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WO2004083185A2 - Composes imidazole - Google Patents

Composes imidazole Download PDF

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Publication number
WO2004083185A2
WO2004083185A2 PCT/EP2004/002831 EP2004002831W WO2004083185A2 WO 2004083185 A2 WO2004083185 A2 WO 2004083185A2 EP 2004002831 W EP2004002831 W EP 2004002831W WO 2004083185 A2 WO2004083185 A2 WO 2004083185A2
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Prior art keywords
optionally substituted
alkyl
formula
pharmaceutically acceptable
compound according
Prior art date
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PCT/EP2004/002831
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English (en)
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WO2004083185A3 (fr
Inventor
Gerard Martin Paul Giblin
Adrian Hall
Xiao Qing Lewell
Neil Derek Miller
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Glaxo Group Ltd
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Glaxo Group Ltd
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Publication of WO2004083185A3 publication Critical patent/WO2004083185A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • This invention relates to imidazole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, in particular their use in the treatment of conditions mediated by the action of PGE 2 at EP-i receptors.
  • the EP T receptor is a 7-transmembrane receptor and its natural ligand is the prostaglandin PGE 2 .
  • PGE 2 also has affinity for the other EP receptors (types EP 2 , EP 3 and EP 4 ).
  • the EP T receptor is associated with smooth muscle contraction, pain (in particular inflammatory, neuropathic and visceral), inflammation, allergic activities, renal regulation and gastric or enteric mucus secretion.
  • pain in particular inflammatory, neuropathic and visceral
  • inflammation in particular inflammatory, neuropathic and visceral
  • allergic activities in particular inflammatory, neuropathic and visceral
  • renal regulation renal regulation
  • gastric or enteric mucus secretion we have now found a novel group of compounds which bind with high affinity to the EPi receptor.
  • Prostaglandin E 2 exerts allodynia through the EP receptor subtype and hyperalgesia through EP 2 and EP 3 receptors in the mouse spinal cord. Furthermore an article from The Journal of Clinical Investigation, 2001 , 107 (3), 325 shows that in the EPi knock-out mouse ⁇ pain-sensitivity responses are reduced by approximately 50%.
  • Anesthesia and Analgesia Two papers from Anesthesia and Analgesia have shown that (2001, 93, 1012-7) an EPi receptor antagonist (ONO-8711) reduces hyperalgesia and allodynia in a rat model of chronic constriction injury, and that (2001 , 92, 233-238) the same antagonist inhibits mechanical hyperalgesia in a rodent model of post-operative pain. S.
  • the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
  • these agents may have enhanced efficacy over NSAIDS and/or COX-2 inhibitors.
  • studies suggest that PGE 2 - induced hyperthermia in the rat is mediated predominantly through the EPi receptor.
  • WO 96/06822 (March 7, 1996), WO 96/11902 (April 25, 1996), EP 752421 -A1 (January 08, 1997) and WO 01/19814 (22 March 2001) disclose compounds as being useful in the treatment of prostaglandin mediated diseases.
  • A represents an optionally substituted aryl, or an optionally, substituted 5- or 6- membered heterocyclyl ring, or an optionally substituted bicyclic heterocyclyl group;
  • B represents a phenyl or pyridyl ring
  • Z represents O, S, SO, or SO 2 ;
  • R 1 represents C0 2 R 4 , CN, CONR 5 R 6 , CH 2 CO 2 R 4 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted SO 2 alkyl, SO 2 NR 5 R 6 , NR 5 CONR 5 R 6 , COalkyl,
  • R a and R 2 independently represents hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, CN, SO 2 alkyl, SR 5 , NO 2 , optionally substituted aryl, CONR 5 R 6 or optionally substituted heteroaryl;
  • R x represents optionally substituted alkyl wherein 1 or 2 of the non-terminal carbon atoms are optionally replaced by a group independently selected from NR 4 , O and SO n , wherein n is 0, 1 or 2: or R x represents optionally substituted CQ a Q b -heterocyclyl, optionally substituted CQ a Q b -bicyclic heterocyclyl or optionally substituted CQ a Q b -aryl;
  • R 4 represents hydrogen or an optionally substituted alkyl
  • R 5 represents hydrogen or an optionally substituted alkyl
  • R 6 represents hydrogen or optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted SO 2 aryl, optionally substituted SO 2 alkyl, optionally substituted SO 2 heteroaryl, CN, optionally substituted CQ a Q b aryl, optionally substituted
  • R 7 represents hydrogen, optionally substituted alkyl, optionally substituted heteroaryl or optionally substituted aryl; either Q is carbon and T is nitrogen, or
  • Q is nitrogen and T is carbon; and the dotted line represents alternating single and double bonds;
  • R 8 and R 9 independently represent hydrogen, halogen, C 1- alkyl or CF 3 ;
  • Q a and Q b are independently selected from hydrogen and CH 3 ; wherein when A is a 6-membered ring the R substituent and imidazole ring are attached to carbon atoms 1 ,2-, 1 ,3- or 1 ,4- relative to each other, and when A is a five-membered ring or bicyclic heterocyclyl group the R 1 substituent and imidazole ring are attached to substitutable carbon atoms 1 ,2- or 1 ,3- relative to each other; and derivatives thereof.
  • the present invention provides compounds of formula (la):
  • A represents an optionally substituted phenyl, or an optionally substituted 5- or 6- membered heterocyclyl ring, or an optionally substituted bicyclic heterocyclyl group;
  • R 1 represents C0 2 R 4 , CONR 5 R 6 , CH 2 C0 2 R 4 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted SO 2 alkyl, SO 2 NR 5 R 6 , NR 5 CONR 5 R 6 , CONR 5 R 6 , 2H-tetrazol-5-yl-methyl or optionally substituted heterocyclyl;
  • R 2a and R 2b independently represents halo, optionally substituted alkyl, CN, SO 2 R 5 , SR 5 , NO 2 , optionally substituted aryl, CONR 5 R 6 or optionally substituted heteroaryl;
  • R x represents optionally substituted alkyl wherein 1 or 2 of the non-terminal carbon atoms may optionally be replaced by a group independently selected from NR 4 , O or SO n , wherein n is 0, 1 or 2: or R x may be optionally substituted CQ 2 -heterocyclyl or optionally substituted CQ 2 -phenyl wherein Q is independently selected from hydrogen and CH 3 ;
  • R 4 represents hydrogen or an optionally substituted alkyl;
  • R 5 represents hydrogen or an optionally substituted alkyl;
  • R represents hydrogen or an optionally substituted alkyl, optionally substituted SO 2 aryl, optionally substituted SO 2 heterocyclyl group, CN, optionally substituted CH 2 aryl or COR
  • R 1 is attached to the group A in the 3 position relative to the bond attaching A to the imidazole ring.
  • A is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl, all of which may be optionally substituted. More suitably A is pyridyl or an optionally substituted phenyl; most suitably A is optionally substituted phenyl.
  • Optional substituents for A include up to four substituents, preferably 0 or 1 substituent, independently selected from halogen, CN, optionally substituted CO 2 C lJ3 alkyl, CONR 5 R 6 , : NR 5 R 6 , optionally substituted NR 5 COC ⁇ alkyl, Optionally substituted NR 5 COphenyl, optionally substituted NR 5 COpiperidinyl, optionally substituted NR 5 COheterocyclyl, optionally . substituted NR 5 SO 2 C 1 _ 3 alkyl, OH, optionally substituted OC 1-6 alkyl, optionally substituted d.
  • R 10 and R 11 together with the nitrogen atom to which they are attached form a morpholine ring, a 5- or 6-membered lactam ring or a 5- or 6-membered cyclic sulphonamide, wherein R 5 and R 6 are as defined above for compounds of formula (I).
  • optional substituents for A when a phenyl group include up to four substituents, preferably 0 or 1 substituent, independently selected from halogen, NR 5 R 6 , NR 5 COC 1-6 alkyl, NR 5 SO 2 C «alkyl, OR 5 , C ⁇ alkyl and NR 10 R 11 wherein R 10 and R 11 together with the nitrogen atom to which they are attached form a morpholine ring, a 5- or 6-membered lactam ring or a 5- or 6-membered cyclic sulphonamide, wherein R 5 and R 6 are as defined above.
  • optional substituents for A when a 5- or 6-membered heterocyclyl group include NH 2 .
  • A When A is pyridyl it may be substituted on the ring nitrogen by an oxygen to give a pyridine N-oxide.
  • R x represents an optionally substituted alkyl this group is preferably C ⁇ alkyl, suitably the alkyl group is CH 2 C 5 ⁇ cycloalkyl.
  • R x includes optionally substituted C 1-8 alkyl, optionally substituted CH 2 phenyl, CH 2 pyridyl, or CH 2 thienyl.
  • R x represents CH 2 phenyl optionally substituted by one, two or three, 5 preferably one or two substituents selected from Cl, Br, F, CF 3 , C 1-4 alkyl and OC 1-4 alkyl, or R x is CH 2 C 5-6 cycloalkyl.
  • A is phenyl
  • B is phenyl
  • Z is O.
  • R 1 represents CO 2 R 4 , wherein R 4 is hydrogen or C 1-4 alkyl. More suitably R 1 15 represents CO 2 H.
  • R 2a is hydrogen
  • R 2b is selected from hydrogen, CF 3 and halogen, e.g. chloro and bromo. More 2 . 0, suitably R 2b is selected from hydrogen, and halogen, e.g. chloro and bromo
  • R is positioned 1 ,4-relative to the Z substituent and 1 ,3-relative to the imidazole , ring.
  • R 3a and R 3 are each hydrogen.
  • R 4 represents hydrogen or C 1-3 alkyl, more preferably R 4 is hydrogen. ⁇ 5
  • R represents hydrogen or C 1-3 alkyl.
  • R 6 represents hydrogen or C 1-3 alkyl.
  • R 7 represents hydrogen
  • R and R are each selected from hydrogen, Cl, CH 3 or CF 3 . More suitably R ,8 and R 9 each represents hydrogen.
  • compounds of formula (I) are compounds of formula (lb):
  • R 1 is CO 2 R 4 ;
  • R 2a and R 2a are independently selected from hydrogen, halo, optionally substituted d.
  • R and R independently represents halo or an optionally substituted O(C 1-6 )alkyl, or d- 6 alkyl;
  • R 4 is hydrogen or an optionally substituted C 1-6 alkyl
  • W, X, Y and Z represents CH or N wherein at least one of W, X, Y or Z is CH; either O is carbon and T is nitrogen, or Q is nitrogen and T is carbon; and the dotted line represents alternating single and double bonds; and derivatives thereof.
  • the derivatives are pharmaceutically acceptable derivatives.
  • R 3a and R 3b independently represent hydrogen, halo or optionally substituted 0(C ⁇ - e)alkyl.
  • R is hydrogen
  • Compounds of formula (I) include: 3-[5-(2-Benzyloxy-phenyl)-imidazol-1 -yl]-benzoic acid; 3-[5-(2-Benzyloxy-5-chloro-phenyl)-imidazol-1-yl]-benzoic acid; 3-[5-(2-Benzyloxy-5-bromo-phenyl)-imidazol-1 -yl]-benzoic acid; 3-[5-(2-Benzyloxy-phenyl)-3 -/-imidazol-4-yl]-benzoic acid; and derivatives thereof.
  • Preferably compounds are selective for EPi over EP 3 . More preferably the compounds are 100 fold selective, more preferably 1000 fold selective for EPi over EP 3 .
  • Derivatives of the compounds of formula (I) include pharmaceutically acceptable derivatives.
  • the invention is described using the following definitions unless otherwise indicated.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, ester, salt of such ester or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I).
  • the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds, and that the compounds of formula (I) may be derivatised at more than one position.
  • salts referred to above will be pharmaceutically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19:
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium; potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non- - : toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acid.
  • Preferred examples of pharmaceutically acceptable salts include those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids.
  • salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated.
  • This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • halogen or halo are used to represent fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine.
  • alkyl as a group or part of a group means a straight, branched or cyclic chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, 1 ,1-dimethylethyl, cyclopentyl or cyclohexyl or combinations thereof such as cyclohexylmethyl and cyclopentylmethyl.
  • alkyl is C 1-8 alkyf, more preferably "alkyl” is C 1-6 alkyl.
  • alkoxy as a group or part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
  • alkoxy is C ⁇ alkoxy.
  • heterocyclyl as a group or as part of a group means an aromatic or non- aromatic five or six membered ring which contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur and unsubstituted or substituted by, for example, up to three substituents.
  • 5- membered heterocyclyl groups include furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl or tetrazolyl.
  • 6-membered heterocyclyl groups are pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl ortetrazinyl.
  • aryl as a group or part of a group means a 5- or 6- membered aromatic ring, for example phenyl, or a 7 to 12 membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl.
  • An aryl group may be optionally substituted by one or more substituents, for example up to 4, 3 or 2 substituents.
  • the aryl group is phenyl.
  • heteroaryl as a group or as part of a group means a monocyclic five or six membered aromatic ring, or a fused bicyclic aromatic ring system comprising two of such monocyclic five or six membered aromatic rings. These heteroaryl rings contain one or more heteroatoms selected from nitrogen, oxygen or sulfur, where N-oxides, sulfur oxides and sulfur dioxides are permissible heteroatom substitutions. A heteroaryl group may be optionally substituted by one or more substituents, for example up to 3 or up to 2 substituents.
  • heteroaryl used herein include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, indolyl, and indazolyl.
  • bicyclic heterocyclyl when used herein means a fused bicyclic aromatic or non- aromatic bicyclic heterocyclyl ring system comprising up to four, preferably one or two, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a bicyclic heteroaromatic ring system may include a carbocyclic ring.
  • bicyclic heterocyclyl groups include quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benzthiadiazolyl, indolyl,, benztriazolyl or naphthyridinyl.
  • the nitrogen atom When the heteroatom nitrogen replaces a! carbon atom in an alkyl group, or when nitrogen is present in a heteroaryl, heterocyclyl or bicyclic heterocyclyl group, the nitrogen atom will, where appropriate be substituted by one or two substituents selected from hydrogen and .
  • alkyl groups unless hereinbefore defined are OH, CO 2 R 4 , NR 4 R 5 , (O), OC ⁇ alkyl or halo, wherein R 4 and R 5 are as herein before defined.
  • An alkyl or alkenyl group may be substituted by one or more optional substituents, for example up to 5, 4, 3, or 2 optional substituents.
  • optional substituents for aryl, heteroaryl or heterocyclyl moieties as a group or part of a group are selected from optionally substituted C J3 alkyl, optionally substituted C ⁇ alkoxy and halogen.
  • Alternative optional substituents include C 1-6 alkyl, C ⁇ alkoxy and halogen.
  • R 8a hydrogen or C 1 . 3 alkyl
  • R 9a hydrogen R 8 and /or R 9 groups
  • P is an optional protecting group
  • A, B, Z, R 2a , R 2b , R 1 , R 8 , R 9 and R x are as defined for compounds of formula (I).
  • Compounds of formula (IA) wherein R 8 is Cl may be prepared, for example, by treating a compound of formula (IIA) wherein R 8a is hydrogen with a source of electrophilic chlorine, e.g. N-chlorosuccinimide, followed if necessary by deprotection.
  • a source of electrophilic chlorine e.g. N-chlorosuccinimide
  • Compounds of formula (IA) wherein R 8 is F may be prepared, for example, by treating a compound of formula (IIA) wherein R 8a is hydrogen with a source of electrophilic fluorine, e.g. SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)], followed if necessary by deprotection.
  • SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)
  • Compounds of formula (IA) wherein R 8 is CF 3 may be prepared, for example, by treating a compound of formula (IIA) wherein R 8a is hydrogen with N-iodosuccinimide followed by isopropyl magnesium chloride, followed by sequential treatment with CO 2 then SF and subsequent deprotection if necessary.
  • Compounds of formula (IA) wherein R 9 is Cl may be prepared, for example, by treating a compound of formula (IIA) with lithium diisopropylamide followed by a source of electrophilic chlorine, e.g. N-chlorosuccinimide, followed if necessary by deprotection.
  • a source of electrophilic chlorine e.g. N-chlorosuccinimide
  • Compounds of formula (IA) wherein R 9 is F may be prepared by treating a compound of formula (IIA) with lithium diisopropylamide followed by a source of electrophilic fluorine, e.g. SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)], followed if necessary by deprotection.
  • SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)
  • Compounds of formula (IA) wherein R is C 1-3 alkyl may be prepared, for example by treating a compound of formula (IIA) with lithium diisopropylamide followed by a C h alky! iodide, followed if necessary by deprotection.
  • Compounds of formula (IA) wherein R 9 is CF 3 may be prepared, for example by treating a compound of formula (IIA) with lithium diisopropylamide followed by sequential treatment 1 with CO 2 then SF 4 , followed if necessary by deprotection.
  • the present invention also provides a process for the preparation of a compound of formula (IA) or a derivative thereof:
  • A represents an optionally substituted aryl, or an optionally substituted 5- or 6- membered heterocyclyl ring, or an optionally substituted bicyclic heterocyclyl group;
  • B represents a phenyl or pyridyl ring
  • Z represents O, S, SO, or SO 2 ;
  • R 1 represents CO 2 R 4 , CN, CONR 5 R 6 , CH 2 CO 2 R 4 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted SO 2 alkyl, SO 2 NR 5 R 6 , NR 5 CONR 5 R 6 , COalkyl,
  • R 2a and R 2b independently represents hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, CN, SO 2 alkyl, SR 5 , NO 2 , optionally substituted aryl, CONR 5 R 6 or optionally substituted heteroaryl;
  • R x represents optionally substituted alkyl wherein 1 or 2 of the non-terminal carbon atoms are optionally replaced by a group independently selected from NR 4 , O and SO n , wherein n is 0, 1 or 2: or R x represents optionally substituted CQ a Q b -heterocyclyl, optionally substituted CQ a Q b -bicyclic heterocyclyl or optionally substituted CQ a Q b -aryl;
  • R 4 represents hydrogen or an optionally substituted alkyl
  • R 5 represents hydrogen or an optionally substituted alkyl
  • R 6 represents hydrogen or optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted SO 2 aryl, optionally substituted SO 2 alkyl, optionally substituted
  • R 7 represents hydrogen, optionally substituted alkyl, optionally substituted heteroaryl or optionally substituted aryl
  • R 8 and R 9 independently represent hydrogen, halogen, C 1-3 alkyl or CF 3 ;
  • Q a and Q b are independently selected from hydrogen and CH 3 ; wherein when A is a 6-membered ring the R 1 substituent and. imidazole ring are attached to carbon atoms 1 ,2-, 1 ,3- or 1 ,4- relative to each other, and when A is a five-membered ring or bicyclic heterocyclyl group the R 1 substituent and imidazole ring are attached to> substitutable carbon atoms 1 ,2- or 1 ,3- relative to each other:
  • R ,8a is hydrogen or C 1-3 alkyl; and where required, and in any order, converting: a group R 8a to a group R 8 ; a group R 9a to a group R 9 , and/or one group R x to another group R x ; and where required carrying out the following optional steps in any order: effecting deprotection; and/or converting one group R 1 to another group R 1 ; and/or forming a derivative of the compound of formula (IA) so formed.
  • Compounds of formula (IB) wherein R 9 is F may be prepared, for example, by treating a compound of formula (IIB) wherein R 9b is hydrogen with a source of electrophilic fluorine, e.g. SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)], followed if necessary by deprotection.
  • SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)
  • Compounds of formula (IB) wherein R 9 is CF 3 may be prepared, for example, by treating a compound of formula (IIB) wherein R 9b is hydrogen with N-iodosuccinimide followed by isopropyl magnesium chloride, followed by sequential treatment with CO 2 then SF 4 , followed by deprotection if necessary.
  • Compounds of formula (IB) wherein R 8 is Cl may be prepared, for example, by treating a compound of formula (IIB) with lithium diisopropylamide followed by a source of electrophilic chlorine, e.g. N-chlorosuccinimide, followed if necessary by deprotection.
  • a source of electrophilic chlorine e.g. N-chlorosuccinimide
  • Compounds of formula (IB) wherein R 8 is F may be prepared by treating a compound of formula (IIB) with lithium diisopropylamide followed by a source of electrophilic fluorine, e.g. SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)], followed if necessary by deprotection.
  • SELECTFLUOR TM [1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2.]octane bis(tetrafluoroborate)
  • Compounds of formula (IB) wherein R 8 is C 1-3 alkyl may be prepared, for example by treating a compound of formula (IIB) with lithium diisopropylamide followed by a C -3 alkyl iodide, followed if necessary by deprotection.
  • Compounds of formula (IB) wherein R 8 is CF 3 may be prepared, for example by treating a compound of formula (IIB) with lithium diisopropylamide followed by sequential treament with CO 2 then SF , followed if necessary by deprotection.
  • the present invention also provides a process for the preparation of a compound of formula (IB) or a derivative thereof:
  • A represents an optionally substituted aryl, or an optionally substituted 5- or 6- membered heterocyclyl ring, or an optionally substituted bicyclic heterocyclyl group;
  • B represents a phenyl or pyridyl ring
  • Z represents O, S, SO, or SO 2 ;
  • R 1 represents CO 2 R 4 , CN, CONR 5 R 6 , CH 2 CO 2 R 4 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted SO 2 alkyl, SO 2 NR 5 R 6 , NR 5 CONR 5 R 6 , COalkyl,
  • R 2a and R 2b independently represents hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, CN, SO 2 alkyl, SR 5 , NO 2 , optionally substituted aryl, CONR 5 R 6 or optionally substituted heteroaryl;
  • R x represents optionally substituted alkyl wherein 1 or 2 of the non-terminal carbon atoms are optionally replaced by a group independently selected from NR 4 , O and SO n , wherein n is 0, 1 or 2: or R x represents optionally substituted CQ a Q b -heterocyclyl, optionally substituted CQ a Q b -bicyclic heterocyclyl or optionally substituted CQ a Q b -aryl;
  • R 4 represents hydrogen or an optionally substituted alkyl
  • R 5 represents hydrogen or an optionally substituted alkyl
  • R 6 represents hydrogen or optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted SO 2 aryl, optionally substituted SO 2 alkyl, optionally substituted SO 2 heteroaryl, CN, optionally substituted CQ a Q b aryl, optionally substituted
  • R 7 represents hydrogen, optionally substituted alkyl, optionally substituted heteroaryl or optionally substituted aryl
  • R 8 and R 9 independently represent hydrogen, halogen, C 1-3 alkyl or CF 3 ;
  • Q a and Q b are independently selected from hydrogen and CH 3 ; wherein when A is a 6-membered ring the R 1 substituent and imidazole ring are attached to carbon atoms 1 ,2-, 1 ,3- or 1 ,4- relative to each other, and when A is a five-membered ring or bicyclic heterocyclyl group the R 1 substituent and imidazole ring are attached to substitutable carbon atoms 1 ,2- or 1 ,3- relative to each other:
  • R 9b is hydrogen or C 1-3 alkyl; and where required, and in any order, converting: a group R 8b to a group R 8 ; a group R 9b to a group R 9 , and/or one group R x to another group R x ; and where required carrying out the following optional steps in any order: effecting deprotection; and/or converting one group R 1 to another group R 1 ; and/or forming a derivative of the compound of formula (IB) so formed.
  • a group R 1 may be converted to another group R 1 by use of conventional organic transformations known to those skilled in the art and as described in, for example, Richard Larock, Comprehensive Organic Transformations, 2nd edition, Wiley-VCH, ISBN 0-471- 19031-4.
  • substituents in any of the reaction intermediates and compounds of formula (I) may be converted to other substituents by conventional methods known to those skilled in the art.
  • substituents which may be converted include one group R x to another group R x ; and one substituent on a group A to another substituent on a group A.
  • transformations include the reduction of a nitro group to give an amino group; alkylation and amidation of amino groups; hydrolysis of esters, alkylation of hydroxy and amino groups; and amidation and esterification of carboxylic acids.
  • Such transformations are well known to those skilled in the art and are described in for example, Richard Larock, Comprehensive Organic Transformations, 2nd edition, Wiley-VCH, ISBN 0-471-19031-4.
  • R x is p-methoxy benzyl
  • cleavage of the ether to give the phenol or pyridinol is carried out using, for example, using acid e.g. HCI/dioxane or HBr/acetic acid.
  • R x is methyl
  • cleavage of the ether to give the phenol is carried out using, for example, sodium methanethiolate.
  • Cleavage of the ether to give a pyridinol is carried out in the presence of, for example, trifluoroacetic acid.
  • R x group for example a substituted benzyl group
  • conversion to another R x group may be effected by reaction of the phenol or pyridinol with a suitable substituted benzyl bromide.
  • the skilled person will appreciate that conversion of the protecting group P to another protecting group P may also occur under the reaction conditions used.
  • R x is benzyl
  • cleavage of the ether to give the phenol or pyridinol may be carried out by hydrogenation according to known methods e.g. H 2 - Pd/C or NH 4 CO 2 H-Pd/C.
  • the resulting phenol or pyridinol can then be converted to another group R x as described above.
  • examples of P include methyl, ethyl or substituted benzyl esters.
  • Suitable reaction conditions for the deprotection of a compounds of formula (Ha) and (lib) include heating in ethanolic sodium hydroxide solution.
  • Imidazole functionalisation is described in, for example, J. Med. Chem., 2003, 46, 3463- 3475, and in patent applications WO 00/23426 and WO 01/70704.
  • Suitable conditions for the reaction of a compound of formula (IV) with a compound of formula (III) to give a compound of formula (I la), or a compound of formula (VI) with a compound of formula (V) to give a compound of formula (lib), include heating with sodium sulfate in a solvent, for example toluene, followed by treatment by heating with a tosylmethyl isocyanide in a solvent such as ethanol in the presence of a base, for example potassium carbonate (D. Van Leusen and A.M. Van Leusen, Organic Reactions, vol 57, 417-666, L. Overman (Ed.).
  • amines of formula (III) and formula (VI) may be made by methods described in The Amino Group, S. Patai (Ed), Interscience, New York 1968, and references cited therein. The preparation of amines is also described in Richard Larock, Comprehensive Organic Transformations, 2nd edition, pages 753 to 879, Wiley-VCH, ISBN 0-471-19031- 4.
  • Aldehydes of formula (IV) or formula (V) may be made by methods described in The Chemistry of the Carbonyl Group, S. Patai (Ed), Interscience, New York, 1966, and references cited therein.
  • Tosylmethyl isocyanide (TosMIC) is commercially available.
  • C ⁇ alkyl may be prepared by alkylation of TosMIC with a C h alky! iodide, for example under phase transfer catalysis conditions ⁇ Tetrahedron, 1988, 44(23). 7243-7254).
  • the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the compounds of the invention bind to the EP-, receptor and they are therefore considered to be useful in treating conditions mediated by the action of PGE 2 at EP T receptors.
  • Conditions mediated by the action of PGE 2 at EP-i receptors include pain; fever; inflammation; immunological diseases; abnormal platelet function diseases; impotence or erectile dysfunction; bone disease; hemodynamic side effects of non-steroidal anti- inflammatory drugs; cardiovascular diseases; neurodegenerative diseases and neurodegeneration; neurodegeneration following trauma; tinnitus; dependence on a de ' pendence-inducing agent; complications of Type I diabetes; and kidney dysfunction.
  • the compounds of formula (I) are considered to be useful as analgesics. They are therefore considered useful in the treatment or prevention of pain.
  • the compounds of formula (I) are considered useful as analgesics to treat acute pain, chronic pain, neuropatic pain, inflammatory pain, visceral pain, pain associated with cancer and fibromyalgia, pain associated with migraine, tension headache and cluster headaches, and pain associated with functional bowel disorders, non-cardiac chest pain and non-ulcer dispepsia.
  • the compounds of formula (I) are considered useful in the treatment of chronic articular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • chronic articular pain e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spond
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • the compounds of formula (I) are also considered useful in the treatment of fever.
  • the compounds of formula (I) are also considered useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g.
  • an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin
  • the compounds of formula (I) are also considered useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • the compounds of formula (I) are also effective in increasing the latency of HIV infection.
  • the compounds of formula (I) are also considered useful in the treatment of diseases relating to abnormal platelet function (e.g. occlusive vascular diseases).
  • the compounds of formula (I) are also considered useful for the preparation of a drug with diuretic action.
  • the compounds of formula (I) are also considered useful in the treatment of impotence or erectile dysfunction.
  • the compounds of formula (I) are also considered useful in the treatment of bone disease characterised by abnormal bone metabolism or resorbtion such as osteoporosis ⁇ (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancer caechexia, calculosis, lithiasis (especially urolithiasis), solid carcinoma, gout and ankylosing spondylitis, tendinitis and bursitis.
  • osteoporosis ⁇ especially postmenopausal osteoporosis
  • hyper-calcemia hyperparathyroidism
  • Paget's bone diseases osteolysis
  • hypercalcemia of malignancy with or without bone metastases rheumatoid arthritis
  • periodontitis osteoarthritis
  • the compounds of formula (I) are also considered useful for attenuating the hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAID's) and cyclooxygenase-2 (COX-2) inhibitors.
  • NSAID's non-steroidal anti-inflammatory drugs
  • COX-2 cyclooxygenase-2
  • the compounds of formula (I) are also considered useful in the treatment of cardiovascular diseases such as hypertension or myocardiac ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • cardiovascular diseases such as hypertension or myocardiac ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • the compounds of formula (I) are also considered useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism;
  • the compounds of formula (I) are also considered useful in the treatment of neuroprotection and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • the compounds of formula (I) are also considered useful in the treatment of tinnitus.
  • the compounds of formula (I) are also considered useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent.
  • dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
  • the compounds of formula (I) are also considered useful in the treatment of complications of Type 1 diabetes (e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
  • Type 1 diabetes e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic ne
  • the compounds of formula (I) are also considered useful in the treatment of kidney ! dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the action of PGE 2 at EP 1 receptors.
  • a method of treating a human or animal subject suffering from a condition which is mediated by the action of PGE 2 at EP-i receptors which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • a method of treating a human or animal subject suffering from a pain, or an inflammatory, immunological, bone, neurodegenerative or renal disorder which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • a method of treating a human or animal subject suffering from inflammatory pain, neuropathic pain or visceral pain comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as a pain, or an inflammatory, immunological, bone, neurodegenerative or renal disorder.
  • a compound of formula (l).or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as inflammatory pain, > neuropathic pain or visceral pain.
  • compositions are conveniently administered in the form of pharmaceutical compositions.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner. They 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 pharmaceutical composition may take the form of, for example, tablets (including sub-lingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
  • the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
  • the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously).
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • formulatory agents such as suspending, stabilising and/or dispersing agents.
  • parenteral administration these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle.
  • 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 EPi receptor compounds for use in the instant invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib or COX-189; 5-lipoxygenase inhibitors; NSAID's, such as diclofenac, indomethacin, nabumetone or ibuprofen; leukotriene receptor antagonists; DMARD's such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin and related compounds; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HT ⁇ agonists, such as tript
  • the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995 US5,633,272; US5,466,823, US6.310,099 and US6,291 ,523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, WO99/12930, WO00/26216, WO00/52008, WO00/38311 , WO01/58881 and WO02/18374.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
  • 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.
  • a proposed daily dosage of compounds of formula (1) or their pharmaceutically acceptable derivatives for the treatment of man is from 0.01 to 30 mg/kg body weight per day and more particularly 0.1 to 10 mg/kg body weight per day, calculated as the free base, which may be administered as a single or divided dose, for example one to four times per day
  • the dose range for adult human beings is generally from 8 to 2000 mg/day, such as from 20 to 1000 mg/day, preferably 35 to 200 mg/day, calculated as the free base.
  • the precise amount of the compounds of formula (I) administered to a host, particularly a human patient, will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration.
  • the column used is typically a Supelco ABZ+ column whose dimensions are 10mm internal diameter by 100mm in length.
  • the stationary phase particle size is 5 ⁇ m.
  • Aqueous solvent Water + 0.1% Formic Acid
  • the compounds of formula (I) can be tested using the following assays to demonstrate their prostanoid antagonist or agonist activity in vitro and in vivo and their selectivity.
  • the prostaglandin receptors investigated are DP, EP 1 f EP 2 , EP 3 , EP 4 , FP, IP and TP.
  • the ability of compounds to antagonise EPi & EP 3 receptors may be demonstrated using a functional calcium mobilisation assay. Briefly, the antagonist properties of compounds are assessed by their ability to inhibit the mobilisation of intracellular calcium ([Ca 2+ ],) in response to activation of EP-i or EP 3 receptors by the natural agonist hormone prostaglandin E 2 (PGE 2 ).
  • Increasing concentrations of antagonist reduce the amount of calcium that a given concentration of PGE 2 can mobilise.
  • the net effect is to displace the PGE 2 concentration-effect curve to higher concentrations of PGE 2 .
  • the amount of calcium produced is assessed using a calcium-sensitive fluorescent dye such as Fluo-3, AM and a suitable instrument such as a Fluorimetric Imaging Plate Reader (FLIPR).
  • FLIPR Fluorimetric Imaging Plate Reader
  • Increasing amounts of [Ca 2+ ], produced by receptor activation increase the amount of fluorescence produced by the dye and give rise to an increasing signal.
  • the signal may be detected using the FLIPR instrument and the data generated may be analysed with suitable curve- fitting software.
  • the human EP ! or EP 3 calcium mobilisation assay (hereafter referred to as 'the calcium assay') utilises Chinese hamster ovary-K1 (CHO-K1 ) cells into which a stable vector containing either EP ! or EP 3 cDNA has previously been transfected.
  • Cells are cultured in suitable flasks containing culture medium such as DMEM:F-12 supplemented with 10% v/v foetal calf serum, 2mM L-glutamine, 0.25mg/ml geneticin and 10 ⁇ g/ml puromycin.
  • cells are harvested using a proprietary reagent that dislodges cells such as Versene. Cells are re-suspended in a suitable quantity of fresh culture media for introduction into a 384-well plate. Following incubation for 24 hour ' s at 37°C the culture media is replaced with a medium containing fluo-3 and the detergent pluronic acid, and a further incubation takes place. Concentrations of compounds are then added to the plate in order to construct concentration-effect curves. This may be performed on the FLIPR in order to assess the agonist properties of the compounds. Concentrations of PGE 2 are then added to the plate in order to assess the antagonist properties of the compounds.
  • a proprietary reagent that dislodges cells such as Versene.
  • the data so generated may be analysed by means of a computerised curve-fitting routine.
  • the concentration of compound that elicits a half-maximal inhibition of the calcium mobilisation induced by PGE 2 (p!C 50 ) may then be estimated.
  • Compound potencies are determined using a radioligand binding assay. In this assay compound potencies are determined from their ability to compete with tritiated prostaglandin E 2 ([ 3 H]-PGE 2 ) for binding to the human EPi receptor.
  • This assay utilises Chinese hamster ovary-K1 (CHO-K1 ) cells into which a stable vector containing the EP cDNA has previously been transfected.
  • Cells are cultured in suitable flasks containing culture medium such as DMEM:F-12 supplemented with 10% v/v foetal calf serum, 2mM L-glutamine, 0.25mg/ml geneticin, 10 ⁇ g/ml puromycin and 10 ⁇ M indomethacin.
  • Cells are detached from the culture flasks by incubation in calcium and magnesium free phosphate buffered saline containing 1 mM disodium ethylenediaminetetraacetic acid (Na 2 EDTA) and 10 ⁇ M indomethacin for 5 min.
  • the cells are isolated by centrifugation at 250xg for 5mins and suspended in an ice cold buffer such as 50 mM Tris, 1mM Na 2 EDTA, 140mM NaCI, 10 ⁇ M indomethacin (pH 7.4).
  • the cells are homogenised using a Polytron tissue disrupter (2x10s burst at full setting), centrifuged at 48,000xg for 20mins and the pellet containing the membrane fraction is washed three times by suspension and centrifugation at 48,000xg for 20mins.
  • the final membrane pellet is suspended in an assay buffer such as 10mM 2-[N-morpholino]ethanesulphonic acid, 1mM Na 2 EDTA, 10mM MgCI 2 (pH 6). Aliquots are frozen at -80°C until required.
  • the cell membranes For the binding assay the cell membranes, competing compounds and [ 3 H]-PGE 2 (3nM final assay concentration) are incubated in a final volume of 100 ⁇ l for 30 min at 30°C. All reagents are prepared in assay buffer. Reactions are terminated by rapid vacuum filtration over GF/B filters using a Brandell cell harvester. The filters are washed with ice cold assay buffer, dried and the radioactivity retained on the filters is measured by liquid scintillation counting in Packard TopCount scintillation counter.
  • compounds of the examples had an antagonist plC 50 value of between 7.0 and 9.5 at EP-i receptors and plC50 value of ⁇ 6.0 at EP 3 receptors.

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Abstract

L'invention concerne des composés de formule (I) ou un dérivé pharmaceutiquement acceptable de ceux-ci. Dans cette formule, A, B, Z, R1, R2a, R2b, Rx, R8, R9, Q et T sont définis dans la description. L'invention concerne un procédé de préparation de tels composés, des compositions pharmaceutiques comprenant de tels composés et l'utilisation de tels composés en médecine.
PCT/EP2004/002831 2003-03-19 2004-03-17 Composes imidazole Ceased WO2004083185A2 (fr)

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WO2005037786A1 (fr) * 2003-10-08 2005-04-28 Glaxo Group Limited Composes heterocyclyle
WO2005040128A1 (fr) * 2003-10-24 2005-05-06 Glaxo Group Limited Composes heterocyclyles
WO2007113289A1 (fr) * 2006-04-05 2007-10-11 Glaxo Group Limited Composés de benzofurane utilisés comme antagonistes du récepteur de la protéine ep1
EP2053042A1 (fr) 2004-12-23 2009-04-29 Glaxo Group Limited Dérivés de la pyridine au traitement de maladies induites par prostaglandine.
WO2010007943A1 (fr) 2008-07-17 2010-01-21 旭化成ファーマ株式会社 Composé hétérocyclique azoté
WO2010007944A1 (fr) 2008-07-17 2010-01-21 旭化成ファーマ株式会社 Composé hétérocyclique bicyclique azoté
CN104220422A (zh) * 2011-09-16 2014-12-17 埃斯特韦实验室有限公司 Ep1受体配体
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
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EP1216238B1 (fr) * 1999-09-14 2004-02-18 Merck Frosst Canada & Co. Acides carboxyliques et acylsulfonamides, compositions contenant de tels composes et methodes de traitement
ES2159489B1 (es) * 2000-03-23 2002-04-16 Uriach & Cia Sa J Nuevos derivados de imidazol con actividad antiinflamatoria.
WO2002015902A1 (fr) * 2000-08-23 2002-02-28 Merck & Co., Inc. Procede pour traiter et prevenir l'incontinence urinaire par utilisation d'antagonistes de recepteur ep1 de prostanoide
GB0212785D0 (en) * 2002-05-31 2002-07-10 Glaxo Group Ltd Compounds

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WO2005037786A1 (fr) * 2003-10-08 2005-04-28 Glaxo Group Limited Composes heterocyclyle
WO2005040128A1 (fr) * 2003-10-24 2005-05-06 Glaxo Group Limited Composes heterocyclyles
US7759369B2 (en) 2004-12-23 2010-07-20 Glaxo Group Limited Pyridine compounds for the treatment of prostaglandin mediated diseases
EP2053042A1 (fr) 2004-12-23 2009-04-29 Glaxo Group Limited Dérivés de la pyridine au traitement de maladies induites par prostaglandine.
WO2007113289A1 (fr) * 2006-04-05 2007-10-11 Glaxo Group Limited Composés de benzofurane utilisés comme antagonistes du récepteur de la protéine ep1
US7994202B2 (en) 2008-07-17 2011-08-09 Asahi Kasei Pharma Corporation Bicyclic nitrogen-containing heterocyclic compounds
WO2010007944A1 (fr) 2008-07-17 2010-01-21 旭化成ファーマ株式会社 Composé hétérocyclique bicyclique azoté
US7960392B2 (en) 2008-07-17 2011-06-14 Asahi Kasei Pharma Corporation Nitrogen-containing heterocyclic compounds
WO2010007943A1 (fr) 2008-07-17 2010-01-21 旭化成ファーマ株式会社 Composé hétérocyclique azoté
CN104220422A (zh) * 2011-09-16 2014-12-17 埃斯特韦实验室有限公司 Ep1受体配体
CN104220422B (zh) * 2011-09-16 2017-11-07 埃斯特韦实验室有限公司 Ep1受体配体
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10689383B2 (en) 2014-08-04 2020-06-23 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11254681B2 (en) 2014-08-04 2022-02-22 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US12441704B2 (en) 2019-12-20 2025-10-14 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

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