imgf000086_0001
with a compound of formula (IV) as defined in (a); or
(d) when A is NR4 reacting a compound of formula (VII):
Figure imgf000086_0002
with a compound of formula (VIII):
Figure imgf000086_0003
and optionally after (a), (b), (c) or (d) carrying out one or more of the following: • converting the compound to a further compound of the invention or
• forming a pharmaceutically acceptable salt of the compound.
PCT/SE2006/000168 2005-02-11 2006-02-07 Thiazole derivatives, their process for their preparation and their use in therapy WO2006085815A1 (en)

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