WO2005073189A1 - Fused heteroyral derivatives for use as p38 kinase inhibitors - Google Patents
Fused heteroyral derivatives for use as p38 kinase inhibitors Download PDFInfo
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- WO2005073189A1 WO2005073189A1 PCT/GB2005/000265 GB2005000265W WO2005073189A1 WO 2005073189 A1 WO2005073189 A1 WO 2005073189A1 GB 2005000265 W GB2005000265 W GB 2005000265W WO 2005073189 A1 WO2005073189 A1 WO 2005073189A1
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- Prior art keywords
- fluoro
- indazol
- methyl
- compound
- phenyl
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- 0 *c1cc(C(C=C2)=C[C@@]3C2=CC=CC=C/C=C3)c(*)c(*)c1* Chemical compound *c1cc(C(C=C2)=C[C@@]3C2=CC=CC=C/C=C3)c(*)c(*)c1* 0.000 description 4
- QSBACAJBXNKUDK-UHFFFAOYSA-N CC(C)(C)OC(c1cc(F)c(C)c(-c2cc([nH]nc3)c3cc2)c1)=O Chemical compound CC(C)(C)OC(c1cc(F)c(C)c(-c2cc([nH]nc3)c3cc2)c1)=O QSBACAJBXNKUDK-UHFFFAOYSA-N 0.000 description 2
- JVKLWUNCLZVPCV-UHFFFAOYSA-N Brc1ccc2c(-c3ccccn3)n[nH]c2c1 Chemical compound Brc1ccc2c(-c3ccccn3)n[nH]c2c1 JVKLWUNCLZVPCV-UHFFFAOYSA-N 0.000 description 1
- LKUZXLWDUNTDOT-CWBNJTAUSA-N C/C=C(/C[n]1ncc2cc(-c3c(C)c(F)cc(C(NC4CC4)=O)c3)ccc12)\N=C/C=C Chemical compound C/C=C(/C[n]1ncc2cc(-c3c(C)c(F)cc(C(NC4CC4)=O)c3)ccc12)\N=C/C=C LKUZXLWDUNTDOT-CWBNJTAUSA-N 0.000 description 1
- NERLNTOFKNVJDI-UHFFFAOYSA-N C=C1C=C2Oc3cc(N)cc(OC(c4c5ccc(C(NCc(cc6)ccc6-c6nc(-c(cc7O)ccc7Cl)c(-c7ccncc7)[nH]6)=O)c4)=O)c3C5=C2C=C1 Chemical compound C=C1C=C2Oc3cc(N)cc(OC(c4c5ccc(C(NCc(cc6)ccc6-c6nc(-c(cc7O)ccc7Cl)c(-c7ccncc7)[nH]6)=O)c4)=O)c3C5=C2C=C1 NERLNTOFKNVJDI-UHFFFAOYSA-N 0.000 description 1
- AYDYGCMPSHUUIP-KGENOOAVSA-N CC(C)(C)OC(N/N=C(\c(c(F)c1)ccc1Br)/c1cnccn1)=O Chemical compound CC(C)(C)OC(N/N=C(\c(c(F)c1)ccc1Br)/c1cnccn1)=O AYDYGCMPSHUUIP-KGENOOAVSA-N 0.000 description 1
- MIHYVOUSMGCHBY-FYJGNVAPSA-N CC(C)(C)OC(N/N=C(\c(c(F)c1)ccc1Br)/c1ncccn1)=O Chemical compound CC(C)(C)OC(N/N=C(\c(c(F)c1)ccc1Br)/c1ncccn1)=O MIHYVOUSMGCHBY-FYJGNVAPSA-N 0.000 description 1
- PTNFHQBHZSPMNI-UHFFFAOYSA-N CC1(C)OS(c2cc(C(OC)=O)cc(F)c2C)OC1(C)C Chemical compound CC1(C)OS(c2cc(C(OC)=O)cc(F)c2C)OC1(C)C PTNFHQBHZSPMNI-UHFFFAOYSA-N 0.000 description 1
- STAXMSTYOSCIDV-UHFFFAOYSA-N CCNC(c1cc(F)c(C)c(-c2ccc3c(-c(cc4)ccc4Cl)n[nH]c3c2)c1)=O Chemical compound CCNC(c1cc(F)c(C)c(-c2ccc3c(-c(cc4)ccc4Cl)n[nH]c3c2)c1)=O STAXMSTYOSCIDV-UHFFFAOYSA-N 0.000 description 1
- HCOCFQKLKQSGLE-UHFFFAOYSA-N CCNC(c1cc(F)c(C)c(-c2ccc3c(-c4cccnc4OC)n[nH]c3c2)c1)=O Chemical compound CCNC(c1cc(F)c(C)c(-c2ccc3c(-c4cccnc4OC)n[nH]c3c2)c1)=O HCOCFQKLKQSGLE-UHFFFAOYSA-N 0.000 description 1
- URKFFXAJFKGGMM-UHFFFAOYSA-N CCNC(c1ccc(C)c(-c2ccc3c(I)n[nH]c3c2)c1)=O Chemical compound CCNC(c1ccc(C)c(-c2ccc3c(I)n[nH]c3c2)c1)=O URKFFXAJFKGGMM-UHFFFAOYSA-N 0.000 description 1
- YBIGIBMLDGEKJR-UHFFFAOYSA-N COc(nc1)ccc1-c1n[nH]c2cc(Br)ccc12 Chemical compound COc(nc1)ccc1-c1n[nH]c2cc(Br)ccc12 YBIGIBMLDGEKJR-UHFFFAOYSA-N 0.000 description 1
- YLBAVEANQBZRHG-UHFFFAOYSA-N Cc(c(-c(cc1)cc2c1[n](-c1ccccc1)nc2)cc(C(NC1CCC1)=O)c1)c1F Chemical compound Cc(c(-c(cc1)cc2c1[n](-c1ccccc1)nc2)cc(C(NC1CCC1)=O)c1)c1F YLBAVEANQBZRHG-UHFFFAOYSA-N 0.000 description 1
- HJGITLRGVZIQKV-UHFFFAOYSA-N Cc(c(-c1ccc2[n](-c3ccccc3)ncc2c1)cc(C(O)=O)c1)c1F Chemical compound Cc(c(-c1ccc2[n](-c3ccccc3)ncc2c1)cc(C(O)=O)c1)c1F HJGITLRGVZIQKV-UHFFFAOYSA-N 0.000 description 1
- OPFZUBYOSBMHPJ-UHFFFAOYSA-N Cc(c(-c1ccc2[n](Cc(cc3)cc[n+]3[O-])ncc2c1)cc(C(NC1CC1)=O)c1)c1F Chemical compound Cc(c(-c1ccc2[n](Cc(cc3)cc[n+]3[O-])ncc2c1)cc(C(NC1CC1)=O)c1)c1F OPFZUBYOSBMHPJ-UHFFFAOYSA-N 0.000 description 1
- LWLJCPQBFXTRMF-UHFFFAOYSA-N Cc(c(-c1ccc2c(-c(cc3)ccc3F)n[nH]c2c1)cc(C(Nc1n[nH]cc1)=O)c1)c1F Chemical compound Cc(c(-c1ccc2c(-c(cc3)ccc3F)n[nH]c2c1)cc(C(Nc1n[nH]cc1)=O)c1)c1F LWLJCPQBFXTRMF-UHFFFAOYSA-N 0.000 description 1
- LCZCYDAXLUAHIR-UHFFFAOYSA-N Cc(c(-c1ccc2c(-c(cc3)ccc3OC)n[o]c2c1)cc(C(NC1CC1)=O)c1)c1F Chemical compound Cc(c(-c1ccc2c(-c(cc3)ccc3OC)n[o]c2c1)cc(C(NC1CC1)=O)c1)c1F LCZCYDAXLUAHIR-UHFFFAOYSA-N 0.000 description 1
- KAPZJAGYFQABCJ-UHFFFAOYSA-N Cc1n[n](C)c(C(c(ccc(Br)c2)c2F)=O)c1 Chemical compound Cc1n[n](C)c(C(c(ccc(Br)c2)c2F)=O)c1 KAPZJAGYFQABCJ-UHFFFAOYSA-N 0.000 description 1
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- This invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors, for the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase.
- novel compounds that are inhibitors of p38 kinase. According to the invention there is provided a compound of formula (I):
- A is a fused 5-membered heteroaryl ring substituted by -(CH2) aryl or - (CH2)mh et eroaryl wherein the aryl or heteroaryl is optionally substituted by one or more substituents independently selected from oxo, Chalky!, halogen, -CN, trifluoromethyl, - OR 3 , -(CH 2 ) n CO2 3 , -NR3R4, -(CH 2 ) n CONR 3 R 4 , -NHCOR 3 -SO 2 NR 3 R 4 , -NHSO 2 R 3 and -S(O) p R 3 , and A is optionally further substituted by one substituent selected from -0R5 halogen, trifluoromethyl, -CN, -CC ⁇ R ⁇ and C- ⁇ alkyl optionally substituted by hydroxy; R1 is selected from methyl and chloro; R 2 is selected from -NH-CO-R 6 and -
- A includes fused 5-membered heteroaryl rings containing up to two heteroatoms independently selected from oxygen, nitrogen and sulfur. In another embodiment, A includes fused 5-membered heteroaryl rings containing up to two heteroatoms independently selected from oxygen and nitrogen. In a further embodiment, A includes 5-membered heteroaryl rings containing two heteroatoms independently selected from oxygen and nitrogen, for example rings containing a nitrogen atom and one additional heteroatom selected from oxygen and nitrogen. Examples of suitable A groups include fused isoxazolyl, pyrazolyl, pyrrolyl and thiazolyl rings such as those shown below:
- a groups include fused isoxazolyl, pyrazolyl and pyrrolyl rings such as those shown below:
- A may be a fused pyrazolyl ring such as those shown below:
- a representative example of a compound of formula (I) is wherein ring A is substituted by -(CH2) m aryl or -(CH2) m heteroaryl, located on any position on the ring.
- compounds of formula (I) include compounds wherein ring A is substituted by -(CH2) m aryl or -(CH2) m heteroaryl located in position (i), (ii), (iii) or (iv), for example position (ii) or (iii), as shown below:
- the -(CH2) m aryl group is -(CH2)mPhenyl.
- the -(CH2) heteroaryl group is a group wherein the heteroaryl is a 5- or 6-membered heteroaryl ring containing up to two heteroatoms independently selected from oxygen, nitrogen and sulfur.
- roup include groups wherein the heteroaryl is a 5- or 6-membered heteroaryl ring containing up to two heteroatoms independently selected from oxygen and nitrogen, for example pyridyl, isoxazolyl, pyrazolyl, imidazolyl, pyrimidinyl or pyrazinyl.
- Representative examples of the - (CH2)m neteroar y' 9 rou P include groups wherein the heteroaryl is a 5- or 6-membered heteroaryl ring containing up to two heteroatoms independently selected from oxygen and nitrogen, for example pyridyl, isoxazolyl or pyrimidinyl.
- -(CH2)mheteroaryl group examples include groups wherein the heteroaryl is a 5- or 6-membered heteroaryl ring containing up to two heteroatoms independently selected from oxygen and nitrogen, for example pyrazolyl, imidazolyl or pyrazinyl.
- d -(CH2) m heteroaryl groups are optionally substituted and the substituents may be located on any position on the aryl or heteroaryl.
- the aryl or heteroaryl is optionally substituted by one or two substituents independently selected from oxo, C- ⁇ galkyl, halogen, -CN, trifluoromethyl, - OR 3 , -(CH 2 )nCO 2 R 3 , -NR 3 R 4 , -(CH 2 ) n CONR 3 R 4 , -NHCOR 3 , -SO 2 NR 3 R 4 , -NHSO 2 R 3 and -S(O)pR 3 .
- the aryl is optionally substituted by one or two substituents i ndependently selected from C -
- substituents for the aryl include one or two substituents independently selected from C-j.galkyl, in particular methyl, halogen, -CN, trifluoromethyl, -OR 3 , -NR 3 R 4 -(CH 2 ) n CONR 3 R 4 and -S(O) D R 3 .
- aryl is optionally substituted by halogen, in particular fluorine, -OR 3 , in particular methoxy, or -(CH2) n CONR 3 R 4 .
- the heteroaryl is optionally substituted by one or two substituents independently selected from oxo, C- ⁇ galkyl, halogen, -OR 3 , -NR 3 R 4 and -(CH2) n CONR 3 R 4 .
- substituents for the heteroaryl include one or two substituents independently selected from oxo and C-
- substituents for the heteroaryl include one or two substituents independently selected from halogen, -OR 3 , - NR 3 R 4 and -(CH 2 ) n CONR 3 R 4 .
- a representative example of R 1 is methyl.
- a representative example of R 2 is -CO-NH-(CH2)q-R 7 .
- R 3 include hydrogen; -(CH2)r-C3-7cycloalkyl, in particular -(CH2)r-cyclohexyl; -(CH2) r heterocyclyl, in particular wherein the heterocyclyl is a 5- or 6-membered heterocyclyl containing one heteroatom selected from oxygen, nitrogen and sulfur such a tetrahydrofuran or tetrahydropyran; and C ⁇
- a representative example of R 4 is hydrogen.
- R 3 and R 4 together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 10 , in particular morpholinyl.
- R ⁇ is selected from hydrogen and C- ⁇ - ⁇ alkyl.
- R 6 is a -(CH2) s heteroaryl optionally substituted by R 1 1 and/or
- R1 2 Representative examples of PJ include hydrogen; C-
- gcycloalkyl such as cyclopropyl, cyclobutyl and cyclopentyl; phenyl optionally substituted by RU and/or R 12 ; and heteroaryl, in particular a 5- or 6-membered heteroaryl containing two heteroatoms selected from nitrogen and oxygen, for example pyrazolyl, pyridazinyl and pyrimidinyl, optionally substituted by RU and/or R 12 .
- R 8 and R 9 include hydrogen and C ⁇ alkyl, in particular hydrogen and methyl.
- R ⁇ 1 is selected from C ⁇ _galkyl, in particular C ⁇ alkyl such as methyl or ethyl, or halogen, in particular fluorine.
- R 12 is selected from C ⁇ .galkyl, in particular C- ⁇ alkyl such as methyl or ethyl, or halogen, in particular fluorine.
- a representative example of R 1 1 and R ⁇ 2 is halogen, in particular fluorine.
- a further representative example of R 1 1 and R 12 is C-
- R 13 and R 14 are each independently hydrogen or C ⁇
- R15 and R 18 together with the nitrogen atom to which they are bound, form a 5- or 6-membered heterocyclic ring optionally further containing one additional oxygen atom.
- X and Y are each independently selected from hydrogen, chlorine and fluorine. Representative examples of X include hydrogen and fluorine. A representative example of Y is hydrogen. In one embodiment, when A is a fused 5-membered heteroaryl ring substituted by -
- (CH2) m aryl and m is 0, 1 or 2, or A is a fused 5-membered heteroaryl ring substituted by - (CH2) m heteroaryl and m is 1 or 2, the aryl or heteroaryl is optionally substituted by one or more substituents independently selected from oxo, C-
- heteroaryl is a 5-membered heteroaryl ring substituted by one or more substituents independently selected from oxo, C3_galkyl, halogen, -CN, trifluoromethyl, -OR 3 , -(CH 2 ) n CO 2 R 3 , -NR 3 R 4 , -(CH 2 ) n CONR 3 R 4 , -NHCOR 3 , -
- the heteroaryl is a 5-membered heteroaryl ring substituted by C- ⁇ alkyl and one or more substituents independently selected from oxo, C- ⁇ .
- the heteroaryl is a 6-membered heteroaryl ring optionally substituted by one or more substituents independently selected from oxo, C- ⁇ galkyl, halogen, -CN, trifluoromethyl, -OR 3 , -(CH2) n CO2R 3 , -NR 3 R 4 , - (CH 2 ) n CONR 3 R 4 -NHCOR 3 , -SO 2 NR 3 R 4 , -NHSO 2 R 3 and -S(O) p R 3 .
- Representative examples of m include 0 and 1. In one embodiment, n is selected from 0 and 1. A representative example of n is 1. A further representative example of n is 0. A representative example of p is 2. Representative examples of q include 0 and 1. Representative examples of r include 0 and 1. In one embodiment, s is 0. In one embodiment, t is 0. It is to be understood that the present invention covers all combinations of the embodiments and the particular and preferred groups described hereinabove. It is also to be understood that the present invention encompasses compounds of formula (I) in which a particular group or parameter, for example R 3 , R 4 , R 8 , R 9 , R10, R12 R15 R16 n> p> q_ r or t, may occur more than once.
- a particular group or parameter for example R 3 , R 4 , R 8 , R 9 , R10, R12 R15 R16 n> p> q_ r or t, may occur more than once.
- each group or parameter is independently selected from the values listed.
- Particular compounds according to the invention include those mentioned in the Examples. Specific examples which may be mentioned include: ⁇ /-cyclopropyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide; ⁇ /-cyclopropyl-3-fluoro-5-[1 -(4-fluorophenyl)-1 H-indazol-5-yl]-4-methylbenzamide;
- salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the countehon or associated solvent is pharmaceutically acceptable.
- salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
- the term "pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, solvate or prodrug, e.g. ester, of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof.
- Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
- Preferred pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters.
- Particularly preferred pharmaceutically acceptable derivatives are salts, solvates and esters. Most preferred pharmaceutically acceptable derivatives are salts and esters, in particular salts.
- the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
- a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- Salts of the compounds of the present invention may, for example, comprise acid addition salts resulting from reaction of an acid with a nitrogen atom present in a compound of formula (I).
- Salts encompassed within the term "pharmaceutically acceptable salts" refer to n on-toxic s alts of the c ompounds o f this i nvention. S Desible a ddition s alts a re formed from acids which form non-toxic salts and examples are acetate, benzenesulfonate, benzoate, bicarbonate, b isulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaph
- salts include formate salts such as the mono- and di-formate salts.
- Pharmaceutically acceptable base salts include ammonium salts such as a trimethylammonium salt, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D- glucamine.
- Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized.
- solvates refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
- solvents for the purpose of the invention may not interfere with the biological activity of the solute.
- suitable solvents include water, methanol, ethanol and acetic acid.
- the solvent used is a pharmaceutically acceptable solvent.
- suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.
- the solvent used is water.
- a complex with water is known as a "hydrate”. Solvates of the compounds of the invention are within the scope of the invention.
- prodrug means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
- Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which are incorporated herein by reference.
- Prodrugs are any covalently bonded carriers that release a compound of formula (I) in vivo when s uch p rodrug i s administered to a patient.
- Prodrugs a re generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
- Prodrugs include, for example, compounds of this invention wherein hydroxy or amine groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy or amine groups.
- representative examples of prodrugs include ( but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of formula (I).
- esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
- alkyl refers to straight o r b ranched h ydrocarbon chains containing the specified number of carbon atoms.
- C-j.galkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms.
- alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and t-butyl.
- _4alkyl group is preferred, for example methyl, ethyl, isopropyl or t-butyl.
- the said alkyl groups may be optionally substituted with one or more fluorine atoms for example, trifluoromethyl.
- alkoxy refers to a straight or branched chain alkoxy groups containing the specified number of carbon atoms.
- C- ⁇ galkoxy means a straight or branched alkoxy containing at least 1 , and at most 6, carbon atoms.
- alkoxy as used herein include, but are not limited to methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.
- a C- ⁇ alkoxy group is preferred, for example methoxy or ethoxy.
- cycloalkyl refers to a non-aromatic hydrocarbon ring containing the s pecified n umber o f c arbon a toms w hich m ay o ptionally c ontain u p t o o ne double bond.
- C3_7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms.
- Examples of "cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- a C 3_gcycloalkyl g roup i s p referred, for example, cyclopropyl, cyclopentyl o r cyclohexyl.
- aryl refers to an aromatic carbocyclic ring such as phenyl, biphenyl or naphthyl. Preferably the aryl is phenyl.
- heteroaryl ring and “heteroaryl”, unless otherwise defined, refer to a monocyclic 5- to 7-membered unsaturated hydrocarbon ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur.
- the heteroaryl ring has five or six ring atoms.
- heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyhdazinyl, pyrimidinyl, pyrazinyl and triazinyl.
- the said ring may be optionally substituted by one or more substituents independently selected from C-
- heterocyclic ring or “heterocyclyl”, unless otherwise defined refer to a monocyclic 3 - to 7-membered saturated h ydrocarbon ring containing a t least one heteroatom independently selected from oxygen, nitrogen and sulfur.
- the heterocyclyl ring has five or six ring atoms.
- heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl, tetrahydrofuranyl, a nd t hiomorpholino.
- T he s aid ring may be o ptionally substituted by one or more substituents independently selected from C-
- halogen or “halo” refer to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. A particularly preferred halogen is fluorine or chlorine.
- halogen or “halo” refer to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. A particularly preferred halogen is fluorine or chlorine.
- the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
- substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
- Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or m ore asymmetric carbon atoms or may exhibit cis-trans isomerism). T he individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
- the present invention also covers the individual isomers of the compounds represented by formula ( I) a s m ixtures with i somers thereof in which one or more chiral centres are inverted.
- compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. A stereoisomeric mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C.
- a compound of formula (I) may be prepared by reacting a compound of formula (II)
- a compound of formula (I) or a compound of formula (II) may be prepared by reacting a compound of formula (V)
- a compound of formula (V) wherein A 2 is A and A is a fused pyrazolyl ring may, for example, be prepared by reacting a compound of formula (VII)
- a compound of formula (V) wherein A 2 is A and A is a fused pyrazolyl ring may, for example, be prepared by reacting a compound of formula (IX)
- a compound of formula (V) wherein A 2 is A and A is a fused isoxazolyl ring may, for example, be prepared by reacting a compound of formula (IX) as hereinbefore defined with hydroxylamine, followed by cyclisation in the presence of a base such as DBU.
- a compound of formula (VIA) may be prepared by, for example, reacting a compound of formula (XI)
- a compound of formula (VIB) may be prepared by, for example, reacting a compound of formula (XI) as hereinbefore defined, with n-butyl lithium and triisopropyl borate in a solvent such as THF.
- a compound of formula (XI) may be prepared by reacting an amine of formula (XII) (XII) in which R 1 , X, Y and Z 3 are as hereinbefore defined, with an acid compound of formula (XIII)
- Suitable amide forming conditions include adding a base such as DIPEA to a mixture of the amine of formula (XII), the acid of formula (XIII), and HATU in a solvent such as DMF.
- a base such as DIPEA
- R 2 is -CO-NH-(CH2)q-R 7
- a compound of formula (XI) may readily be prepared from a corresponding acid compound of formula (XIV)
- Suitable amide forming conditions include treating a solution of the acid of formula (XIV), or the activated form thereof, in for example DMF, with an amine of formula (XV) in the presence of a base such as triethylamine.
- a compound of formula (I) may be prepared from a corresponding acid compound of formula (XVI) (XVI) in which A, R 1 , X and Y are as hereinbefore defined, by reacting the acid with an amine compound of formula (XV) as hereinbefore defined under the conditions described above.
- A is a fused pyrazolyl
- another general method for preparing compounds of formula (I) comprises reacting a compound of formula (XVII)
- a further general method comprises final stage modification of one compound of formula ( I) into another compound of formula (I).
- Suitable f unctional g roup transformations for converting one compound of formula (I) into another compound of formula (I) are well known in the art and are described in, for instance, Comprehensive Heterocyclic Chemistry II, eds. A. R. Katritzky, C. W. Rees and E. F. V.
- Scheme 2 For example, another method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 3 below.
- Scheme 6 For example, a further method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 7 below.
- Suitable protecting groups for use according to t he p resent i nvention a re ell k nown to t hose s killed i n t he a rt a nd may b e u sed i n a conventional manner. See, for example, "Protective groups in organic synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Veriag 1994).
- suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).
- acyl type protecting groups e.g. formyl, trifluoroacetyl, acetyl
- aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
- aliphatic urethane protecting groups e.g. 9-flu
- suitable oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
- alky silyl groups such as trimethylsilyl or tert-butyldimethylsilyl
- alkyl ethers such as tetrahydropyranyl or tert-butyl
- esters such as acetate.
- the compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions eg when the agent is in admixture with a suitable pharmaceutical excipient, diluent and/or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, in association with one or more pharmaceutically acceptable excipients, diluents and/or carriers.
- the excipient, diluent or carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deletrious to the recipient thereof.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising, as active ingredient, at least one compound of the invention or a pharmaceutically acceptable derivative thereof, in association one or more pharmaceutically acceptable excipients, diluents and/or carriers for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by an inhibitor of p38 kinase.
- the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the present invention and a pharmaceutically acceptable excipient, diluent and/or carrier (including combinations thereof).
- a process of preparing a pharmaceutical composition comprises mixing at least one compound of the invention or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable excipient, diluent and/or carrier.
- the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable excipient, diluent or carrier.
- Acceptable carriers or diluents for therapetic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
- the choice of pharmaceutical excipient, diluent or carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice.
- the pharmaceutical compositions may c omprise as - o r i n a ddition to - the e xcipient, d iluent or e arrier a ny suitable binder(s), lubricant(s), suspending agent(s), coating agent(s) and solubilising agent(s).
- Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
- the agents of the present invention may also be used in combination with a cyclodextrin.
- Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug- cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e. g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma- cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148.
- the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
- Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see WO 02/00196 (SmithKline Beecham). There may be different composition/formulation requirements dependent on the different delivery systems.
- the pharmaceutical composition of the present i nvention m ay b e formulated to b e d elivered u sing a m ini-pump o r b y a m ucosal route for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
- the formulation may be designed to be delivered by both routes.
- the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
- compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
- compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
- buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
- the routes for administration include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g.
- an injectable form gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.
- gastrointestinal intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.
- compositions may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration.
- the pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives.
- the agents of the present invention are delivered systemically such as orally, buccally or sublingually.
- a particularly preferred method of administration, and corresponding formulation, is oral administration.
- the pharmaceutical composition may take the form of, and be administered as, for example, tablets (including sub-lingual tablets) and capsules (each including timed release and sustained release formulations), ovules, pills, powders, granules, elixirs, tinctures, emulsions, solutions, syrups or suspensions prepared by conventional means with acceptable excipients for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- the tablets may also contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
- excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
- disintegrants such as starch (preferably corn, potato or tapioca starch), sodium star
- Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
- the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
- Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
- Capsules can be made by preparing a powder mixture as described above, and filling formed g elatin sheaths.
- Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
- a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
- a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
- the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
- the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
- the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
- the lubricated mixture is then compressed into tablets.
- the compounds of the present invention can also be combined with free flowing inert c arrier a nd c ompressed i nto t ablets d irectly without g oing through t he g ranulating o r slugging steps.
- a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided.
- Dyestuffs can be added to these coatings to distinguish different unit dosages.
- Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
- Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
- Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
- Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.
- dosage unit formulations for oral administration can be microencapsulated.
- the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
- the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- the compounds of the present invention can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- the present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (I) in combination with a pharmaceutically acceptable carrier.
- the composition may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intraperitoneal, intraarticular, subcutaneous or intramuscular, inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
- the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
- the compound of the present invention is administered parenterally
- examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the agent; and/or by using infusion techniques.
- the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously).
- compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory a gents s uch as s uspending, s tabilizing a nd/or d ispersing a gents.
- F or administration by injection these may take the form of a unit dose presentation or as a multidose p resentation preferably with a n a dded p reservative.
- a Iternatively for p arenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle.
- t he compound i s best u sed i n the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
- suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
- the compositions of the present invention may be administered by direct injection.
- the compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- the composition may be formulated for topical application, for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear d rops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
- Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.
- Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
- the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
- the compound of the present invention can be administered in the form of a s uppository o r p essary, o r i t may be a pplied topically i n the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
- the compounds of the present invention may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route.
- the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkoni ⁇ m chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
- the pharmaceutical compositions generally are administered in an amount effective for treatment or prophylaxis of a specific condition or conditions. Initial dosing in humans is accompanied by clinical monitoring of symptoms, such symptoms for the selected condition. In general, the compositions are administered in an amount of active agent of at least about 100 5 ⁇ g/kg body weight.
- dose is from about 100 ⁇ g/kg to about 5 mg/kg body weight, daily.
- the daily dosage level of the active agent will be from 0. 1 mg/kg to 10 mg/kg and typically around 1 mg/kg. It will be appreciated that 0 optimum dosage will be determined by standard methods for each treatment modality and indication, taking into account the indication, its severity, route of administration, complicating conditions and the like.
- the physician in any event will determine the actual dosage which will be most suitable for an individual and will vary with the activity of the specific compound to be employed, the metabolic stablity and length of action of that compound, age, weight, 5 general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition and response of the particular individual.
- the effectiveness of a selected actual dose can readily be determined, for example, by measuring clinical symptoms or standard anti-inflammatory indicia after administration of the selected dose.
- the above dosages are exemplary of the average case. There can, of course, be individual 0 instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
- the daily dosage level of the agent may be in single or divided doses.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof, for use in therapy.
- the compounds of the present invention are generally inhibitors of the serine/threonine kinase p38 and are therefore also inhibitors of cytokine production which is mediated by p38 kinase.
- inhibitors of the serine/threonine are generally inhibitors of the serine/threonine kinase p38 and are therefore also inhibitors of cytokine production which is mediated by p38 kinase.
- the compounds of the invention may be selective for one or more of the isoforms of p38, for example p38 ⁇ , p38 ⁇ , p38 ⁇ and/or p38 ⁇ . In one embodiment, the compounds of the invention selectively inhibit the p38 ⁇ isoform. In another embodiment, the compounds of the invention selectively inhibit the p38 ⁇ isoform. In another embodiment, the compounds of the invention selectively inhibit the p38 ⁇ isoform. In another
- the compounds of the invention selectively inhibit the p38 ⁇ isoform.
- the compounds of the invention selectively inhibit the p38 ⁇ and p38 ⁇ isoforms.
- Assays for determining the selectivity of compounds for the p38 isoforms are described in, for example, WO 99/61426, WO 00/71535 and WO 02/46158. It is known that p38 kinase activity can be elevated (locally or throughout the body),
- [0 p38 kinase can be incorrectly temporally active or expressed, p38 kinase can be expressed or a ctive i n a n i nappropriate I ocation, p 38 kinase can b e constitutively expressed, o r p 38 kinase expression can be erratic; similarly, cytokine production mediated by p38 kinase activity can be occurring at inappropriate times, inappropriate locations, or it can occur at detrimentally high levels.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment or prophylaxis of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase.
- the present invention also provides a method for the treatment of a condition or disease state mediated by p38 kinase activity, or mediated by cytokines produced by the activity of p38 kinase, in a subject which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
- the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a m ixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
- the present invention also provides a method of inhibiting cytokine production which is mediated by p38 kinase activity in a subject, e.g. a human, which comprises administering to said subject in need of cytokine production inhibition a therapeutic, or cytokine-inhibiting, amount of a compound of the present invention.
- the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
- the present invention treats these conditions by providing a therapeutically effective amount of a compound of this invention.
- therapeutically effective amount is meant a symptom-alleviating or symptom-reducing amount, a cytokine-reducing amount, a cytokine- inhibiting amount, a kinase-regulating amount and/or a kinase-inhibiting amount of a compound.
- the compounds of the present invention can be administered to any subject in need of inhibition or regulation of p38 kinase or in need of inhibition or regulation of p38 mediated cytokine production.
- the compounds may be administered to mammals.
- mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably, humans.
- the present invention provides methods of treating or reducing symptoms in a human or animal subject suffering from, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs.
- rheumatoid arthritis arthritis
- osteoarthritis asthma
- psoriasis eczema
- a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
- a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
- a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, chronic pulmonary inflammation, chronic obstructive pulmonary disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
- a further aspect of the invention provides a method of treatment of a human or animal subject suffering from any type of pain including chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post operative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, post-hepatic neuralgia, inflammatory neuropathies and migraine pain which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
- a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for use in the treatment of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by p38 kinase activity.
- the compounds of formula (I) and their derivatives may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions.
- the invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
- combination with other chemotherapeutic or antibody agents is envisaged.
- Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other pharmaceutically active agent.
- the compound(s) of formula (I) or pharmaceutically acceptable salt(s) or solvate(s) thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order.
- the amounts of the compound(s) of formula (I) or pharmaceutically acceptable salt(s) or solvate(s) thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Appropriate doses will be readily appreciated by those skilled in the art.
- rheumatoid arthritis therapy examples include: immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti- TNF ⁇ agents such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interieukin 1 1 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interieukin 1 receptor antagonists such as anakinra; CD8 antagonists such as amiprilose hydrochloride
- compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
- the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
- administration either the compound of the invention or the second therapeutic agent may be administered first.
- administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
- the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
- they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
- 4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide, 4-methyl-3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid and 4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoic acid may be prepared by the procedures described in WO 03/068747.
- (4-Fluoro-2-methylphenyl)boronic acid may be prepared by the procedure described by J.B.
- 5-Bromoindazole may be prepared by the procedure described by A.
- Solvent A 10mM Aqueous ammonium acetate + 0.1% formic acid.
- Solvent B 10mM Aqueous ammonium acetate + 0.1% formic acid.
- reaction mixture was acidified with 2M hydrochloric acid then diluted with ethyl acetate.
- the organic layer was separated using a hydrophobic filter tube, the solvent was evaporated and the residue was purified on an SPE cartridge (silica) eluting with a petroleum ether/ethyl acetate gradient containing 0.1% acetic acid to give the title compound as a colourless solid (227mg).
- SPE cartridge sica
- the reaction mixture was diluted with dichloromethane and stirred rapidly with saturated aqueous sodium bicarbonate.
- the organic layer was separated using a hydrophobic filter tube and concentrated under vacuum.
- the residue was purified by column chromatography o n s ilica, e luting with cyclohexane:ethyl a cetate ( 100:0 to 0 :100).
- the isolated product, in THF (4.5ml) was treated with 1 ,8-diazabicyclo[5.4.0]undec-7-ene (150 ⁇ l) and heated in a sealed tube in a microwave oven at 150°C for 30min.
- 2-Pyrimidinecarboxylic a cid 350mg
- i n thionyl chloride 3mL
- the solvent was removed under vacuum to give the 2- pyrimidinecarbonyl chloride as a grey solid (403mg).
- (4-Bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran 0.5M, 5.65mL
- 5-Pyrimidinecarboxylic a cid 500mg
- i n thionyl c hloride 5mL
- the solvent was evaporated under vacuum to give 5- pyrimidinecarbonyl chloride as a brown oil (505mg).
- Aqueous ammonium c hloride ( 1 M, 5 mL) was a dded a nd the m ixture was a bsorbed o nto s ilica a nd purified by chromatography on a silica column eluting with a cyclohexane/ethyl acetate gradient to give the title compound (712mg).
- LC-MS Rt 2.65min.
- 2-Pyrazinecarboxylic acid (1.5g) in thionyl chloride (10mL) was stirred at 110°C under nitrogen for 2h. The solvent was evaporated under vacuum to give 2-pyrazinecarbonyl chloride as a dark purple solid(1.5g).
- (4-Bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran (0.5M, 7.02mL) was added slowly to a stirred mixture of the acid chloride (1g) and tetrakis(triphenylphosphine)palladium(0) (406mg) in tetrahydrofuran (5mL) at room temperature under nitrogen then stirred for 2h.
- Example 1 The procedure for Example 1 was followed using 5-bromo-1-(4-fluorophenyl)-1H- indazole (Intermediate 2, 36.6mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyljboronic acid (30mg), tetrakis(triphenylphophine) palladium (3mg) and aqueous sodium hydrogen carbonate (1 M, 0.63ml) in isopropanol (2ml) to g ive the title compound (30.7mg).
- Example 4 The procedure for Example 4 was followed using ⁇ /-cyclopropyl-3-fluoro-5-(1H- indazol-5-yl)-4-methylbenzamide (Intermediate 5, 31 mg), sodium hydride (60% dispersion in mineral oil, 4mg), 1-(bromomethyl)-4-(trifluoromethyl)benzene (19 ⁇ l) and DMF (1.6ml) to give the title compound (6mg).
- Example 4 The procedure for Example 4 was followed using ⁇ /-cyclopropyl-3-fluoro-5-(1/-/- indazol-5-yl)-4-methylbenzamide (Intermediate 5, 31 mg), sodium hydride (60% dispersion in mineral oil, 4mg), (bromomethyl)benzene (14 ⁇ l) and DMF (1.6ml) to give the title compound (9mg).
- Example 7 The procedure for Example 7 was followed using /V-cyclopropyl-3-fluoro-5-(1H- indazol-5-yl)-4-methylbenzamide (Intermediate 5, 45mg), sodium hydride (60% in mineral oil, 18mg), 2-(bromomethyl)pyridine (40mg) and DMF (5ml) to give the title compound as a colourless glass (10mg).
- the crude acid chloride was dissolved in chloroform (3.1ml) and an aliquot (300 ⁇ l) was treated with an amine (50 ⁇ mol) in chloroform (1ml). After 1h the reaction mixture was diluted with chloroform and washed with 1 M aqueous hydrochloric acid followed by aqueous sodium hydrogen carbonate. The organic layer was separated using a hydrophobic filter tube then concentrated under vacuum to give the title compound.
- Example 21 The procedure for Example 21 was followed using 5-bromo-1-(3-pyridinyl)-1H-indole (27mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl ⁇ boronic acid (26mg), tetrakis(triphenylphosphine)palladium (0) (1mg) and aqueous sodium hydrogen carbonate (1 M, 0.3ml) in isopropanol (0.6ml) to give the title compound (18mg).
- Example 21 The procedure for Example 21 was followed using 4-(5-bromo-1r7-indol-1- yl)benzonitrile (Intermediate 10, 30mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyfjboronic acid (26mg), tetrakis(triphenylphosphine)palladium (0) (1mg) and aqueous sodium hydrogen carbonate (1M, 0.3ml) in isopropanol (0.6ml) to give the title compound (2.7mg).
- LC-MS Rt 3.64, MH + 410.
- Example 24 3-ri-(3-Cvanophenv ⁇ -1H-indol-5-v ⁇ -/V-cvclopropyl-5-fluoro-4- methylbenzamide
- Example 21 The procedure for Example 21 was followed using 3-(5-bromo-1/-/-indol-1- yl)benzonitrile (30mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl ⁇ boronic acid (26mg), tetrakis(triphenylphosphine)palladium (0) (1 mg) and aqueous sodium hydrogen carbonate (1 M, 0.3ml) in isopropanol (0.6ml) to give the title compound (2.9mg).
- Example 26 A-Cvclopropyl-3-fluoro-4-methyl-5- ⁇ 1 -f4-(trifluoromethyl)phenv ⁇ -1 H- indazol-5-yl)benzamide
- Example 25 The procedure for Example 25 was followed using 5-bromo-1-[4- (trifluoromethyl)phenyl]-1 H-indazole (Intermediate 12, 202mg), ⁇ 5-
- Example 27 ⁇ /-Cyclopropyl-3-fluoro-4-methyl-5-f 1 -f4-(methylsulfonyl)phenyll-1 H- indazol-5-yl benzamide
- Example 25 The procedure for Example 25 was followed 5-bromo-1-[4-(methylsulfonyl)phenylj- 1H-indazole (Intermediate 13, 210mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3-fluoro-2- methylphenyljboronic acid (167mg), tetrakis(triphenylphosphine)palladium (13.8mg) and aqueous sodium hydrogen carbonate (1M, 1.2ml) in isopropanol (2.8ml) to give the title compound as a pale yellow foam (156mg).
- Example 28 ⁇ /-Cvclopropyl-3-fluoro-4-methyl-5-(1- ⁇ 4-r2-(methylamino)-2- oxoethyllphenyl)-1f -indazol-5-yl)benzamide
- Example 25 The procedure for Example 25 was followed using 2-[4-(5-bromo-1r-/-indazol-1- yl)phenyl]- ⁇ /-methylacetamide (Intermediate 15, 206mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3- fluoro-2-methylphenyl ⁇ boronic acid (167mg), tetrakis(triphenylphosphine)palladium (13.8mg) and aqueous sodium hydrogen carbonate (1 M, 1.2ml) in isopropanol (2.8ml).
- Example 30 3-(1 - ⁇ 4-f(Cvclohexylmethyl)amino1phenyl>-1 H-indazol-5-yl)- ⁇ /- cyclopropyl-5-fluoro-4-methylbenzamide. formate salt
- Example 32 ⁇ /-Cyclopropyl-3-fluoro-4-methyl-5- ⁇ 1 -r4-(tetrahydro-2H-pyran-4- ylamino)phenyll-1H-indazol-5-yl)benzamide. formate salt
- Example 35 A-Cyclopropyl-3-ri-(4-fr3-(dimethylamino)propynamino phenyl)-1H- indazol-5-yll-5-fluoro-4-methylbenzamide, diformate salt
- Example 38 /V-Cyclopropyl-3-fluoro-4-methyl-5-H -(6-oxo-1 ,6-dihydro-4-pyrimidinyl)- 1 H-indazol-5-yllbenzamide
- Example 39 A/-Cvclopropyl-3-fluoro-4-methyl-5-(3-r4-(methyloxy)phenyl1-1.2- benzisoxazol-6-yl)benzamide
- Example 39 The procedure for Example 39 was followed using 4-(6-bromo-1,2-benzisoxazol-3- yl)phenol (60mg), ⁇ 5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl ⁇ boronic acid (52mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and saturated aqueous sodium hydrogen carbonate (0.5ml) in isopropanol (2ml).
- Example 4 The procedure for Example 4 was followed using ⁇ /-cyclopropyl-3-fluoro-5-(1H- indazol-5-yl)-4-methylbenzamide (Intermediate 5, 70mg), sodium hydride (60% dispersion in mineral oil, 22mg), 3-(bromomethyl)pyridine hydrobromide (63mg) and DMF (5ml) to give the title compound as a colourless glass (12mg).
- Example 4 The procedure for Example 4 was followed using ⁇ /-cyclopropyl-3-fluoro-5-(1H- indazol-5-yl)-4-methylbenzamide (Intermediate 5, 70mg), sodium hydride (60% dispersion in mineral oil, 22mg), 4-(bromomethyl)pyridine hydrobromide (63mg) and DMF (5ml) to give the title compound as a colourless glass (11mg).
- Example 43 The procedure for Example 43 was followed using /V-cyclopropyl-3-fluoro-4-methyl-5-[1-(3- pyridinylmethyl)-1/7-indazol-5-yl]benzamide (Example 41, 7mg) m-CPBA (5.2mg) and chloroform (3ml) to give the title compound as a white solid (7mg).
- Example 43 The procedure for Example 43 was followed using ⁇ /-cyclopropyl-3-fluoro-4-methyl-5- [1-(3-pyridinylmethyl)-1H-indazol-5-yl]benzamide (Example 42, 8mg) m-CPBA (5.9mg) and chloroform (2ml) to give the title compound as a white solid (8mg).
- the crude acid chloride (187mg) was dissolved in chloroform (10ml) and an aliquot (1.0ml) was added to a solution of the appropriate amine (100 ⁇ mol) in a mixture (0.5ml) prepared by the addition of diisopropylethylamine (69 ⁇ l), and dimethylaminopyridine (6mg) to DMF (20ml).
- the resulting mixture was left at room temperature for 16h, diisopropylethylamine (12 ⁇ l) was added and the mixture was heated at 50°C for 24h under nitrogen
- the resulting gums were purified by preparative HPLC.
- Example 48 3-Fluoro-4-methyl-5-(1 -phenyl-1 H-indazol-5-yl)- ⁇ /-3-pyridazinylbenzamide
- a m ixture of 5 -bromo-1 -phenyl-1 H-indazole (Intermediate 1 , 39mg), ⁇ /-cyclobutyl-4- methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (Intermediate 23, 50mg), tetrakis(triphenylphoshine)palladium (0) (3mg) and 2M aqueous sodium bicarbonate in isopropanol (1 ml) was heated at 150°C for 10min in a microwave oven.
- Example 51 The procedure for Example 51 was followed using 6-bromo-3-(4-fluorophenyl)-1/-/- indazole (Intermediate 20, 27mg), ⁇ /-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzamide (30mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1 M, 1ml) in isopropanol (2ml) to give the title compound (20mg).
- Example 51 The procedure for Example 51 was followed using 6-bromo-3-(4-methoxyphenyl)-1 H- indazole (Intermediate 22, 23r ⁇ g), ⁇ /-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzamide (Intermediate 18, 30mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1M, 1ml) in isopropanol (2ml) to give the title compound (18mg).
- Example 51 The procedure for Example 51 was followed using 6-bromo-3-(4-methoxyphenyl)-1H- indazole (Intermediate 22, 23mg), ⁇ /-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzamide (30mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1 M, 1ml) in isopropanol (2ml) to give the title compound (22mg).
- Example 55 The procedure for Example 55 was followed using N-ethyl-3-(3-iodo-1H-indazol-6-yl)- 4-methylbenzamide (Intermediate 24, 33mg), (4-ethoxyphenyl)boronic acid (16mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1M, 0.2ml) in isopropanol (1 ml) to give the title compound (16mg). LC-MS: 3.59min, MH + 400.
- Example 55 The procedure for Example 55 was followed using N-ethyl-3-(3-iodo-1 H-indazol-6-yl)- 4-methylbenzamide (Intermediate 24, 33mg) [4-(methylsulfonyl)phenyl]-boronic acid (19mg) tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1M, 0.2ml) in isopropanol (1ml) to give the title compound (16mg). LC-MS: 3.07min, MH + 434.
- Example 58 The procedure for Example 58 was followed using an aliquot (0.2ml) of the /V-ethyl-3- fluoro-5-(3-iodo-1/-/-indazol-6-yl)-4-methylbenzamide (Intermediate 28) and tetrakis(triphenylphosphine)palladium in propan-2-ol mixture, [4-
- Example 58 The procedure for Example 58 was followed using an aliquot (0.2ml) of the ⁇ /-ethyl-3- fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide (Intermediate 28) and tetrakis(triphenylphosphine)palladium in propan-2-ol mixture, [4(4-chlorophenyl)boronic acid (12mg) and sodium hydrogen carbonate solution (1M, 0.1 ml) to give the title compound as a colourless glass 8.4mg).
- LCMS Rt 3.72min, MH+ 408.
- a mixture of 6-bromo-3-(2-pyridinyl)-1H-indazole (Intermediate 33, 74mg), ⁇ /-ethyl-3- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (Intermediate 31 , 98mg), tetrakis(triphenylphosphine)palladium(0) (10mg) and aqueous sodium hydrogen carbonate (1 M, 2.5ml) in 2-propanol (2.5ml) in a sealed vessel was heated at 150°C for 15min in a microwave oven.
- Example 68 The procedure for Example 68 was followed using 6-bromo-3-(2-pyrimidinyl)-1 H- indazole (Intermediate 48, 17mg), N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzamide (Intermediate 31 , 19mg), sodium hydrogen carbonate (1 M, 124 ⁇ L) and tetrakis(triphenylphosphine)palladium(0) (1.4mg) in isopropanol (2.5ml) to give the title compound (1.7mg).
- Example 72 The procedure for Example 72 was followed using 3-(3-bromo-1H-indazol-6-yl)- ⁇ /- ethyl-5-fluoro-4-methylbenzamide (Intermediate 55, 50mg) [2-(methyloxy)-3-pyridinyl]boronic acid (24mg) tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (0.125ml) in isopropanol (0.5ml) to give the title compound (22mg).
- LC-MS Rt 3.1min, MH+ 405.
- Example 72 The procedure for Example 72 was followed using 3-(3-bromo-1H-indazol-6-yl)-/V- ethyl-5-fluoro-4-methylbenzamide ( Intermediate 55, 50mg) (4-fluoro-2-methylphenyl)boronic acid (31 mg) tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (0.125ml) in isopropanol (0.5ml) to give the title compound (23mg).
- Example 75 A/-Ethyl-3-f luoro-4-methyl-5-r3-(3-pyridinyl)-1 H-indazol-6-yllbenzamide
- the procedure for Example 72 was followed using 3-(3-bromo-1H-indazol-6-yl)- ⁇ - ethyl-5-fluoro-4-methylbenzamide (Intermediate 55, 50mg) 3-pyridinylboronic acid (20mg) tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (0.125ml) in isopropanol (0.5ml).
- Example 72 The procedure for Example 72 was followed using 3-(3-bromo-1H-indazol-6-yl)-/V- ethyl-5-fluoro-4-methylbenzamide (Intermediate 55, 50mg), (3,5-dimethyl-4- isoxazolyl)boronic acid (22.5mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (0.125ml) in isopropanol (0.5ml). Heating was continued for a further 30min and a similar work-up and purification by preparative HPLC gave the title compound (6mg). LC-MS: Rt 3.2min, MH+ 393.
- Example 78 ⁇ -(1.4-Dimethyl-1 H-pyrazol-5-yl)-3-fluoro-5-r3-(4-fluorophenyl)-1 H-indazol- 6-yl1-4-methylbenzamide
- Example 80 A/-(3.5-Dimethyl-4-isoxazolyl)-3-r3-(4-fluorophenyl)-1 H-indazol-6-yll-4- methylbenzamide
- BIOLOGICAL EXAMPLES The activity of compounds of formula (I) as p38 inhibitors may be determined by the following in vitro assays:
- Fluorescence anisotropy kinase binding assay 1 The kinase enzyme, fluorescent ligand and a variable concentration of test compound are incubated together to reach thermodynamic equilibrium under conditions such that in the absence of test compound the fluorescent ligand is significantly (>50%) enzyme bound and in the presence of a sufficient concentration (>10x K,) of a potent inhibitor the anisotropy of the unbound fluorescent ligand is measurably different from the bound value.
- the concentration of kinase enzyme should preferably be ⁇ 1 x K f .
- concentration of fluorescent ligand required will depend on the instrumentation used, and the fluorescent and physicochemical properties.
- the concentration used must be lower than the concentration of kinase enzyme, and preferably less than half the kinase enzyme concentration.
- a typical protocol is: All components dissolved in Buffer of f inal composition 62.5 mM HEPES, pH 7.5, 1.25 mM CHAPS, 1.25 mM DTT, 12.5 mM MgCI 2 3.3% DMSO.
- Enzyme concentration 12 nM Fluorescent ligand concentration: 5 nM Test compound concentration: 0.1 nM - 100 ⁇ M Components incubated in 30 ⁇ l final volume in NUNC 384 well black microtitre plate until equilibrium reached (5-30 mins) Fluorescence anisotropy read in LJL Acquest.
- Kj dissociation constant for inhibitor binding
- K f dissociation constant for fluorescent ligand binding
- the fluorescent ligand is the following compound:
- the kinase enzyme, fluorescent ligand and a variable concentration of test compound are incubated together to reach thermodynamic equilibrium under conditions such that in the absence of test compound the fluorescent ligand is significantly (>50%) enzyme bound and in the presence of a sufficient concentration (>10 x Ki) of a potent inhibitor the anisotropy of the unbound fluorescent ligand is measurably different from the bound value.
- the concentration of kinase enzyme should preferably be 2 x Kf.
- the concentration of fluorescent ligand required will depend on the instrumentation used, and the fluorescent and physicochemical properties.
- the concentration used must be lower than the concentration of kinase enzyme, and preferably less than half the kinase enzyme concentration.
- the fluorescent ligand is the following compound: which is derived from 5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2- chlorophenol and rhodamine green.
- Recombinant human p38 ⁇ was expressed as a GST-tagged protein.
- 3.5 ⁇ M unactivated p38 ⁇ was incubated in 50 mM Tris-HCI pH 7.5, 0.1 mM EGTA, 0.1% 2- mercaptoethanol, 0.1 mM sodium vanadate, 10mM MgAc, 0.1 mM ATP with 200nM MBP- MKK6 DD at 30 degrees for 30 mins.
- p38 ⁇ was re-purified and the activity assessed using a standard filter-binding assay.
- Protocol All components are dissolved in buffer of composition 62.5 mM HEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCI 2 with final concentrations of 12nM p38 ⁇ and 5nM fluorescent ligand. 30 ⁇ l of this reaction mixture is added to wells containing 1 ⁇ l of various concentrations of test compound (0.28 nM - 16.6 ⁇ M final) or DMSO vehicle (3% final) in NUNC 384 well black microtitre plate and equilibrated for 30-60 mins at room temperature. Fluorescence anisotropy is read in Molecular Devices Acquest (excitation 485nm/emission 535nm).
- Ki dissociation constant for inhibitor binding
- Kf dissociation constant for fluorescent ligand binding
- Fluorescence anisotropy kinase binding assay 3 (micro volume assay)
- the kinase enzyme, fluorescent ligand and a variable concentration of test compound are incubated together to reach thermodynamic equilibrium under conditions such that in the absence of test compound the fluorescent ligand is significantly (>50%) enzyme bound and in the presence of a sufficient concentration (>10 x Ki) of a potent inhibitor the anisotropy of the unbound fluorescent ligand is measurably different from the bound value.
- the concentration of kinase enzyme should preferably be 2 x Kf.
- the concentration of fluorescent ligand required will depend on the instrumentation used, and the fluorescent and physicochemical properties.
- the concentration used must be lower than the concentration of kinase enzyme, and preferably less than half the kinase enzyme concentration.
- the fluorescent ligand is the following compound: which is derived from 5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1 H-imidazol-4-yl]-2- chlorophenol and rhodamine green.
- Recombinant human p38 ⁇ was expressed as a GST-tagged protein.
- 3.5 ⁇ M unactivated p38 ⁇ was incubated in 50 mM Tris-HCI pH 7.5, 0.1 mM EGTA, 0.1 % 2- mercaptoethanol, 0.1 mM sodium vanadate, 10mM MgAc, 0.1 mM ATP with 200nM MBP- MKK6 DD at 30 degrees for 30 mins.
- p38 ⁇ was re-purified and the activity assessed using a standard filter-binding assay.
- Protocol All components are dissolved in buffer of composition 62.5 mM HEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCI 2 with final concentrations of 12nM p38 ⁇ and 5nM fluorescent l igand. 6 ⁇ l of this reaction m ixture is added to wells containing 0.2 ⁇ I of various concentrations of test compound (0.28 nM - 16.6 ⁇ M final) or DMSO vehicle (3% final) in Greiner 384 well black low volume microtitre plate and equilibrated for 30-60 mins at room temperature. Fluorescence anisotropy is read in Molecular Devices Acquest (excitation 485nm/emission 535nm).
- Ki dissociation constant for inhibitor binding
- Kf dissociation constant for fluorescent ligand binding
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DE602005009318T DE602005009318D1 (en) | 2004-01-30 | 2005-01-27 | CONDENSED HETEROYRAL DERIVATIVES FOR USE AS P38 KINASE INHIBITORS |
JP2006550294A JP2007519692A (en) | 2004-01-30 | 2005-01-27 | Fused heteroaryl derivatives for use as p38 kinase inhibitors |
EP05702022A EP1708996B1 (en) | 2004-01-30 | 2005-01-27 | Fused heteroyral derivatives for use as p38 kinase inhibitors |
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Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008001929A1 (en) | 2006-06-28 | 2008-01-03 | Aska Pharmaceutical Co., Ltd. | Treatment agent for inflammatory bowel disease |
WO2008099615A1 (en) | 2007-02-16 | 2008-08-21 | Aska Pharmaceutical Co., Ltd. | Pharmaceutical composition containing fine particle oil-based suspension |
WO2008137176A1 (en) * | 2007-05-07 | 2008-11-13 | Amgen Inc. | Pyrazolo-pyridinone compounds, process for their preparation, and their pharmaceutical use |
WO2008136948A1 (en) * | 2007-05-07 | 2008-11-13 | Amgen Inc. | Pyrazolo-pyridinone and pyrazolo-pyrazinone compounds as p38 modulators, process for their preparation, and their pharmaceutical use |
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Families Citing this family (1)
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002016359A1 (en) * | 2000-08-22 | 2002-02-28 | Glaxo Group Limited | Fused pyrazole derivatives being protein kinase inhibitors |
WO2004010995A1 (en) * | 2002-07-31 | 2004-02-05 | Smithkline Beecham Corporation | Fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of i.a. rheumatoid arthristis |
Family Cites Families (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4200750A (en) * | 1977-01-07 | 1980-04-29 | Westwood Pharmaceuticals Inc. | 4-Substituted imidazo [1,2-a]quinoxalines |
MX16687A (en) * | 1988-07-07 | 1994-01-31 | Ciba Geigy Ag | BIARILE COMPOUNDS AND PROCEDURE FOR THE PREPARATION. |
GB9816837D0 (en) * | 1998-08-04 | 1998-09-30 | Zeneca Ltd | Amide derivatives |
US5246943A (en) * | 1992-05-19 | 1993-09-21 | Warner-Lambert Company | Substituted 1,2,3,4-tetahydroisoquinolines with angiotensin II receptor antagonist properties |
US5236934A (en) * | 1992-08-26 | 1993-08-17 | E. I. Du Pont De Nemours And Company | 1,2,3,4-tetrahydroisoquinolines useful in the treatment of CNS disorders |
IL108630A0 (en) * | 1993-02-18 | 1994-05-30 | Fmc Corp | Insecticidal substituted 2,4-diaminoquinazolines |
GB9408577D0 (en) * | 1994-04-29 | 1994-06-22 | Fujisawa Pharmaceutical Co | New compound |
US5521213A (en) * | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
IL118544A (en) * | 1995-06-07 | 2001-08-08 | Smithkline Beecham Corp | Imidazole derivatives, process for their preparation and pharmaceutical compositions comprising them |
AU6709596A (en) * | 1995-08-22 | 1997-03-19 | Japan Tobacco Inc. | Amide compounds and use of the same |
US6323227B1 (en) * | 1996-01-02 | 2001-11-27 | Aventis Pharmaceuticals Products Inc. | Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides |
US6080767A (en) * | 1996-01-02 | 2000-06-27 | Aventis Pharmaceuticals Products Inc. | Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides |
US5756499A (en) * | 1996-01-11 | 1998-05-26 | Smithkline Beecham Corporation | Substituted imidazole compounds |
FR2754260B1 (en) * | 1996-10-04 | 1998-10-30 | Adir | NOVEL SUBSTITUTED DERIVATIVES OF BIPHENYL OR PHENYLPYRIDINE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US6147080A (en) * | 1996-12-18 | 2000-11-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
US5945418A (en) * | 1996-12-18 | 1999-08-31 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
RU2249591C2 (en) * | 1997-05-22 | 2005-04-10 | Дж.Д. Серл Энд Ко. | 3-(5)-heteroaryl-substituted pyrazoles as kinase p38 inhibitors |
US6087496A (en) * | 1998-05-22 | 2000-07-11 | G. D. Searle & Co. | Substituted pyrazoles suitable as p38 kinase inhibitors |
US20020156104A1 (en) * | 1997-06-13 | 2002-10-24 | Jerry L. Adams | Novel pyrazole and pyrazoline substituted compounds |
US6060491A (en) * | 1997-06-19 | 2000-05-09 | Dupont Pharmaceuticals | 6-membered aromatics as factor Xa inhibitors |
WO1999001452A1 (en) * | 1997-07-02 | 1999-01-14 | Smithkline Beecham Corporation | Novel cycloalkyl substituted imidazoles |
DE69833464T2 (en) * | 1997-09-05 | 2006-08-24 | Glaxo Group Ltd., Greenford | A pharmaceutical composition containing 2,3-diaryl-pyrazolo1,5-bPyridazine derivatives |
AU735737B2 (en) * | 1997-10-14 | 2001-07-12 | Asahi Kasei Kabushiki Kaisha | Biphenyl-5-alkanoic acid derivatives and use thereof |
DE19817461A1 (en) * | 1998-04-20 | 1999-10-21 | Basf Ag | New benzamide derivatives useful as cysteine protease inhibitors for treating neurodegenerative diseases, neuronal damage, stroke, cranial trauma, Alzheimer's disease, etc. |
CN1185211C (en) * | 1998-05-15 | 2005-01-19 | 阿斯特拉曾尼卡有限公司 | Benzamide derivatives for the treatment of diseases mediated by cytokines |
US6448257B1 (en) * | 1998-05-22 | 2002-09-10 | Scios, Inc. | Compounds and methods to treat cardiac failure and other disorders |
US6130235A (en) * | 1998-05-22 | 2000-10-10 | Scios Inc. | Compounds and methods to treat cardiac failure and other disorders |
US6867209B1 (en) * | 1998-05-22 | 2005-03-15 | Scios, Inc. | Indole-type derivatives as inhibitors of p38 kinase |
US6184226B1 (en) * | 1998-08-28 | 2001-02-06 | Scios Inc. | Quinazoline derivatives as inhibitors of P-38 α |
JP2002526482A (en) * | 1998-09-18 | 2002-08-20 | バーテックス ファーマシューティカルズ インコーポレイテッド | inhibitors of p38 |
EP1140840B1 (en) * | 1999-01-13 | 2006-03-22 | Bayer Pharmaceuticals Corp. | -g(v)-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
US6545054B1 (en) * | 1999-02-11 | 2003-04-08 | Millennium Pharmaceuticals, Inc. | Alkenyl and alkynyl compounds as inhibitors of factor Xa |
US6498166B1 (en) * | 1999-02-27 | 2002-12-24 | Smithkline Beecham Corporation | Pyrazolopyridines |
US6509361B1 (en) * | 1999-05-12 | 2003-01-21 | Pharmacia Corporation | 1,5-Diaryl substituted pyrazoles as p38 kinase inhibitors |
WO2000071510A2 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
DE19932571A1 (en) * | 1999-07-13 | 2001-01-18 | Clariant Gmbh | Process for the preparation of biarylene using palladophosphacyclobutane catalysis |
GB9919778D0 (en) * | 1999-08-21 | 1999-10-27 | Zeneca Ltd | Chemical compounds |
US6576632B1 (en) * | 1999-08-27 | 2003-06-10 | Pfizer Inc | Biaryl compounds useful as anticancer agents |
DE10059418A1 (en) * | 2000-11-30 | 2002-06-20 | Aventis Pharma Gmbh | Ortho, meta-substituted bisaryl compounds, processes for their preparation, their use as medicaments and pharmaceutical preparations containing them |
DE10060807A1 (en) * | 2000-12-07 | 2002-06-20 | Aventis Pharma Gmbh | Ortho, ortho-substituted nitrogen-containing bisaryl compounds, processes for their preparation, their use as medicaments and pharmaceutical preparations containing them |
DE10063008A1 (en) * | 2000-12-16 | 2002-06-20 | Merck Patent Gmbh | carboxamide |
US6677368B2 (en) * | 2000-12-20 | 2004-01-13 | Sugen, Inc. | 4-aryl substituted indolinones |
DE10110749A1 (en) * | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituted aminodicarboxylic acid derivatives |
MXPA03008144A (en) * | 2001-03-09 | 2003-12-12 | Pfizer Prod Inc | Triazolopyridines as anti-inflammatory agents. |
RU2003132706A (en) * | 2001-04-06 | 2005-04-20 | Байокрист Фармасьютикалз, Инк. (Us) | DIARYL COMPOUNDS AS SERINE PROTEASES INHIBITORS |
FR2824827B1 (en) * | 2001-05-17 | 2004-02-13 | Fournier Lab Sa | NOVEL 5-PHENYL-1H-INDOLE ANTAGONIST DERIVATIVES OF INTERLEUKIN-8 RECEPTORS |
AR037233A1 (en) * | 2001-09-07 | 2004-11-03 | Euro Celtique Sa | PIRIDINAS ARIL REPLACED, PHARMACEUTICAL COMPOSITIONS AND THE USE OF SUCH COMPOUNDS FOR THE PREPARATION OF A MEDICINAL PRODUCT |
GB0124848D0 (en) * | 2001-10-16 | 2001-12-05 | Celltech R&D Ltd | Chemical compounds |
GB0124936D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124939D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124932D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124931D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124934D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124933D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124938D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
GB0124941D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
EP1474395B1 (en) * | 2002-02-12 | 2007-10-17 | Smithkline Beecham Corporation | Nicotinamide derivates useful as p38 inhibitors |
US20030225089A1 (en) * | 2002-04-10 | 2003-12-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors |
GB0209891D0 (en) * | 2002-04-30 | 2002-06-05 | Glaxo Group Ltd | Novel compounds |
US20040116479A1 (en) * | 2002-10-04 | 2004-06-17 | Fortuna Haviv | Method of inhibiting angiogenesis |
US7136850B2 (en) * | 2002-12-20 | 2006-11-14 | International Business Machines Corporation | Self tuning database retrieval optimization using regression functions |
ES2312972T3 (en) * | 2003-03-07 | 2009-03-01 | Eli Lilly And Company | ANTIGONISTS OF THE OPIOD RECEIVER. |
GB0308185D0 (en) * | 2003-04-09 | 2003-05-14 | Smithkline Beecham Corp | Novel compounds |
GB0308201D0 (en) * | 2003-04-09 | 2003-05-14 | Smithkline Beecham Corp | Novel compounds |
GB0308186D0 (en) * | 2003-04-09 | 2003-05-14 | Smithkline Beecham Corp | Novel compounds |
BRPI0412918A (en) * | 2003-07-25 | 2006-09-26 | Novartis Ag | p38 kinase inhibitors |
GB0318814D0 (en) * | 2003-08-11 | 2003-09-10 | Smithkline Beecham Corp | Novel compounds |
GB0402138D0 (en) * | 2004-01-30 | 2004-03-03 | Smithkline Beecham Corp | Novel compounds |
GB0402137D0 (en) * | 2004-01-30 | 2004-03-03 | Smithkline Beecham Corp | Novel compounds |
GB0402140D0 (en) * | 2004-01-30 | 2004-03-03 | Smithkline Beecham Corp | Novel compounds |
US20080051416A1 (en) * | 2004-10-05 | 2008-02-28 | Smithkline Beecham Corporation | Novel Compounds |
-
2004
- 2004-01-30 GB GBGB0402143.2A patent/GB0402143D0/en not_active Ceased
-
2005
- 2005-01-27 EP EP05702022A patent/EP1708996B1/en active Active
- 2005-01-27 DE DE602005009318T patent/DE602005009318D1/en active Active
- 2005-01-27 WO PCT/GB2005/000265 patent/WO2005073189A1/en active IP Right Grant
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002016359A1 (en) * | 2000-08-22 | 2002-02-28 | Glaxo Group Limited | Fused pyrazole derivatives being protein kinase inhibitors |
WO2004010995A1 (en) * | 2002-07-31 | 2004-02-05 | Smithkline Beecham Corporation | Fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of i.a. rheumatoid arthristis |
Non-Patent Citations (2)
Title |
---|
COURTENY, S.M.; ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 3269 - 3273, XP002334547 * |
HENRY, J.R.; ET AL., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 8, 1998, pages 3335 - 3340, XP002334548 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1708996B1 (en) | 2008-08-27 |
EP1708996A1 (en) | 2006-10-11 |
JP2007519692A (en) | 2007-07-19 |
US20090023725A1 (en) | 2009-01-22 |
DE602005009318D1 (en) | 2008-10-09 |
ATE406351T1 (en) | 2008-09-15 |
ES2313283T3 (en) | 2009-03-01 |
GB0402143D0 (en) | 2004-03-03 |
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