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WO2004080999A1 - Composes de pyrazole utilises dans le traitement de l'inflammation - Google Patents

Composes de pyrazole utilises dans le traitement de l'inflammation Download PDF

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Publication number
WO2004080999A1
WO2004080999A1 PCT/GB2004/001054 GB2004001054W WO2004080999A1 WO 2004080999 A1 WO2004080999 A1 WO 2004080999A1 GB 2004001054 W GB2004001054 W GB 2004001054W WO 2004080999 A1 WO2004080999 A1 WO 2004080999A1
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compound
optionally substituted
alkyl
formula
group
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PCT/GB2004/001054
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Inventor
Anders Hallberg
Wesley Schaal
Mats Larhed
Kristofer Olofsson
Benjamin Pelcman
Andrei Sanin
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Biolipox Ab
Mcneeney, Stephen, Phillip
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Priority claimed from SE0300705A external-priority patent/SE0300705D0/xx
Application filed by Biolipox Ab, Mcneeney, Stephen, Phillip filed Critical Biolipox Ab
Priority to EP04720088A priority Critical patent/EP1603897A1/fr
Priority to US10/547,996 priority patent/US20060183780A1/en
Priority to JP2006505952A priority patent/JP2006520373A/ja
Publication of WO2004080999A1 publication Critical patent/WO2004080999A1/fr

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Definitions

  • the invention relates to novel pharmaceutically-useful compounds.
  • the invention further relates to compounds that are useful in the inhibition of the activity of 15-lipoxygenase and thus in the treatment of inflammatory diseases and of inflammation generally.
  • the invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • Asthma is a chronic inflammatory disease affecting of 6% to 8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen.
  • Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists. Patients with more severe asthma are typically treated with anti- inflammatory compounds on a regular basis. There is a considerable under-treatment of asthma, which is due at least in part to perceived risks with existing maintenance therapy (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, resulting in unnecessary morbidity and mortality. As an alternative to steroids, leukotriene receptor antagonists (LTRas) have been developed. These drugs may be given orally, but are considerably less efficacious than inhaled steroids and usually do not control airway inflammation satisfactorily.
  • LTRas leukotriene receptor antagonists
  • Rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. Indeed, non-allergic conditions of this class are in many cases more difficult to treat.
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrosis this is less common than COPD, but is a serious disorder with a very bad prognosis. No curative treatment exists);
  • inflammatory bowel disease a group of disorders with a high morbidity rate. Today only symptomatic treatment of such disorders is available); and
  • Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several malignancies are known to have inflammatory components adding to the symptomatology of the patients.
  • the mammalian hpoxygenases are a family of structurally-related enzymes, which catalyze the oxygenation of arachidonic acid.
  • Three types of human hpoxygenases are known, which catalyze the insertion of molecular oxygen into arachidonic acid at carbon positions 5, 12 and 15.
  • the enzymes are thus named 5-, 12- and 15-lipoxygenase, respectively.
  • Arachidonic acid metabolites that are formed following the action of hpoxygenases are known to have pronounced pathophysiological activity including pro-inflammatory effects.
  • the primary product of the action of 5-lipoxygenase on arachidonic acid is further converted by a number of enzymes to a variety of physiologically and pathophysiologically important metabolites.
  • the most important of these, the leukotrienes are strong broncho constrictors.
  • Drugs that have been developed to this end include 5-lipoxygenase inhibitors, inhibitors of FLAP (Five Lipoxygenase Activating Protein) and, as mentioned previously, leukotriene receptor antagonists (LTRas).
  • arachidonic acid metabolites that are produced by this process include prostaglandins, thromboxanes and prostacyclin, all of which possess physiological or pathophysiological activity.
  • the prostaglandin PGE 2 is a strong pro-inflammatory mediator, which also induces fever and pain. Consequently, a number of drugs have been developed to inhibit the formation of PGE 2 , including "NSAIDs” (non- steroidal antiinflammatory drugs) and “coxibs” (selective cyclooxygenase-2 inhibitors). These classes of compounds act predominantly by way of inhibition of one or several cyclooxygenases.
  • agents that are capable of blocking the formation of arachidonic acid metabolites are likely to be of benefit in the treatment of inflammation.
  • Heterocyclic compounds including pyrazoles
  • Other heterocyclic compounds with antithrombotic activity have been disclosed in WO 02/00651. Neither of these documents discloses or suggests the use of the compounds disclosed therein in the treatment of inflammation.
  • R represents an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 1 and B 1 , which B 1 group may itself be further substituted by one or more substituents selected from G 2 , Z (provided that Z is not directly attached to an aryl or a heteroaryl group) and B 2 (which B 2 group is optionally further substituted by one or more substituents selected from G 3 , B 3 and Z, provided that Z is not attached to an aryl or a heteroaryl group); and
  • R" represents H or C 1- alkyl, which latter group is optionally substituted by one or more halo groups; or when R represents C 1-6 alkyl optionally substituted by halo, R and R may be linked together forming a further 5- to 7-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is itself optionally substituted by one or more substituents selected from G , Z (provided that the ring is not aromatic in nature) and B 1 (which B 1 group is optionally substituted as described above);
  • R represents C ⁇ -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl, all of which groups are optionally substituted by one or more substituents selected from G l , Z (provided that Z is not directly attached to an aryl or a heteroaryl group) and B 1 (which B 1 group is optionally substituted as described above);
  • X represents a direct bond, -O- or -N(R 4 )- Y represents -C(O)-, -C(S)- or -S(0) 2 -;
  • B , B and B independently represent, on each occasion when used above, C ⁇ _ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl;
  • G , G a , G and G independently represent, on each occasion when used above, halo, cyano, -N 3 , -N0 2 , -ON0 2 or -A*-R 4 ;
  • A represents a spacer group selected from -C(Z)A -, -N(R )A -, -OA 4 -, -S- or -S(0) n A 5 -, in which: A 2 represents a single bond, -0-, -S- or -N(R 5 )-;
  • a 3 represents A 6 , -C(Z)N(R 5 )C(Z)N(R 5 )-, -C(Z)N(R 5 )C(Z)0- 5 -C(Z)N(R 5 )S(0) n N(R 5 )-, -C(Z)S-, -S(0) n -, -S(0) n N(R 5 )C(Z)N(R 5 )-, -S(0) n N(R 5 )C(Z)0-, -S(0) n N(R 5 )S(0) n N(R 5 )-, -C(Z)0-, -S(0) n N(R 5 )- or -S(0) n O-;
  • a 4 represents A 6 , -S(0) n -, -C(Z)0-, -S(0) n N(R 5 )- or -S(0) n O-;
  • a 5 represents a single bond, -N(R 5
  • R 4 and R 5 independently represent, on each occasion when used above, H or B , which B group is itself optionally substituted by one or more substituents selected from G , Q (provided that Q is not directly attached to an aryl or a heteroaryl group) and B 5 (which B 5 group is itself optionally substituted by one or more substituents selected from G 5 , Q (provided that Q is not directly attached to an aryl or a heteroaryl group) and B ); or when R and R 5 both represent optionally substituted B groups, then any pair thereof may, for example when present on the same atom or on adjacent atoms, be linked together to form, with those, or other relevant, atoms, a 5- to 7-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is itself optionally substituted by one or more substituents selected from G 6 , Q (provided that the ring is not aromatic in nature) and B 4 (which B 4 group is optionally substituted as described
  • B 4 , B 3 and B independently represent on each occasion when used above C ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl;
  • G 4 , G 5 and G independently represent on each occasion when used above, halo, cyano, N 3 , -N0 2 , -0N0 2 or -A 7 -R 6 ; wherein A represents a spacer group selected from — C(Q)A -, -N(R )A -,
  • A represents a single bond, -0-, -S- or -N(R )-;
  • a 9 represents A 12 , -C(Q)S-, -S(0) n -, -C(Q)0-, -S(0) n N(R 7 )- or -S(0) n O-;
  • a 9a represents -C(Q)N(R 7 )C(Q)N(R 7 )-, -C(Q)N(R 7 )C(Q)0-, -C(Q)N(R 7 )S(0) n N(R 7 )-, -S(0) n N(R 7 )C(Q)N(R 7 )-, -S(0) n N(R 7 )C(Q)0-,
  • a 10 represents A 12 , -S(0) n -, -C(Q)0-, -S(0) n N(R 7 )- or -S(0) n O-;
  • A represents a single bond, -N(R )- or -0-;
  • a 12 represents a single bond, -C(Q)- or -C(Q)N(R 7 )-;
  • R , R 7 and R 7a independently represent, on each occasion when used above, H, C ⁇ . 6 alkyl, C 2 , 6 alkenyl, C 2 - 6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl or heteroaryl, which latter seven groups are optionally substituted by one or more groups selected from halo, C ⁇ -6 alkyl (optionally substituted by one or more halo groups), -N(R 8 )R 9 , -OR 8 , -ON0 2 and -SR 8 ; or provided that they do not represent H, any pair of R ⁇ and R 7 may, for example when present on the same atom or on adjacent atoms, be linked together to form, with those, or other relevant, atoms, a 5- to 7-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is itself optionally substituted by one or more groups selected from halo, C
  • R and R independently represent, on each occasion when used above, H or C 1-6 alkyl, which latter group is optionally substituted by one or more halo groups;
  • n represents, on each occasion when used above, 1 or 2;
  • R represents H
  • Y represents -C(O)- and:
  • A) X represents a direct bond and: i) R represents phenyl, then R does not represent phenyl, 2-methoxyphenyl, 2-thiazolyl or 6-methyl-2-pyridinyl; ii) R represents 4- fluorophenyl, then R does not represent 2-carbomethoxyphenyl, 3-carbomethoxyphenyl or 2,4- dimethylphenyl; iii) R 3 represents 2-chlorophenyl, then R 1 does not represent phenyl, 3-bromophenyl or 4-bromophenyl; iv) R 3 represents 3-chlorophenyl, then R 1 does not represent phenyl, 2-fluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2,5-dichlorophenyl; v) R represents 4-chlorophenyl, then R does not represent 3-bromophenyl
  • R represents 2,4-dichlorophenyl, then R does not represent 4-chlorophenyl or 2,3-dichlorophenyl; viii) R represents 3,5-dinitrophenyl, then R does not represent
  • R represents 2,3-dichlorophenyl; ix) R represents 2,4-dimethyl-6-oxo-6H-pyran-3-yl, then R does not represent 3-carbomethoxyphenyl; x) R represents methyl, then R does not represent 3,4-dichlorophenyl, 2-methoxyphenyl, 2-thiazolyl, 4-methyl-
  • R 3 represents 4-chlorophenyl, then R 1 does not represent
  • R represents 2'-sulfamoylbiphenyl-4-yl, then R does not represent 5-bromo-2-pyridinyl; vi) R represents 1-propyl, then R does not represent phenyl; vii) R represents 1 -butyl, then R 1 does not represent 4- bromophenyl or 2,4-dimethylphenyl; viii) R represents cyclohexyl, then R does not represent 4-methoxyphenyl; (C) X represents -O- and: i) R° represents phenyl, then R 1 does not represent phenyl or 6-methyl-2-pyridinyl; ii) R represents methyl, then R does not represent phenyl, 2-fluorophenyl, 2,4-dimethylphenyl, 4-acetylphenyl or 2- thiazolyl; iii) R represents ethyl, then
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Compounds of formula I may contain double bonds and may thus exist as E (entadel) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica).
  • C 1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight- chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain.
  • C ⁇ -6 - alkyl groups that may be mentioned include methyl, ethyl, w-propyl, isopropyl, /2-butyl, sec-butyl, isobutyl, tert-butyl, w-pentyl, isopentyl, n- hexyl, and isohexyl.
  • C 2-q alkenyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain. Such alkenyl groups may contain one or more double bonds.
  • C 2-6 -alkenyl groups that may be mentioned include vinyl, 1 -propenyl, 2-propenyl, propadienyl, 1 -butenyl, 2-butenyl, 3 -butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, and 5-hexenyl.
  • C 2-q alkynyl groups (where q is the upper limit of the range) defined herein may be straight- chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain. Such alkynyl groups may contain one or more triple bonds.
  • C 2 - 6 -alkynyl groups that may be mentioned include ethynyl, 1 -propynyl, 2 -propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, and 5- hexynyl.
  • C 3-q cycloalkyl groups (where q is the upper limit of the range) that may be mentioned include monocyclic or bicyclic alkyl groups.
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bond (forming for example a C 3-q cycloalkenyl or a C 3-q cycloalkynyl group).
  • C 3-8 -cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl.
  • Substituents may be attached at any point on the cycloalkyl group. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the cycloalkyl group, forming a so-called "spiro"-compound.
  • C 3-q heterocycloalkyl groups (where q is the upper limit of the range) that may be mentioned include monocyclic or bicyclic alkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a hetereoatom). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 3-q heterocycloalkenyl or a C 3-q heterocycloalkynyl group.
  • C 3-q heterocycloalkyl groups that may be mentioned include aziridinyl, azetidinyl, dihydropyranyl, dihydropyridinyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sul
  • Substituents on the heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the heteocycloalkyl group, forming a so- called "spiro"-compound. The point of attachment of a heterocycloalkyl group may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • Aryl groups that may be mentioned include C 6- ⁇ o aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 10 ring carbon atoms, in which at least one ring is aromatic.
  • C 6- ⁇ o aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, and indenyl. The point of attachment of aryl groups may be via any atom of the ring system.
  • Heteroaryl groups that may be mentioned include those which have between 5 and 10 members. Such groups may be monocyclic, bicyclic or tricyclic, in which at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom).
  • Heterocyclic groups that may be mentioned include acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl (including 2,1,3-benzothiazolyl), benzoxadiazolyl (including 2,1,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-l,4- benzoxazinyl), benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothiophenyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2- ⁇ ]pyridinyl,
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • Heteroatoms that may be mentioned include oxygen, nitrogen, sulphur and selenium.
  • Preferred compounds of the invention include those in which:
  • R represents an aryl or heteroaryl group, both of which are optionally substituted as hereinbefore defined;
  • G 1 represents halo, cyano or -A ! -R 4 ;
  • G la represents halo, cyano, -N0 2 or -A ! -R 4 ;
  • G 2 represents halo, cyano, -ON0 2 or -A ! -R 4 ;
  • B 2 represents C[ -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, all of which are optionally substituted by one or more G and or B groups;
  • G 3 represents halo, -ON0 2 , -N(R 5 )(R 4 ) or -OR 4 ;
  • B represents C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; when A 1 represents -N(R 5 )A 3 -, A 3 represents A 6 , -C(Z)S-, -S(0) n -, -C(Z)0- or -S(0) n N(R 5 )-; when A 1 represents -OA -, A 4 represents A 6 ; when A 1 represents -S(0) n A 5 -, A 5 represents a single bond or -N(R 5 )-;
  • G represents halo, cyano, -ONO 2 or -A -R ;
  • B 5 represents C ⁇ -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, all of which are optionally substituted by one or more G 5 and/or B ⁇ groups;
  • G 5 represents halo, -ON0 2 , -N(R 7 )(R 6 ) or -OR 6 ;
  • B represents .e alkyl, C 2-6 alkenyl or C 2 _ 6 alkynyl; represents halo, cyano or -A
  • R ⁇ , R 7 and R 7a independently represent H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, all of which groups are optionally substituted by one or more groups selected from halo, C 1-6 alkyl, -N(R 8 )R 9 , OR 8 and -ON0 2 ; and/or when any pair of R and R are linked together to form a ring, that ring is optionally substituted by one or more groups selected from halo, C 1-6 alkyl (optionally substituted by one or more halo groups), -N(R 8 )R 9 , -OR 8 and -ON0 2 .
  • More preferred compound include those in which:
  • B 1 represents a C ⁇ -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 4-7 heterocycloalkyl, or phenyl, group, all of which are optionally substituted as described hereinbefore;
  • G 2 represents halo (e.g. fluoro or chloro);
  • B represents C ⁇ -6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, all of which are optionally substituted by one or more halo groups; when A 1 represents -C(Z)A -, A 2 represents a single bond, -O- or -N(R 5 )-; when A 1 represents -N(R 5 )A 3 -, A 3 represents A 6 ; when A 1 represents -S(0) n A , A 5 represents a single bond; A represents a single bond;
  • B 4 represents a C ⁇ -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 4-7 heterocycloalkyl, or phenyl, group, all of which are optionally substituted as described hereinbefore;
  • G 4 represents halo;
  • B 4 represents C 2 _ 6 alkenyl, C 2 - 6 alkynyl or, preferably, C ⁇ _ 6 alkyl;
  • G 6 represents halo
  • R , R and/or R a represent H, C ⁇ -6 alkyl optionally substituted by one or more halo groups.
  • R 4 and/or R 5 independently represent H or C 1-6 alkyl, which latter group is optionally substituted by one or more fluoro groups.
  • B 1 represents a C l-6 alkyl, C 2- alkenyl, C 3-6 cycloalkyl, C 5-6 heterocycloalkyl, or phenyl, group, all of which are optionally substituted as described hereinbefore;
  • G la represents halo, -N0 2 or -A ⁇ R 4 ;
  • a 1 represents -C(Z)A 2 -, -N(R 5 )A 3 - and -OA 4 -;
  • Preferred compounds of the invention include those in which R 1 represents an optionally substituted phenyl, naphthyl, pyrrolidinyl, piperidinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl (e.g.
  • R 1 does not represent naphthyl, pyrrolidinyl, piperidinyl, indazolyl, oxindolyl or benzothiazolyl.
  • Particularly preferred values of R 1 include optionally substituted phenyl, pyridinyl (especially 2- and 3-pyridinyl), thiophenyl (especially 2-thiophenyl), pyrazolyl (especially 4-pyrazolyl), isoxazolyl (especially 5-isoxazolyl), benzodioxolyl (especially 1,3-benzodioxolyl), indazolyl, benzothiazolyl, and quinolinyl, groups.
  • R groups are optionally substituted by one or more substituents selected from: halo (e.g. fluoro, chloro or bromo); cyano; Ci -6 alkyl, which alkyl group may be linear or branched (e.g. C 1- alkyl
  • C 2-6 alkenyl e.g. 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 1- pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl;
  • C 3 - 6 cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • phenyl a heterocyclic group selected from a pyrrolidinyl (including 1-pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), a piperidinyl (including 1 -piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl and l-methyl-4-piperidinyl), a piperazinyl (including 1-piperazinyl and 4-methyl-l-piperazinyl), a tetrahydro furanyl (including 2-tetrahydrofuranyl and 3 -tetrahydro furanyl), a tetrahydropyranyl (including 1-tetrahydropyranyl, 2-tetrahydropyranyl and 3-tetrahydropyranyl), or a
  • R 12 represents phenyl, C 1-6 alkyl (such as methyl, ethyl, n-propyl, / ' -propyl, //-butyl or t-butyl), which alkyl group is optionally substituted by one or more fluoro atom, C 2-6 alkenyl or C 3-6 cycloalkyl.
  • C 1-6 alkyl such as methyl, ethyl, n-propyl, / ' -propyl, //-butyl or t-butyl
  • R 1 represents:
  • R 10 is preferably H, methyl (optionally substituted by 1 to 3 fluoro atoms, e.g. CF 3 ), ethyl, //-propyl or z ' -propyl;
  • R 10 is preferably H, methyl, ethyl, /-propyl, / ' -propyl, n- butyl or t-butyl and/or R 11 is preferably H, methyl or ethyl;
  • R 1 is preferably methyl, ethyl or /-propyl
  • R 10 is preferably methyl, ethyl or t-butyl
  • R 10 and R u are preferably H or methyl; --NN((RR 1 ⁇ 0 ⁇ ))S(0) 2 R' , then R 10 is preferably H or methyl and R 12 is preferably methyl.
  • Particularly preferred optional substituents on R 1 include carbomethoxy, methyl, dimethylamino, cyano, chloro, fluoro, trifluoromethyl, bromo, methoxy and trifluoromethoxy.
  • Preferred compounds of the invention include those in which R represents an optionally substituted C ⁇ -6 alkyl, C 3-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl (especially 4-piperidinyl), piperazinyl (especially 4-piperazinyl), pyn-olyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl (e.g.
  • Particularly prefened groups include an optionally substituted C ⁇ -6 alkyl (such as methyl, pentyl or hexyl), cyclohexyl, phenyl, thiophenyl (especially 2-thiophenyl), furanyl (especially 2-furanyl and 3- furanyl), pyrrolyl (especially 2-pyrrolyl), naphthyl (especially 1 -naphthyl), benzofuranyl, piperazinyl (especially 4-piperazinyl), piperidinyl (especially 4-piperidinyl), or benzodioxolyl (especially 1,3-benzodioxolyl), group.
  • C ⁇ -6 alkyl such as methyl, pentyl or hexyl
  • cyclohexyl such as methyl, pentyl or hexyl
  • phenyl thiophenyl (especially 2-thiophenyl)
  • furanyl especially 2-furanyl and 3- furany
  • R groups are optionally substituted by one or more substituents selected from: halo; -N0 2 ; cyano; C ⁇ _ 6 alkyl, which alkyl group may be linear or branched (e.g. C 1-4 alkyl (including methyl, ethyl, /-propyl, / ' -propyl, //-butyl, s-butyl, / ' -butyl or t- butyl), /z-pentyl, z ' -pentyl, /2-hexyl or z ' -hexyl), substituted by one or more halo (e.g. fluoro) group (e.g.
  • C ⁇ -6 alkyl group e.g. methyl or ethyl
  • C 2-6 alkenyl group or C 3-6 cycloalkyl group e.g. cyclopropylmethyl, so forming, for example, a cyclopropylmethyl group
  • halo e.g. fluoro
  • Cj -6 alkyl groups
  • C 2 - 6 alkenyl e.g. 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 1- pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl
  • optionally substituted with one or more C 1-6 alkyl groups e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • optionally substituted with one or more halo e.g. fluoro
  • phenyl optionally substituted with one or more halo (e.g.
  • a heterocyclic group selected from a pynolidinyl (including 1-pynolidinyl, 2 -pynolidinyl and 3 -pynolidinyl), a piperidinyl (including 1 -piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl and l-methyl-4-piperidinyl), a piperazinyl (including 1-piperazinyl and 4-methyl-l -piperazinyl), a tetrahydro furanyl (including 2-tetrahydrofuranyl and 3 -tetrahydro furanyl), a tetrahydropyranyl (including 1 -tetrahydropyranyl, 2-tetrahydropyranyl and
  • R 13 and R independently represent, on each occasion when used above, H, phenyl, C [-6 alkyl (such as methyl, ethyl, n -propyl, / ' -propyl, //- butyl or t-butyl) which alkyl group is optionally substituted by one or more fluoro atom, C 2-6 alkenyl or C 3-6 cycloalkyl; or
  • R 13 and R 14 may be linked together to form, with the nitrogen atom to which they are attached, a 5- to 7-membered ring, optionally containing one additional heteroatom and optionally substituted with one or more C 1-6 alkyl groups, which alkyl groups are themselves optionally substituted by one or more halo (e.g. fluoro) groups (for example a morpholine, a piperazine, or a
  • R 15 represents phenyl, C ⁇ -6 alkyl (such as methyl, ethyl, /-propyl, / ' -propyl,
  • alkyl group is optionally substituted by one or more fluoro atom, C 2-6 alkenyl or C 3- cycloalkyl.
  • R is preferably H, methyl (optionally substituted by 1 to 3 fluoro atoms, e.g. -CF 3 ), ethyl, //-propyl or / ' -propyl; -N(R 13 )R 1 , then R 13 is preferably H, methyl, ethyl, n-propyl, / ' -propyl, //- butyl or t-butyl and/or R 14 is preferably H, methyl or ethyl;
  • R is preferably methyl, ethyl or / ' -propyl; -C(0)R lj , then R 13 is preferably methyl, -CF 3 , ethyl or t-butyl; -C(0)N(R 13 )R 14 or -S(0) 2 N(R 13 )R 14 , then R 13 and R 14 are preferably H or methyl
  • R 13 is preferably H or methyl and R 15 is preferably methyl.
  • R represents C 1-6 alkyl or C 2- e alkenyl substituted by other alkyl or alkenyl groups (which may be further substituted by alkyl/alkenyl, as indicated above), groups that may be mentioned include 1-octyl, 1- tridecanyl, 1-pentadecanyl, 1-heptadecanyl, l-heptadec-8-enyl, 1- heptadeca-8,l l-dienyl, l-heptadeca-8,l l,14-trienyl and 1-nonadeca- 4,7, 10,13 -tetraenyl groups.
  • R 2 represents H or C 1-3 alkyl
  • X represents a direct bond, -0-, -N(H)- or -N(Me)-.
  • R 2 More preferred values of R 2 include H, methyl and ethyl, particularly H or methyl.
  • Compounds of the invention that may also be mentioned include those in which:
  • R 1 is phenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4- fluorophenyl, 2,6-dichlorophenyl, 5-chloro-2-cyanophenyl, 2-fluoro-5- trifluoromethylphenyl, 2-bromo-4-trifluoromethoxyphenyl, 2-methoxy-6- methylphenyl, 3-cyanophenyl, 4-trifluoromethylphenyl, 4- dimethylaminophenyl, 4-carbomethoxyphenyl, 1 ,3 ,5-trimethyl- lH-pyrazol- 4-yl, 3-methylisoxazol-5-yl, 3-pyridinyl, 2-chloro-3-pyridinyl, 3-methyl-2- pyridinyl, 3-carbomethoxythiophen-2-yl or 1,3-benzodioxolyl; R 2 is hydrogen or methyl;
  • R 3 is methyl, //-butyl, /z-pentyl, 1-octyl, oleoyl, (lR,2 ⁇ S,5R)-(-)-menthyl, 2- chlorobenzyl, benzyl, phenyl, 3 -fluorophenyl, 3-chlorophenyl, 4- chlorophenyl, 2- ⁇ luoro-5-iodophenyl, 5-fluoro-2-methylphenyl, 4-tert-butyl- phenyl, 4-pentylphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-nitrophenyl, 2-ethoxyphenyl, 1-naphthyl, 2-furanyl, 2, 5 -dimethyl- 3- furanyl, 2-carbomethoxy-5-furanyl, 1 -methyl- lH-pynol-2-yl, 3-methyl-2- benzo furanyl, 3-methyl
  • R 1 is 2-chlorophenyl, 5-chloro-2-cyanophenyl, 4-dimethylaminophenyl, 4-carbomethoxyphenyl, l,3,5-trimethyl-lH-pyrazol-4-yl, 3-methylisoxazol- 5-yl, 3-pyridinyl, or 3-carbomethoxythien-2-yl;
  • R is hydrogen or methyl;
  • R 3 is methyl, 1-octyl, oleoyl, (lR,2S,5R)-(-)-menthyl, 2-chlorobenzyl, phenyl, 3-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluoro-5- iodophenyl, 5-fluoro-2-methylphenyl, 4-tert-butylphenyl, 4-pentylphenyl, 3 -trifluoromethylphenyl, 4-nitrophenyl, 2-ethoxyphenyl, 1 -naphthyl, 2- furanyl, 2,5-dimethyl-3-furanyl, 2-carbomethoxy-5-furanyl, 1-methyl-lH- ⁇ yrrol-2-yl, 3 -methyl-2-benzo furanyl, or 3-methyl-2-thiophenyl; Y is -C(O)-, -C(S)- or -S(0) ; and
  • Particularly prefened compounds of the invention include those of the examples described hereinafter.
  • R 3 -X a -Y-L 1 III wherein X a represents a direct bond or -N(B 4 )- when Y represents -S(0) 2 - or, for all other values of Y, represents X as hereinbefore defined, R and Y are as hereinbefore defined and L 1 represents a suitable leaving group, such as halo (e.g. chloro or bromo), or, when X a is a direct bond, a carboxylate (e.g. a -0-C(0)-R ) group or a sulfonylate (e.g.
  • X a is -N(B 4 )-, an N-imidazolyl group, for example at around room temperature or above (e.g. up to 40-180°C) in the presence of a suitable base (e.g.
  • methylpolystyrene -4-(methylamino)pyridine or mixtures thereof
  • an appropriate solvent e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, dimethylformamide, trifluoromethylbenzene or triethylamine.
  • Prefened base/solvent systems for compounds of formula III in which Y is — C(O)- and X is a direct bond include sodium hydride in tetrahydrofuran, DMF or mixtures thereof.
  • Prefened base/solvent systems for compounds of formula III in which Y is -C(O)- and X a is -O- or - ⁇ R 4 - or when Y is -S(0) 2 - and X a is a direct bond include dimethylaminopyridine/dichloromethane, or a mixture of triethylamine and dimethylaminopyridine in dichloromethane;
  • R 3 C(0)OH IV wherein R is as hereinbefore defined for example under similar conditions to those described under process step (i) above, in the presence of a suitable coupling reagent (e.g. l,r-carbonyldiimidazole, N,rL- dicyclohexylcarbodiimide, 1 -(3 -dimethylaminopropyl)-3 -ethylcarbo- diimide (or hydrochloride thereof), N j N'-disuccinimidyl carbonate, benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluoro- phosphate, 2-( 1 H-benzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexa- fluorophosphate, benzotriazol- 1 -yloxytris-pynolidinophosphonium hexafluorophosphat
  • R 3 Y a V wherein Y a represents either -C(O)- (so forming a ketene) or -C(S)- (so ffoorrmmiinngg aa tthhiiookkeetteennee)) aanndd RR iiss as hereinbefore defined, under conditions known to those skilled in the art;
  • reaction may be performed in a suitable solvent (e.g. acetone) in the presence of a suitable base (e.g. potassium carbonate) at room temperature;
  • a suitable solvent e.g. acetone
  • a suitable base e.g. potassium carbonate
  • R 3 M IX wherein M represents a metal such as Mn, Fe, Ni, Cu, Zn, Pd or Ce, or a salt or complex thereof and R is as hereinbefore defined; (2) for compounds of formula I wherein X represents O, reaction with an alcohol of fonnula X,
  • R 3 OH X wherein R is as hereinbefore defined; or ( (33)) ffoorr ccoommppoouunnddss ooff ffoo:rmula I wherein X represents -N(R )-, reaction with an amine of formula XI,
  • R 1 and R 2 are as hereinbefore defined under coupling conditions, for example as described in process step (ii) above.
  • compounds of formula XIII may first be activated by treatment with a suitable reagent (e.g. oxalyl chloride, thionyl chloride, etc) in an appropriate solvent (e.g. dichloromethane, dimethylformamide, THF or benzene), resulting in the fonnation of the respective acyl chloride.
  • a suitable reagent e.g. oxalyl chloride, thionyl chloride, etc
  • an appropriate solvent e.g. dichloromethane, dimethylformamide, THF or benzene
  • R , R , Y and X are as hereinbefore defined, with a compound of formula XVI, R -L 2 XVI wherein L represents a suitable leaving group, such as halo (e.g. chloro, bromo and iodo), -OS0 2 CF 3 , -B(OH) 2 , -Sn(R z ) 3 (wherein R z is preferably methyl or butyl) or -Bi(R') 2 , and R 1 is as hereinbefore defined, for example in the presence of a catalyst containing, preferably, Pd or Cu, and a base.
  • L represents a suitable leaving group, such as halo (e.g. chloro, bromo and iodo), -OS0 2 CF 3 , -B(OH) 2 , -Sn(R z ) 3 (wherein R z is preferably methyl or butyl) or -Bi(R') 2 , and
  • Compounds of formula XIII may be prepared by reaction of lH-pyrazole-3- carboxylic acid, or an O-protected derivative thereof, with an appropriate reagent under similar conditions to those described in respect any of process steps (i) to (vii) above.
  • Dipyrazolo[l,5- ⁇ ;l',5'- ]pyrazine-4,9-dione may be prepared from 1H- pyrazole-3-carboxylic acid under dimerising conditions, for example in the presence of thionyl chloride (optionally in the presence of DMF) at reflux.
  • dimerising reagents include carbodiimides, such as 1,3- dicyclohexylcarbodiimide.
  • lH-Pyrazole-3-carboxylic acid and protected derivatives thereof may be prepared from 3 -methyl- l(2)H-pyrazole, for example as described hereinafter.
  • the substituents R , R and R as hereinbefore defined may be modified one or more times, after or during the processes described above for preparation of compounds of fonnula I by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, hydrolyses, esterif ⁇ cations, and etherifications.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
  • prodrug of a compound of formula I we include compounds that form a compound of formula I, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration.
  • Compounds of formula I and salts thereof are useful because, in particular, they may inhibit the activity of Hpoxygenases (and particularly 15- lipoxygenase), i.e. they prevent the action of 15-lipoxygenase or a complex of which the 15-lipoxygenase enzyme forms a part and/or may elicit a 15- lipoxygenase modulating effect, for example as may be demonstrated in the test described below.
  • Compounds of formula I may thus be useful in the treatment of those conditions in which inhibition of a lipoxygenase, and particularly 15-lipoxygenase, is required.
  • inflammation will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
  • inflammation will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain and/or fever.
  • compounds of formula I may be useful in the treatment of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, allergic disorders, rhinitis, inflammatory bowel disease, ulcers, inflammatory pain, fever, atherosclerosis, coronary artery disease, vasculitis, pancreatitis, arthritis, osteoarthritis, rheumatoid arthritis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, autoimmune diseases, Alzheimer's disease, multiple sclerosis, sarcoidosis, Hodgkin's disease and other malignancies, and any other disease with an inflammatory component.
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrosis allergic disorders, rhinitis, inflammatory bowel disease, ulcers, inflammatory pain, fever, atherosclerosis, coronary artery disease, vasculitis, pancreatiti
  • Compounds of formula I and pharmaceutically acceptable salts thereof may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds of formula I and pharmaceutically acceptable salts thereof may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects. Compounds of formula I are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a lipoxygenase (such as 15-lipoxygenase), and/or a method of treatment of a disease in which inhibition of the activity of a lipoxygenase, and particularly 15-lipoxygenase, is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined but without the provisos, to a patient suffering from, or susceptible to, such a condition.
  • a lipoxygenase such as 15-lipoxygenase
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • Compounds of formula I will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of fonnula I may be administered alone, but are preferably administered by way of known phannaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined but without the provisos, in admixture with a pharmaceutically acceptable adjuvant, diluent or canier.
  • Compounds of formula I may also be combined with other therapeutic agents that are useful in the treatment of inflammation as defined herein (e.g. NSAIDs, coxibs, corticosteroids, analgesics, inhibitors of 5- lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), and leukotriene receptor antagonists (LTRas), and/or other therapeutic agents that are useful in the treatment of inflammation).
  • NSAIDs e.g., NSAIDs, coxibs, corticosteroids, analgesics, inhibitors of 5- lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), and leukotriene receptor antagonists (LTRas)
  • NSAIDs e.g., piroxibs, corticosteroids, analgesics, inhibitors of 5- lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), and leukotriene
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or canier.
  • Such combination products provide for the administration of compound of formula I or salt thereof in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I/salt, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I/salt and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined but without the provisos, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically- acceptable adjuvant, diluent or carrier;
  • Oral dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day.
  • the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient.
  • the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during constant rate infusion.
  • compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of formula I and salts thereof may have the advantage that they are effective and/or selective inhibitors of Hpoxygenases, and particularly 15-lipoxygenase.
  • Compounds of formula I and salts thereof may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the stated indications or otherwise.
  • the assay employed takes advantage of the ability of lipid hydroperoxides to oxidize the non-fluorescent diphenyl-1-pyrenylphosphine (DPPP) to its conesponding fluorescent phosphine. oxide. Fluorescence is measured using a dual-scanning microplate spectrofluorometer, Spectramax Gemini, from Molecular Devices. DPPP was purchased from Molecular Probes. Linoleic acid was from Biomol and PBS (phosphate buffered saline) from Gibco Life Technologies. The assay is performed in 96-well plates at room temperature (20-22°C).
  • each well 35 ⁇ l of Dulbecco's phosphate buffered saline (PBS); b) inhibitor (i.e. compound) or vehicle (0.5 ⁇ l DMSO); c) 10 ⁇ L of a 5 x concentrated 15-lipoxygenase solution in PBS.
  • the plates are incubated for 5 minutes at room temperature; d) 5 ⁇ l of 2 mM linoleic acid in PBS. The plate is then incubated for 20 minutes at room temperature; e) the enzymatic reaction is terminated by the addition of 50 ⁇ l methanol; and f) 50 ⁇ l of 200 ⁇ M DPPP in methanol is added to each well.
  • the fluorescence can be read using an excitation wavelength of 358 nm and an emission wavelength of 379 nm.
  • Example 4 l-(3-Methyl-2-thienoyl -lH-pyrazole-3-carboxylic acid pyridin-3-ylamide
  • the title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid pyridin-2-ylamide (see Example 1(c)) and 3- methyl-2-thienoyl chloride.
  • Example 6 The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid pyridin-2-ylamide (see Example 1(c)) and 4- pentylbenzoyl chloride. MS (M + +H) /z 363.
  • Example 6 The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid pyridin-2-ylamide (see Example 1(c)) and 4- pentylbenzoyl chloride. MS (M + +H) /z 363.
  • Example 6 Example 6
  • Example 1(d) The title compound was prepared as described in Example 1(d) from 2-[(lH-pyrazole-3-carbonyl)amino]thiophene-3-carboxylic acid methyl ester (see Example 6(b)) and 5-fluoro-2-methylbenzoyl chloride.
  • Example 12 l-f3-Methyl-2-benzofuroyl)-lH-pyrazole-3 -carboxylic acid ( 3,5-tri- methyl- lH " -pyrazol-4-yl)amide
  • Example 6(b) The title compound was prepared as described in Example 6(b) from dipyrazolo[l,5- ⁇ ; l ',5'-fiT
  • Example 14(a) The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid (3-methylisoxazol-5-yl)amide (see Example 14(a)) and 2-furoyl chloride.
  • Example 18 The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid (3-methylisoxazol-5-yl)amide (see Example 14(a)) and 1-naphthoyl chloride. MS (M + +H) m/z 347.
  • Example 18
  • Example 20 The title compound was prepared as described in Example 1(d) from 4-[(lH-pyrazole-3-carbonyl)amino]benzoic acid methyl ester (see Example 18(a)) and 5-fluoro-2-methylbenzoyl chloride. MS (M + +H) /z 382.
  • Example 20 The title compound was prepared as described in Example 1(d) from 4-[(lH-pyrazole-3-carbonyl)amino]benzoic acid methyl ester (see Example 18(a)) and 5-fluoro-2-methylbenzoyl chloride. MS (M + +H) /z 382.
  • Example 20 The title compound was prepared as described in Example 1(d) from 4-[(lH-pyrazole-3-carbonyl)amino]benzoic acid methyl ester (see Example 18(a)) and 5-fluoro-2-methylbenzoyl chloride. MS (M + +H) /z 382.
  • Example 20 The title compound was prepared as described in Example 1(d
  • Example 23 l- 4-Pentylbenzoyl -lH- ⁇ yrazole-3-carboxylic acid (4-dimethylamino- phenyl) amide
  • the title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid (4-dimethylaminophenyl)amide (see Example 22(a)) and 4-pentylbenzoyl chloride.
  • Example 22(a) The title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid (4-dimethylaminophenyl)amide (see Example 22(a)) and 3-methyl-2-thienoyl chloride.
  • Example 26 1 -(2-Ethoxybenzoyl)- lH-pyrazole-3-carboxylic acid ( 5-chloro-2-cyano- phenyl amide
  • Example 27 l-(5-Fluoro-2-methylbenzoyl)-lH-pyrazole-3-carboxylic acid (5-chloro-2- cyanophenyl) amide
  • Example 29 l-(l-Naphthoyl)-lH-pyrazole-3-carboxylic acid (5-chloro-2-cyanophenyl)- amide
  • the title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid (5-chloro-2-cyanophenyl)amide (see Example 26(a)) and 1-naphthoyl chloride.
  • Example 30(b) The title compound was prepared as described in Example 30(b) from lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and NN-dimethylcarbamoyl chloride. MS (M + +H) m/z 293.
  • Example_35 lH-Pyrazole-l,3-dicarboxylic acid 1- [(3-chlorophenyl) amide] 3-[ ⁇ (2-chloro- phenyDamidel
  • Example 35 The title compound was prepared as described in Example 35 from lH-pyrazole-3-carboxylic acid (2-chloro ⁇ henyl)amide (see Example 30(a)) and 3-fluoro ⁇ henylisocyanate. MS (M + +H) /z 359.
  • Example 37 lH-Pyrazole-l,3-dicarboxylic acid 3-IY2-chlorophenyl amide1 l-[Y3-tri- fluoromethylphenvDamidel
  • Example 30(b) The title compound was prepared as described in Example 30(b) from lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 3-chlorobenzenesulfonyl chloride. MS (M + +H) m/z 396.
  • Example 41 l-(4-tgrt-Butylbenzenesulfonyl -lH-pyrazole-3-carboxylic acid (2-chlorophenyl) amide
  • the title compound was prepared as described in Example 30(b) from lH- ⁇ yrazole-3-carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 4-t ⁇ rt-butylbenzenesulfonyl chloride.
  • Example 30(b) The title compound was prepared as described in Example 30(b) from lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 5-carbomethoxy-2-furansulfonyl chloride. MS (M + +H) m/z 410.
  • Example 46 l-(3-Chlorobenzenesulfonyl)-lH-pyrazole-3-carboxylic acid (2-chloro- phenyDmefhylamide
  • the title compound was prepared as described in Example 30(b) from lH-pyrazole-3 -carboxylic acid (2-chlorophenyl)methylamide (see Example 43(a)) and 3-chlorobenzenesulfonyl chloride.
  • N-(2-Chloro-4-fluorophenyl)-lH-pyrazole-3-carboxamide 50 mg, 209 ⁇ mol, 1 equiv.; see step (a) above
  • the hydrochloride salt of 4-methyl-piperazine-l -carbonyl chloride 83 mg, 410 ⁇ mol, 2 equiv.
  • DMAP 50 mg, 410 ⁇ mol, 2 equiv.
  • the reaction mixture was left stining for 16 h and then cooled.
  • the precipitate from the reaction mixture was collected and recrystallised from EtOH/EtOAc to yield the hydrochloride salt of the title compound (a white powder).
  • Example 53 l-(3-Chlorobenzoyl)-lH-pyrazole-3-carboxylic acid methylphenylamide A mixture of lH-pyrazole-3-carboxylic acid methylphenylamide (0.100 g, 0.497 mmol; see Example 50(a)), 3-chlorobenzoyl chloride (0.104 g, 0.596 mmol), 4-(NN-dimethylamino) ⁇ yridine (0.073 g, 0.596 mmol) and dichloromethane (5 ml) was stirred at 40 °C for 48 h. The reaction mixture was then cooled to room temperature, dichloromethane (10 ml) was added and the mixture was washed twice with water (10 ml).
  • Example 57(b) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid (2- chloropyridin-3-yl) amide (see Example 57(a)) and ethyl 6- isocyanatohexanoate.
  • Example 57(b) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid 2-chloro-4- fluorophenylamide (see Example 48 (a)) and pentyl isocyanate.
  • Example 57(b) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 3-chloro-4- fluorophenyl-amide (see Example 81(a)) and pentyl isocyanate.
  • Example 23 44%
  • Example 26 45%

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Abstract

L'invention concerne un composé représenté par la formule (I), dans laquelle R1, R2, R3, X et Y sont tels que présentés dans la description, et des sels acceptables d'un point de vue pharmaceutique de celui-ci, lesdits composés étant utilisés dans le traitement des maladies dans lesquelles l'inhibition de l'activité d'une lipoxygénase (par exemple une 15-lipoxygénase) est souhaitable et/ou nécessaire et, en particulier, dans le traitement de l'inflammation.
PCT/GB2004/001054 2003-03-14 2004-03-12 Composes de pyrazole utilises dans le traitement de l'inflammation WO2004080999A1 (fr)

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WO2006032851A1 (fr) * 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
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WO2006032852A1 (fr) * 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2006032851A1 (fr) * 2004-09-20 2006-03-30 Biolipox Ab Composés de pyrazole utiles dans le traitement d'une inflammation
WO2007042816A1 (fr) * 2005-10-12 2007-04-19 Biolipox Ab Benzoxazoles convenant pour le traitement d'une inflammation
WO2007042817A1 (fr) * 2005-10-13 2007-04-19 Biolipox Ab Naphthalene-disulfonamides convenant pour le traitement d'une inflammation
WO2007045868A1 (fr) * 2005-10-20 2007-04-26 Biolipox Ab Pyrazoles utiles dans le traitement de l'inflammation
WO2007051981A1 (fr) * 2005-10-31 2007-05-10 Biolipox Ab Utilisation de pyrazoles dans le traitement de l'inflammation
WO2007051982A1 (fr) * 2005-10-31 2007-05-10 Biolipox Ab Utilisation de triazoles comme inhibiteurs de la lipoxygenase
WO2007052000A1 (fr) * 2005-11-01 2007-05-10 Biolipox Ab Utilisation de pyrazoles dans le traitement de l'inflammation
WO2008001079A1 (fr) * 2006-06-27 2008-01-03 Biolipox Ab Méthodes pour l'identification de modulateurs de formation d'eoxin
WO2008129276A1 (fr) * 2007-04-19 2008-10-30 Boehringer Ingelheim International Gmbh Disulfonamides utiles dans le traitement de l'inflammation
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