EP1603897A1 - Pyrazole compounds useful in the treatment of inflammation - Google Patents

Pyrazole compounds useful in the treatment of inflammation

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Publication number
EP1603897A1
EP1603897A1 EP04720088A EP04720088A EP1603897A1 EP 1603897 A1 EP1603897 A1 EP 1603897A1 EP 04720088 A EP04720088 A EP 04720088A EP 04720088 A EP04720088 A EP 04720088A EP 1603897 A1 EP1603897 A1 EP 1603897A1
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European Patent Office
Prior art keywords
compound
optionally substituted
alkyl
formula
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04720088A
Other languages
German (de)
French (fr)
Inventor
Anders Uppsala Univ. Biomedical Centre HALLBERG
Wesley Biolipox AB SCHAAL
Mats Uppsala Univ. Biomedical Centre LARHED
Kristofer Biolipox AB OLOFSSON
Benjamin Biolipox Ab Pelcman
Andrei Biolipox AB SANIN
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Biolipox AB
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Biolipox AB
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Priority claimed from SE0300705A external-priority patent/SE0300705D0/en
Application filed by Biolipox AB filed Critical Biolipox AB
Publication of EP1603897A1 publication Critical patent/EP1603897A1/en
Withdrawn legal-status Critical Current

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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

There is provided a compound of formula (I), wherein R1, R2, R3, X and Y have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.

Description

PYRAZOLE COMPOUNDS USEFUL IN THE TREATMENT OF INFLAMMATION
Field of the Invention
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.
Background
There are many diseases/disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
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 β-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.
This combination of factors has led to at least 50% of all asthma patients being inadequately treated.
A similar pattern of under-treatment exists in relation to allergic disorders, where drugs are available to treat a number of common conditions but are underused in view of apparent side effects. 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.
Chronic obstructive pulmonary disease (COPD) is a common disease affecting 6% to 8% of the world population. The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of COPD.
Other inflammatory disorders which may be mentioned include:
(a) pulmonary fibrosis (this is less common than COPD, but is a serious disorder with a very bad prognosis. No curative treatment exists); (b) inflammatory bowel disease (a group of disorders with a high morbidity rate. Today only symptomatic treatment of such disorders is available); and
(c) rheumatoid arthritis and osteoarthritis (common disabling inflammatory disorders of the joints. There are currently no curative, and only moderately effective symptomatic, treatments available for the management of such conditions).
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.
Thus, a new and/or alternative anti-inflammatory treatment would be of benefit to all of the above-mentioned patient groups. In particular, there is a real and substantial unmet clinical need for an effective anti-inflammatory drug capable of treating inflammatory disorders, such as asthma, with no real or perceived side effects.
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. For example, 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. Huge efforts have been devoted towards the development of drugs that inhibit the action of these metabolites as well as the biological processes that fonn them. 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).
Another class of enzymes that metabolize arachidonic acid are the cyclooxygenases. Arachidonic acid metabolites that are produced by this process include prostaglandins, thromboxanes and prostacyclin, all of which possess physiological or pathophysiological activity. In particular, the prostaglandin PGE2 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 PGE2, 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.
Thus, in general, agents that are capable of blocking the formation of arachidonic acid metabolites are likely to be of benefit in the treatment of inflammation.
Prior Art
Certain pyrazole compounds that are structurally related to those described herein are commercially available. However, to the knowledge of the applicant, these compounds have never been disclosed in any printed publication and as such have no perceived utility ascribed to them.
Certain pyrazolecarboxylic acid hydrazides, structurally unrelated to the compounds described herein, have been disclosed as anti-inflammatory agents in Tihanyi et al, Eur. J. Med. Chem. - Chim. Tlier., 1984, 19, 433 and Goel et al, J. Chem. Inf. Comput. Sci. 1995, 35, 510.
Heterocyclic compounds (including pyrazoles) with anticonvulsant activity have been disclosed in US 5,258,397. 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.
Disclosure of the Invention
According to the invention there is provided a compound of formula I,
wherein
either
R represents an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G1 and B1, which B1 group may itself be further substituted by one or more substituents selected from G2, Z (provided that Z is not directly attached to an aryl or a heteroaryl group) and B2 (which B2 group is optionally further substituted by one or more substituents selected from G3, B3 and Z, provided that Z is not attached to an aryl or a heteroaryl group); and
R" represents H or C1- alkyl, which latter group is optionally substituted by one or more halo groups; or when R represents C1-6 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 B1 (which B1 group is optionally substituted as described above);
R represents Cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl or heteroaryl, all of which groups are optionally substituted by one or more substituents selected from Gl , Z (provided that Z is not directly attached to an aryl or a heteroaryl group) and B1 (which B1 group is optionally substituted as described above);
X represents a direct bond, -O- or -N(R4)- Y represents -C(O)-, -C(S)- or -S(0)2-;
B , B and B independently represent, on each occasion when used above, Cι_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl or heteroaryl; G , G a, G and G independently represent, on each occasion when used above, halo, cyano, -N3, -N02, -ON02 or -A*-R4; wherein A represents a spacer group selected from -C(Z)A -, -N(R )A -, -OA4-, -S- or -S(0)nA5-, in which: A2 represents a single bond, -0-, -S- or -N(R5)-;
A3 represents A6, -C(Z)N(R5)C(Z)N(R5)-, -C(Z)N(R5)C(Z)0-5 -C(Z)N(R5)S(0)nN(R5)-, -C(Z)S-, -S(0)n-, -S(0)nN(R5)C(Z)N(R5)-, -S(0)nN(R5)C(Z)0-, -S(0)nN(R5)S(0)nN(R5)-, -C(Z)0-, -S(0)nN(R5)- or -S(0)nO-; A4 represents A6, -S(0)n-, -C(Z)0-, -S(0)nN(R5)- or -S(0)nO-; A5 represents a single bond, -N(R5)- or -0-; A6 represents a single bond, -C(Z)- or -C(Z)N(R5)-;
Z represents, on each occasion when used above, a substituent connected by a double bond, which is selected from =0, =S, =NR4, =NN(R4)(R5), =NOR4, =NS(0)2N(R4)(R5), =NCN, =CHN02 and =C(R4)(R5);
R4 and R5 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 B5 (which B5 group is itself optionally substituted by one or more substituents selected from G5, Q (provided that Q is not directly attached to an aryl or a heteroaryl group) and B ); or when R and R5 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 G6, Q (provided that the ring is not aromatic in nature) and B4 (which B4 group is optionally substituted as described above);
B4, B3 and B independently represent on each occasion when used above Cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl or heteroaryl;
G4, G5 and G independently represent on each occasion when used above, halo, cyano, N3, -N02, -0N02 or -A7-R6; wherein A represents a spacer group selected from — C(Q)A -, -N(R )A -,
-N(R7a)A9a-, -OA10-, -S- or -S(0)nAu-, in which:
A represents a single bond, -0-, -S- or -N(R )-;
A9 represents A12, -C(Q)S-, -S(0)n-, -C(Q)0-, -S(0)nN(R7)- or -S(0)nO-;
A9a represents -C(Q)N(R7)C(Q)N(R7)-, -C(Q)N(R7)C(Q)0-, -C(Q)N(R7)S(0)nN(R7)-, -S(0)nN(R7)C(Q)N(R7)-, -S(0)nN(R7)C(Q)0-,
-S(0)nN(R7)S(0)nN(R7)-;
A10 represents A12, -S(0)n-, -C(Q)0-, -S(0)nN(R7)- or -S(0)nO-;
1 ϊ *7
A represents a single bond, -N(R )- or -0-;
A12 represents a single bond, -C(Q)- or -C(Q)N(R7)-;
Q represents, on each occasion when used above, a substituent connected by a double bond, which is selected from =0, =S, =NR6, =NN(R6)(R7), =NOR6, =NS(0)2N(R )(R7), =NCN, =CHN02 and =C(R6)(R7);
R , R7 and R7a independently represent, on each occasion when used above, H, Cι.6 alkyl, C2,6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl or heteroaryl, which latter seven groups are optionally substituted by one or more groups selected from halo, Cι-6 alkyl (optionally substituted by one or more halo groups), -N(R8)R9, -OR8, -ON02 and -SR8; or provided that they do not represent H, any pair of Rδ and R7 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, C1-6 alkyl (optionally substituted by one or more halo groups), -N(R8)R9, -OR8, -ONO2 and -SR8;
R and R independently represent, on each occasion when used above, H or C1-6 alkyl, which latter group is optionally substituted by one or more halo groups; and
n represents, on each occasion when used above, 1 or 2;
or a pharmaceutically-acceptable salt thereof,
provided that, when 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) R3 represents 2-chlorophenyl, then R1 does not represent phenyl, 3-bromophenyl or 4-bromophenyl; iv) R3 represents 3-chlorophenyl, then R1 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 or 4-methoxyphenyl; vi) R represents 3-iodophenyl, then R does not represent 2-methoxyphenyl or 2,4-dimethylphenyl;
^ 1 vii) 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
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-
2-ρyridinyl, 6-methyl-2-ρyridinyl or 4-acetylρhenyl; xi) R represents ethyl, then R does not represent phenyl,
2,3-dichlorophenyl, 4-methoxyphenyl, 2-carbomethoxy- phenyl, 2-thiazolyl or 4-methyl-2-pyridinyl; (B) X represents -N(H)- and: i) R represents phenyl, then R does not represent 4- methoxyphenyl, 2,4-dimethylphenyl or 2-thiazolyl; ii) R3 represents 3-chlorophenyl, then R1 does not represent
4-methylphenyl; iii) R3 represents 4-chlorophenyl, then R1 does not represent
3-bromophenyl; iv) R represents 3,4-dichlorophenyl, then R does not represent
4-methyl-2-pyridinyl or 6-methyl-2-pyridinyl; v) 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 R1 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 R1 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 R does not represent phenyl, 2-fluorophenyl, 4-acetylphenyl or 4-methyl-2-pyridinyl; iv) R3 represents 1 -butyl, then R1 does not represent 2-fluorophenyl, 2-methoxyphenyl, 4-methyl-2-pyridinyl or 6-methyl-2-pyridinyl; v) R3 represents 2-butyl, then R1 does not represent 2-thiazolyl or 4-acetylphenyl; vi) R3 represents 2-methyl- 1-propyl, then R1 does not represent phenyl or 3-nitrophenyl,
which compounds and salts are referred to hereinafter as "the compounds of the invention".
Pharmaceutically-acceptable 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 (entgegen) 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 exhibit tautomerism. All tautomeric forms 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. Alternatively 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). All stereoisomers and mixtures thereof are included within the scope of the invention. Unless otherwise specified, C1-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. Cι-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.
C2-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. C2-6-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.
C2-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. C2-6-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.
C3-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 C3-q cycloalkenyl or a C3-q cycloalkynyl group). C3-8-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.
C3-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 C3-q heterocycloalkenyl or a C3-q heterocycloalkynyl group. C3-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-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. 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.
The term "halo", when used herein, includes fluoro, chloro, bromo and iodo.
Aryl groups that may be mentioned include C6-ιo 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. C6-ιo 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-α]pyridinyl, indazolyl, indolinyl, indolyl, isobenzo furanyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1,5-naphthyridinyl and 1,8- naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroiso- quinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazolyl (including 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on 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.
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which R1 and R3 are both aryl groups substituted by one or more Cι-6 alkyl groups, the alkyl groups in question may be the same or different. Similarly, when groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent.
Compounds of the invention that may be mentioned include those of formula I, and pharmaceutically-acceptable salts thereof, in which any one, or more (including all), of the specific compounds that are excluded by way of the above provisos are not so excluded.
Compounds that may be mentioned include those in which B4, R6 and/or R7 do not represent a heteroaryl group.
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; G1 represents halo, cyano or -A!-R4;
Gla represents halo, cyano, -N02 or -A!-R4;
G2 represents halo, cyano, -ON02 or -A!-R4;
B2 represents C[-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which are optionally substituted by one or more G and or B groups; G3 represents halo, -ON02, -N(R5)(R4) or -OR4;
B represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; when A1 represents -N(R5)A3-, A3 represents A6, -C(Z)S-, -S(0)n-, -C(Z)0- or -S(0)nN(R5)-; when A1 represents -OA -, A4 represents A6; when A1 represents -S(0)nA5-, A5 represents a single bond or -N(R5)-;
Z represents =0 or =NR4; when any pair of R4 and R5 are linked together to form a ring, they are optionally substituted with G and/or B4;
G represents halo, cyano, -ONO2 or -A -R ; B5 represents Cι-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which are optionally substituted by one or more G5 and/or Bδ groups;
G5 represents halo, -ON02, -N(R7)(R6) or -OR6;
B represents .e alkyl, C2-6 alkenyl or C2_6 alkynyl; represents halo, cyano or -A A7 represents-C(Q)A8-, -N(R7)A9-, -OA10-, -S- or -S(0)nAπ-; when A7 represents -N(R7)A9-, A9 represents A12, -C(Q)S-, -S(0)n-, -C(Q)0- or -S(0)nN(R7)-; when A7 represents -OA10-, A10 represents A12; when A7 represents -S(0)nA -, A11 represents a single bond or -N(R7)-; Q represents =0 or =NR ;
Rδ, R7 and R7a independently represent H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which groups are optionally substituted by one or more groups selected from halo, C1-6 alkyl, -N(R8)R9, OR8 and -ON02; 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, C1-6 alkyl (optionally substituted by one or more halo groups), -N(R8)R9, -OR8 and -ON02.
More preferred compound include those in which:
B1 represents a Cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 heterocycloalkyl, or phenyl, group, all of which are optionally substituted as described hereinbefore;
G2 represents halo (e.g. fluoro or chloro); B represents Cι-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which are optionally substituted by one or more halo groups; when A1 represents -C(Z)A -, A2 represents a single bond, -O- or -N(R5)-; when A1 represents -N(R5)A3-, A3 represents A6; when A1 represents -S(0)nA , A5 represents a single bond; A represents a single bond;
Z represents =0;
B4 represents a Cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 heterocycloalkyl, or phenyl, group, all of which are optionally substituted as described hereinbefore; G4 represents halo;
B5 represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which groups are optionally substituted by one or more halo groups; when A represents -C(Q)A -, A represents a single bond, -O- or -N(R )-; when A represents -N(R )A -, A represents A ; when A represents -S(0)nA , A represents a single bond; A12 represents a single bond; Q represents =0.
Further preferred compounds include those in which:
B4 represents C2_6 alkenyl, C2-6 alkynyl or, preferably, Cι_6 alkyl;
G6 represents halo;
R , R and/or R a represent H, Cι-6 alkyl optionally substituted by one or more halo groups.
Further preferred compounds include those in which:
R4 and/or R5 independently represent H or C1-6 alkyl, which latter group is optionally substituted by one or more fluoro groups.
Further preferred compounds include those in which:
B1 represents a Cl-6 alkyl, C2- alkenyl, C3-6 cycloalkyl, C5-6 heterocycloalkyl, or phenyl, group, all of which are optionally substituted as described hereinbefore;
Gla represents halo, -N02 or -A^R4; A1 represents -C(Z)A2-, -N(R5)A3- and -OA4-;
1 9 9 when A represents -C(Z)A -, A represents a single bond or -0-.
Preferred compounds of the invention include those in which R1 represents an optionally substituted phenyl, naphthyl, pyrrolidinyl, piperidinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), indazolyl, indolyl, indolinyl, isoindolinyl, oxindolyl, quinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothiophenyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, benzothiazolyl, and/or benzodioxanyl, group. It is preferred in the above list that R1 does not represent naphthyl, pyrrolidinyl, piperidinyl, indazolyl, oxindolyl or benzothiazolyl. Particularly preferred values of R1 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.
Such 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. C1- alkyl
(including methyl, ethyl, /2-propyl, z-propyl, //-butyl, s-butyl, /'-butyl or t- butyl), /2-pentyl, z'-pentyl, n-hexyl or z'-hexyl), substituted by one or more fluoro group (e.g. -CH2F, -CHF2 or -CF3), and/or substituted by a C3-6 cycloalkyl (e.g. cyclopropyl) group, so forming, for example, a cyclopropylmethyl group;
C2-6 alkenyl (e.g. 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 1- pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl);
C3-6 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 4-morpholinyl, group; thiomethyl, mefhylsuliϊnyl, methylsulfonyl; -OR10; -N(R10)RU; -C(0)OR10; -C(0)R10; -C(O)N(R10)Rn; -S(O)2N(R10)Ru; and/or -N(R10)S(O)2R12; wherein R10 and R11 independently represent, on each occasion when used above, H, phenyl, Cι-6 alkyl (such as methyl, ethyl, /2-propyl, /'-propyl, n- butyl or t-butyl), which alkyl group is optionally substituted by one or more fluoro atom, C2-6 alkenyl or C3-6 cycloalkyl; or R10 and R11 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 Cι-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 4-methylpiperazine, group); and
R12 represents phenyl, C1-6 alkyl (such as methyl, ethyl, n-propyl, /'-propyl, //-butyl or t-butyl), which alkyl group is optionally substituted by one or more fluoro atom, C2-6 alkenyl or C3-6 cycloalkyl. When one or more of the above optional substituents on R1 represents:
-OR10, then R10 is preferably H, methyl (optionally substituted by 1 to 3 fluoro atoms, e.g. CF3), ethyl, //-propyl or z'-propyl;
-N(R10)RH, then R10 is preferably H, methyl, ethyl, /-propyl, /'-propyl, n- butyl or t-butyl and/or R11 is preferably H, methyl or ethyl;
-C(0)OR10, then R1 is preferably methyl, ethyl or /-propyl;
-C(0)R10, then R10 is preferably methyl, ethyl or t-butyl;
-C(O)N(R10)RU or -S(O)2N(R10)Ru, then R10 and Ru are preferably H or methyl; --NN((RR1ι0υ))S(0)2R' , then R10 is preferably H or methyl and R12 is preferably methyl.
Particularly preferred optional substituents on R1 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 Cι-6 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl (especially 4-piperidinyl), piperazinyl (especially 4-piperazinyl), pyn-olyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl or 4- pyridinyl), indazolyl, indolyl, indolinyl, isoindolinyl, oxindolyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothiophenyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, benzothiazolyl and/or benzodioxanyl group. Particularly prefened groups include an optionally substituted Cι-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.
Such R groups are optionally substituted by one or more substituents selected from: halo; -N02; cyano; Cι_6 alkyl, which alkyl group may be linear or branched (e.g. C1-4 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. -CH2F, -CHF2 or -CF3), Cι-6 alkyl group (e.g. methyl or ethyl), C2-6 alkenyl group or C3-6 cycloalkyl group (e.g. cyclopropylmethyl, so forming, for example, a cyclopropylmethyl group), which latter three groups are themselves optionally substituted with one or more halo (e.g. fluoro) and or Cj-6 alkyl groups;
C2-6 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 C1-6 alkyl groups; -6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally substituted with one or more halo (e.g. fluoro) group; phenyl, optionally substituted with one or more halo (e.g. fluoro or, especially, chloro) groups; 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
3 -tetrahydropyranyl), or a 4-morpholinyl, group; thiomethyl, methylsulfmyl, methylsulfonyl;
=0; -OR13;
-N(R13)R14;
-C(0)OR13;
-C(0)R13;
-C(0)N(R13)R14; -S(0)2N(R13)R14; and/or
-N(R13)S(0)2R15; wherein R13 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, C2-6 alkenyl or C3-6 cycloalkyl; or
R13 and R14 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 C1-6 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
4-methylpiperazine, group); and
R15 represents phenyl, Cι-6 alkyl (such as methyl, ethyl, /-propyl, /'-propyl,
//-butyl or t-butyl), which alkyl group is optionally substituted by one or more fluoro atom, C2-6 alkenyl or C3- cycloalkyl.
When one or more of the above optional substituents on R represents: -OR , then R is preferably H, methyl (optionally substituted by 1 to 3 fluoro atoms, e.g. -CF3), ethyl, //-propyl or /'-propyl; -N(R13)R1 , then R13 is preferably H, methyl, ethyl, n-propyl, /'-propyl, //- butyl or t-butyl and/or R14 is preferably H, methyl or ethyl;
-C(0)OR , then R is preferably methyl, ethyl or /'-propyl; -C(0)Rlj, then R13 is preferably methyl, -CF3, ethyl or t-butyl; -C(0)N(R13)R14 or -S(0)2N(R13)R14, then R13 and R14 are preferably H or methyl
-N N((RR13;)S(0)2Rι;ι, then R13 is preferably H or methyl and R15 is preferably methyl.
When R represents C1-6 alkyl or C2-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.
Particularly prefened optional substituents on R include methyl, ethyl, ethoxy, trifluoromethyl, fluoro, chloro, iodo, phenyl, chlorophenyl (such as 2-chlorophenyl and 4-chlorophenyl), n-pentyl, /'-propyl, nitro, t-butyl, -CH2CH=CHC8Hι7, trifluoroacetyl, carbomethoxy, carboethoxy and trifluoromethoxy.
Further prefen-ed compounds of the invention include those in which: R2 represents H or C1-3 alkyl; X represents a direct bond, -0-, -N(H)- or -N(Me)-.
More preferred values of R2 include H, methyl and ethyl, particularly H or methyl. Compounds of the invention that may also be mentioned include those in which:
R1 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; R2 is hydrogen or methyl;
R3 is methyl, //-butyl, /z-pentyl, 1-octyl, oleoyl, (lR,2ιS,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-2-thiophenyl, l(N)-methyl-4-piperazinyl, 1(N)- (2,2,2-trifluoroacetyl)piperidin-4-yl, ethylhexanoate or 1,3-benzodioxolyl; Y is -C(O)-, -C(S)- or -S(0)2-; and X is a bond, -Ν(H)-, -N(Me)-, or -0-.
Further compounds of the invention that may also be mentioned include those in which:
R1 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;
R3 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- ρyrrol-2-yl, 3 -methyl-2-benzo furanyl, or 3-methyl-2-thiophenyl; Y is -C(O)-, -C(S)- or -S(0) ; and X is a bond, -N(H)-, -N(Me)-, or -0-.
Particularly prefened compounds of the invention include those of the examples described hereinafter.
Compounds of formula I may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises:
(i) for compounds of formula I in which, when Y is -S(0)2-, X represents a ddiirreecctt bboonndd oor -N(R4)-, in which R4 represents B4, reaction of a compound of formula II,
1 9 wherein R and R are as hereinbefore defined, with a compound of formula III,
R3-Xa-Y-L1 III wherein Xa represents a direct bond or -N(B4)- 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 L1 represents a suitable leaving group, such as halo (e.g. chloro or bromo), or, when Xa is a direct bond, a carboxylate (e.g. a -0-C(0)-R ) group or a sulfonylate (e.g. a -0-S(0)2-R ) group, or, when Xa is -N(B4)-, 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. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridme, di-z'so-propylamine, l,8-diazabicyclo[5.4.0]undec- 7-ene, sodium hydroxide, N-ethyl-di-z'so-propylamine, N-
(methylpolystyrene)-4-(methylamino)pyridine or mixtures thereof) and 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 Xa is -O- or -ΝR4- or when Y is -S(0)2- and Xa is a direct bond include dimethylaminopyridine/dichloromethane, or a mixture of triethylamine and dimethylaminopyridine in dichloromethane;
(ii) for compounds of formula I in which X represents a single bond and Y represents -C(O)-, reaction of a compound of formula II as hereinbefore defined with a compound of formula IV,
R3C(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), NjN'-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 hexafluorophosphate, bromo-tris-pyrrolidinophosponium hexafluoro- phosphate, 2-( 1 H-benzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium tetra- fluorocarbonate) or l-cyclohexylcarbodiimide-3-propyloxymethyl polystyrene, a suitable base (e.g. as mentioned in process step (i) above) and an appropriate solvent (e.g. as mentioned in process step (i) above). Alternatively an azodicarboxylate may be employed under Mitsunobo conditions known to those skilled in the art;
(iii) for compounds of formula I in which X represents a direct bond and Y represents a -C(O)- or a -C(S)- group, reaction of a compound of formula II as hereinbefore defined with a compound of formula V,
R3=Ya V wherein Ya 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;
(iv) for compounds of formula I, in which X represents -ΝH- and Y represents -C(O)- or -C(S)-, reaction of a compound of formula II as hereinbefore defined with a compound of formula VI, R3Ν=Ya „ VI wherein R and Ya are as hereinbefore defined (so forming an isocyanate or an isothiocyanate, as appropriate), under conditions known to those skilled in the art. For example, for compounds of formula VI in which Y is -C(O)-, reaction may be performed in a suitable solvent (e.g. toluene) at elevated temperature (e.g. 100°C). For compounds of formula VI in which
Y is -C(S)-, 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;
(v) for compounds of formula I in which Y represents -C(O)- or -C(S)-, reaction of a compound of formula II with:
(a) a compound of formula VII,
Cl-Ya-Cl VII (b) a compound of formula VIII,
wherein, in both cases, Ya is as hereinbefore defined; or
(c) when Y represents -C(O)-, triphosgene, followed by: (1) for compounds of formula I in which X represents a direct bond, reaction with a organometallic reagent of formula IX,
R3M 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,
R3OH 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,
R3N(H)R4 XI wherein R3 and R4 are as hereinbefore defined, in all cases under reaction condition that are known to those skilled in the art;
(vi) for compounds of formula I in which X represents -N(R4)-, and R4 is other than hydrogen, reaction of a conesponding compound of formula I in which X represents -N(H)- with a compound of formula XII,
R4-L XII wherein R and L are as hereinbefore defined under standard reaction conditions;
(vii) for compounds of formula I in which Y represents -C(S)-, reaction of a conesponding compound of formula I in which Y represents — C(O)- with a suitable reagent for the conversion of a carbonyl group to a thiocarbonyl group, such as P2S5 or Lawesson's reagent, under conditions known to the person skilled in the art;
(viii) reaction of a compound of formula XIII,
wherein R , Y and X are as hereinbefore defined, with a compound of formula XIV,
HN(R1)(R2) XIV wherein R1 and R2 are as hereinbefore defined under coupling conditions, for example as described in process step (ii) above. Alternatively, 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. This activated intermediate may then be reacted with a compound of formula XIV under standard conditions, such as those described hereinbefore in process step (i) above; or
(ix) reaction of a compound of fonnula XV,
wherein R , R , Y and X are as hereinbefore defined, with a compound of formula XVI, R -L2 XVI wherein L represents a suitable leaving group, such as halo (e.g. chloro, bromo and iodo), -OS02CF3, -B(OH)2, -Sn(Rz)3 (wherein Rz is preferably methyl or butyl) or -Bi(R')2, and R1 is as hereinbefore defined, for example in the presence of a catalyst containing, preferably, Pd or Cu, and a base.
Compounds of formula II and protected derivatives thereof may be prepared by reaction of a compound of fonnula XIV as hereinbefore defined with either:
(I) dipyrazolo[l,5-<2;r35'-(i]pyrazine-4,9-dione, for example under standard conditions, for example as described hereinbefore in process step (i); or (II) lH-pyrazole-3 -carboxylic acid, an N-protected, and/or an O-activated derivative, thereof, for example under conditions such as those described hereinbefore in process step (viii) above.
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.
Compounds of formula XV may be prepared by reaction of a compound of formula XVII,
H2NR2 XVII wherein R is as hereinbefore defined with a compound of formula XIII as hereinbefore defined, for example under conditions such as those described hereinbefore in respect of process step (viii) above.
Dipyrazolo[l,5-α;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. Other 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.
Compounds of fonnulae III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIV, XVI and XVII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.
ϊ 9 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, esterifϊcations, 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.
Compounds of the formula I may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
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.
The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3 edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).
Medical and Pharmaceutical Uses
Compounds of formula I and salts thereof are useful because they possess pharmacological activity. Such compounds are therefore indicated as pharmaceuticals.
To the applicant's knowledge, compounds of formula I have not been disclosed before for use as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined but without the provisos, for use as a pharmaceutical.
Although compounds of formula I and salts thereof may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of formula I may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to fonn compounds of formula I. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised), may therefore be described as "prodrugs" of compounds of formula I. All prodrugs of compounds of formula I are included within the scope of the invention.
By "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.
Compounds of formula I, and pharmaceutically acceptable salts thereof, are thus expected to be useful in the treatment of inflammation.
The term "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.
The term "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.
Accordingly, 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, iritis, 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.
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.
According to a further aspect of the present invention, there is provided 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.
"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.
According to a further aspect of the invention there is thus provided 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).
According to a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of the invention, as hereinbefore defined but without the provisos; and
(B) another therapeutic agent that is useful in the treatment of inflammation, wherein 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).
Thus, there is further provided:
(1) 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; and
(2) a kit of parts comprising components:
(a) 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; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or canier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
Compounds of formula I and salts thereof may be administered at varying doses. 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. For oral administration, 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. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during constant rate infusion. Advantageously, 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.
In any event, 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. Biological Test
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). The following are added (in the following order) to each well: a) 35 μl of Dulbecco's phosphate buffered saline (PBS); b) inhibitor (i.e. compound) or vehicle (0.5 μl DMSO); c) 10 μL of a 5 x concentrated 15-lipoxygenase solution in PBS. The plates are incubated for 5 minutes at room temperature; d) 5 μl 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 μl methanol; and f) 50 μl of 200 μM DPPP in methanol is added to each well.
After 30 minutes at room temperature, the fluorescence can be read using an excitation wavelength of 358 nm and an emission wavelength of 379 nm.
Examples
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed: DMF dimethylformamide
DMSO dimethylsulfoxide EtOAc ethyl acetate
MS mass spectrum
NMR nuclear magnetic resonance
THF tetrahydrofuran
Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma- Aldrich Fine Chemicals.
Example 1 l-Benzoyl-lH-pyrazole-3-carboxylic acid pyridin-3-ylamide
(a) lH-Pyrazole-3-carboxylic acid
An aqueous solution of KMn0 (40.9 g, 0.26 mol) was added to a stined solution of 3-methyl-l(2)H-pyrazole (9.8 ml, 0.12 mol) in 0.5 L water. The mixture was heated at reflux for 5 h. The black suspension was cooled, filtered and the filtrate concentrated to a small volume. The solution was acidified with 3 N HC1 and the white solid that formed was collected and washed with Et20 to give the sub-title compound in 100 % yield. 1H NMR (DMSO-^, 200 MHz) δ 7.75 (d, J= 1.5 Hz, IH) and 6.75 (d, J= 1.5 Hz, IH).
(b) lH-Pyrazole-3-carbonyl chloride.
Thionyl chloride (20 mL) was added to a solution of lH-pyrazole-3- carboxylic acid (5.0 g, 44.6 mmol; see step (a) above) in THF (40 mL) at room temperature. The mixture was heated at reflux for 1 h, and concentrated to dryness to afford the sub-title compound. The solid was used without further purification. (c lH-Pyrazole-3-carboxylic acid pyridin-2-ylamide.
NaH (60 % dispersion in mineral oil, 1.34 g, 33.5 mmol) was added to a solution of pyridin-2-ylamine (3.0 g, 31.9 mmol) in THF (150 mL). The solution was stined at room temperature for 1 hour and freshly prepared pyrazole-3-carbonyl chloride (4.66 g, 35.7 mmol; see step (b) above) was added. The mixture was stined for 1 h and 10 mL water was added. The mixture was concentrated to a small volume and extracted twice with EtOAc. The combined extracts were washed with H20, dried with Na2S0 and concentrated to dryness to afford the sub-title compound. 1H NMR (CDC13, 200 MHz) δ 10.07 (s, IH), 8.49 (d, J = 8 Hz, IH), 8.38 (d, J = 6 Hz, IH), 7.83 (dd, J - 6 Hz, J = 8 Hz, IH), 7.68 (d, J = 2.5 Hz, IH), 7.14 (dd, /= 6 Hz, J= 8 Hz, IH), 7.02 (d, J= 2.5 Hz, IH)
(d) l-Benzoyl-lH-pyrazole-3-carboxylic acid pyridin-3-ylamide. A solution of lH-pyrazole-3-carboxylic acid pyridin-2-ylamide (100 mg, 0.53 mmol; see step (c) above) in anhydrous TΗF (2mL) was added to NaΗ (60% dispersion in mineral oil, 22 mg, 0.56 mmol) with stkring at room temperature. After 1 h, benzoyl chloride (65μL, 0.56 mmol) was added and the mixture was stined for an additional hour. Water (1 mL) was added and the mixture was concentrated to dryness. EtOAc (2 mL) *and Na2C03 (0.2 M, 1 mL) were added and the phases were separated. The organic layer was washed with NaCl (aq. sat.), passed through a short column of silica gel and concentrated to dryness. The residue was triturated with Et20 to afford the title compound (40 mg) as a white solid. Example 2 l-(2.5-Dimethyl-3-furoyl -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 2,5-dimethyl-3-furoyl chloride. MS (M++H) /z 311.
Example 3 1-fl -Methyl- lH-pynol-2-yl)-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 1- methyl-2-pyrroyl chloride. MS (M++H) m/z 296.
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. MS (M++H) m/z 313.
Example 5 1 -(4-Pentylbenzoyl)- 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 4- pentylbenzoyl chloride. MS (M++H) /z 363. Example 6
2-{fl-(2-Ethoxybenzoyl)-lH-pyrazole-3-carbonyllamino}thiophene-3- carboxylic acid methyl ester
(a) Dipyrazolof 1,5-g; r,5'-gT[pyrazine-4,9-dione
A mixture of pyrazole-3-carboxylic acid (44.0 g, 0.39 mol; see Example 1(a) above), DMF (0.5 mL), and thionyl chloride (150 mL) was heated at reflux for 3 days. The solvents were evaporated and the residue dried under high- vacuum, to give the sub-title compound which was used without further purification.
(b) 2-["(lH-Pyrazole-3-carbonyl)amino]thiophene-3-carboxylic acid methyl ester NaH (60% dispersion in mineral oil, 0.61 g, 15.4 mmol) was added to a solution of dipyrazolo[l,5-a;r,5'-d]pyrazine-4,9-dione (2.4 g, 12.7 mmol; see step (a) above) and 2-aminothiophene-3 -carboxylic acid methyl ester (2.0 g, 12.7 mmol) in THF (100 mL) at room temperature. The mixture was stined for 1 h and 10 mL water was added. The mixture was concentrated to a small volume and extracted twice with EtOAc. The combined extracts were washed with H20, dried with Na2S04 and concentrated to dryness providing the sub-title compound.
1H NMR DMSO-d6, 200 MHz) δ 8.0 (d, J= 2 Hz, IH), 7.21 (d, J= 5.8 Hz, IH), 7.06 (d, J= 5.8 Hz, IH), 6.87 (d, J= 2 Hz, IH) and 3.86 (s, 3H). (c) 2-{ri-(2-Ethoxybenzoyl -liJr-pyrazole-3-carbonyl]amino)-thioρhene-3- carboxylic acid methyl ester
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 step (b) above) and 2-ethoxybenzoyl chloride. MS (M++H) m/z 400.
Example 7
2-{[l-(3-Trifluoromethylbenzoyl)-lH-pyrazole-3-carbonyllamino thiophene-3 -carboxylic acid methyl ester
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 3-trifluorobenzoyl chloride.
MS (M++Η) m/z 424.
Example 8
2-{[l-(5-Fluoro-2-methylbenzoyl)-lH-pyrazole-3-carbonyl]amino}- thiophene-3 -carboxylic acid methyl ester
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.
MS (M++H) m/z 388.
Example 9 2-{[l-(3-Methyl-2-thienoyl)-lHr-pyrazole-3-carbonyllamino}thiophene-3- carboxylic acid methyl ester
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 3-methyl-2-thienoyl chloride. MS (M++H) m/z 376.
Example 10 l-{2,5-Dimethyl-3-furoyl)-lH-pyrazole-3-carboxylie acid (1,3,5-trimethyl- lH-pyrazol-4-yl)amide
(a) lH-Pyrazole-3 -carboxylic acid fl ,5-trimethyl-lH-pyrazol-4-yl)amide The title compound was prepared as described in Example 6(b) from dipyrazolo[l,5-α;l',5'-(i]pyrazine-4,9-dione (see Example 6(a)) and 1,3,5- trimethyl-lH-pyrazol-4-ylamine.
1H NMR (DMSO-d6, 200 MHz) δ 11.7 (m, IH), 9.27 (m, IH), 7.86 (m, IH), 3.64 (s, 3H), 2.04 (s, 3H) and 1.95 (s, 3H).
(b) l-(2,5-Dimethyl-3-furoyl)-lH"-pyrazole-3-carboxylic acid (L3,5-tri- methyl- lH-pyrazol-4-yl)amide
The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid (l,3,5-trimethyl-lH-pyrazol-4-yl)amide (see step (a) above) and 2,5-dimethyl-3-furoyl chloride. MS (M++H) m/z 342.
Example 11
1-(1 -Methyl- lH-pyrrol-2-yl -lH-pyrazole-3 -carboxylic acid (1,3,5-tri- methyl- lH-ρyrazol-4- vQamide
The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid (l,3,5-trimethyl-lH-pyrazol-4-yl)amide (see Example 10(a)) and l-methyl-2-pynoyl chloride. MS (M++H) m/z 327. Example 12 l-f3-Methyl-2-benzofuroyl)-lH-pyrazole-3 -carboxylic acid ( 3,5-tri- methyl- lH"-pyrazol-4-yl)amide
The title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid (l ,3,5-trimethyl-lH-pyrazol-4-yl)amide (see Example 10(a)) and 3-methyl-2-benzofuroyl chloride. MS (M++H) m/z 378.
Example 13 l-(2-Fluoro-5-iodobenzoyl)-lH"-pyrazole-3-carboxylic acid (1,3,5-tri- methyl- lH-pyrazol-4-yl)amide
The title compound was prepared as described in Example 1(d) from lH-pyrazole-3-carboxylic acid (l,3,5-trimethyl-lH-pyrazol-4-yl)amide (see
Example 10(a)) and 2-fluoro-5-iodobenzoyl chloride. MS (M++H) /z 468.
Example 14 l-(2-Ethoxybenzoyl)-lH-pyrazole-3-carboxylic acid (3-methylisoxazol-5- yl) amide
(a) lH-Pyrazole-3 -carboxylic acid (3-methylisoxazol-5-yl amide
The title compound was prepared as described in Example 6(b) from dipyrazolo[l,5-α; l ',5'-fiT|pyrazine-4,9-dione (see Example 6(a)) and 3- methylisoxazol-5-ylamine. 1H NMR (DMSO-rftf, 200 MHz) δ 7.85 (d, J= 2 Hz, IH), 6.86 (d, J= 2 Hz,
IH), 6.24 (s, IH), 2.2 (s, 3H). (b) l-f2-Ethoxybenzoyl)-lH-pyrazole-3-carboxylic acid (3-methylisoxazol- ^ J amide
The title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid (3-methylisoxazol-5-yl)aιnide (see step (a) above) and 2-ethoxybenzoyl chloride. MS (M++H) m/z 341.
Example 15
1 -(3-Methyl-2-benzofuroyl - lH-ρyrazole-3-carboxylic acid (3-methyl- isoxazol-5-yl)amide
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 3-methyl-2-benzofuroyl chloride.
MS (M++H) m/z 351.
Example 16 l-(2-Furoyl)- lH-pyrazole-3 -carboxylic acid (3-methylisoxazol-5-yl)amide
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.
MS (M++H) m/z 287.
Example 17 l-( 1 -Naphthoyl)- lH-pyrazole-3 -carboxylic acid (3-methylisoxazol-5- yl)amide
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
4-{ri-(2<5-Dimethyl-3-furoyl -lH"-pyrazole-3-carbonyl]amino}benzoic acid methyl ester
(a) 4-[(lH-Pyrazole-3-carbonyl)amino']benzoic acid methyl ester.
Freshly prepared pyrazole-3 -carbonyl chloride (5.80 g, 44.6 mmol; see Example 1 (b)) was added to a solution of 4-aminobenzoic acid methyl ester (2.7 g, 17.9 mmol) in pyridine (50 mL). The solution was stined at 85 °C for 3 h and concentrated. The residue was extracted twice with EtOAc and the combined extracts were washed with H20, dried with Na2S0 and concentrated to dryness. The solid was washed with Et20 to give the subtitle compound.
Η NMR (CDC13, 200 MHz) δ 9.0 (s, IH), 8.1 (d, J= 6 Hz, 2 H), 7.8 (d, J= 6 Hz, 2 H), 7.7 (s, J=2 Hz, IH), 7.05 (s, J=2 Hz, IH), 3.93 (s, 3H).
(b) 4-{ l-(2,5-Dimethyl-3-furoyl -lH-pyrazole-3-carbonyl]amino}benzoic acid methyl ester
The title compound was prepared as described in Example 1(d) from
4-[(lH-pyrazole-3-carbonyl)amino]benzoic acid methyl ester (see step (a) above) and 2,5-dimethyl-3-furoyl chloride.
MS (M++H) m/z 368.
Example 19
4-{ri-(5-Fluoro-2-methylbenzoyl)-lH-pyrazole-3-carbonyl1amino}benzoic acid methyl ester
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
4-( l-(4-Pentylbenzoyl -lH-pyrazole-3-carbonyl]amino}benzoic acid methyl ester 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 4-pentylbenzoyl chloride. MS (M++H) m/z 420.
Example 21
4-{[l-(2-Furoyl)-lH-pyrazole-3-carbonyl]amino}benzoic acid methyl ester 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 2-furoyl chloride. MS (M++H) m/z 340.
Example 22 l-(l-Methyl-lH-pyrrol-2-yl)-liJr-pyrazole-3-carboxylic acid (4-dimethyl- aminophenypamide
(a) lH-Pyrazole-3-carboxylic acid (4-dimethylaminophenyl)amide Dipyrazolo[l,5-α; r,5'- ]pyrazine-4,9-dione (1.0 g, 5.3 mmol; see Example 6(a)) was added to a solution of dimethylaminophenylamine dihydrochloride (2.0 g ; 11.6 mmol) and Et3N (3.2 mL, 23.2 mmol) in DMF (20 mL). The mixture was stirred at 85°C for 1 h and then concentrated. The residue was extracted twice with EtOAc and the combined extracts were washed with H20, dried with Na2S0 and concentrated to dryness. The residue was purified by chromatography to afford the sub-title compound. 1H NMR (CDCI3, 200 MHz) δ 8.55 (s, IH), 7.6 (d, J = 2.5 Hz, 1 H), 7.52 (d, J= 9 Hz, 2 H), 6.91 (d, .7=2.5 Hz, IH), 6.74 (s, J=9 Hz, 2H), 2.92 (s, 6 H)
(b) 1-(T -Methyl- lH-pyrrol-2-yl)- lH-pyrazole-3-carboxylic acid (4-di- methyl aminophen yl) amide
The title compound was prepared as described in Example 1(d) from lH-pyrazole-3 -carboxylic acid (4-dimethylaminophenyl)amide (see step (a) above) and l-methyl-2-pynoyl chloride. MS (M++Η) m/z 338.
Example 23 l- 4-Pentylbenzoyl -lH-ρyrazole-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. MS (M++H) m/z 405.
Example 24 l-(3-Methyl-2-thienoyl)- lH-pyrazole-3-carboxylic acid (4-dimethylamino- phenyDamide
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.
MS (M++H) m/z 355. Example 25 l-fl-NaphthoylVlH-pyrazole-3-carboxylic acid (4-dimefhylaminophenyl)- amide
The title compound was prepared as described in Example 1(d) from lH-ρyrazole-3 -carboxylic acid (4-dimethylaminophenyl)amide (see Example 22(a)) and 1-naphthoyl chloride. MS (M++H) m/z 385.
Example 26 1 -(2-Ethoxybenzoyl)- lH-pyrazole-3-carboxylic acid ( 5-chloro-2-cyano- phenyl amide
(a) lH-Pyrazole-3-carboxylic acid (5-chloro-2-cyanophenyl)amide. The title compound was prepared as described in Example 6(b) from dipyrazolo[l,5-α;l',5'- ]pyrazine-4,9-dione (see Example 6(a)) and 5- chloro-2-cyanoaniline.
1H NMR (CDC13, 200 MHz) δ 10.3 (s, IH), 8.03 (m, 1 H), 7.98 (m, 1 H), 7.93 (d, J=8 Hz, IH) , 7.48 (2, J=8 Hz, IH), 6.86 (m, 1 H).
(b) 1 -(2-Ethoxybenzoyl)- lH-pyrazole-3-carboxylic acid (5-chloro-2-cyano- phenyl amide
The title compound was prepared as described in Example 1(d) from l/J-pyrazole-3-carboxylic acid (5-chloro-2-cyanophenyl)amide (see step (a) above) and 2-ethoxybenzoyl chloride. MS (M++H) m/z 395. Example 27 l-(5-Fluoro-2-methylbenzoyl)-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 5-fluoro-2-methylbenzoyl chloride. MS (M++H) m/z 383.
Example 28 l-(2-Furoyl)-lH-pyrazole-3-carboxylic acid f5-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 2-furoyl chloride. MS (M++H) m/z 341.
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. MS (M++H) m/z 401.
Example 30
1 -Oleoyl- lH-ρyrazole-3-carboxylic acid (2-chlorophenyl)amide
(a) lH-Pyrazole-3 -carboxylic acid (2-chlorophenyl)amide A mixture of dipyrazolo[l,5- ;r,5'-J]pyrazine-4,9-dione (1.88 g, 10 mmol; see Example 6(a)), 2-chloroaniline (6.38 g, 50 mmol) and 4-(N,N- dimethylamino)pyridine (1.22 g, 10 mmol) was stirred at 120°C for 30 min. After cooling to room temperature, EtOH (20 mL), followed by water (100 mL) and isohexane (100 mL) was added. The mixture was shaken for 10 min. The solid was filtered off, washed with 50% aqueous EtOH (20 mL), water (50 mL) and isohexane (50 mL), and dried in vacuum, to give the sub-title compound (yield: 2.45 g, 55%).
(b) 1 -Oleoyl- lH-pyrazole-3-carboxylic acid (2-chlorophenyDamide A mixture of lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (55 mg, 0.25 mmol; see step (a) above), oleoyl chloride (146 mg, 0.30 mmol) and 4- (NN-dimethylamino)pyridine (36 mg, 0.30 mmol) in CH2C12 (5 mL) was stirred at 40°C for 2 days. The mixture was diluted with CH2C12 (10 mL), washed with water (2x 10 mL) and concentrated. Chromatographic purification gave the title compound (yield: 83 mg, 68%). MS (M++H) m/z 486.
1H ΝMR (CDC13, 400 MHz) δ 9.41 (s, IH), 8.56 dd, J = 8 Hz, 1 Hz, IH), 8.30 (d, J = 3 Hz, IH), 7.42 (dd, J= 8 Hz, 1 Hz, IH), 7.33 (td, J = 8 Hz, 1 Hz, IH), 7.08 (td, J= 8 Hz, 1 Hz, IH), 7.03 (d, J = 3 Hz, IH), 5.36 (ddd, J = 11 Hz, 6 Hz, 3 Hz, IH), 5.32 ddd, J= 41 Hz, 6 Hz, 3 Hz, IH), 3.17 (t, J = 8 Hz, 2H), 1.96-2.08 (m, 4H), 1.78-1.88 (m, 2H), 1.18-1.50 (m, 20H), 0.86 (t, J= 7 Hz, 3H). 13C NMR (CDCI3, 100.5 MHz) δ 172.03, 158.7, 150.2, 134.4, 130.3, 130.2, 129.8, 129.2, 128.0, 124.9, 123.0, 121.3, 109.5, 33.92, 32.0, 29.85, 29.77, 29.6, 29.4 (2C), 29.31, 29.25, 29.18, 27.3, 27.2, 24.6, 22.8, 14.2.
Example 31
3-(2-Chlorophenylcarbamoyl)-lH-pyrazole-l -carboxylic acid (IR,2S,5R)- (-)-menthol ester
A mixture of lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (56 mg, 0.25 mmol; see Example 30(a)), (-)-menthyl chloroformate (82 mg, 0.38 mmol), and 4-(NN-dimethylamino)pyridine (45 mg, 375 μmol) in dichloromethane (5 mL) was stirred at 40°C for 16 h. The mixture was concentrated, dissolved in EtOAc, washed with water, and dried with MgS04. Chromatographic purification afforded the title product (yield: 69 mg, 69%). MS (M++H) m/z = 404.
1H NMR (CDCI3, 400 MHz) δ 9.42 (s, IH), 8.49 (dd, J = 9, 2 Hz, IH), 8.18 (d, J = 3 Hz, IH), 7.41 (dd, J = 9, 2 Hz, IH), 7.31 (dt, J = 9, 2 Hz, IH), 7.07 (dt, J = 9, 2 Hz, IH), 7.01 (d, J = 3 Hz, IH), 4.92 (dt, J = 12, 4 Hz, IH), 2.25 (m, IH), 2.01 (dsept, J = 8, 3 Hz, IH), 1.80-1.70 (m, 2H), 1.70- 1.50 (m, 2H), 1.29-1.08 (m, 2H), 0.95 (dd, J = 7, 2 Hz, 7H), 0.84 (d, J = 7 Hz, 3H).
13C NMR (100.5 MHz) δ 158.7, 150.5, 148.3, 134.3, 132.6, 129.2, 127.7, 124.8, 123.4, 121.5, 109.1, 80.5, 47.0, 40.4, 33.9, 31.4, 26.7, 23.8, 21.9, 20.5, 16.7. Example 32
3 -(2-Chlorophenylcarbamoyl)- lH-p yrazole- 1 -carboxylic acid 2-chloro- benzyl ester
The title compound was prepared as described in Example 31 from lH-pyrazole-3 -carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 2-chlorobenzyl chloroformate. MS (M++H) m/z 390.
1H NMR (CDC13, 400 MHz) δ 9.44 (s, IH), 8.49 (dd, J = 8 Hz, 1 Hz, IH), 8.21 (d, J = 3 Hz, IH), 7.59 (dd, J = 1 Hz, IH), 7.39-7.47 (m, 2H), 7.28- 7.38 (m, 3H), 7.07 (td, J = 8 Hz, 1 Hz, IH), 7.02 (d, J= 3 Hz, IH), 5.62 (s, 2H).
13C NMR (100.5 MHz) δ 151.0, 148.5, 134.3, 134.0, 133.1, 131.9, 130.5, 130.4, 130.0, 129.3, 127.8, 127.2, 125.0, 123.5, 121.6, 109.5.
Example 33
3-(2-Chlorophenylcarbamoyl)- lH-pyrazole- 1 -carboxylic acid 4-chlorophenyl ester
The title compound was prepared as described in Example 31 from lH-pyrazole-3 -carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 4-chlorophenyl chloroformate. MS (M++H) m/z 376.
Example 34 lH-Pyrazole-L3-dicarboxylic acid 3-f"(2-ctιlorophenyl)amidel 1-dimefhyl- _ amide
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 A mixture of lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (55 mg, 0.25 mmol; see Example 30(a)), 3-chlorophenylisocyanate (46 mg, 0.30 mmol) and toluene (5 mL) was stined at 100°C for 18 h. The solution was concentrated and isohexane (10 mL) was added. The title compound was filtered off and washed with isohexane (10 mL) (yield: 65 mg, 69°Lo). MS (M++H) m/z 375.
1H NMR (C6D6, 400 MHz) δ 9.05 (s, IH), 8.91 (d, J = 8 Hz, IH), 8.31 (s, IH), 7.72 (d, J= 3 Hz, IH), 7.61 (s, IH), 7.07 (d, J= 8 Hz, IH), 6.94 (t, J = 8 Hz, IH), 6.85 (d, J= 8 Hz, IH), 6.72 (t, J= 8 Hz, IH), 6.69 (d, J = 3 Hz, IH), 6.58 (t, J= 8 Hz, IH). 13C NMR (100.5 MHz) δ 158.1, 149.1, 145.3, 137.5, 135.0, 134.7, 130.6, 130.1, 129.0, 128.4, 124.9, 124.7, 122.5, 121.3, 119.6, 117.5, 109.4.
Example 36 lH-Pyrazole-L3-dicarboxylic acid 3-[(2-chlorophenyl)amide] l-[~(3-fluoro- phenyPamide]
The title compound was prepared as described in Example 35 from lH-pyrazole-3-carboxylic acid (2-chloroρhenyl)amide (see Example 30(a)) and 3-fluoroρhenylisocyanate. MS (M++H) /z 359. Example 37 lH-Pyrazole-l,3-dicarboxylic acid 3-IY2-chlorophenyl amide1 l-[Y3-tri- fluoromethylphenvDamidel
The title compound was prepared as described in Example 35 from lZ7-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 3-trifluoromethylphenylisocyanate. MS (M++Η) m/z 409.
Example 38 IH-Pyrazole- S-dicarboxylic acid 3-[(2-chlorophenyl amide] l-[(4-nitro- phenyl) amide]
The title compound was prepared as described in Example 35 from lH-pyrazole-3 -carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 4-nitrophenylisocyanate. MS (M++H) m/z 386.
Example 39
1 -(Octane- 1 -sulfonyl)- lH-pyrazole-3 -carboxylic acid (2-chlorophenyl)- amide 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 1-octanesulfonyl chloride. MS (M++H) m z 398.
Exar p_le 40
1 -Q^Chlorobenzenesulfonyl)- lH-pyrazole-3-carboxylic acid (2-chloro- phenvDamide
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.
1H NMR (CDC13, 400 MHz) δ 9.25 (s, IH), 8.45 (dd, J = 8 Hz, 1 Hz, IH), 8.17 (d, J= 3 Hz, IH), 8.09 (t, J= 2 Hz, IH), 7.97 (dt, J= 8 Hz, 1 Hz, IH), 7.68 (ddd, J= 8 Hz, 2 Hz, 1 Hz, IH), 7.54 (t, J= 8 Hz, IH), 7.41 (dd, J= 8 Hz, 1 Hz, IH), 7.29 (td, / = 8 Hz, 1 Hz, IH), 7.07 (td, J = 8 Hz, 1 Hz, IH), 7.00 (d, J= 3 Hz, IH).
13C NMR (100.5 MHz) δ 152.0, 137.8, 136.0, 135.5, 134.1, 133.1, 131.0, 129.3, 128.7, 127.9, 126.6, 125.1, 123.3, 121.4, 121.3, 109.2.
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-ρyrazole-3-carboxylic acid (2-chlorophenyl)amide (see Example 30(a)) and 4-tβrt-butylbenzenesulfonyl chloride. MS (M++H) m/z 418.
1H NMR (CDC16, 400 MHz) δ 9.27 (s, IH), 8.45 (dd, J = 8 Hz, 1 Hz, IH), 8.16 (d, J = 3 Hz, IH), 7.98-8.02 (m, 2H), 7.56-7.61 (m, 2H), 7.40 (dd, J = 8 Hz, 1 Hz, IH), 7.29 (td, J = 8 Hz, 1 Hz, IH), 7.07 (td, J = 8 Hz, 1 Hz, IH), 6.96 (d, = 3 Hz, IH), 1.33 (s, 9H).
13C NMR (100.5 MHz) δ 159.6, 158.3, 151.3, 134.3, 133.1, 132.9, 129.3, 128.6 (2C), 127.9, 126.8 (2C), 125.0, 123.2, 121.4, 108.8, 35.6, 31.0 (3C). Example 42
5-[3-f2-Chlorophenylcarbamoviy lH-pyrazole- 1 -sulfonyl] furan-2- carboxylic acid methyl ester
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 43 l-(3-Chlorobenzoyl)-lH"-pyrazole-3-carboxylic acid (2-chlorophenyl)- methylamide
(a) lH-Pyrazole-3-carboxylic acid (2-chlorophenyl)methylamide.
The title compound was prepared as described in Example 30(a) from dipyrazolo[l,5-α;r,5'-fiT]pyrazine-4,9-dione (see Example 6(a)) and 2- chloro-N-methylaniline. MS (M++H) m/z 236.
(b) l-(3-Chlorobenzoyl)-lH-pyrazole-3-carboxylic acid (2-chlorophenyl)- methylamide
The title compound was prepared as described in Example 30(b) from lH-pyrazole-3 -carboxylic acid (2-chlorophenyl)methylamide (see step (a) above) and 3-chlorobenzoyl chloride. MS (M++H) m/z 374.
Example 44 lH-Pyrazole-L3-dicarboxylic acid l-[Y3-chlorophenyl)amide] 3-|"(2-chloro- phenvDmethylamide]
The title compound was prepared as described in Example 35 from liϊ-pyrazole-3 -carboxylic acid (2-chlorophenyl)methylamide (see Example 43(a)) and 3-chlorophenylisocyanate. MS (M++H) m/z 389.
Example 45 3 - (2-Chlorophenyl)methylcarbamoyl]-lH-pyrazole-l -carboxylic acid 2- chlorobenzyl ester
The title compound was prepared as described in Example 31 from lH-pyrazole-3-carboxylic acid (2-chlorophenyl)methylamide (see Example
43(a)) and 2-chlorobenzyl chloroformate. MS (M++H) m/z 404.
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. MS (M++H) m/z 410.
Example 47
1 -Phenylthiocarbamoyl- lH-pyrazole-3-carboxylic acid (2-chlorophenvP- amide
A mixture of lH-pyrazole-3-carboxylic acid (2-chlorophenyl)amide (10 mg,
44.5 μmol; see Example 43(a)), phenylisothiocyanate (30 mg, 0.22 mmol) and anhydrous K2Cθ3 (69 mg, 0.5 mmol) in dry acetone (2 mL) was stirred for 5 h at room temperature. The reaction mixture was then filtered and concentrated. Purification by chromatography gave the title compound (yield: 12 mg, 76%) as a white solid. MS (M++H) m/z 357.
1H NMR (400 MHz) δ 10.52 (s, IH), 9.22 (s, IH), 8.84 (d, J = 3 Hz, IH), 8.55 (dd, J= 9, 2 Hz, IH), 7.80 (m [app d, J= 8 Hz], 2H), 7.50 (m [app t, J = 8 Hz], 2H), 7.43 (dd, J= 9, 2 Hz, IH), 7.35 (m [app dq, J = 7, 1 Hz], 2H), 7.11 (dt, J= 8,l Hz, lH), 7.06 (d, J= 3 Hz, IH). 13C NMR (100.5 MHz) δ 172.0, 158.3, 148.7, 136.7, 134.1, 133.2, 129.23, 129.16, 128.0, 127.4, 125.0, 123.6, 122.9, 121.4, 110.0.
Example 48
N-(2-Chloro-4-fluorophenyl)- 1 -(1 -methylpiperazine-4-carbonyl)- \H- pyr azole- 3 - carb oxamide
(a) N-(2-Chloro-4-fluorophenyl)-lH-pyrazole-3-carboxamide The sub-title compound was prepared according to the procedure described above in Example 30(a) using dipyrazolo[l,5-α;l,,5l-βT|pyrazine-4,9-dione (see Example 6(a)) and 2-chloro-4-fluoroaniline. MS (M+) m/z = 239.
1H ΝMR (DMSO-D6, 300 MHz) δ 13.48 (broad s, IH), 9.67 (s, IH), 7.99 (m, IH), 7.91 (d, IH), 7.56 (dd, IH), 7.28 (ddd, IH), 6.81 (d, IH).
(b) N-(2-Chloro-4-fluorophenyl)-l-(l-methylpiperazine-4-carbonyl)-lH- pyrazole-3-carboxamide
N-(2-Chloro-4-fluorophenyl)-lH-pyrazole-3-carboxamide (50 mg, 209 μmol, 1 equiv.; see step (a) above) was mixed with the hydrochloride salt of 4-methyl-piperazine-l -carbonyl chloride (83 mg, 410 μmol, 2 equiv.) and DMAP (50 mg, 410 μmol, 2 equiv.) in toluene (5 mL) at 90°C. 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). 0.5 M NaOH (aq.) and ethyl acetate were added to the salt. The organic phase was dried and concentrated to afford the free base of the title compound as an off-white solid. MS: m z = 366 (M+ + l).
1H NMR (CDC13): δ 9.21 (br s, IH), 8.56 (m, IH), 8.17 (d, J = 3 Hz, IH), 7.18 (m, IH), 7.07 (m, IH), 6.98 (d, /= 3 Hz, IH), 3.99 (m, 4H), 2.68 (m, 4H), 2.44 (s, 3H).
Example 49 N3-(2-Chlorophenyl)-N1-(l-(2,2,2-trifluoroacetyl piperidin-4-yl)-lH- pyrazole- 1 ,3-dicarboxamide lH-Pyrazole-3-carboxylic acid (2-chlorophenyl)amide (50 mg, 226 μmol, 1 equiv.; see Example 30(a)), 2,2,2-trifluoro-l-(4-isocyanatopiperidin-l- yl)ethanone (76 mg, 338 μmol, 1.5 equiv.) and DMAP (33mg, 270 μmol, 1.2 equiv.) were added to toluene at room temperature. The reaction was left stining for 24 h, after which the excess solvent removed. Purification by chromatography afforded the title compound. MS: m/z = 444 (M+ + l).
1H ΝMR (dmso- 6): δ 9.86 (s, IH), 8.52 (d, J = 8 Hz, IH), 8.45 (d, J = 3 Hz, IH), 7.76 (dd, J= 8, 1 Hz, IH), 7.60 (dd, J= 8, 1 Hz, IH), 7.42 (dt, J = 8, 1 Hz, IH), 7.31 (dt, J= 8 Hz, IH); 6.99 (d, J = 3 Hz, IH), 4.31 (m, IH), 4.12-4.02 (m, IH), 3.91 (m, IH), 3.43 (t, J= 12 Hz, IH), 3.08 (t, J= 12 Hz, IH), 2.09-1.99 (m, 2H), 1.71-1.56 (m, 2H). Example 50
Pyrazole-l,3-dicarboxylic acid-l-[(3-chlorophenyl)amide1-3-(methylphen- ylamide)
fa) lH-Pyrazole-3-carboxylic acid methylphenylamide
A mixture of dipyrazolo[l,5-a;l',5'-d]pyrazine-4,9-dione (1.00 g, 5.30 mmol; see Example 6(a)), N-methyl aniline (5.00 g, 0.38 mmol), and 4- (NN-dimethylamino)pyridine (0.650 g, 5.30 mmol) was stirred at 120°C for 4 h. After cooling to room temperature, EtOH (15 ml), water (50 ml) and z'sø-hexane (50 ml) were added. The resulting mixture was shaken and then the aqueous phase was separated. The organic phase was concentrated to afford the crude product (1.27 g). Purification by recrystallisation from EtOH afforded the sub-title compound (yield: 0.990 g, 47%) MS (M++H) m/z = 202. 1H NMR (DMSO-Dό, 400 MHz) δ 7.60 (s, IH), 7.55-7.10 (m, 5H), 6.15 (s, lH), 3.35 (s, 3H).
(b) Pyrazole-L3-dicarboxylic acid-l-[(3-chlorophenyl amide]-3-(methyl- phenylamide) A mixture of lH-pyrazole-3 -carboxylic acid methylphenylamide (0.200 g, 0.994 mmol; see step (a) above), l-chloro-3-isocyanatobenzene (0.183 g, 1.19 mmol) and toluene (5 ml) was stirred at 100°C for 18 h. The reaction mixture was then cooled to room temperature and the solvent was evaporated. wø-Hexane (10 ml) was then added and the resulting precipitate was filtered off. The precipitate was then washed with isohexane (20 ml) and then dried under reduced pressure to give the title compound (yield: 0.212 g, 60 %). MS (M++H) m/z = 356. 1H NMR (CDCI3, 400 MHz) δ 8.45 (s, IH), 8.05 (s, IH), 7.60-7.00 (m, 9H), 6.35 (s, IH), 3.50 (s, 3H).
Example 51 1 -(4-tβrt-Butylbenzenesulfonyl)- lH-pyrazole-3-carboxylic acid methylphenylamide
A mixture of lH-pyrazole-3-carboxylic acid methylphenylamide (0.200 g, 0.994 mmol; see Example 50(a)), 4-tert-butylbenzenesulfonyl chloride (0.278 g, 1.19 mmol), 4-(NN-dimethylamino)pyridine (0.146 g, 1.19 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). The organic phase was filtered through a short silica plug (eluting with acetone) and concentrated. The crude product was purified by recrystallisation from hexane to afford the title compound (yield: 0.257 g, 65%). MS (M++Η) m/z = 399.
1H NMR (CDCI3, 400 MHz) δ 7.87 (s, IH), 7.73-7.58 (m, 2H), 7.53-7.41 (m, 2H), 7.25-6.95 (m, 5), 6.38 (s, IH), 3.40 (s, 3H), 1.29 (s, 9H). 13C NMR (CDCI3, 100.5 MHz) δ 162.4, 158.7, 151.8, 144.0, 133.5, 131.0, 129.1, 128.2, 127.3, 126.5, 110.0, 38.4, 35.5, 31.0.
Example 52
1 -(3 -Chlorobenzenesulfonyiy 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-chlorobenzenesulfonyl chloride (0.126 g, 0.596 mmol), 4-(N,N-dimethylamino)pyridine (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 (20 ml) was added and the mixture was washed twice with water (10 ml). The organic phase was filtered through a short silica plug (eluting with acetone) and concentrated. The crude product was purified by recrystallisation from isohexane to afford the title compound (yield: 0.140 g, 75%) as white crystals. MS (M++H) /z = 376.
Η NMR (CDC13, 400 MHz) δ 7.92 (s, IH), 7.74 (s, IH), 7.67-7.50 (m, 2H), 7.48-7.34 (m, IH), 7.33-6.92 (m, 5H), 6.50 (s, IH), 3.50 (s, 3H). 13C NMR (CDCI3, 100.5 MHz) δ 162.0, 152.4, 143.9, 138.1, 135.5, 134.9, 131.2, 130.7, 129.1 , 128.3, 127.5, 127.2, 126.5, 110.5, 38.4.
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)ρyridine (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). The organic phase was filtered through a short silica plug (eluting with acetone) and concentrated. The crude product was purified by recrystallisation from isohexane, benzene and diethyl ether to afford the title compound (yield: 0.025 g, 15%) as white crystals. MS (M++H) m/z = 340. 1H ΝMR (CDC13, 400 MHz) δ 8.26 (s, IH), 7.84 (s, IH), 7.58-7.10 (m, 8H), 6.65 (s, IH), 3.50 (s, 3H). Example 54
3-fMethylphenylcarbamoyl)pyrazole-l -carboxylic acid 2-chlorobenzyl ester A mixture of lH-pyrazole-3 -carboxylic acid methylphenylamide (0.100 g, 0.497 mmol; see Example 50(a)), 2-chlorobenzyl chloroformate (0.122 g, 0.596 mmol), 4-(NN-dimethylamino)pyridine (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). The organic phase was separated and concentrated. The crude product was then purified by recrystallisation from iso-hex&ne, then from MeOH and finally from benzene to afford the title compound (yield: 0.050 g, 27%) as white crystals.
MS (M++H) m/z = 370. 1H NMR (CDC13, 400 MHz) δ 7.90 (s, IH), 7.55-7.05 (m, 9H), 6.20 (s, IH), 5.48 (s, 2H), 3.50 (s, 3H).
Anal, calcd for C19Hι6ClN303: C, 61.71; H, 4.36; Found: C, 61.29: H, 4.66.
Example 55
Pyrazole- 3-dicarboxylic acid 1-butylamide 3-[(2-chlorophenyl)methyl- amide]
A mixture of lH-pyrazole-3-carboxylic acid (2-chlorophenyl)methylamide (0.052 g, 0.220 mmol; see Example 43(a)), 1-isocyanatobutane (0.026 g, 0.265 mmol), and toluene (5 ml) was stirred at 100°C for 20 h. The reaction mixture was then cooled to room temperature. The solvent was then evaporated, diethyl ether (30 ml) was added and the resulting precipitate was filtered off. The mother liquor was evaporated to afford the title compound (yield: 0.054 g, 73%) as a thick oil. MS (M++H) m/z = 335. Example_56
Pyrazole-l,3-dicarboxylic acid 1-benzylamide 3-[(2-chlorophenyl)methyl- amide]
A mixture of lH-ρyrazole-3-carboxylic acid (2-chlorophenyl)methylamide (0.052 g, 0.220 mmol; see Example 43(a)), isocyanatomethylbenzene
(0.036 g, 0.270 mmol), and toluene (5 ml) was stirred at 100°C for 24 h.
The reaction mixture was then cooled to room temperature, filtered, concentrated and then dried under high vacuum for three days to give the pure title compound (yield: 0.048 g, 58%). MS (M++H) m/z = 369.
1H NMR (CDC13, 400 MHz) δ 7.98 (m, IH), 7.48-7.10 (m, 7H), 7.08-7.0
(m, IH), 6.91-6.83 (m, IH), 6.61-6.55 (m, IH), 6.45 (br s, IH), 4.50-4.30
(m, 2H), 3.35 (s, 3H);
13C NMR (CDCI3, 100.5 MHz) δ 161.9, 149.0, 148.4, 142.0, 136.9, 133.2, 130.1, 130.0, 129.2, 128.9, 128.6, 128.5, 128.2, 127.5, 110.4, 44.5, 37.1.
Example 57
Pyrazole-L3-dicarboxylic acid l-(benzo[ 3]dioxol-5-ylamide 3-(2-chloro- pyridin-3-yl)amide
(a) lH-Pyrazole-3-carboxylic acid (2-chloropyridin-3-yl)amide A mixture of dipyrazolo[l,5-a;r,5'-d]pyrazine-4,9-dione (2.66 mmol, 500 mg, see Example 6(a)), 3-amino-2-chloropyridme (6.64 mmol, 854 mg), and DMAP (1.33 mmol, 162 mg) was heated at 190°C for 5 minutes using microwaves with a Smith synthesizer from Personal Chemistry. The reaction mixture was allowed to cool and mixed with water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x5 mL). The combined organic phases were concentrated and purified by preparative HPLC to give 139 mg of the sub-title compound as a white solid. MS (M+) m/z = 222.
!H NMR (DMSO-D6, 300 MHz) δ 13.63 (broad s, IH), 9.60 (broad s, IH), 8.48 (d, IH), 8.22 (dd, IH), 7.95 (d, IH), 7.50 (dd, IH), 6.83 (d, IH).
(b) Pyrazole-L3-dicarboxylic acid l-(benzo[L3]dioxol-5-ylamide) 3-(2- chloro-pyridin-3-yDamide
A mixture of lH-pyrazole-3-carboxylic acid (2-chloropyridin-3-yl)amide (0.25 mmol, 55 mg; see step (a) above), 3,4-methylenedioxyphenyl isocyanate (0.30 mmol, 49 mg) and toluene (0.5 mL) was heated at 180°C for 10 min using microwaves with a Smith synthesizer from Personal
Chemistry. The title compound was precipitated by addition of isohexane
(4 mL) and collected by filtration (yield 34 mg). MS (M+) m/z = 385.
1H NMR (CDC13, 300 MHz) δ 9.22 (s, IH), 8.92 (dd, IH), 8.79 (s, IH),
8.43 (d, IH), 8.20 (dd, IH), 7.37 (dd, IH), 7.31 (d, IH), 7.10 (d, IH), 6.95
(dd, IH), 6.86 (d, IH), 6.04 (s, 2H).
Example 58
6-{[3-(2-Chloropyridin-3-ylcarbamoyl)pyrazole-l-carbonyl]- aminoU exanoic acid ethyl ester
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.
MS (M+) m/z = 407. 1H NMR (CDCI3, 300 MHz) δ 9.19 (s, IH), 8.88 (dd, IH), 8.33 (d, IH), 8.18 (dd, IH), 7.35 (ddd, IH), 7.10 (t, IH), 7.02 (d, IH), 4.12 (q, 2H), 3.52 (q, 2H), 2.35 (t, 2H), 1.80-1.66 (m, 4H), 1.54-1.42 (m, 2H), 1.25 (t, 3H).
Example 59
Pyrazole-l,3-dicarboxylic acid 3-(2-chloropyridin-3-yl)amide) 1-pentyl- amide
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 pentyl isocyanate. MS (M+) m/z = 335.
1H NMR (CDCI3, 300 MHz) δ 9.17 (s, IH), 8.89 (dd, IH), 8.32 (d, IH), 8.17 (dd, IH), 7.33 (dd, IH), 7.05 (t, IH), 7.01 (d, IH), 3.50 (q, 2H), 1.76- 1.64 (m, 2H), 1.46-1.37 (m, 4H), 0.99-0.90 (m, 3H).
Example 60
Pyrazole-l,3-dicarboxylic acid l-benzo[L3]dioxol-5-ylamide 3-(2-fluoro-5- trifluoiOinethylphenylamide)
(a) lH-Pyrazole-3 -carboxylic acid 2-fluoro-5-trifluoromethylphenylamide The sub- title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a; r,5'-d]pyrazine-4,9-dione (see Example 6(a)) and 2-fluoro-5-(trifluoromethyl)aniline. MS (M+) m/z = 273. 1H NMR (DMSO-D6, 300 MHz) δ 12.94 (broad s, IH), 9.45 (broad s, IH), 8.26 (dd, IH), 7.91 (d, IH), 7.62 (dd, IH), 7.55 (dd, IH), 6.83 (d, IH). (b) Pyrazole-l,3-dicarboxylic acid l-benzo[l,3]dioxol-5-ylamide 3-(2- fluoro-5-trifluoromethylphenylamide)
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 2-fluoro-5- trifluoromethylphenylamide (see step (a) above) and 3,4-
(methylenedioxy)phenyl isocyanate.
MS (M+) m/z = 436.
1H NMR (DMSO-D6, 300 MHz) δ 10.43 (broad s, IH), 10.17 (broad s, IH),
8.55 (d, IH), 8.29 (dd, IH), 7.70 (ddd, IH), 7.60 (dd, IH), 7.31 (d, IH), 7.12 (dd, IH), 7.06 (d, IH), 6.98 (d, IH), 6.06 (s, 2H).
Example 61
Pyrazole-L3-dicarboxylic acid 3-(2-fluoro-5-trifluoromethylphenylamide)
1 -(3 -trifluoromethylphenylamide) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 2-fluoro-5- trifluoromethylphenylamide (see Example 60(a)) and 3- trifluoromethylphenyl isocyanate.
MS (M+) m/z = 460. Η NMR (CDC13, 400 MHz) δ 9.00 (s, IH), 8.90-8.86 (m, 2H), 8.44 (d,
IH), 7.96 (dd, IH), 7.88 (dd, IH), 7.59 (dd, IH), 7.51 (ddd, IH), 7.43
(dddd, IH), 7.30 (ddd, IH), 7.13 (d, IH).
Example 62
Pyrazole- 3-dicarboxylic acid 3-(3-cvanophenylamide) l-(4-trifluoro- methoxyphenylamide
(a) lH-Pyrazole-3-carboxylic acid 3-cyanophenylamide
The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a;r,5'-d]pyrazine-4,9-dione (see Example 6(a)) and 3-cyanoaniline. MS (M+) m/z = 212. 1H NMR (DMSO-D6, 300 MHz) δ 13.53 (s, IH), 10.45 (s, IH), 8.28 (s, IH), 8.10 (dd, IH), 7.90 (s, IH), 7.50-7.60 (m, 2H), 6.80 (s, IH).
(b) Pyrazole- 3-dicarboxylic acid 3-(3-cyanophenylamide) l-(4-trifluoro- methoxyphenylamide) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid 3- cyanophenylamide (see step (a) above) and 4-(trifluoromethoxy)phenyl isocyanate.
MS (M+) m/z = 415. 1H NMR (CDC13, 300 MHz) δ 9.00 (s, IH), 8.75 (s, IH), 8.43 (s, IH), 8.10-
8.03 (m, 2H), 7.77-7.70 (m, 2H), 7.53 (dd, IH), 7.46 (ddd, IH), 7.35-7.29
(m, 2H), 7.12 (d, IH).
Example 63
Pyrazole- 3-dicarboxylic acid 3-(2-chloro-4-fluorophenylamide) l-(4-tri- fluoromethoxyphenylamide
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 4-(trifluoromethoxy)phenyl isocyanate. MS (M+) m/z = 442.
Η NMR (CDC13, 300 MHz) δ 9.07 (s, IH), 8.95 (s, IH), 8.60-8.34 (m, 2H), 7.70-7.60 (m, 2H), 7.40-7.18 (m, 3H), 7.17-7.00 (m, 2H).
Example 64
Pyrazole- 3-dicarboxylic acid l-(benzo[ 3]dioxol-5-ylamide) 3-(2-chloro-
4-fluorophenylamide 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 3,4-(methylenedioxy)phenyl isocyanate.
MS (M+) m/z = 402. 1H NMR (CDCI3, 300 MHz) δ 9.09 (s, IH), 8.79 (s, IH), 8.52 (dd, IH),
8.41 (d, IH), 7.30 (d, IH), 7.23 (dd, IH), 7.09 (ddd, IH), 7.08 (d, IH), 6.95
(dd, IH), 6.86 (d, IH), 6.04 (s, 2H).
Example 65 6-{[3-(2-Chloro-4-fluoroρhenylcarbamoyl)ρyrazole-l-carbonyl]-amino}- hexanoic acid ethyl ester
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 ethyl 6-isocyanatohexanoate. MS (M+) m/z = 424.
1H NMR (CDCI3, 300 MHz) δ 9.06 (s, IH), 8.48 (dd, IH), 8.32 (d, IH),
7.21 (dd, IH), 7.10 (t, IH), 7.08 (ddd, IH), 7.02 (d, IH), 4.12 (q, 2H), 3.51
(q, 2H), 2.35 (t, 2H), 1.79-1.65 (m, 4H), 1.53-1.41 (m, 2H), 1.25 (t, 3H).
Example 66
Pyrazole-l,3-dicarboxylic acid 3-f2-chloro-4-fluorophenylamide) 1-pentyl- amide
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.
MS (M+) m/z = 352.
1H NMR (CDCI3, 300 MHz) δ 9.08 (s, IH), 8.51 (dd, IH), 8.32 (d, IH),
7.21 (dd, IH), 7.13-7.00 (m, IH), 3.50 (q, 2H), 1.78-1.65 (m, 2H), 1.47-1.38 (m, 4H), 1.00-0.92 (m, 3H).
Example 67
Pyrazole-l,3-dicarboxylic acid 3-(2,6-dichloiOphenylamide l-(4-trifluoro- methoxyphenylamide)
(a) lH-Pyrazole-3-carboxylic acid 2,6-dichlorophenylamide
The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a;r,5'-d]pyrazine-4,9-dione
(see Example 6(a)) and 2,6-dichloroaniline. MS (M+) m/z = 255.
1H NMR (DMSO-D6, 300 MHz) δ 13.45 (broad s, IH), 10.03 (broad s, IH),
7.87 (s, IH), 7.56 (d, 2H), 7.37 (t, IH), 6.77 (s, IH). (b) Pyrazole- 3-dicarboxylic acid 3-(2,6-dichlorophenylamide l-(4- trifluoro-methoxyphenylamide)
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid 2,6- dichlorophenylamide (see step (a) above) and 4-(trifluoromethoxy)phenyl isocyanate.
MS (M+) m/z = 458.
1H NMR (CDC13, 300 MHz) δ 9.01 (s, IH), 8.41 (d, IH), 8.36 (s, IH), 7.74-
7.68 (m, 2H), 7.47-7.42 (m, 2H), 7.33-7.26 (m, 3H), 7.12 (d, IH).
Example 68
Pyrazole- 1 ,3-dicarboxylic acid 3-(2-bromo-4-trifluoromethoxyphenyl- amide) 1 -(3-trifluoromethylphenylamide)
(a) lH-Pyrazole-3-carboxylic acid 2-bromo-4-trifluoromethoxyphenylamide The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a;r,5'-d]pyrazine-4,9-dione (see Example 6(a)) and 2-bromo-4-trifluoromethoxyaniline. MS (M+) m/z = 349. 1H NMR (DMSO-D6, 300 MHz) δ 13.63 (broad s, IH), 9.70 (broad s, IH), 8.21 (d, IH), 7.93 (d, IH), 7.82 (dd, IH), 7.49 (ddd, IH), 6.83 (d, IH).
(b) Pyrazole- 3-dicarboxylic acid 3-(2-bromo-4-trifluoromethoxyphenyl- amide) 1 -(3-trifluoromethylphenylamide) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 2-bromo-4- trifluoromethoxyphenylamide (see step (a) above) and 3- trifluoromethylphenyl isocyanate. MS (M+) m/z = 536. 1H NMR (DMSO-D6, 300 MHz) δ 13.57 (s, IH), 9.70 (s, IH), 8.21 (d, IH), 7.95 (d, IH), 7.83 (dd, IH), 7.54-7.47 (m, IH), 7.20 (t, IH), 6.86-6.73 (m, 3H).
Example 69
Pyrazole- 1,3-dicarboxylic acid l-(benzo[ 3]dioxol-5-ylamide) 3-(2-bromo-
4-trifluoromethoxyphenylamide)
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 2-bromo-4- trifluoromethoxyphenylamide (see Example 68(a)) and 3,4-
(methylenedioxy)phenyl isocyanate.
MS (M+) m/z = 512.
1H NMR (CDC13, 300 MHz) δ 9.24 (s, IH), 8.81 (s, IH), 8.62 (d, IH), 8.42
(d, IH), 7.54 (dq, IH), 7.34-7.29 (m, 2H), 7.09 (d, IH), 6.94 (dd, IH), 6.86 (d, IH), 6.04 (s, 2H).
Example 70
Pyrazole- 1 ,3-dicarboxylic acid 3-(2-bromo-4-trifluoromethoxyphenyl- amide) 1-pentylamide The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 2-bromo-4- trifluoromethoxyphenylamide (see Example 68(a)) and pentyl isocyanate.
MS (M+) m/z = 462.
Η NMR (CDCI3, 300 MHz) δ 9.22 (s, IH), 8.61 (d, IH), 8.33 (d, IH), 7.52 (d, IH), 7.29 (dd, IH), 7.05 (t, IH), 7.03 (t, IH), 3.51 (q, 2H), 1.78-1.65 (m,
2H), 1.47-1.37 (m, 4H), 1.00-0.93 (m, 3H). Example 71
6- { [3-(2-Bromo-4-trifluoromethoxyphenylcarbamoyl)pyrazole- 1 -carbonyl]- aminolhexanoic acid ethyl ester
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 2-bromo-4- trifluoromethoxyphenylamide (see Example 68(a)) and ethyl 6- isocyanatohexanoate. MS (M+) m/z = 534.
1H NMR (CDC13, 300 MHz) δ 9.20 (s, IH), 8.58 (d, IH), 8.33 (d, IH), 7.52 (dq, IH), 7.29 (dd, IH), 7.09 (t, IH), 7.03 (d, IH), 4.12 (q, 2H), 3.52 (q, 2H), 2.36 (t, 2H), 1.79-1.66 (m, 4H), 1.54-1.42 (m, 2H), 1.26 (t, 3H).
Example 72
6- {[3-(3-Methylpyridin-2-ylcarbamoyl)pyrazole-l-carbonyl]amino}- hexanoic acid ethyl ester
(a) lH-Pyrazole-3-carboxylic acid (3-methylpyridin-2-yl amide The sub- title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a; l,,5'-d]pyrazine-4,9-dione (see Example 6(a)) and 2-amino-3-methylpyridine. MS (M+) m/z = 202.
1H NMR (DMSO-D6, 300 MHz) δ 13.44 (s, IH), 10.09 (s, IH), 8.29 (dd, IH), 7.84 (s, IH), 7.71 (dd, IH), 7.24 (dd, IH), 6.84 (s, IH), 2.21 (s, 3H).
(b) 6-{[3-(3-Methylpyridin-2-ylcarbamoyl)ρyrazole-l-carbonyl]amino}hex- anoic acid ethyl ester
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid (3- methylpyridin-2-yl) amide (see step (a) above) and ethyl 6- isocyanatohexanoate. MS (M+) m/z = 387.
1H NMR (DMSO-D6, 300 MHz) δ 10.30 (s, 1H)3 8.69 (t, IH), 8.39 (d, IH), 8.33 (dd, IH), 7.77 (dd, IH), 7.30 (dd, IH), 6.97 (d, IH), 4.02 (q, 2H), 3.30 (dt, 2H), 2.29 (t, 2H), 2.23 (s, 3H), 1.64-1.50 (m, 4H), 1.40-1.27 (m, 2H), 1.15 (t, 3H).
Example 73 Pyrazole- 1,3-dicarboxylic acid 3-(3-methylpyridin-2-yl)amide) 1- pentylamide
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid (3- methylpyridin-2-yl)amide (see Example 72(a)) and pentyl isocyanate. MS (M+) m/z = 315.
1H NMR (CDC13, 300 MHz) δ 9.07 (s, IH), 8.30 (d, IH), 8.28 (d, IH), 7.65 (d, IH), 7.18 (dd, IH), 7.12 (t, IH), 6.98 (d, IH), 3.44 (q, 2H), 2.38 (s, 3H), 1.71-1.59 (m, 2H), 1.43-1.33 (m, 4H), 0.97-0.89 (m, 3H).
Example 74
6- {[3-(2-Methoxy-6-methylphenylcarbamoyl)pyrazole-l-carbonyl]amino}- hexanoic acid ethyl ester
(a) lH-Pyrazole-3-carboxylic acid 2-methoxy-6-methylphenylamide The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a;r,5'-d]pyrazine-4,9-dione (see Example 6(a)) and 2-methoxy-6-methylaniline.
MS (M+) m/z = 231. 1H NMR (DMSO-D6, 300 MHz) δ 13.35 (s, IH), 9.15 (s, IH), 7.83 (s, IH), 7.17 (dd, IH), 6.89 (d, IH), 6.85 (d, IH), 6.75 (s, IH), 3.73 (s, 3H), 2.15 (s, 3H).
(b) 6-{[3-(2-Methoxy-6-memylphenylcarbamoyl pyrazole-l-carbonyl1- amino) hexanoic acid ethyl ester
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid 2-methoxy-6- methylphenylamide (see step (a) above) and ethyl 6-isocyanatohexanoate. MS (M+) m/z = 416.
1H NMR (CDC13, 300 MHz) δ 8.29 (d, IH), 8.26 (s, IH), 7.28 (s, IH), 7.26- 7.16 (m, IH), 7.00 (d, IH), 6.91 (d, IH), 6.81 (d, IH), 4.08 (q, 2H), 3.84 (s, 3H), 3.50 (q, 2H), 2.35 (t, 2H), 2.32 (s, 3H), 1.78-1.64 (m, 4H), 1.54-1.41 (m, 2H), 1.22 (t, 3H).
Example 75
Pyrazole- 1,3-dicarboxylic acid l-(benzo[l,3]dioxol-5-ylamide) 3-(4- trifluoromethylphenylamide)
(a) lH-Pyrazole-3-carboxylic acid 4-trifluoromethylphenylamide
The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a;l',5'-d]pyrazine-4,9-dione (see Example 6(a)) and 4-trifluoromethylaniline. MS (M+) m/z = 255. 1H NMR (DMSO-D6, 300 MHz) δ 13.58 (s, IH), 10.46 (s, IH), 8-.04 (d, 2H), 7.89 (d, IH), 7.69 (d, 2H), 6.84 (d, IH). (b) Pyrazole- 3-dicarboxylic acid l-(benzo[l,3]dioxol-5-ylamide 3-(4-tri- fluoromethylphenylamide
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 4- trifluoromethyl-phenylamide (see step (a) above) and 3,4- (methylenedioxy)phenyl isocyanate. MS (M+) m/z = 418.
1H NMR (CD3CN, 300 MHz) δ 9.52 (s, IH), 9.47 (s, IH), 8.36 (d, IH), 8.00 (d, 2H), 7.70 (d, 2H), 7.34 (d, IH), 7.11 (dd, IH), 6.99 (d, IH), 6.88 (d, IH), 6.01 (s, 2H).
Example 76 amide) The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid 4- trifluoromethylphenylamide (see Example 75(a)) and pentyl isocyanate. MS (M+) m/z = 368. 1H NMR (CDC13, 300 MHz) δ 8.67 (s, IH), 8.31 (d, IH), 7.83 (d, 2H), 7.64 (d, 2H), 7.06 (t, IH), 7.02 (d, IH), 3.48 (q, 2H), 1.76-1.65 (m, 2H), 1.45- 1.36 (m, 4H), 0.98-0.90 (m, 3H).
Example 77
6-{[3-(4-Trifluoromethylphenylcarbamoyl)pyrazole-l-carbonyl]amino}hex- anoic acid ethyl ester
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid 4- trifluoromethyl-phenylamide (see Example 75(a)) and ethyl 6- isocyanatohexanoate. MS (M+) m/z = 440.
1H NMR (CDCI3, 300 MHz) δ 8.86 (s, IH), 8.31 (d, IH), 7.87 (d, 2H), 7.65 (d, 2H), 7.19 (t, IH), 7.03 (d, IH), 4.10 (q, 2H), 3.52 (q, 2H), 2.38 (t, 2H), 1.80-1.68 (m, 4H), 1.55-1.43 (m, 2H), 1.23 (t, 3H).
Example 78
Pyrazole- 1,3-dicarboxylic acid bis(benzo[l,3]dioxol-5-ylamide)
(a) lH-Pyrazole-3-carboxylic acid benzo[l,3]dioxol-5-ylamide The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a; r,5'-d]pyrazine-4,9-dione
(see Example 6(a)) and 3, 4- (methylenedioxy) aniline.
MS (M+) m/z = 231.
1H NMR (DMSO-D6, 300 MHz) δ 13.39 (s, IH), 9.97 (s, IH), 7.88 (s, IH), 7.47 (s, IH), 7.27 (d, IH), 6.87 (d, IH), 6.74 (s, IH), 5.99 (s, 2H).
(b) Pyrazole- 3-dicarboxylic acid bis(benzo[l,3]dioxol-5-ylamide)
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid benzo[l,3]dioxol-5-ylamide (see step (a) above) and 3,4- (methylenedioxy)phenyl isocyanate. MS (M+) m/z = 394.
1H NMR (CD3CN, 300 MHz) δ 9.42 (s, IH), 9.18 (s, IH), 8.37 (d, IH), 7.47 (dd, IH), 7.34 (dd, IH), 7.17-7.07 (m, 2H), 6.97 (d, IH), 6.93-6.85 (m, 2H), 6.02 (s, 2H), 6.00 (s, 2H). _ Example 79
Pyrazole- 1,3-dicarboxylic acid 3-(benzo[L3]dioxol-5-ylamide) 1- pentyl amide
The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3-carboxylic acid benzo[l,3]dioxol-5-ylamide (see Example 78(a)) and pentyl isocyanate. MS (M+) m/z = 344.
1H NMR (CDC13, 300 MHz) δ 8.46 (s, IH), 8.27 (d, IH), 7.39 (d, IH), 7.08 (t, IH), 6.98 (d, IH), 6.95 (d, IH), 6.78 (d, IH), 5.98 (s, 2H), 3.46 (q, 2H), 1.74-1.63 (m, 2H), 1.43-1.35 (m, 4H), 0.97-0.89 (m, 3H).
Example 80
6- {[3-(Benzo[l,3]dioxol-5-ylcarbamoyl)pyrazole-l-carbonyl]-amino}- hexanoic acid ethyl ester The title compound was prepared according to the procedure described above in Example 57(b) from lH-pyrazole-3 -carboxylic acid benzo[l,3]dioxol-5-ylamide (see Example 78(a)) and ethyl 6- isocyanatohexanoate.
MS (M+) m/z = 416. 1H NMR (CDCI3, 300 MHz) δ 8.63 (s, IH), 8.27 (d, IH), 7.40 (d, IH), 7.22
(t, IH), 6.99 (dd, IH), 6.98 (d, IH), 6.78 (d, IH), 5.98 (s, 2H), 4.10 (q, 2H),
3.48 (q, 2H), 2.35 (t, 2H), 1.77-1.64 (m, 4H), 1.52-1.39 (m, 2H), 1.23 (t,
3H).
Example 81
Pyrazole-l,3-dicarboxylic acid l-(benzo[ 3]dioxol-5-ylamide 3-(3-chloro-
4-fluorophenylamide)
(a) 17J"-Pyrazole-3-carboxylic acid 3-chloro-4-fluorophenylamide
The sub-title compound was prepared according to the procedure described above in Example 57(a) using dipyrazolo[l,5-a;l',5,-d]pyrazine-4,9-dione (see Example 6(a)) and 3-chloiO-4-fluoroaniline. MS (M+) m/z = 239. 1H NMR (DMSO-D6, 300 MHz) δ 13.60 (broad s, IH), 10.30 (broad s, IH), 8.09 (dd, IH), 7.87 (s, IH), 7.77 (ddd, IH), 7.48 (t, IH), 6.80 (s, IH).
(b) Pyrazole- 1,3-dicarboxylic acid l-(benzo[ 3]dioxol-5-ylamide 3-(3- chloro-4-fluorophenylamide) 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 step (a) above) and 3,4-(methylenedioxy)phenyl isocyanate.
MS (M+) m/z = 402. 1H NMR (CDC13, 300 MHz) δ 8.76 (s, IH), 8.56 (s, IH), 8.40 (d, IH), 7.88
(dd, IH), 7.58 (ddd,lH), 7.29 (d, IH), 7.18 (dd, IH), 7.07 (d, IH), 6.98 (dd,
IH), 6.85 (d, IH), 6.04 (s, 2H).
Example 82 6-{[3-(3-Chloro-4-fluorophenylcarbamoyl)pyrazole-l-carbonyl]amino}hex- anoic acid ethyl ester
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 ethyl 6-isocyanatohexanoate. MS (M+) m/z = 424.
1H NMR (CDCI3, 300 MHz) δ 8.74 (s, IH), 8.29 (d, IH), 7.86 (dd, IH),
7.58 (ddd, IH), 7.19 (t, IH), 7.14 (dd, IH), 7.00 (d, IH), 4.09 (q, 2H), 3.50
(q, 2H), 2.37 (t, 2H), 1.79-1.66 (m, 4H), 1.53-1.41 (m, 2H), 1.23 (t, 3H).
Example 83
Pyrazole- 1,3-dicarboxylic acid 3-(3-chloro-4-fluorophenylamide 1-ρentyl- amide
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.
MS (M+) m/z = 352.
1H NMR (CDCI3, 300 MHz) δ 8.53 (s, IH), 8.30 (d, IH), 7.83 (dd, IH),
7.54 (ddd, IH), 7.14 (dd, IH), 7.07 (t, IH), 6.99 (d, IH), 3.47 (q, 2H), 1.75- 1.62 (m, 2H), 1.45-1.34 (m, 4H), 0.98-0.89 (m, 3H).
Example 84.
The inhibition of 15-lipoxygenase obtained using the biological test method described above is exemplified by the compounds of the above examples, as listed in the following table:
Example 1 : 45%
Example 8: 50%
Example 14: 39%
Example 23: 44% Example 26: 45%

Claims

Claims
A compound of formula I,
wherein
either R1 represents an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G and B , which B1 group may itself be further substituted by one or more substituents selected from G , Z (provided that Z is not directly attached to an aryl or a heteroaryl group) and B (which B group is optionally further substituted by one or more substituents selected from G , B and Z, provided that Z is not attached to an aryl or a heteroaryl group); and
R represents H or C1-6 alkyl, which latter group is optionally substituted by one or more halo groups; or when R2 represents C!-6 alkyl optionally substituted by halo, R1 and R2 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 G1, Z (provided that the ring is not aromatic in nature) and B1 (which B1 group is optionally substituted as described above); R3 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl or heteroaryl, all of which groups are optionally substituted by one or more substituents selected from Gla, Z (provided that Z is not directly attached to an aryl or a heteroaryl group) and B (which B group is optionally substituted as described above);
X represents a direct bond, -O- or -N(R4)-; Y represents -C(O)-, -C(S)- or-S(0)2-;
B1, B2 and B3 independently represent, on each occasion when used above, .6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3_8 heterocycloalkyl, aryl or heteroaryl;
Gl, G , G2 and G3 independently represent, on each occasion when used above, halo, cyano, -N3, -N02, -ON02 or -A^R4;
1 9 ^ wherein A represents a spacer group selected from -C(Z)A -, -N(R )A -, -OA4-, -S- or -S(0)nA5-, in which:
9 ^
A represents a single bond, -0-, -S- or -N(R )-; A3 represents A6, -C(Z)N(R5)C(Z)N(R5)-, -C(Z)N(R5)C(Z)0-, -C(Z)N(R5)S(0)nN(R5)-, -C(Z)S-, -S(0)n-, -S(0)nN(R5)C(Z)N(R5)-, -S(0)nN(R5)C(Z)0-, -S(0)nN(R5)S(0)nN(R5)-, -C(Z)0-, -S(0)nN(R5)- or -S(0)nO-;
A represents A0, -S(0)n-, -C(Z)0-, -S(0)nN(R3)- or -S(0)nO-;
A5 represents a single bond, -N(R5)- or -0-;
A6 represents a single bond, -C(Z)- or -C(Z)N(R5)-; Z represents, on each occasion when used above, a substituent connected by a double bond, which is selected from =0, =S, =NR4, =NN(R4)(R5), =NOR4, =NS(0)2N(R4)(R5), =NCN, =CHN02 and =C(R4)(R5); .
R4 and R5 independently represent, on each occasion when used above, H or B4., 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 B5 (which B5 group is itself optionally substituted by one or more substituents selected from G5, Q (provided that Q is not directly attached to an aryl or a heteroaryl group) and B6); or when R4 and R5 both represent optionally substituted B4 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 , Q (provided that the ring is not aromatic in nature) and B (which B group is optionally substituted as described above);
B , B and B independently represent on each occasion when used above Cι_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3_8 heterocycloalkyl, aryl or heteroaryl;
G4, G and G independently represent on each occasion when used above, halo, cyano, N3, -N02, -ON02 or -A7-R6; wherein A represents a spacer group selected from -C(Q)A -, -N(R )A -, -N(R7a)A9\ -OA10-, -S- or -S(0)nAπ-, in which:
A represents a single bond, -0-, -S- or -N(R )-;
A9 represents A12, -C(Q)S-, -S(0)n-, -C(Q)0-, -S(0)nN(R7)- or ~S(0)nO-; A9a represents -C(Q)N(R7)C(Q)N(R7)-, -C(Q)N(R7)C(Q)0-,
-C(Q)N(R7)S(0)nN(R7)-, -S(0)nN(R7)C(Q)N(R7)-, -S(0)nN(R7)C(Q)0-, -S(0)nN(R7)S(0)nN(R7)-;
A10 represents A12, -S(0)n-, -C(Q)0-, -S(0)nN(R7)- or -S(0)nO-; 5 A11 represents a single bond, -N(R7)- or -0-;
A12 represents a single bond, -C(Q)- or -C(Q)N(R7)-;
Q represents, on each occasion when used above, a substituent connected by a double bond, which is selected from =0, =S, =NR6, =N (R6)(R7), l o =NORδ, =NS(0)2N(R6)(R7), =NCN, =CHN02 and =C(R6)(R7) ;
R , R7 and R7a independently represent, on each occasion when used above, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3,8 heterocycloalkyl, aryl or heteroaryl, which latter seven groups are 15 optionally substituted by one or more groups selected from halo, Cι-6 alkyl (optionally substituted by one or more halo groups), -N(R8)R9, -OR8, -ON02 and -SR8; or f 7 provided that they do not represent H, any pair of R and R may, for example when present on the same atom or on adjacent atoms, be linked 0 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, C1-6 alkyl (optionally substituted by one or more halo groups),
-N(R8)R9, -OR8, -ON02 and -SR8 5 o n
R and R independently represent, on each occasion when used above, H or C1-6 alkyl, which latter group is optionally substituted by one or more halo groups; and n represents, on each occasion when used above, 1 or 2;
or a phannaceutically-acceptable salt thereof,
provided that, when 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-carbomβthoxyphenyl or 2,4- dimethylphenyl; 1 iii) R represents 2-chlorophenyl, then R does not represent phenyl, 3-bromophenyl or 4-bromophenyl; iv) R represents 3-chlorophenyl, then R 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 or 4-methoxyphenyl; vi) R represents 3-iodophenyl, then R does not represent 2-methoxyρhenyl or 2,4-dimethylphenyl; vii) 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 2 , 3 -dichlorophenyl ; ix) R represents 2,4-dimethyl-6-oxo-6H-pyran-3-yl, then R does not represent 3-carbomethoxyphenyl; x) R3 represents methyl, then R1 does not represent 3,4-dichlorophenyl, 2-methoxyphenyl, 2-thiazolyl, 4-methyl- 2-pyridinyl, 6-methyl-2-pyridinyl or 4-acetylphenyl; xi) RJ represents ethyl, then R1 does not represent phenyl, 2,3-dichlorophenyl, 4-methoxyphenyl, 2-carbomefhoxy- phenyl, 2-thiazolyl or 4-methyl-2-pyridinyl; (B) X represents -N(H)- and: i) R represents phenyl, then R1 does not represent 4- methoxyphenyl, 2,4-dimethylphenyl or 2-thiazolyl;
"λ 1 ii) R represents 3-chlorophenyl, then R does not represent
4-methylphenyl; iii) R represents 4-chlorophenyl, then R does not represent 3-bromophenyl; iv) R represents 3,4-dichlorophenyl, then R does not represent
4-methyl-2-pyridinyl or 6-methyl-2-pyridinyl; v) R represents 2'-sulfamoylbiphenyl-4-yl, then R does not represent 5-bromo-2-ρyridinyl; vi) R represents 1-propyl, then R does not represent phenyl; vii) R3 represents 1 -butyl, then Rl does not represent 4- bromophenyl or 2,4-dimethylphenyl; viii) R3 represents cyclohexyl, then R1 does not represent 4-methoxyphenyl; (C) X represents -O- and: i) R3 represents phenyl, then R1 does not represent phenyl or
6-methyl-2 -pyridinyl; ii) R3 represents methyl, then R1 does not represent phenyl, 2-fluoroρhenyl, 2,4-dimethylphenyl, 4-acetylphenyl or 2- thiazolyl; iii) R represents ethyl, then R does not represent phenyl, 2-fluorophenyl, 4-acetylphenyl or 4-methyl-2-pyridinyl; iv) R represents 1 -butyl, then R1 does not represent 2-fluorophenyl, 2-methoxyphenyl, 4-methyl-2-pyridinyl or 6-methyl-2-pyridinyl; v) R represents 2-butyl, then R does not represent 2-thiazolyl or 4-acetylphenyl; vi) R 3 represents 2-methyl- 1-propyl, then R 1 does not represent phenyl or 3-nitrophenyl.
2. A compound as claimed in Claim 1, wherein R represents an aryl or heteroaryl group, both of which are optionally substituted as defined in Claim 1.
3. A compound as claimed in Claim 1 or Claim 2, wherein G1 represents halo, cyano or — Ar-R .
4. A compound as claimed in any one of the preceding claims, wherein B1 represents an optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C -7 heterocycloalkyl, or phenyl, group.
5. A compound as claimed in any one of the preceding claims, wherein Gla represents halo, cyano, -NO2 or -A^R4.
6. A compound as claimed in any one of the preceding claims, wherein G2 represents halo, cyano, -ON02 or -A'-R4.
7. A compound as claimed in any one of the preceding claims, wherein B2 represents Cι_6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which are optionally substituted by one or more G and/or B groups.
8. A compound as claimed in any one of the preceding claims, wherein G3 represents halo, -ON02, -N(R5)(R4) or -OR4.
9. A compound as claimed in any one of the preceding claims, wherein B represents Cι-6 alkyl, C2-6 alkenyl or C2-6 alkynyl.
10. A compound as claimed in any one of the preceding claims, wherein wwhheenn AA11 rreepprreesseents -N(R5)A3-, A3 represents A6, -C(Z)S-, -S(0)n-, -C(Z)0- or -S(0)nN(R5)-
11. A compound as claimed in any one of Claims 1 to 9, wherein when A1 represents -OA4-, A4 represents A6.
12. A compound as claimed in any one of Claims 1 to 9, wherein when A1 represents -S(0)nA5-, A5 represents a single bond or
-N(R5)-.
13. A compound as claimed in any one of Claims 1 to 9, wherein when
1 9
A represents -C(Z)A -, A represents a single bond, -O- or -N(R )-.
14. A compound as claimed in any one of Claims 1 to 11 or 13 wherein A1 represents -C(Z)A2-, -N(R5)A3- or -OA4-.
15. A compound as claimed in any one of the preceding claims, wherein Z represents =0 or =NR4.
16. A compound as claimed in any one of the preceding claims, wherein when any pair of R4 and R5 are linked together to form a ring, they are optionally substituted with G6 and or B4.
17. A compound as claimed in any one of the preceding claims, wherein G4 represents halo, cyano, -ON02 or -A7-R6.
18. A compound as claimed in any one of the preceding claims, wherein B5 represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, all of which are optionally substituted by one or more G5 and/or B groups.
19. A compound as claimed in any one of the preceding claims, wherein G5 represents halo, -ON02, -N(R7)(R6) or -OR6.
20. A compound as claimed in any one of the preceding claims, wherein B6 represents C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl.
21. A compound as claimed in any one of the preceding claims, wherein f I f
G represents halo, cyano or -A -R .
22. A compound as claimed in any one of the preceding claims, wherein A7 represents-C(Q)A8-, -N(R7)A9-, -OA10-, -S- or -S(0)nAπ-.
23. A compound as claimed in any one of the preceding claims, wherein when A7 represents -N(R7)A9-, A9 represents A12, -C(Q)S-, -S(0)n-, -C(Q)0- or -S(0)nN(R7)-.
24. A compound as claimed in any one of Claims 1 to 22, wherein when A7 represents -OA10-, A10 represents A12.
25. A compound as claimed in any one of Claims 1 to 22, wherein when
7 1 1 1 1 7
A represents — S(0)nA -, A represents a single bond or -N(R )-.
26. A compound as claimed in any one of Claims 1 to 22, wherein when A7 represents -C(Q)A8-, A8 represents a single bond, -O- or-N(R7)-.
27. A compound as claimed in any one of the preceding claims, wherein Q represents =0 or =NR .
28. A compound as claimed in any one of the preceding claims, wherein Rδ, R7 and R7a independently represent H, C1-6 alkyl, C2.6 alkenyl or C2-6 alkynyl, all of which groups are optionally substituted by one or more groups selected from halo, C1-6 alkyl, -N(R8)R9, OR8 and -ON02.
29. A compound as claimed in any one of Claims 1 to 27 wherein when f 7 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, Cι-6 alkyl (optionally substituted by one or more halo groups), -N(R8)R9, -OR8 and -ON02.
30. A compound as claimed in any one of the preceding claims, wherein B4 represents an optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3- cycloalkyl, C4- heterocycloalkyl, or phenyl, group.
31. A compound as claimed in any one of the preceding claims wherein R R44 aanndd//oorr RR55 iinnddeeppeennddeennttllyy rreepprreesseenntt HH oorr CCιι--66 aallkkyl, which latter group is optionally substituted by one or more fluoro groups
32. A compound as claimed in any one of the preceding claims, wherein X represents a direct bond, -0-, — N(H)- or -N(Me)-.
33. A compound as claimed in any one of the preceding claims wherein R2 represents H, methyl or ethyl.
34. A compound as claimed in any one of Claims 1, 32 or 33, wherein R1 represents an optionally substituted phenyl, naphthyl, pyrrolidinyl, piperidinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, indazolyl, indolyl, indolinyl, isoindolinyl, oxindolyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothiophenyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, benzothiazolyl, or benzodioxanyl, group.
35. A compound as claimed in Claim 34, wherein R1 represents optionally substituted phenyl, 2-pyridmyl, 3-pyridinyl, 2-thiophenyl, 4- pyrazolyl, 5-isoxazolyl, 1,3-benzodioxolyl, indazolyl, benzothiazolyl, or quinolinyl, group.
36. A compound as claimed in Claim 34 or Claim 35, wherein the optional substituent(s) are selected from halo, cyano, Cι-6 alkyl (which alkyl group may be linear or branched, and/or substituted by one or more fluoro and/or C3-6 cycloalkyl groups), C2-6 alkenyl, C3-6 cycloalkyl, phenyl, pyrrolidinyl piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomethyl, methylsulfmyl, methylsulfonyl, -OR10, -N(R10)Rn, -C(0)OR10, -C(0)R10, -C(O)N(R10)Rn, -S(O)2N(R10)Rn and -N(R10)S(O)2R12, wherein R10 and R11 independently represent H, phenyl, C1-6 alkyl (which alkyl group is optionally substituted by one or more fluoro atom), C2-6 alkenyl or C3-6 cycloalkyl; or R10 and R11 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 .6 alkyl groups, which alkyl groups are themselves optionally substituted by one or more halo groups; and R12 represents phenyl, Cι_6 alkyl (which alkyl group is optionally substituted by one or more fluoro atom), C2- alkenyl or C3-6 cycloalkyl.
37. A compound as claimed in Claim 36, wherein the optional substituent(s) are selected from carbomethoxy, methyl, dimethylamino, cyano, chloro, fluoro, trifluoromethyl, bromo, methoxy and trifluoromethoxy.
38. A compound as claimed in any one of Claims 1 or 32 to 37, wherein R3 represents an optionally substituted C1-6 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pynolidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, indazolyl, indolyl, indolinyl, isoindolinyl, oxindolyl, quinolinyl, 1,2,3,4- tetrahydroquinolinyl, isoquinolinyl, 1 ,2,3 ,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothiophenyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, benzothiazolyl, or benzodioxanyl, group.
39. A compound as claimed in Claim 38, wherein R represents an optionally substituted Cι.6 alkyl, cyclohexyl, phenyl, 2-thiophenyl, 2- furanyl, 3 -furanyl, 2-pynolyl, 1 -naphthyl, 4-piperazinyl, 4-piperidinyl, benzofuranyl, or 1,3-benzodioxolyl, group.
40. A compound as claimed in Claim 38 or Claim 39, wherein the optional substituent(s) are selected from halo, -N02, cyano, C1- alkyl (which alkyl group may be linear or branched, and/or optionally substituted with one or more halo, C1-6 alkyl, C2-6 alkenyl and/or C3-6 cycloalkyl, groups, which latter three groups are themselves optionally substituted with one or more halo and/or C1-6 alkyl groups), C2,6 alkenyl (optionally substituted with one or more C1-6 alkyl groups), C3-6 cycloalkyl (optionally substituted with one or more halo groups), phenyl (optionally substituted with one or more halo groups), pynolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomethyl, methylsulfmyl, methylsulfonyl, =0, -OR13, -N(R13)R14, -C(0)OR13, -C(0)R13, -C(0)N(R13)R14, -S(0)2N(R13)R14 and -N(R13)S(0)2R15, wherein R13 and R14 independently represent H, phenyl, C 6 alkyl (which alkyl group is optionally substituted by one or more fluoro atom), C2-6 alkenyl or C3-6 cycloalkyl; or R13 and R14 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 C1-6 alkyl groups, which alkyl groups are themselves optionally substituted by one or more halo groups; and R 3 represents phenyl, Cj- alkyl (which alkyl group is optionally substituted by one or more fluoro atom), C2-6 alkenyl or C3-6 cycloalkyl.
41. A compound as claimed in Claim 40, wherein the optional substituent(s) are selected from methyl, ethyl, ethoxy, trifluoromethyl, fluoro, chloro, iodo, phenyl, 2-chlorophenyl, 4-chlorophenyl, /2-pentyl, z- propyl, nitro, t-butyl, -CH2CH=CHC8Hι7, trifluoroacetyl, carbomethoxy, carboethoxy and trifluoromethoxy.
42. A compound as claimed in any one of Claims 1 or 32 to 41, wherein R 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-trifluoromethoxyρhenyl, 2-methoxy-6- methylphenyl, 3-cyanophenyl, 4-trifluoromethylρhenyl, 4- dimethylaminophenyl, 4-carbomethoxyphenyl, 1 ,3,5-trimethyl- lH-pyrazol- 4-yl, 3-mefhylisoxazol-5-yl, 3-pyridinyl, 2-chloro-3-pyridinyl, 3-methyl-2- pyridinyl, 3-carbomethoxythiophen-2-yl or 1,3-benzodioxolyl; R2 is hydrogen or methyl;
R3 is methyl, /z-butyl, /z-pentyl, 1-octyl, oleoyl, (lR,2£,5R)-(-)-menthyl, 2- chlorobenzyl, benzyl, phenyl, 3 -fluorophenyl, 3-chlorophenyl, 4- chlorophenyl, 2-fluoro-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-ρyrrol-2-yl, 3-methyl-2- benzofuranyl, 3-methyl-2-thiophenyl, l(N)-methyl-4-piperazinyl, 1(N)- (2,2,2-trifluoroacetyl)piperidin-4-yl, ethylhexanoate or 1,3-benzodioxolyl; Y is -C(O)-, -C(S or -S(0)2-; and X is a bond, -N(H>, -N(Me)-, or -0-.
43. A compound of formula I as defined in any one of Claims 1 to 42, but without the provisos, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
44. A pharmaceutical fonnulation including a compound of formula I, as defined in any one of Claims 1 to 42, but without the provisos, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or canier.
45. A use of a compound of formula I, as defined in any one of Claims 1 to 42, but without the provisos, or a phannaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of the activity of a lipoxygenase is desired and/or required.
46. A use as claimed in Claim 45 wherein the lipoxygenase is 15- lipoxygenase.
47. A use as claimed in Claim 45 or Claim 46, wherein the disease is inflammation and/or has an inflammatory component.
48. A use as claimed in Claim 47 wherein the inflammatory disease is asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, an allergic disorder, rhinitis, inflammatory bowel disease, an ulcer, inflammatory pain, fever, atherosclerosis, coronary artery disease, vasculitis, pancreatitis, arthritis, osteoarthritis, rheumatoid arthritis, conjunctivitis, iritis, scleritis, uveitis, a wound, dermatitis, eczema, psoriasis, stroke, diabetes, autoimmune diseases, Alzheimer's disease, multiple sclerosis, sarcoidosis, Hodgkin's disease or another malignancy.
49. A method of treatment of a disease in which inhibition of the activity of a lipoxygenase is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 42, but without the provisos, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
50. A combination product comprising:
(A) a compound of formula I as defined in any one of Claims 1 to 42, but without the provisos; and
(B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
51. A combination product as claimed in Claim 50 which comprises a pharmaceutical fomiulation including a compound of fonnula I as defined in any one of Claims 1 to 42, but without the provisos, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
52. A combination product as claimed in Claim 50 which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of fonnula I as defined in any one of Claims 1 to 42, but without the provisos, in admixture with a pharmaceutically-acceptable adjuvant, diluent or canier; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
53. A process for the preparation of a compound as defined in Claim 1, which comprises:
(i) for compounds of foπnula I in which, when Y is -S(0)2-, X represents a - direct bond or -N(R4)-, in which R4 represents B4, reaction of a compound of formula II, wherein R and R" are as defined in Claim 1 , with a compound of formula III,
R3-Xa-Y-L1 III wherein Xa represents a direct bond or -N(B4)- when Y represents -S(0)2- or, for all other values of Y, represents X as defined in Claim 1, R3 and Y are as defined in Claim 1 and L1 represents a suitable leaving group; (ii) for compounds of formula I in which X represents a single bond and Y represents -C(O)-, reaction of a compound of formula II as defined above with a compound of formula IV,
R3C(0)OH IV wherein R is as defined in Claim 1 ;
(iii) for compounds of formula I in which X represents a direct bond and Y represents a -C(O)- or a -C(S)- group, reaction of a compound of formula II as defined above with a compound of formula V,
R3=Ya V wherein Y represents -C(O)- or -C(S)- and R3 is as defined in Claim 1; (iv) for compounds of fonnula I, in which X represents -NH- and Y represents -C(O)- or -C(S)-, reaction of a compound of formula II as defined above with a compound of formula VI,
R3N=Ya VI wherein R3 is as defined in Claim 1 and Ya is as defined above; (v) for compounds of formula I in which Y represents -C(O)- or -C(S)-, reaction of a compound of formula II as defined above with: (a) a compound of fonnula VII,
Cl-Ya-Cl VII (b) a compound of formula VIII,
wherein, in both cases, Ya is as defined above; or (c) when Y represents -C(O)-, triphosgene, followed by:
(1) for compounds of formula I in which X represents a direct bond, reaction with a compound of formula IX,
R3M 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 defined in Claim 1;
(2) for compounds of formula I wherein X represents O, reaction with a compound of formula X,
R3OH X wherein R3 is as defined in Claim 1; or (3) for compounds of formula I wherein X represents -N(R4)-, reaction with a compound of formula XI,
R3N(H)R4 XI wherein R3 and R4 are as defined in Claim 1 ;
(vi) for compounds of formula I in which X represents -N(R4)- and R4 is other than hydrogen, reaction of a con-esponding compound of formula I in which X represents -N(H)- with a compound of formula XII,
R4-L XII wherein R4 is as defined in Claim 1 and L1 is as defined above;
(vii) for compounds of formula I in which Y represents -C(S)-, reaction of a conesponding compound of foπnula I in which Y represents -C(O)- with a suitable reagent for the conversion of a carbonyl group to a thiocarbonyl group;
(viii) reaction of a compound of formula XIII, wherein R , Y and X are as defined in Claim 1, with a compound of formula XIV,
HN(RJ)(R2) XIV
. 1 * wherein R and R" are as defined m Claim 1; or (ix) reaction of a compound of formula XV,
wherein R2, R3, Y and X are as defined in Claim 1, with a compound of fonnula XVI, R!-L2 XVI wherein L2 represents a suitable leaving group and R1 is as defined in Claim
1.
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Publication number Priority date Publication date Assignee Title
JP2008513427A (en) * 2004-09-20 2008-05-01 バイオリポックス エービー Pyrazole compounds useful for the treatment of inflammation
EP1794145A1 (en) * 2004-09-20 2007-06-13 Biolipox AB Pyrazole compounds useful in the treatment of inflammation
WO2007042816A1 (en) * 2005-10-12 2007-04-19 Biolipox Ab Benzoxazoles useful in the treatment of inflammation
EP1934173A1 (en) * 2005-10-13 2008-06-25 Biolipox AB Naphthalene-disulfonamides useful for the treatment of inflammation
TW200800911A (en) * 2005-10-20 2008-01-01 Biolipox Ab Pyrazoles useful in the treatment of inflammation
TW200732320A (en) * 2005-10-31 2007-09-01 Biolipox Ab Pyrazoles useful in the treatment of inflammation
US20090186918A1 (en) * 2005-10-31 2009-07-23 Benjamin Pelcman Triazole Compounds as Lipoxygenase Inhibitors
US20090088463A1 (en) * 2005-11-01 2009-04-02 Benjamin Pelcman Pyrazoles Useful in the Treatment of Inflammation
US20090247634A1 (en) * 2006-06-27 2009-10-01 Hans-Erik Claesson Methods for identifying modulators of eoxin formation
WO2008129276A1 (en) * 2007-04-19 2008-10-30 Boehringer Ingelheim International Gmbh Disulfonamides useful in the treatment of inflammation
WO2008129280A1 (en) * 2007-04-20 2008-10-30 Biolipox Ab Pyrazoles useful in the treatment of inflammation
EA015952B1 (en) 2007-05-03 2011-12-30 Пфайзер Лимитед 2-pyridinecarboxamide derivatives as sodium channel modulators
WO2008135767A1 (en) * 2007-05-07 2008-11-13 Biolipox Ab New triazole compounds useful in the treatment of inflammation
MX2010001462A (en) * 2007-08-27 2010-03-01 Basf Se Pyrazole compounds for controlling invertebrate pests.
WO2010034737A1 (en) 2008-09-24 2010-04-01 Basf Se Pyrazole compounds for controlling invertebrate pests
ES2710701T3 (en) 2008-09-24 2019-04-26 Basf Se Pyrazole compounds for the control of invertebrate pests
US8710056B2 (en) 2009-07-06 2014-04-29 Basf Se Pyridazine compounds for controlling invertebrate pests
EP2451804B1 (en) 2009-07-06 2014-04-30 Basf Se Pyridazine compounds for controlling invertebrate pests
US9125414B2 (en) 2009-07-24 2015-09-08 Basf Se Pyridine derivatives compounds for controlling invertebrate pests
US9238643B2 (en) 2010-09-06 2016-01-19 Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences Amide compounds
WO2018217805A1 (en) * 2017-05-23 2018-11-29 Abide Therapeutics, Inc. Pyrazole magl inhibitors
WO2021072487A1 (en) * 2019-10-15 2021-04-22 TroBio Therapeutics Pty Ltd Sulfonamide compounds and the use thereof in the treatment of cancer

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPP042397A0 (en) * 1997-11-18 1997-12-11 Fujisawa Pharmaceutical Co., Ltd. 5-arylpyrazole compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004080999A1 *

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