CA2216809A1 - Imidazo[1,2-a]pyridine derivatives - Google Patents
Imidazo[1,2-a]pyridine derivatives Download PDFInfo
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- CA2216809A1 CA2216809A1 CA002216809A CA2216809A CA2216809A1 CA 2216809 A1 CA2216809 A1 CA 2216809A1 CA 002216809 A CA002216809 A CA 002216809A CA 2216809 A CA2216809 A CA 2216809A CA 2216809 A1 CA2216809 A1 CA 2216809A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention provides the compounds of formula (I) and pharmaceutically acceptable derivatives thereof in which: R0 represents halogen; R1 and R2 are independently selected from H, halogen, C1-4alkyl, C1-4alkyl substituted by one or more fluorine atoms, C1-4alkoxy, C1-4hydroxyalkyl, SC1-4alkyl, C(O)H or C(O)C1-4alkyl; and R3 represents C1-4alkyl. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.
Description
IMID~ZO [1,2a ~ PYRIDINE DERIVATIVES
This invention relates to imidazo~1,2-a]pyridine derivatives, to processes for their pre,udr~lion, to pl,a""~ Jtic~l composilions containing them and to their use in medicine.
The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, encloloxin, hormones, cytokines and growth factors.
Prostaglandins generalted by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is responsible for the important physiological functions such as mainte, Idl ,ce of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflalllr"atoly agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.
The invention thus provides the compounds of formula (I) R 02S _~N~, and pharmaceutically acceptable derivatives thereof in which:
R~ represents halogen;
R' and R2 are independently selected from H, halogen, C,~alkyl, C1 4alkyl substituted by one or more fluorine atoms, C1~alkoxy, C'4hydroxyalkyl, SC14alkyl, C(O)H or C(O)C,4alkyl; and R3 represents C,~alkyl.
By pharmaceutically acce,ulable derivative is meant any ,c l Idl "~oe~ ~tic~lly acceptaL31e salt, solvate or ester, or salt or solvate of such ester, of the co",,.,ounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a cG,.,pound of formula (I) or an active metabolite or residue thereof.
It will be appreciated that, for pl,ar",~ce~tic~l use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparalio" of ccjrnpounds of formula (I) and the physiologicallyacceplable salts thereof.
Suitable phar"~aceutically acceplable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
The term halogen is used to represent fluorine, chlorine, bromine or iodine.
The term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group, for exa",pl~ a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
The substituents R' and R2 may be at the 5-, 6-, 7- or 8- positions of the pyridine ring of formula (I), as defined hereinbelow:
P,ererably, R' is at the 8- position; and R2 is at the 7- position or, when R' is other than H, the 5-, 6- or 7-position. More preferably, R' is at the 8- position;
and R2 is at the 7- position or, when R' is C,4alkyl (e.g. methyl), the 5- or 7-position.
Preferably, R~ represents fluorine.
Preferably, R' represents H, chlorine, bromine, C,~alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2F or CF3), C,4hydroxyalkyl CA 022l6809 l997-09-29 (e.g. CH20H or CH(OH)CH3), SC,~alkyl (e.g. SCH3), C(O)H or C(O)C.~alkyl (e.g. C(O)CH3). Mor~ prererably, R1 represe,)ls H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(C))H or C(O)CH3. Most ~,-erer~ly R' represents C(O)CH3.
Preferably, R2 represents H, chlorine, bromine, or C~alkyl (e.g. methyl). More preferably, R2 represents H, bromine or methyl.
P,~rerably, R3 represents methyl.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R~' represents fluorine; R' represents H, chlorine, bromine, C~alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g.
CH2F or CF3), C,~hy~droxyalkyl (e.g. CH20H or CH(OH)CH3), SC,~alkyl (e.g.
SCH3), C(O)H or C(~))C,~alkyl (e.g. C(O)CH3); R2 represents H, chlorine, bromine, or C~alkyl (e.g. methyl); and R3 represents methyl.
Within group A there is provided the sub-group of compounds wherein: R~
represents fluorine; R~ represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(l~))CH3; R2 represents H, bromine or methyl; and R3 represents methyl.
Within the invention there is provided another group of compounds of formula (I)(group B) wherein R~ represents fluorine; R'is at the 8- position and representsH, chlorine, bromine, C,~alkyl (e.g. methyl), methyl substituted by one to threefluorine atoms (e.g. CH2F or CF3), C,~hydroxyalkyl (e.g. CH20H or CH(OH)CH3), SC,~alkyl (e.g. SCH3), C(O)H or C(O)C,4alkyl (e.g. C(O)CH3); R2 is at the 7- position or, when R' is other than H, the 5-, 6- or 7- position, and represents H, chlorine, bromine, or C,~alkyl (e.g. methyl); and R3 represents methyl.
Within group B there is provided the sub-group of compounds wherein: R~
represents fluorine; R'is at the 8- position and represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(O)CH3; R2 is at the 7- position or, when R' is methyl, the 5- or 7- position, and represents H, bromine or methyl; and R3represents methyl.
Within the invention there is provided a further group of compounds of formula (I) (group C) wherein R~ represents fluorine; R' is at the 8- position and W O96/31509 PCT~EP96/01438 r~rese"Ls H, chlorine, Lro",i"e, C,4alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2F or CF3), C,~hydroxyalkyl (e.g. CH20H or CH(OH)CH3), SC,4alkyl (e.g. SCH3), C(O)H or C(O)C,4alkyl (e.g. C(O)CH3); R2 represents H; and R3 represenls methyl.
Within group C there is provided the sub-group of co~pounds wherein: R~
represents fluorine; R1 is at the 8- position and represents H, chlorine, bromine, methyl, CH2F, CF3, CH(OH)CH3, SCH3, C(O)H or C(O)CH3; R2 represents H;
and R3 represents methyl.
Within the above groups (and prerer, ed groups) of compounds, espe,_ially preferred groups of compounds are those wherein R' represents C(O)CH3.
It is to be understood that the present invention encompasses all isomers of thecompounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g.
racemic mixtures).
Prefer, ed compounds of the invention are:
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-trifluoromethyl-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2~4-methanesulfonyl)-7-methyl-imidazo[1 ,2-a]pyridine;
8-chloro-3-(4-fluoro-phenyl)-2-(4-melha"esulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methanesulfanyl-imidazo[1,2-a]pyridine;
8-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;
8-fluoromethyl-3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-7,8-dimethyl-imidazo[1,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine-8-carbaldehyde;
5-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)~-methyl-i~ la~o[1,2-a]pyridine;
6-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)~-methyl-il l IIJd~0[1 ,2-a]pyridine;
[3-(4-fluoro-phenyl)-2-(4-l l l~:Li ,~nesulfonyl-phenyl)-imidazo[1 ,2-a]pyridin-8-yl]-methanol;
(:t) 1-[3-(4-fluoro-phen~1)-2-(4-",elh dl ~esulphonyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-ethan-1-ol;
and phal " ,aceutically acceptable derivatives thereof.
A particularly preferred co",pound of the invention is:
8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine; and pha",)aceutically accep~able derivatives thereof.
Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illu~ ated by their ability to selectively inhibit COX-2 over COX-1.
In view of their selective COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularlyin the treatment of the pain, fever and inflan",ldlion of a variety of conditions and diseases. Such conditions and diseases are well known in the art and include rheumatic fe~er; sy,llptoms ~ssoci~ted with influenza or other viral inre.;lions, such as the com,llon cold; lower back and neck pain; headache;
toothache; sprains and sl,ai"s; myositis; neuralgia; synovitis; alllllilis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
The compounds of the invention may also be useful for the treatment of other conditions mediated by selective inhibition of COX-2.
For example, the compounds of the invention may inhibit cellular and neoplastic ll cl ,src,r" ,ation and metastatic tumour growth and hence be useful in the treatment of certain cancerous diseases, such as colonic cancer.
Compounds of the invention may also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore W O96131509 PCT~EP96/01438 may be of use in the treatment of stroke; epilepsy; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).
Compounds of the invention also inhibit proslanoid-induced smooth muscle conl,aclion and hence may be of use in the treatment of dysmenorrhoea and premature labour.
Compounds of the invention inhibit inflar"r"alo,y processes and therefore may be of use in the treatment of asthma, allergic rhinitis and respiratory distresssyndrome; gastroinleslinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; andthe inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.
Compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.
Compounds of the invention may also be useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV i"rec~io"), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in humanor veterinary medicine.
According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by selective inhibition of COX-2.
W O96/31509 PCT~EP96/01438 Accc,rdi. ,9 to a further aspect of the invention, we provide a method of 1, ealing a human or animal subject suffering from a condition which is medi~ted by selective jIIhj~ ;GII of COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pl,d,-,!aceutically acceptable derivative.
Acc~r~ir~g to another aspect of the invention, we provide the use of a compound of formula (I) or a ,~l ,dr",aceutically accep~able derivative thereof for the manufacture of a therapeutic agent for the treatment of inflammatory disorders.
Accor-ling to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
It is to be understood that reference to treatment includes both treatment of established sy",pLo",s and prophylactic treatment, unless explicitly stated 1 5 otherwise.
It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Exampies of suitable agents for adjunctive therapy include pain relievers such as a glycine antagonist, a sodium channel inhibitor (e.g. Iamotrigine), a substance P
antagonist (e.g. an NK~ antagonist), aceta")il,ophen or phenac~tin; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (e.g. an iNOS
or an nNOS inhibitor); an inhibilor of the release, or action, of tumour necrosis factor a; an antibody therapy (e.g. a monoclonal antibody therapy); a stimulant,including caffeine; an H2-anl&go"ist, such as ranitidine; an antacid, such as 2~ aluminium or magnesium hydroxide; an antiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive, such as codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan; a diuretic; or a sedating or non-sedating antihistamine. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.
The compounds of formula (I) and their ,ul,d,."~Ge~tic~lly acceplable derivatives are conveniently administered in the form of pl ,a" "~ce~ ~tic~l compositions.
Thus, in another aspect of the invention, we provide a ,uha~ m~cel lti~l co~ JosiliGn comprising a compound of formula (I) or a ~I ,d""aceutically acceplable derivative thereof adapted for use in human or veteri"dry medicine.
Such coi ",oosilions may convenientiy be ,urt:se, ~led for use in conventional manner in admixture with one or more physiologically acceplable carriers or excipients.
The compounds of formula (I) and their pharmaceutically acceplable derivatives may be formulated for admini~l,dlion in any suitable ~"d""er. They may, for example, be formulated for topical administration or adminislralio" by inhalation or, more prererably, 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 acceplable 1 5 derivatives.
For oral administration, 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.
For transdermal administration, the pharmaceutical composilion may be given in the form of a transdermal patch, such as a l, ~"sde" "al ion~opl ,o, elic patch.
For parenteral administration, 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 aq~ ~eous vehicles and may cGnlai,) formulatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
Alternatively for parenteral administration 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 sl~hclIt~neously or intraml'sc~ rly) or by intram~sc~ 3r injection. Thus for ~3xa..~ple the cc,-,pounds of the invention may be formulated with suitable polymeric or hyd~o,ch~L~ic ~. IdLel ials (for example as an emulsion in an acc~pla~le oil) or ion ~exo~,dnge resins or as sparingly soluble derivatives forexample as a spa, ingly soluble salt.
As stated above th0 compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides in a further ~cpect a combination comprising a compound of formula (I) or a l l,ar",aceutically acceptable derivative thereof together with a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in the form of a ,cl,a""aceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient ccsi",crise a further aspect of the invention The individual components of such co")binations may be administered either sequentially or simulLaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same clise~-se state the dose of each co"",ound may differ from that when the compound is used alone. App(c,priate doses will be readily appreciated by those skilled in the art.
A proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 500 mg/kg such as 0.05mg/kg to 100mg/kg e.g. 0.1mg/kg to 50mg/kg which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus for example a daily dose of 0.25mg/kg to 1 Omg/kg may be suitable for systemic administration.
Compounds of formula (I) and pharmaceutically acceptable derivatives thereof ~ 30 may be prepared by any method known in the art for the preparation of compounds of analogous structure.
W O96/31509 PCT~EP96/01438 Suitable methods for the preparalion of compounds of formula (I) and pha",~aceutically acce,utable derivatives thereof are desc,iL,ed below. In the formulae that follow R~ to R3 are as d~ined in formula (I) above unless otherwise stated and Lg represents a leaving group such as a sulphonate (e.g.
",~ll,d"esulphonate) or a halogen (e.g. br~r"ine).
Thus accor(:li. ,9 to a first prc,cess (A) compounds of formula (l~ may be prepared by reacting a compound of formula (Il) '~0 ~--Lg R~ (ll~
or a protected derivative thereof with a cor"pound of formula (Ill) R~ R2 H2N~
N~ (~
or a protected derivative thereof. The reaction is conveniently carried out in asolvent such as a polar solvent (e.g. acetonitrile or isoprc,,uar,ol); at elevated temperature e.g. reflux; and optionally in the presence of a base such as an alkali metal bicarbonate or carbonate (e.g. potassium carbonate).
Suitable leaving atoms or groups in respect of Lg in formula (Il) are described in many standard texts on organic chemistry for example in table 10.10 on page 357 of Advanced Organic Chemistry by Jerry March fourth edition (Wiley 1992). It will be appreciated by a person skilled in the art that the choice of a particular leaving group in the above reaction may depend upon the meanings of R~ to R3 (and hence the compound of formula tl) desired~ and the reaction conditions employed.
According to a another process (B), cc",pounds of formula (I) may be prepared by reacting a con"~ound of formula (IV) P~3S~
R~~ RR2 or a protected derivative thereof with an oxidising agent. Conveniently the oxidation is effected using a mol,o,~,er~ulfate compound, such as potassium peroxymonosulfate (known as OxoneTM) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between -78~C and ambient temperature.
Acc~rding to another process (C) compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.
Thus, for example, ~ompounds of formula (I) wherein R1 or R2 represent chlorine, bromine or iodine may be prepared from the corresponding compound of formula (I) wherein R1 or R2 represent H, by treatment with an appropriate halogenating agent (i.e. chloro-, bromo- or iodinating agent). Suitable agents include the corresponding N-halosuccinimdes. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g.
chlol L~ror~ and at ambient temperature.
Compounds of formula (I) wherein R' or R2 represent C1~alkyl substituted by one or more fluorine atoms may be prepared from the compound of formula (I) wherein R1 or R2 represents the corresponding C,~hydroxyalkyl by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for exampie, diethylaminosulphur trifluoride. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g.
dichloromethane), anci at reciuce~ temperature, such as -78~C.
Compounds of formula (I) wherein R' or R2 represent C(O)H may be prepared from the corresponding compound of formula (I) wherein R1 or R2 represent CH2OH by oxidation. Suitable oxidising agents include, for example, manganese (IV) oxide. Conveniently the oxidation is effected in the presence of a solvent, such as a halogenaled hyd~ocalL,G,I (e.g. chicsrorc".,), and at elevated temperature (e.g. reflux).
Compounds of formula (I) wherein R' or R2 represent C,4hydroxyalkyl, and wherein the hydroxy group is attached to the carbon linked to the pyridine ring,may be p,t:~ared by reduction of the compound of formula (I) wherein R' or R2 represent the cor,esponding aldehyde or ketone. Suitable reducing agents include hydride reducing agents, such as diisobutylaluminium hydride.
Conveniently the reduction is effected in the presence of a solvent, such as a halogenated h~/dlocalL,oll (e.g. dichloromethane), and at reduced temperature, such as -78~C.
As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the above described processes to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.
Another process (D) for preparing compounds of formula (I) thus comprises deprotecting protecled derivatives of compounds of formula (I).
The protecting groups used in the preparalion of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'P, otecli"e Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups.
Compounds of formula (Il) may be prepared from compounds of formula (V) R302S ~
W~~
R~
by conventional means.
Thus, compounds of formula (Il) wherein Lg represents a halogen may be udl~d from cc,r"pounds of formula (V) by treatment with a halo~~e"~li"~
agent at red~ ~c~l ten ,per~ re and in a solvent such as a ol ,lori"dled h~llu~lLJull. For ex~"",le, where Lg represents bromine, the reac~ion is conveniently ~rracled with a brominating agent, such as bromine in the presence of a strong acid (e.g. hyd~ol~rcr,.ic acid in acetic acid).
Compounds of formula (Il) wherein Lg represents a sulphonate may be ~,re~.ared from compounds of formula (V) firstly by oxidation to the corresponding a-hydroxy ketone, followed by treatment with a sulphonating agent. Suitable oxidising agents include for example Pb(OAc)4 dimethyldioxirane and those desc,il.ed in F A Davis, J. Org. Chem., 1984, 49~17) 3284. Suitable sulphonating agents include sulphonylhalides such as sulphonylchlorides (e.g. " ,eLi ,anesulphonylchloride). The sulphonylation i conveniently effected in the presence of a base, such as an amine (e.g.
triethylamine); and in a solvent, such as a halGyelldled hydrocarbon.
Compounds of formula (V) may be l.re~.ared from compounds of formula (Vl) F~
~0 ,~
il R~~ (Vl) by treatment with an alkali sulphinate such as a sodium sulphinate.
Conveniently, the reaction is carried out in a polar solvent such as dimethyl sulphoxide, and at elevated temperature.
Compounds o~ formula (Ill) are either known compounds or may be prepared by literature methods such as those described in for example J A Turner, J. Org.
Chem., 1983, ~, 3401; M Malinowski, Bull. Soc. Chim. Belg., 1988, ~Z, 51; W
0 Siegl, J. Hef. Chem., 1981, ~, 1613-18; or F.Trecourt et al, J. Chem. Soc., Perkin Trans.1 1990, ~, 2409-2415.
Compounds of formula (Vl) are either known compounds or may be prepared by literature methods such as those described in for example N Seko ~L Chem.
Pharm. Bull., 1991, ;~, (3) 651-7 or I Lalazori et al, J.Med.Chem. 1971, 14, 1 138-40.
Compounds of formula (IV) or protected derivatives thereof may be prepared using conventional chemistry, for example chemistry analogous to that herein described for the preparalion of co",~Jounds of formula (I) Certain intermediates des~,iL,ed above are novel compounds, and it is to be understood that all novel i"ler" ledidles herein form further aspects of the present invention. Compounds of formula (Il) and (IV) are key intermediates and represent particular aspects of the present invention.
Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically accepta~le acid addition salts of the compounds of the invention may be prepared using conventional means.
Solvates (e.g. hydrates) of a co",pound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.
The following Examples illustrate the invention but do not limit the invention in any way. All temperatures are in ~C. Flash chror"atography was carried out using Merck 9385 silica. Thin layer chromatography (Tlc) was carried out on silica plates. NMR was carried out on a Brucker 300Mhz spectrometer, using CDCI3 as solvent. Chemical shifts are given in ~ ppm with respect to tetramethylsilane as intemal chemical shift reference. The following abbreviations are used: Et = ethyl, s = singlet, d = doublet, t = triplet and m =
multiplet.
Interrnediate 1 2-(4-Fluoro-phenyl)-1 -(4-methanesulfonvl-PhenYl)-ethanone A mixture of the 2-(4-fluoro-phenyl)-1-(4-fluoro-phenyl)-ethanone' (3g) and sodium methane sulphinate (1.589) in dry dimethyl sulphoxide (1 Oml) was heated to 105-110~ under nitrogen for 18h. The cooled reaction mixture was poured into water (500ml) and the mixture extracted with ethyl acetate. The combined organic extracts were adsorbed onto silica and purified by flash cl ,romalography eluting with ethyl acetate:hexane (1 :1) to give the title compound as a white solid (2.19).
m.p.115-116~
' Ref: I Lalazori et al, J.Med.Chem. 1971, 14, 113840.
W O 96131S09 PCT~EP96/01438 Intermediate 2 2-Bromo-2-(4-fluoro-PhenYI)-1 -(4-methanesulfonvl-PhenYI)~L! Idl 1~1 ,e A solution of the 2-~4-fluoro-phenyl)-1-(4-~eli Idl ~esulfonyl-phenyl)-ethanone (1.69) in dichloromethane (30ml) and glacial acetic acid (.15ml) was cooled to 0~
and llt:dled with 48% h~ lJrc,mic acid (3 drops). A solution of bromine (875mg) in acetic acid (2ml) was added and stirring continued for 4 hours. The mixture was diluted with dichlGro",t:ll,ane (35ml) and the solution was washed with water dried and co"ce"l,dlec~ to give the title compound as a yellow solid (2.09).
m.p. 124-126~
Intermediate 3 3-Trifluoromethvl-pvridin-2-vlamine A mixture of 2-chloro-3-trifluorùinelhyl-pyridine (59) copper(1) iodide (59) andliquid ar"",o,1ia (50ml) was heated in an autoclave at 80~ (internal temperature) for 28 hours. The cooled reaction mixture was slurried with methanol/chlo,urul,l, (1/1-250 ml) and filtered. The filtrate was absorbed onto silica and purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to yield the title comPound as a white solid (1.49).
m.p. 71-72~
MH~ = 163 Tlc sio2, Rf 0.50 (ethyl acetate/hexane (1/1)) detection UV/KMnO4 Intermediate 4 2-(4-Fluoro-phenyl)-1 -~4-methanesulfanYI-PhenYI)~ll Idl lone A mixture of 2-(4-fluoro-phenyl)-1 -(4-fluoro-phenyl)-ethanone (10.0g) sodium methanethiolate (3.0g~ and di,netl,),rl sulphoxide (10ml) was heated at -100~ for 8h under nitrogen. The cooled mixture was added to water (250ml) stirred for 10 min and filtered. The resulting solid was crystallised from isopropanol (100ml) twice to give the title compound as a white solid (5.0g).
m.p.143-144~
Intermediate 5 2-Bromo-2-(4-fluoro-phenyl)-1 -(4-methanesulfanvl-phenYI)-ethanone A solution of 2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone (4.89) in dichloromethane (75ml) and acetic acid (30ml) at 0~ containing 48% HBr (15 drops) was treated dropwise with bromine (2.69) in acetic acid (6ml). The solution was stirred at 0~ for 10 min and at room temperature for 3h, diluted with dichloromethane (100ml) and washed with water (2 x 100ml). The dried (MgSO4) orga~ic phase was evapo,~led and the residue was triturated with diethyl ether (30ml) to give the title cor,ll)ound as a white $olid (4.59).
m.p.117-119~.
Tlc SiO2 (Et20:hexane 1:1) Rf 0.6 det u.v. KMnO4, isopropanol.
Intermediate 6 3-(4-Fluoro-Phenvl)-2-(4-l l lelhal1esulfanvl-Phenvl)-imidazor1,2-a1Pvridine A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone (4.09) and 2-aminopyridine (1.2g) in acetonitrile (25ml) was relluxed under nitrogen for 2h and left at room temperature for 16h. The soluticn was evaporated and the residue purified by flash column chromatography eluting with diethyl ether (applied in CH2CI2) to give the title compound as a white solid (1.69).
m.p. 115-118~
Tlc SiO2 (Et2O) Rf 0.5 det u.v., isopropanol.
Intermediate 7 8-Chloro-3-(4-fluoro-PhenYI)-2-(4-methanesulfanvl-PhenYl)-imidazo~1,2-alpyridine n-Butyllithium in hexane (1.6m; 0.35ml) was added dropwise to a solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (167mg) in tetrahydrofuran (2ml) at -78~ under nitrogen. The solution was stirred at -78~
for 1 h and was treated with l ,exachloroethane (142mg) in tetrahydrofuran (0.25ml). The solution was allowed to warm to room temperature during 30 min and water (2ml) was added. The mixture was extracted with ethyl acetate (2 x 5ml) and the dried (MgSO4) extract was evaporated to give the title compound as a cream solid (180mg).
m.p.148-149~
MH ' = 369 Intermediate 8 3-Methvlsulfanyl-pvridin-2-ylamine A solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide2 (890mg) in dry tetrahydrofuran (30ml) was cooled to -78~ and treated with a solution of n-butyllithium (6.25 ml,1.6M). This solution was stirred at 0~ for 4 hours and a solution of dimethyldisulphide (235mg) in tetrahydrofuran (5ml) was added and stirring continued at ~",~ienl ter"perdlure for 30 minutes. 2N Hydrochloric acid (1ml) was added and the solution col lce~ led in vacuo. A mixture of the residue and 2N hy~ ric acid (15ml) was heated at reflux for 4 hours. The cooled reaction mixture was made basic by addition of solid potassium carbonate. The basic mixture was e~L~a~ed with ethyl ~cet~e (15ml),the organic extract was dried (Na2SO4) and absorbed onto silica. The title compound was obtained by flash c~,rc""dlog,~ully eluting with ethyl acetate/cyclohexane (1/1) as a colourless oil (490mg).
MHt = 141 Tlc, SiO2, Rf 0.48,(ethyl acetate/cyclohexane(1/1)) detec~ion u.v., KMnO4 2 Ref: J A Turner J. Or~3. Chem.1983,48.3401 I. ,l~r " ,ediate 9 3-(4-Fluoro-phenyl)-2-~4-methanesulfonyl-Phenyl)-imidazor1,2-alpvridine-8-ca, ~oxYlic acid methvl ester A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (700mg), and 2-amino-nicotinic acid methyl ester (287mg) in dry aceto, lill ile was heated at reflux overnight. The reaction mixture was concentrated onto silica and the title comPound obtained by flash chromatography eluting with ethyl acetate:cyclohexane 5:1 as a yellow solid (176mg).
MH+ = 425 Tlc, SiO2 Rf 0.21 (ethyl acetate:cyclohexane 5:1) detection uv Intermediate 10 8-Acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfanvl-Phenyl)-imidazo~1,2-alpvridine n-Butyllithium in hexane (1.6m; 0.5ml) was added dropwise to a solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (250mg) in tetrahydrofuran (3ml) at -78~ under nitrogen. The solution was stirred at -78~ for 1 h and was treated with N-methyl,N-methoxyacetamide (9Omg) in tetrahydrofuran (0.25ml). The solution was allowed to warm to room temperature during 60min and water (10ml) was added. The mixture was extracted with ethyl acetate (2 x 5ml) and the dried (MgSO4) extract was W O~6/31509 PCTAEP96/01438 evaporated. The residue was purified on a column of silica, eluting with hexane:diethylether (3:1) to give the title co""~ound as a cream solid (130mg).
MH+ = 377 Tlc SiO2 (Et20) Rf 0.9 det u.v.
ExamPle 1 3-14-Fluoro-PhenYI)-2-(4-methanesulfonYl-phenv~ midazor1,2-alPvridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (233mg) and 2-aminopyridine (59mg) in dry acetonitrile was heated at reflux overnight. The reaction mixture was adsorbed onto silica and purified by flash cl ,rumalography eluting with ethyl ~cet~te to afford the title compound as a cream solid (100mg).
MH+ = 367.2 m.p.198-200~
Example 2 3-(4-Fluoro-Phenvl)-2-(4-methanesulfonvl-Phenvl)-8-methvl-imidazor1,2-alPyridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (233mg) and 2-amino-3-methylpyridine (68mg) in dry acetonitrile (10ml) was heated at reflux overnight. The reaction mixture was adsorbed onto silica and purified by flash cl ,ru" ~dlography eluting with dichloromethane/methanol (19:1) to afford the title cGm~ound as a pale brown solid (61mg).
MH+ = 381 m.p.180-182~
Exampie 3 3-(4-Fluoro-Phenvl)-2-(4-methanesulfonYI-PhenYl~-8-trifluoromethyl-imidazo~1,2-alpyridine A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (742mg), and 3-trifluoromethyl-pyridin-2-ylamine (324mg,) in dry acetonitrile containing potassium carbonate (276mg) was heated at reflux overnight. The reaction mixture was conce,llrdled onto silica and purified by flash chromatography eluting with ethyl acetate, to give a yellow solid. Further PCT~EP96/01438 WO 9613150g purification by recrystallisation from propan-2-ol yielded the title comPound asyellow crystals (21 Omg).
m.p. 260-261~
Analysis: Found: C,57.7; H,3.0; N,6.2; S,7.3 C2,H,4F4N202S Requires: C,58.1; H,3.25;N,6.45;S,7.4%
MH' = 435 Tlc, sio2, Rf 0.25, (ethyl ~cet~te) detection u.v.
Example 4 3-(4-Fluoro-PhenY1)-2-(4-methanesulPhonvl)-7-methvl-imidazor1 ~2-alPvridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1 -(4-methanesulphonyl-phenyl)-ethanone (233mg) an~ 2-amino4-methylpyridine (68mg) in acetonitrile 10ml) was heated at reflux for 18 hours. The cooled reaction mixture was absorbed onto silica and the title comPound obtained by flash chromatography, eluting with ethyl acetate /hexane (111), as a bu~f solid (105mg).
m.p.194-196~
MH+ = 381 Tlc, sio2, Rf 0.26, (ethyl acetate/hexane (2/1)) detection u.v.
Example 5 8-Chloro-3-(4-fluoro-Phenvl)-2-(4-methanesulfonvl-Phenvl~-imidazo~1 2-alpyridine A suspension of 8-chloro-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo~1,2-a]pyridine (150mg) in methanol (8ml) and water (2ml) was treated with Oxone TM (561mg) and stirred for 2h at room temperature. The resulting suspension was treated with water (50ml) and extracted with ethyl acetate (2 x 50ml). The dried (MgSO4) extract was evaporated and the resulting solid was treated with boiling isopropanol (8ml) for (10min) cooled and filtered to give the title compound as a white solid (85mg).
m.p. 242-244~
Tlc SiO2(Et2O) RF 0.5 det u.v., KMnO4 MH+ = 401 Example 6 3-(4-Fluoro-Phenvl)-2-(4-, 1 ,eli Idl ,esulfonyl-phenyl)-8-meU Idl ,esulfanvl-imidazo~1 2-alpvridine A solution of 3-methylsulfanyl-pyridin-2-ylamine (140 mg) and 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (1 5ml) was heated at reflux ove, l ligl ,L. The cooled reaction mixture was absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetdle/cyclohexane (1/1) as a white solid (179 mg).
m.p. 224-226~
MH+=413 Tlc, SiO2, Rf 0.60 (ethyl acetate/cyclohexane(1/1)) detection u.v./KMnO4 Example 7 8-Bromo-3-(4-fluoro-phenYI)-2-(4-l, letl ,a, ~esulfonvl-Phenvl)-imidazo~1 2-alpvridine A solution of 3-bromo-pyridin-2-ylamine3 (173 mg) and 2-bromo-2-(4-fluoro-phenyl)-1-(4-rllell,a"esulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (15ml)was heated at reflux overnight. On cooling to room temperature the title compound crystallised from solution and was isolated by filtration as a white solid (241 mg).
m.p 266-268~
MH ' = 446 Analysis: Found: C,53.5;H,3.0;N,6.2;F,4.3;S,7. 1 C20H,4BrFN2O2S Requires: C,53.9;H,3.2;N,6.3;F,4.3;S,7.2%
Tlc, sio2, Rf 0.61 (Ethyl acetale/cyclohexane(2/1 )) detection u.v., KMnO4 3 Ref: M.Malinowski,Bull. Soc. Chim. Belg. 1988, 97, 51 Example 8 8-Fluoromethvl-3-(4-fluoro-phenvl)-2-t4-methanesulPhonvl-Phenyl)-imidazo~1 ,2-alpyridine A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1,2-a]pyridine-8-methanol (200mg) in dichloromethane (1 Oml) was added to a cooled solution of diethylaminosulphur trifluoride (0.067 ml) in dichloromethane(4 ml) at -78~ over 5 minutes. The solution was allowed to warm to room temperature over 30 minutes. Water (15 ml) was added cautiously with stirring, the organic phase was separated, dried (Na2SO4) and absorbed onto silica.
The title compound was obtained by flash chromatography eluting with ethyl W O 96131509 PCT~EP96101438 ace~ale/cyclol ,e~dne (1/1) as a white solid which was further purified by crystallisation from ,~r~a, l-2~1 (10 ml) yielding white crystals (85 mg).
m.p. 221-222~
MH ' = 399 Analysis Found: C,63.1; H,3.9; N,6.8, F,9.4; S,8.1 C2,H16F2N202S Requires: C,63.3; H,4.05; N,7.1, F;9.5: S,8.05%
Example 9 3-(4-Fluoro-PhenYI)-2 -(4-methanesulfonYI-phenyl)-7~8-dimethyl-imidazor1,2-alPvridine A solution of 3,4~imethyl-pyridin-2-ylamine4 (122 mg) and 2-bromo-2-(4-fluoro-phenyl)-1 -(4-rneli ,anesulphonyl-phenyl)-ethanone (371 mg) in acetonitrile (15ml) containing potassium carbonate (138 mg) was heated at reflux overnight.
The cooled mixture \A~as absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1) as a white solid. Cryst~llis~tion lrom propan-2-ol (10 ml) yielded white crystals (136 mg).m.p. 228-230~
MH+ = 395 Analysis Found: C,66.6; H,4.7; N,6.9; F,4.8; S,8.2 C22H1gN2FO2S Requires: C,67.0; H,4.85; N,7.1; F,4.8; S8.1%
This invention relates to imidazo~1,2-a]pyridine derivatives, to processes for their pre,udr~lion, to pl,a""~ Jtic~l composilions containing them and to their use in medicine.
The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, encloloxin, hormones, cytokines and growth factors.
Prostaglandins generalted by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is responsible for the important physiological functions such as mainte, Idl ,ce of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflalllr"atoly agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.
The invention thus provides the compounds of formula (I) R 02S _~N~, and pharmaceutically acceptable derivatives thereof in which:
R~ represents halogen;
R' and R2 are independently selected from H, halogen, C,~alkyl, C1 4alkyl substituted by one or more fluorine atoms, C1~alkoxy, C'4hydroxyalkyl, SC14alkyl, C(O)H or C(O)C,4alkyl; and R3 represents C,~alkyl.
By pharmaceutically acce,ulable derivative is meant any ,c l Idl "~oe~ ~tic~lly acceptaL31e salt, solvate or ester, or salt or solvate of such ester, of the co",,.,ounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a cG,.,pound of formula (I) or an active metabolite or residue thereof.
It will be appreciated that, for pl,ar",~ce~tic~l use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparalio" of ccjrnpounds of formula (I) and the physiologicallyacceplable salts thereof.
Suitable phar"~aceutically acceplable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
The term halogen is used to represent fluorine, chlorine, bromine or iodine.
The term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group, for exa",pl~ a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
The substituents R' and R2 may be at the 5-, 6-, 7- or 8- positions of the pyridine ring of formula (I), as defined hereinbelow:
P,ererably, R' is at the 8- position; and R2 is at the 7- position or, when R' is other than H, the 5-, 6- or 7-position. More preferably, R' is at the 8- position;
and R2 is at the 7- position or, when R' is C,4alkyl (e.g. methyl), the 5- or 7-position.
Preferably, R~ represents fluorine.
Preferably, R' represents H, chlorine, bromine, C,~alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2F or CF3), C,4hydroxyalkyl CA 022l6809 l997-09-29 (e.g. CH20H or CH(OH)CH3), SC,~alkyl (e.g. SCH3), C(O)H or C(O)C.~alkyl (e.g. C(O)CH3). Mor~ prererably, R1 represe,)ls H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(C))H or C(O)CH3. Most ~,-erer~ly R' represents C(O)CH3.
Preferably, R2 represents H, chlorine, bromine, or C~alkyl (e.g. methyl). More preferably, R2 represents H, bromine or methyl.
P,~rerably, R3 represents methyl.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R~' represents fluorine; R' represents H, chlorine, bromine, C~alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g.
CH2F or CF3), C,~hy~droxyalkyl (e.g. CH20H or CH(OH)CH3), SC,~alkyl (e.g.
SCH3), C(O)H or C(~))C,~alkyl (e.g. C(O)CH3); R2 represents H, chlorine, bromine, or C~alkyl (e.g. methyl); and R3 represents methyl.
Within group A there is provided the sub-group of compounds wherein: R~
represents fluorine; R~ represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(l~))CH3; R2 represents H, bromine or methyl; and R3 represents methyl.
Within the invention there is provided another group of compounds of formula (I)(group B) wherein R~ represents fluorine; R'is at the 8- position and representsH, chlorine, bromine, C,~alkyl (e.g. methyl), methyl substituted by one to threefluorine atoms (e.g. CH2F or CF3), C,~hydroxyalkyl (e.g. CH20H or CH(OH)CH3), SC,~alkyl (e.g. SCH3), C(O)H or C(O)C,4alkyl (e.g. C(O)CH3); R2 is at the 7- position or, when R' is other than H, the 5-, 6- or 7- position, and represents H, chlorine, bromine, or C,~alkyl (e.g. methyl); and R3 represents methyl.
Within group B there is provided the sub-group of compounds wherein: R~
represents fluorine; R'is at the 8- position and represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(O)CH3; R2 is at the 7- position or, when R' is methyl, the 5- or 7- position, and represents H, bromine or methyl; and R3represents methyl.
Within the invention there is provided a further group of compounds of formula (I) (group C) wherein R~ represents fluorine; R' is at the 8- position and W O96/31509 PCT~EP96/01438 r~rese"Ls H, chlorine, Lro",i"e, C,4alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2F or CF3), C,~hydroxyalkyl (e.g. CH20H or CH(OH)CH3), SC,4alkyl (e.g. SCH3), C(O)H or C(O)C,4alkyl (e.g. C(O)CH3); R2 represents H; and R3 represenls methyl.
Within group C there is provided the sub-group of co~pounds wherein: R~
represents fluorine; R1 is at the 8- position and represents H, chlorine, bromine, methyl, CH2F, CF3, CH(OH)CH3, SCH3, C(O)H or C(O)CH3; R2 represents H;
and R3 represents methyl.
Within the above groups (and prerer, ed groups) of compounds, espe,_ially preferred groups of compounds are those wherein R' represents C(O)CH3.
It is to be understood that the present invention encompasses all isomers of thecompounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g.
racemic mixtures).
Prefer, ed compounds of the invention are:
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-trifluoromethyl-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2~4-methanesulfonyl)-7-methyl-imidazo[1 ,2-a]pyridine;
8-chloro-3-(4-fluoro-phenyl)-2-(4-melha"esulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methanesulfanyl-imidazo[1,2-a]pyridine;
8-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine;
8-fluoromethyl-3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1 ,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-7,8-dimethyl-imidazo[1,2-a]pyridine;
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine-8-carbaldehyde;
5-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)~-methyl-i~ la~o[1,2-a]pyridine;
6-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)~-methyl-il l IIJd~0[1 ,2-a]pyridine;
[3-(4-fluoro-phenyl)-2-(4-l l l~:Li ,~nesulfonyl-phenyl)-imidazo[1 ,2-a]pyridin-8-yl]-methanol;
(:t) 1-[3-(4-fluoro-phen~1)-2-(4-",elh dl ~esulphonyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-ethan-1-ol;
and phal " ,aceutically acceptable derivatives thereof.
A particularly preferred co",pound of the invention is:
8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1 ,2-a]pyridine; and pha",)aceutically accep~able derivatives thereof.
Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illu~ ated by their ability to selectively inhibit COX-2 over COX-1.
In view of their selective COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularlyin the treatment of the pain, fever and inflan",ldlion of a variety of conditions and diseases. Such conditions and diseases are well known in the art and include rheumatic fe~er; sy,llptoms ~ssoci~ted with influenza or other viral inre.;lions, such as the com,llon cold; lower back and neck pain; headache;
toothache; sprains and sl,ai"s; myositis; neuralgia; synovitis; alllllilis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
The compounds of the invention may also be useful for the treatment of other conditions mediated by selective inhibition of COX-2.
For example, the compounds of the invention may inhibit cellular and neoplastic ll cl ,src,r" ,ation and metastatic tumour growth and hence be useful in the treatment of certain cancerous diseases, such as colonic cancer.
Compounds of the invention may also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore W O96131509 PCT~EP96/01438 may be of use in the treatment of stroke; epilepsy; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).
Compounds of the invention also inhibit proslanoid-induced smooth muscle conl,aclion and hence may be of use in the treatment of dysmenorrhoea and premature labour.
Compounds of the invention inhibit inflar"r"alo,y processes and therefore may be of use in the treatment of asthma, allergic rhinitis and respiratory distresssyndrome; gastroinleslinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; andthe inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.
Compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.
Compounds of the invention may also be useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV i"rec~io"), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in humanor veterinary medicine.
According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by selective inhibition of COX-2.
W O96/31509 PCT~EP96/01438 Accc,rdi. ,9 to a further aspect of the invention, we provide a method of 1, ealing a human or animal subject suffering from a condition which is medi~ted by selective jIIhj~ ;GII of COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pl,d,-,!aceutically acceptable derivative.
Acc~r~ir~g to another aspect of the invention, we provide the use of a compound of formula (I) or a ,~l ,dr",aceutically accep~able derivative thereof for the manufacture of a therapeutic agent for the treatment of inflammatory disorders.
Accor-ling to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
It is to be understood that reference to treatment includes both treatment of established sy",pLo",s and prophylactic treatment, unless explicitly stated 1 5 otherwise.
It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Exampies of suitable agents for adjunctive therapy include pain relievers such as a glycine antagonist, a sodium channel inhibitor (e.g. Iamotrigine), a substance P
antagonist (e.g. an NK~ antagonist), aceta")il,ophen or phenac~tin; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (e.g. an iNOS
or an nNOS inhibitor); an inhibilor of the release, or action, of tumour necrosis factor a; an antibody therapy (e.g. a monoclonal antibody therapy); a stimulant,including caffeine; an H2-anl&go"ist, such as ranitidine; an antacid, such as 2~ aluminium or magnesium hydroxide; an antiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive, such as codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan; a diuretic; or a sedating or non-sedating antihistamine. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.
The compounds of formula (I) and their ,ul,d,."~Ge~tic~lly acceplable derivatives are conveniently administered in the form of pl ,a" "~ce~ ~tic~l compositions.
Thus, in another aspect of the invention, we provide a ,uha~ m~cel lti~l co~ JosiliGn comprising a compound of formula (I) or a ~I ,d""aceutically acceplable derivative thereof adapted for use in human or veteri"dry medicine.
Such coi ",oosilions may convenientiy be ,urt:se, ~led for use in conventional manner in admixture with one or more physiologically acceplable carriers or excipients.
The compounds of formula (I) and their pharmaceutically acceplable derivatives may be formulated for admini~l,dlion in any suitable ~"d""er. They may, for example, be formulated for topical administration or adminislralio" by inhalation or, more prererably, 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 acceplable 1 5 derivatives.
For oral administration, 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.
For transdermal administration, the pharmaceutical composilion may be given in the form of a transdermal patch, such as a l, ~"sde" "al ion~opl ,o, elic patch.
For parenteral administration, 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 aq~ ~eous vehicles and may cGnlai,) formulatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
Alternatively for parenteral administration 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 sl~hclIt~neously or intraml'sc~ rly) or by intram~sc~ 3r injection. Thus for ~3xa..~ple the cc,-,pounds of the invention may be formulated with suitable polymeric or hyd~o,ch~L~ic ~. IdLel ials (for example as an emulsion in an acc~pla~le oil) or ion ~exo~,dnge resins or as sparingly soluble derivatives forexample as a spa, ingly soluble salt.
As stated above th0 compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides in a further ~cpect a combination comprising a compound of formula (I) or a l l,ar",aceutically acceptable derivative thereof together with a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in the form of a ,cl,a""aceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient ccsi",crise a further aspect of the invention The individual components of such co")binations may be administered either sequentially or simulLaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same clise~-se state the dose of each co"",ound may differ from that when the compound is used alone. App(c,priate doses will be readily appreciated by those skilled in the art.
A proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 500 mg/kg such as 0.05mg/kg to 100mg/kg e.g. 0.1mg/kg to 50mg/kg which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus for example a daily dose of 0.25mg/kg to 1 Omg/kg may be suitable for systemic administration.
Compounds of formula (I) and pharmaceutically acceptable derivatives thereof ~ 30 may be prepared by any method known in the art for the preparation of compounds of analogous structure.
W O96/31509 PCT~EP96/01438 Suitable methods for the preparalion of compounds of formula (I) and pha",~aceutically acce,utable derivatives thereof are desc,iL,ed below. In the formulae that follow R~ to R3 are as d~ined in formula (I) above unless otherwise stated and Lg represents a leaving group such as a sulphonate (e.g.
",~ll,d"esulphonate) or a halogen (e.g. br~r"ine).
Thus accor(:li. ,9 to a first prc,cess (A) compounds of formula (l~ may be prepared by reacting a compound of formula (Il) '~0 ~--Lg R~ (ll~
or a protected derivative thereof with a cor"pound of formula (Ill) R~ R2 H2N~
N~ (~
or a protected derivative thereof. The reaction is conveniently carried out in asolvent such as a polar solvent (e.g. acetonitrile or isoprc,,uar,ol); at elevated temperature e.g. reflux; and optionally in the presence of a base such as an alkali metal bicarbonate or carbonate (e.g. potassium carbonate).
Suitable leaving atoms or groups in respect of Lg in formula (Il) are described in many standard texts on organic chemistry for example in table 10.10 on page 357 of Advanced Organic Chemistry by Jerry March fourth edition (Wiley 1992). It will be appreciated by a person skilled in the art that the choice of a particular leaving group in the above reaction may depend upon the meanings of R~ to R3 (and hence the compound of formula tl) desired~ and the reaction conditions employed.
According to a another process (B), cc",pounds of formula (I) may be prepared by reacting a con"~ound of formula (IV) P~3S~
R~~ RR2 or a protected derivative thereof with an oxidising agent. Conveniently the oxidation is effected using a mol,o,~,er~ulfate compound, such as potassium peroxymonosulfate (known as OxoneTM) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between -78~C and ambient temperature.
Acc~rding to another process (C) compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.
Thus, for example, ~ompounds of formula (I) wherein R1 or R2 represent chlorine, bromine or iodine may be prepared from the corresponding compound of formula (I) wherein R1 or R2 represent H, by treatment with an appropriate halogenating agent (i.e. chloro-, bromo- or iodinating agent). Suitable agents include the corresponding N-halosuccinimdes. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g.
chlol L~ror~ and at ambient temperature.
Compounds of formula (I) wherein R' or R2 represent C1~alkyl substituted by one or more fluorine atoms may be prepared from the compound of formula (I) wherein R1 or R2 represents the corresponding C,~hydroxyalkyl by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for exampie, diethylaminosulphur trifluoride. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g.
dichloromethane), anci at reciuce~ temperature, such as -78~C.
Compounds of formula (I) wherein R' or R2 represent C(O)H may be prepared from the corresponding compound of formula (I) wherein R1 or R2 represent CH2OH by oxidation. Suitable oxidising agents include, for example, manganese (IV) oxide. Conveniently the oxidation is effected in the presence of a solvent, such as a halogenaled hyd~ocalL,G,I (e.g. chicsrorc".,), and at elevated temperature (e.g. reflux).
Compounds of formula (I) wherein R' or R2 represent C,4hydroxyalkyl, and wherein the hydroxy group is attached to the carbon linked to the pyridine ring,may be p,t:~ared by reduction of the compound of formula (I) wherein R' or R2 represent the cor,esponding aldehyde or ketone. Suitable reducing agents include hydride reducing agents, such as diisobutylaluminium hydride.
Conveniently the reduction is effected in the presence of a solvent, such as a halogenated h~/dlocalL,oll (e.g. dichloromethane), and at reduced temperature, such as -78~C.
As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the above described processes to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.
Another process (D) for preparing compounds of formula (I) thus comprises deprotecting protecled derivatives of compounds of formula (I).
The protecting groups used in the preparalion of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'P, otecli"e Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups.
Compounds of formula (Il) may be prepared from compounds of formula (V) R302S ~
W~~
R~
by conventional means.
Thus, compounds of formula (Il) wherein Lg represents a halogen may be udl~d from cc,r"pounds of formula (V) by treatment with a halo~~e"~li"~
agent at red~ ~c~l ten ,per~ re and in a solvent such as a ol ,lori"dled h~llu~lLJull. For ex~"",le, where Lg represents bromine, the reac~ion is conveniently ~rracled with a brominating agent, such as bromine in the presence of a strong acid (e.g. hyd~ol~rcr,.ic acid in acetic acid).
Compounds of formula (Il) wherein Lg represents a sulphonate may be ~,re~.ared from compounds of formula (V) firstly by oxidation to the corresponding a-hydroxy ketone, followed by treatment with a sulphonating agent. Suitable oxidising agents include for example Pb(OAc)4 dimethyldioxirane and those desc,il.ed in F A Davis, J. Org. Chem., 1984, 49~17) 3284. Suitable sulphonating agents include sulphonylhalides such as sulphonylchlorides (e.g. " ,eLi ,anesulphonylchloride). The sulphonylation i conveniently effected in the presence of a base, such as an amine (e.g.
triethylamine); and in a solvent, such as a halGyelldled hydrocarbon.
Compounds of formula (V) may be l.re~.ared from compounds of formula (Vl) F~
~0 ,~
il R~~ (Vl) by treatment with an alkali sulphinate such as a sodium sulphinate.
Conveniently, the reaction is carried out in a polar solvent such as dimethyl sulphoxide, and at elevated temperature.
Compounds o~ formula (Ill) are either known compounds or may be prepared by literature methods such as those described in for example J A Turner, J. Org.
Chem., 1983, ~, 3401; M Malinowski, Bull. Soc. Chim. Belg., 1988, ~Z, 51; W
0 Siegl, J. Hef. Chem., 1981, ~, 1613-18; or F.Trecourt et al, J. Chem. Soc., Perkin Trans.1 1990, ~, 2409-2415.
Compounds of formula (Vl) are either known compounds or may be prepared by literature methods such as those described in for example N Seko ~L Chem.
Pharm. Bull., 1991, ;~, (3) 651-7 or I Lalazori et al, J.Med.Chem. 1971, 14, 1 138-40.
Compounds of formula (IV) or protected derivatives thereof may be prepared using conventional chemistry, for example chemistry analogous to that herein described for the preparalion of co",~Jounds of formula (I) Certain intermediates des~,iL,ed above are novel compounds, and it is to be understood that all novel i"ler" ledidles herein form further aspects of the present invention. Compounds of formula (Il) and (IV) are key intermediates and represent particular aspects of the present invention.
Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically accepta~le acid addition salts of the compounds of the invention may be prepared using conventional means.
Solvates (e.g. hydrates) of a co",pound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.
The following Examples illustrate the invention but do not limit the invention in any way. All temperatures are in ~C. Flash chror"atography was carried out using Merck 9385 silica. Thin layer chromatography (Tlc) was carried out on silica plates. NMR was carried out on a Brucker 300Mhz spectrometer, using CDCI3 as solvent. Chemical shifts are given in ~ ppm with respect to tetramethylsilane as intemal chemical shift reference. The following abbreviations are used: Et = ethyl, s = singlet, d = doublet, t = triplet and m =
multiplet.
Interrnediate 1 2-(4-Fluoro-phenyl)-1 -(4-methanesulfonvl-PhenYl)-ethanone A mixture of the 2-(4-fluoro-phenyl)-1-(4-fluoro-phenyl)-ethanone' (3g) and sodium methane sulphinate (1.589) in dry dimethyl sulphoxide (1 Oml) was heated to 105-110~ under nitrogen for 18h. The cooled reaction mixture was poured into water (500ml) and the mixture extracted with ethyl acetate. The combined organic extracts were adsorbed onto silica and purified by flash cl ,romalography eluting with ethyl acetate:hexane (1 :1) to give the title compound as a white solid (2.19).
m.p.115-116~
' Ref: I Lalazori et al, J.Med.Chem. 1971, 14, 113840.
W O 96131S09 PCT~EP96/01438 Intermediate 2 2-Bromo-2-(4-fluoro-PhenYI)-1 -(4-methanesulfonvl-PhenYI)~L! Idl 1~1 ,e A solution of the 2-~4-fluoro-phenyl)-1-(4-~eli Idl ~esulfonyl-phenyl)-ethanone (1.69) in dichloromethane (30ml) and glacial acetic acid (.15ml) was cooled to 0~
and llt:dled with 48% h~ lJrc,mic acid (3 drops). A solution of bromine (875mg) in acetic acid (2ml) was added and stirring continued for 4 hours. The mixture was diluted with dichlGro",t:ll,ane (35ml) and the solution was washed with water dried and co"ce"l,dlec~ to give the title compound as a yellow solid (2.09).
m.p. 124-126~
Intermediate 3 3-Trifluoromethvl-pvridin-2-vlamine A mixture of 2-chloro-3-trifluorùinelhyl-pyridine (59) copper(1) iodide (59) andliquid ar"",o,1ia (50ml) was heated in an autoclave at 80~ (internal temperature) for 28 hours. The cooled reaction mixture was slurried with methanol/chlo,urul,l, (1/1-250 ml) and filtered. The filtrate was absorbed onto silica and purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to yield the title comPound as a white solid (1.49).
m.p. 71-72~
MH~ = 163 Tlc sio2, Rf 0.50 (ethyl acetate/hexane (1/1)) detection UV/KMnO4 Intermediate 4 2-(4-Fluoro-phenyl)-1 -~4-methanesulfanYI-PhenYI)~ll Idl lone A mixture of 2-(4-fluoro-phenyl)-1 -(4-fluoro-phenyl)-ethanone (10.0g) sodium methanethiolate (3.0g~ and di,netl,),rl sulphoxide (10ml) was heated at -100~ for 8h under nitrogen. The cooled mixture was added to water (250ml) stirred for 10 min and filtered. The resulting solid was crystallised from isopropanol (100ml) twice to give the title compound as a white solid (5.0g).
m.p.143-144~
Intermediate 5 2-Bromo-2-(4-fluoro-phenyl)-1 -(4-methanesulfanvl-phenYI)-ethanone A solution of 2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone (4.89) in dichloromethane (75ml) and acetic acid (30ml) at 0~ containing 48% HBr (15 drops) was treated dropwise with bromine (2.69) in acetic acid (6ml). The solution was stirred at 0~ for 10 min and at room temperature for 3h, diluted with dichloromethane (100ml) and washed with water (2 x 100ml). The dried (MgSO4) orga~ic phase was evapo,~led and the residue was triturated with diethyl ether (30ml) to give the title cor,ll)ound as a white $olid (4.59).
m.p.117-119~.
Tlc SiO2 (Et20:hexane 1:1) Rf 0.6 det u.v. KMnO4, isopropanol.
Intermediate 6 3-(4-Fluoro-Phenvl)-2-(4-l l lelhal1esulfanvl-Phenvl)-imidazor1,2-a1Pvridine A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone (4.09) and 2-aminopyridine (1.2g) in acetonitrile (25ml) was relluxed under nitrogen for 2h and left at room temperature for 16h. The soluticn was evaporated and the residue purified by flash column chromatography eluting with diethyl ether (applied in CH2CI2) to give the title compound as a white solid (1.69).
m.p. 115-118~
Tlc SiO2 (Et2O) Rf 0.5 det u.v., isopropanol.
Intermediate 7 8-Chloro-3-(4-fluoro-PhenYI)-2-(4-methanesulfanvl-PhenYl)-imidazo~1,2-alpyridine n-Butyllithium in hexane (1.6m; 0.35ml) was added dropwise to a solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (167mg) in tetrahydrofuran (2ml) at -78~ under nitrogen. The solution was stirred at -78~
for 1 h and was treated with l ,exachloroethane (142mg) in tetrahydrofuran (0.25ml). The solution was allowed to warm to room temperature during 30 min and water (2ml) was added. The mixture was extracted with ethyl acetate (2 x 5ml) and the dried (MgSO4) extract was evaporated to give the title compound as a cream solid (180mg).
m.p.148-149~
MH ' = 369 Intermediate 8 3-Methvlsulfanyl-pvridin-2-ylamine A solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide2 (890mg) in dry tetrahydrofuran (30ml) was cooled to -78~ and treated with a solution of n-butyllithium (6.25 ml,1.6M). This solution was stirred at 0~ for 4 hours and a solution of dimethyldisulphide (235mg) in tetrahydrofuran (5ml) was added and stirring continued at ~",~ienl ter"perdlure for 30 minutes. 2N Hydrochloric acid (1ml) was added and the solution col lce~ led in vacuo. A mixture of the residue and 2N hy~ ric acid (15ml) was heated at reflux for 4 hours. The cooled reaction mixture was made basic by addition of solid potassium carbonate. The basic mixture was e~L~a~ed with ethyl ~cet~e (15ml),the organic extract was dried (Na2SO4) and absorbed onto silica. The title compound was obtained by flash c~,rc""dlog,~ully eluting with ethyl acetate/cyclohexane (1/1) as a colourless oil (490mg).
MHt = 141 Tlc, SiO2, Rf 0.48,(ethyl acetate/cyclohexane(1/1)) detec~ion u.v., KMnO4 2 Ref: J A Turner J. Or~3. Chem.1983,48.3401 I. ,l~r " ,ediate 9 3-(4-Fluoro-phenyl)-2-~4-methanesulfonyl-Phenyl)-imidazor1,2-alpvridine-8-ca, ~oxYlic acid methvl ester A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (700mg), and 2-amino-nicotinic acid methyl ester (287mg) in dry aceto, lill ile was heated at reflux overnight. The reaction mixture was concentrated onto silica and the title comPound obtained by flash chromatography eluting with ethyl acetate:cyclohexane 5:1 as a yellow solid (176mg).
MH+ = 425 Tlc, SiO2 Rf 0.21 (ethyl acetate:cyclohexane 5:1) detection uv Intermediate 10 8-Acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfanvl-Phenyl)-imidazo~1,2-alpvridine n-Butyllithium in hexane (1.6m; 0.5ml) was added dropwise to a solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (250mg) in tetrahydrofuran (3ml) at -78~ under nitrogen. The solution was stirred at -78~ for 1 h and was treated with N-methyl,N-methoxyacetamide (9Omg) in tetrahydrofuran (0.25ml). The solution was allowed to warm to room temperature during 60min and water (10ml) was added. The mixture was extracted with ethyl acetate (2 x 5ml) and the dried (MgSO4) extract was W O~6/31509 PCTAEP96/01438 evaporated. The residue was purified on a column of silica, eluting with hexane:diethylether (3:1) to give the title co""~ound as a cream solid (130mg).
MH+ = 377 Tlc SiO2 (Et20) Rf 0.9 det u.v.
ExamPle 1 3-14-Fluoro-PhenYI)-2-(4-methanesulfonYl-phenv~ midazor1,2-alPvridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (233mg) and 2-aminopyridine (59mg) in dry acetonitrile was heated at reflux overnight. The reaction mixture was adsorbed onto silica and purified by flash cl ,rumalography eluting with ethyl ~cet~te to afford the title compound as a cream solid (100mg).
MH+ = 367.2 m.p.198-200~
Example 2 3-(4-Fluoro-Phenvl)-2-(4-methanesulfonvl-Phenvl)-8-methvl-imidazor1,2-alPyridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (233mg) and 2-amino-3-methylpyridine (68mg) in dry acetonitrile (10ml) was heated at reflux overnight. The reaction mixture was adsorbed onto silica and purified by flash cl ,ru" ~dlography eluting with dichloromethane/methanol (19:1) to afford the title cGm~ound as a pale brown solid (61mg).
MH+ = 381 m.p.180-182~
Exampie 3 3-(4-Fluoro-Phenvl)-2-(4-methanesulfonYI-PhenYl~-8-trifluoromethyl-imidazo~1,2-alpyridine A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulphonyl-phenyl)-ethanone (742mg), and 3-trifluoromethyl-pyridin-2-ylamine (324mg,) in dry acetonitrile containing potassium carbonate (276mg) was heated at reflux overnight. The reaction mixture was conce,llrdled onto silica and purified by flash chromatography eluting with ethyl acetate, to give a yellow solid. Further PCT~EP96/01438 WO 9613150g purification by recrystallisation from propan-2-ol yielded the title comPound asyellow crystals (21 Omg).
m.p. 260-261~
Analysis: Found: C,57.7; H,3.0; N,6.2; S,7.3 C2,H,4F4N202S Requires: C,58.1; H,3.25;N,6.45;S,7.4%
MH' = 435 Tlc, sio2, Rf 0.25, (ethyl ~cet~te) detection u.v.
Example 4 3-(4-Fluoro-PhenY1)-2-(4-methanesulPhonvl)-7-methvl-imidazor1 ~2-alPvridine A solution of the 2-bromo-2-(4-fluoro-phenyl)-1 -(4-methanesulphonyl-phenyl)-ethanone (233mg) an~ 2-amino4-methylpyridine (68mg) in acetonitrile 10ml) was heated at reflux for 18 hours. The cooled reaction mixture was absorbed onto silica and the title comPound obtained by flash chromatography, eluting with ethyl acetate /hexane (111), as a bu~f solid (105mg).
m.p.194-196~
MH+ = 381 Tlc, sio2, Rf 0.26, (ethyl acetate/hexane (2/1)) detection u.v.
Example 5 8-Chloro-3-(4-fluoro-Phenvl)-2-(4-methanesulfonvl-Phenvl~-imidazo~1 2-alpyridine A suspension of 8-chloro-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo~1,2-a]pyridine (150mg) in methanol (8ml) and water (2ml) was treated with Oxone TM (561mg) and stirred for 2h at room temperature. The resulting suspension was treated with water (50ml) and extracted with ethyl acetate (2 x 50ml). The dried (MgSO4) extract was evaporated and the resulting solid was treated with boiling isopropanol (8ml) for (10min) cooled and filtered to give the title compound as a white solid (85mg).
m.p. 242-244~
Tlc SiO2(Et2O) RF 0.5 det u.v., KMnO4 MH+ = 401 Example 6 3-(4-Fluoro-Phenvl)-2-(4-, 1 ,eli Idl ,esulfonyl-phenyl)-8-meU Idl ,esulfanvl-imidazo~1 2-alpvridine A solution of 3-methylsulfanyl-pyridin-2-ylamine (140 mg) and 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (1 5ml) was heated at reflux ove, l ligl ,L. The cooled reaction mixture was absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetdle/cyclohexane (1/1) as a white solid (179 mg).
m.p. 224-226~
MH+=413 Tlc, SiO2, Rf 0.60 (ethyl acetate/cyclohexane(1/1)) detection u.v./KMnO4 Example 7 8-Bromo-3-(4-fluoro-phenYI)-2-(4-l, letl ,a, ~esulfonvl-Phenvl)-imidazo~1 2-alpvridine A solution of 3-bromo-pyridin-2-ylamine3 (173 mg) and 2-bromo-2-(4-fluoro-phenyl)-1-(4-rllell,a"esulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (15ml)was heated at reflux overnight. On cooling to room temperature the title compound crystallised from solution and was isolated by filtration as a white solid (241 mg).
m.p 266-268~
MH ' = 446 Analysis: Found: C,53.5;H,3.0;N,6.2;F,4.3;S,7. 1 C20H,4BrFN2O2S Requires: C,53.9;H,3.2;N,6.3;F,4.3;S,7.2%
Tlc, sio2, Rf 0.61 (Ethyl acetale/cyclohexane(2/1 )) detection u.v., KMnO4 3 Ref: M.Malinowski,Bull. Soc. Chim. Belg. 1988, 97, 51 Example 8 8-Fluoromethvl-3-(4-fluoro-phenvl)-2-t4-methanesulPhonvl-Phenyl)-imidazo~1 ,2-alpyridine A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulphonyl-phenyl)-imidazo[1,2-a]pyridine-8-methanol (200mg) in dichloromethane (1 Oml) was added to a cooled solution of diethylaminosulphur trifluoride (0.067 ml) in dichloromethane(4 ml) at -78~ over 5 minutes. The solution was allowed to warm to room temperature over 30 minutes. Water (15 ml) was added cautiously with stirring, the organic phase was separated, dried (Na2SO4) and absorbed onto silica.
The title compound was obtained by flash chromatography eluting with ethyl W O 96131509 PCT~EP96101438 ace~ale/cyclol ,e~dne (1/1) as a white solid which was further purified by crystallisation from ,~r~a, l-2~1 (10 ml) yielding white crystals (85 mg).
m.p. 221-222~
MH ' = 399 Analysis Found: C,63.1; H,3.9; N,6.8, F,9.4; S,8.1 C2,H16F2N202S Requires: C,63.3; H,4.05; N,7.1, F;9.5: S,8.05%
Example 9 3-(4-Fluoro-PhenYI)-2 -(4-methanesulfonYI-phenyl)-7~8-dimethyl-imidazor1,2-alPvridine A solution of 3,4~imethyl-pyridin-2-ylamine4 (122 mg) and 2-bromo-2-(4-fluoro-phenyl)-1 -(4-rneli ,anesulphonyl-phenyl)-ethanone (371 mg) in acetonitrile (15ml) containing potassium carbonate (138 mg) was heated at reflux overnight.
The cooled mixture \A~as absorbed onto silica and the title compound obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1) as a white solid. Cryst~llis~tion lrom propan-2-ol (10 ml) yielded white crystals (136 mg).m.p. 228-230~
MH+ = 395 Analysis Found: C,66.6; H,4.7; N,6.9; F,4.8; S,8.2 C22H1gN2FO2S Requires: C,67.0; H,4.85; N,7.1; F,4.8; S8.1%
4 Ref: W O Siegl, J Het. Chem. 1981, 18,1613-18 Example 10 3-~4-Fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazor1 ,2-alPyridine~-carbaldehyde A solution of the [3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-methanol (500mg) and manganese (IV) oxide (1.329) in chlororor", (50ml) was heated at reflux for 16 hours. The cooled reaction mixture was filtered and the filtrate conce, Ill dled onto silica. The title compound was obtained by flash chromatography eluting with ethyl acetate/cyclohexane (4/1) as a bright yellow solid (315mg).
MH+ = 395 Analysis Found: C,63.71; H,3.55; N,6.89; S,8.07;
C2,H,5FN203S Requires: C,63.95; H,3.83; N,7.10; S,8.13%.
ExamPle 1 1 5-Bromo-3-(4-fluoro-PhenYI)-2-(4-methanesulfonvl-PhenYI)-8-methvl-imicl~o~1.2-alPYridine A solution of 3-(4-fluoro-phenyl)-2-(4-mell Idl ~esulfonyl-phenyl)-8-methyl-imidazo[1,2-a]pyridine (380 mg ) in chloror~,lll (20 ml) was treated with solid N-L,r~.r"osl~ccinimide (178 mg) in one portion at ambient temperature, and the resulting solution stirred overnight. Water (50 ml) was added and the organic phase collected, dried (Na2SO4) and absorbed onto silica. The title compound was obtained by flash ~;I,ro",é,lography eluting with cyclohexane/ethyl acetate (1/1) as a white solid (106 mg).
m.p. 277-279~ (dec) MH~ = 461 Tlc, sio2, Rf 0.22(Ethyl acetate/cyclohexane(1/1)) detection uv, KMnO4 ExamPle 12 8-Acetvl-3-(4-fluoro-PhenYI)-2-(4-methanesulfonYl-phenyl)-imidazor1,2-alPYridine A suspension of 8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (130mg) in methanol (8ml) and water (2ml) was treated with Oxone TM (436mg) and stirred for 3h at room temperature. The resulting suspension was treated with water (50ml) and extracted with ethyl acetate (50ml). The dried (MgSO4) extract was evapor~led and the resulting solid was treated with boiling isopropanol (3ml) for (10min), cooled and filtered to give the title comPound as a white solid (85mg).
m.p. 236-237~
Tlc SiO2 (Et20) Rf 0.5 det u.v., KMnO4 MH+ = 401 Example 13 6-Bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonYI-phenYI)-8-methYI-imidazo~1,2-alpyridine A mixture of 1-amino4-bromo-2-methylpyridine (500mg), 2-bromo-2-(4-fluoro-phenyl)-1 -(4-methanesulfonyl-phenyl)-ethanone (1.0g) and acetonitrile (1 Oml) was refluxed under nitrogen for 20h and evaporated. The residue was triturated with diethyl ether (20ml) for 5 min, cooled and flltered. The procedure was repeated to give the title co""~ourld as a beige powder (580mg).
MH+ = 461 Tlc SiO2 (Et20) Rf O.6 ~lel~ctiGn u.v., KMnO4 Example 14 8-Acetvl-3-(4-fluoro-PhenYI)-2-f4-methanesulfonYl-phenvl)-imidazor1,2-alpyridine A solution of 3-acetyl-2-ar"i"o~yridine5 (2.50g) and 2-bromo-2-(4-fluorophenyl)-1-(4-methanesulphonylphenyl)elll~llolle (6.829) in acetonitrile (125ml) containing sodium biG~ Grldle (2.31g) was heated at reflux overnight. The mixture was filtered hot and the filtrate left to cool to room temperature. The title compound crystallise~l from solution and was isolated by filtration as a yellow solid (3.589).
Tlc SiO2 Rf 0.34 (ethyl acetate/hexane,1.3:1) detection u.v., iodine 'H NMR 3.04(3H,s~cH3sor)~ 3.16(3H,s,CH3CO-), 6.90(1H,t,J=7.0Hz,H~), 7.31 (2H,t,J=8.8Hz) & 7.45(2H,dd,J= 5.2Hz,8.8Hz) - C6H4F-, 7.85(2H,d,J=8.4Hz) & 7.91 (2H,d,J=8.4Hz) - C6H4SO2, 7.93(1 H,dd,J=1.1,7.0Hz, H-7), 8.02(1H,dd,J=1.1,7.0~1z, H-5).
5 Ref: F.Trecourt et al, J. Chem. Soc., Perkin Trans.1 1990, 9, 2409-2415 Example 15 r3-(4-Fluoro-Phenvl)-2-(4-methanesulfonYI-PhenYI)-imidazo~1,2-alpyridin-8-yll-methanol A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (1.859) in dry tetrahydrofuran (130ml)was cooled to -78~ and l,~dled with diisobutylaluminium hydride (17.4ml;1.0M
solution in dichloromethane). Once the addition was complete the mixture was allowed to warm up to 25~ and stirring continued for 2 h. Methanol (80ml) was added and the mixture co"ce, lll dled onto silica. The title compound was obtained by flash chromatography eluting with dichloromethane/ethanol/ammonia, 100/8/1, as a white foam (1.549).
MH+ = 397 Tlc (sio2) Rf 0.28 (dichloromethane/ethanol/ammonia,100/8/1) detection U.V.
CA 022l6809 l997-09-29 W 096/31509 PCT~P96/01438 ExamPIe 16 r3~4-fluoro-PhenYI)-2-(4~ ll Id nesulPhonvl-PhenYI)-imidazo~1 2-alPyridin-8-vll-ethan-1-ol A solution of [3-(4-fluoro-phenyl)-2-(4-r,lt:ll,a"esulfonyl-phenyl)-imidazo[1 2-a]pyridin-8-yl]-l"~:ll,anol (204 mg) in dry dichlGro",etl,al,e (10 ml) was cooied to -78~. A solution of ~iisob~tylaluminium hydride (1.0 M in dichloromethane 1ml) was added dropwise and the mixture allowed to warm to ambient te",,~ eralure over 30 minutes. M_;ha~-ol (10 ml) was added in one portion and stirring continued for a further 30 minutes. The reaction mixture was absorbed onto silica and the title co",pound obtained by flash chromatography eluting with ethyl acetale as a white solid (120 mg) m.p.201 -203~
T.l.c. SiO2 Rf 0.45 (ethyl ace~ate) detection U.V.
ExamPle 17 - Tablets a) Compound ofthe invention 5.0mg I ~ctose 95.0mg Microcrystalline Cellulose 90.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0mg Compression weight 200.0mg The compound of the invention microcrystalline cellulose lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with the active blend. The blend is col"pressed into tablets using suitable punches.
b) Compound ofthe invention 5.0mg Lactose 165.0mg Pregelatinised Starch 20.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0m~
Compression weight 200.0mg The compound of the invention l~tose and pre~el~tinised starch are blended together and granulated with water. The wet mass is dried and milled. The magnesium ~leardle and cross-linked polyvinylpyll~lido,le are screened through a 250 micron sieve and blended with the granule. The resultant blend is co""~ressed using suitable tablet punches.
Example 18 - CaPsules a) Compound ofthe invention 5.0mg Lactose 1 93.0mg Magnesium Stearate 2.0m~
Fill weight 200.0mg The compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve blended together and lubricated with magnesium sLearale (meshed through a 250 micron sieve). The blend is filled into hard gelatine capsules of a suitable size.
b) Compound o~ the invention 5.0mg Lactose 1 77.0mg Polyvinylpyrrolidone 8.0mg Cross-linked polyvinylpyrrolidone8.01Tg Magnesium Stearate 2.0m~
Fill weight 200.0mg The compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules. The resultant blend is filled into hard gelatine capsules of a suitable size.
W O96/31509 PCT~EP96/01438 ExamPle 19 - SYruP
a) Compound ofthe invention 5.0mg Hydroxypropyl Methylcellulose 45.0mg Propyl Hydroxybe" oale 1.5mg Butyl Hydroxyber, odle 0.75mg Saccharin Sodium 5.0mg Sorbitol Solution 1 .Oml Suitable Buffers qs Suitable flavours qs Purified Waterto 10.ml The hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxyben~o~es and the solution is allowed to cool to ambient temperature. The sac~harin, sodium flavours and sorbitol solution are added to the bulk solution. The compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability. The solution is made up to volume, filtered and filled into suitable containers.
ExamPle 20 - Iniection Formulation % w/v Compound of the invention 1.00 Waterfor injections B.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH
may be adjusted to that of maximum stability and/or to facilitate solution of the compound of the invention using dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salts may also be included. The solution is clarified, made up to final volume with water and the pH remeasured and adjusted if necessaly, to provide 10mg/ml of the compound of formula (I).
The solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes. The ampoules, vials or syringes may be aseptically filled (e.g. the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e.g. by CA 022l6809 l997-09-29 W O 96/31~09 ~CT~EP96/01438 heali,~g in an ~l~t~ol~ve using one of the acce~,taL,le cycles). The solution may be packed Llnder an inert ~ll"os,~l ,er~ of nitrogen.
r~ ~rer~bly the soll ~tion is filled into ampoules, sealed by fusion of the glass and terminaily sterilised.
Further sterile formulations are ~lepared in a similar manner containing 0.5, 2.0 and 5% w/v of the co",,,~ound of formula (I), so as to provide respectively 5, 20 and 50mg/ml of the c4",,l~0und of formula (I).
Biolo~ical Data Inhibitory activity against human COX-1 and COX-2 was assessed in COS cells which have been stably l,;ansrected with cDNA for human COX-1 and huma COX-2. 24 Hours prior to experiment, COS cells were l,ansrerred from the 175cm2 flasks in whi~h they were grown, onto 24-well cell culture plates using the following procedure. The incubation medium, being Dulbecco's modified eagles medium (DME~M) to which had been added heat inactivated foetal calf serum (10%v/v), penicillin (100U Iml), streptomycin (10011g/ml) and geneticin (600~g/ml), was removed from a flask of confluent cells (1 flask at confluency contains approximately 1x10' cells). 10ml of phosphate buffered saline (PBS) was added to the flask to wash the cells. Having removed the PBS, cells were rinsed in 10ml trypsin for 20 seconds, after which the trypsin was removed and the flask placed in an inc~h~tor (37~) for 1-2 minutes until cells became loose.The flask was then removed from the inc~h~tor and cells resuspended in 10ml of fresh incubation medium. The conlenls of the flask was transferred to a 250ml sterile conlai"er and the volume of incubation medium subsequently made up to 100ml. 1ml cell suspension was pipetted into each well of 4x24-well cell culture plates. The plates were then placed in an incubator (37~C, 95%
air/5% CO2) overnight. If more than 1 flask was used, the cells were combined before being dispensed into the 24-well plates.
Following the overnight incubation, the incubation medium was completely , 30 removed from the 24-well cell culture plates and replaced with 250111 fresh DMEM (37~C). Test compounds were made up to 250x the required test concentration in DM~O and were added to the wells in a volume of 1~L1. Plates were then mixed gently by swirling and then placed in an incubator for 1 hour (37~C, 95% air/5% C02). Following the incubation period, 10111 of arachidonic acid (750~1M) was added to each well to give a final aracl .i ~' . ,ic acid conce"l~lion of 3011M. Plates were then ina Ih:~ted for 15 minutes, after which the inc~ Ih~tion medium was removed from each well of the plates and stored at -20~C, prior to ~leter",i"dlion of prost~ ,din E2 (PGE2) levels using enzyme immunoassay. The inhibitory potency of the test compounds was expressed as an IC50 value, which is defined as the conce, lll dlion of the compound required to inhibit the PGE2 release from the cells by 50%. The selectivity ratio of inhibition of COX-1 versus COX-2 was calculated by con,~arir,g respective IC50 values.
The following IC50 values for inhibition of COX-2 and COX-1 were obtained for compounds of the invention:
. . .
Example l~Jo~COX-2: lC~0~nM)COX-1,. IC~OlnM~
428 >100,000 2 54 >10,445 3 144 >100,000 4 159 >100,000 38 >100,000 6 212 >100,000 7 71 >100,000 8 38 >100,000 9 38 >100,000 476 >100,000 11 18 6,295 12 142 >100,000 13 275 >100,000 750 >100,000 16 650 >100,000 -
MH+ = 395 Analysis Found: C,63.71; H,3.55; N,6.89; S,8.07;
C2,H,5FN203S Requires: C,63.95; H,3.83; N,7.10; S,8.13%.
ExamPle 1 1 5-Bromo-3-(4-fluoro-PhenYI)-2-(4-methanesulfonvl-PhenYI)-8-methvl-imicl~o~1.2-alPYridine A solution of 3-(4-fluoro-phenyl)-2-(4-mell Idl ~esulfonyl-phenyl)-8-methyl-imidazo[1,2-a]pyridine (380 mg ) in chloror~,lll (20 ml) was treated with solid N-L,r~.r"osl~ccinimide (178 mg) in one portion at ambient temperature, and the resulting solution stirred overnight. Water (50 ml) was added and the organic phase collected, dried (Na2SO4) and absorbed onto silica. The title compound was obtained by flash ~;I,ro",é,lography eluting with cyclohexane/ethyl acetate (1/1) as a white solid (106 mg).
m.p. 277-279~ (dec) MH~ = 461 Tlc, sio2, Rf 0.22(Ethyl acetate/cyclohexane(1/1)) detection uv, KMnO4 ExamPle 12 8-Acetvl-3-(4-fluoro-PhenYI)-2-(4-methanesulfonYl-phenyl)-imidazor1,2-alPYridine A suspension of 8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (130mg) in methanol (8ml) and water (2ml) was treated with Oxone TM (436mg) and stirred for 3h at room temperature. The resulting suspension was treated with water (50ml) and extracted with ethyl acetate (50ml). The dried (MgSO4) extract was evapor~led and the resulting solid was treated with boiling isopropanol (3ml) for (10min), cooled and filtered to give the title comPound as a white solid (85mg).
m.p. 236-237~
Tlc SiO2 (Et20) Rf 0.5 det u.v., KMnO4 MH+ = 401 Example 13 6-Bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonYI-phenYI)-8-methYI-imidazo~1,2-alpyridine A mixture of 1-amino4-bromo-2-methylpyridine (500mg), 2-bromo-2-(4-fluoro-phenyl)-1 -(4-methanesulfonyl-phenyl)-ethanone (1.0g) and acetonitrile (1 Oml) was refluxed under nitrogen for 20h and evaporated. The residue was triturated with diethyl ether (20ml) for 5 min, cooled and flltered. The procedure was repeated to give the title co""~ourld as a beige powder (580mg).
MH+ = 461 Tlc SiO2 (Et20) Rf O.6 ~lel~ctiGn u.v., KMnO4 Example 14 8-Acetvl-3-(4-fluoro-PhenYI)-2-f4-methanesulfonYl-phenvl)-imidazor1,2-alpyridine A solution of 3-acetyl-2-ar"i"o~yridine5 (2.50g) and 2-bromo-2-(4-fluorophenyl)-1-(4-methanesulphonylphenyl)elll~llolle (6.829) in acetonitrile (125ml) containing sodium biG~ Grldle (2.31g) was heated at reflux overnight. The mixture was filtered hot and the filtrate left to cool to room temperature. The title compound crystallise~l from solution and was isolated by filtration as a yellow solid (3.589).
Tlc SiO2 Rf 0.34 (ethyl acetate/hexane,1.3:1) detection u.v., iodine 'H NMR 3.04(3H,s~cH3sor)~ 3.16(3H,s,CH3CO-), 6.90(1H,t,J=7.0Hz,H~), 7.31 (2H,t,J=8.8Hz) & 7.45(2H,dd,J= 5.2Hz,8.8Hz) - C6H4F-, 7.85(2H,d,J=8.4Hz) & 7.91 (2H,d,J=8.4Hz) - C6H4SO2, 7.93(1 H,dd,J=1.1,7.0Hz, H-7), 8.02(1H,dd,J=1.1,7.0~1z, H-5).
5 Ref: F.Trecourt et al, J. Chem. Soc., Perkin Trans.1 1990, 9, 2409-2415 Example 15 r3-(4-Fluoro-Phenvl)-2-(4-methanesulfonYI-PhenYI)-imidazo~1,2-alpyridin-8-yll-methanol A solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (1.859) in dry tetrahydrofuran (130ml)was cooled to -78~ and l,~dled with diisobutylaluminium hydride (17.4ml;1.0M
solution in dichloromethane). Once the addition was complete the mixture was allowed to warm up to 25~ and stirring continued for 2 h. Methanol (80ml) was added and the mixture co"ce, lll dled onto silica. The title compound was obtained by flash chromatography eluting with dichloromethane/ethanol/ammonia, 100/8/1, as a white foam (1.549).
MH+ = 397 Tlc (sio2) Rf 0.28 (dichloromethane/ethanol/ammonia,100/8/1) detection U.V.
CA 022l6809 l997-09-29 W 096/31509 PCT~P96/01438 ExamPIe 16 r3~4-fluoro-PhenYI)-2-(4~ ll Id nesulPhonvl-PhenYI)-imidazo~1 2-alPyridin-8-vll-ethan-1-ol A solution of [3-(4-fluoro-phenyl)-2-(4-r,lt:ll,a"esulfonyl-phenyl)-imidazo[1 2-a]pyridin-8-yl]-l"~:ll,anol (204 mg) in dry dichlGro",etl,al,e (10 ml) was cooied to -78~. A solution of ~iisob~tylaluminium hydride (1.0 M in dichloromethane 1ml) was added dropwise and the mixture allowed to warm to ambient te",,~ eralure over 30 minutes. M_;ha~-ol (10 ml) was added in one portion and stirring continued for a further 30 minutes. The reaction mixture was absorbed onto silica and the title co",pound obtained by flash chromatography eluting with ethyl acetale as a white solid (120 mg) m.p.201 -203~
T.l.c. SiO2 Rf 0.45 (ethyl ace~ate) detection U.V.
ExamPle 17 - Tablets a) Compound ofthe invention 5.0mg I ~ctose 95.0mg Microcrystalline Cellulose 90.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0mg Compression weight 200.0mg The compound of the invention microcrystalline cellulose lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with the active blend. The blend is col"pressed into tablets using suitable punches.
b) Compound ofthe invention 5.0mg Lactose 165.0mg Pregelatinised Starch 20.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0m~
Compression weight 200.0mg The compound of the invention l~tose and pre~el~tinised starch are blended together and granulated with water. The wet mass is dried and milled. The magnesium ~leardle and cross-linked polyvinylpyll~lido,le are screened through a 250 micron sieve and blended with the granule. The resultant blend is co""~ressed using suitable tablet punches.
Example 18 - CaPsules a) Compound ofthe invention 5.0mg Lactose 1 93.0mg Magnesium Stearate 2.0m~
Fill weight 200.0mg The compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve blended together and lubricated with magnesium sLearale (meshed through a 250 micron sieve). The blend is filled into hard gelatine capsules of a suitable size.
b) Compound o~ the invention 5.0mg Lactose 1 77.0mg Polyvinylpyrrolidone 8.0mg Cross-linked polyvinylpyrrolidone8.01Tg Magnesium Stearate 2.0m~
Fill weight 200.0mg The compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules. The resultant blend is filled into hard gelatine capsules of a suitable size.
W O96/31509 PCT~EP96/01438 ExamPle 19 - SYruP
a) Compound ofthe invention 5.0mg Hydroxypropyl Methylcellulose 45.0mg Propyl Hydroxybe" oale 1.5mg Butyl Hydroxyber, odle 0.75mg Saccharin Sodium 5.0mg Sorbitol Solution 1 .Oml Suitable Buffers qs Suitable flavours qs Purified Waterto 10.ml The hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxyben~o~es and the solution is allowed to cool to ambient temperature. The sac~harin, sodium flavours and sorbitol solution are added to the bulk solution. The compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability. The solution is made up to volume, filtered and filled into suitable containers.
ExamPle 20 - Iniection Formulation % w/v Compound of the invention 1.00 Waterfor injections B.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH
may be adjusted to that of maximum stability and/or to facilitate solution of the compound of the invention using dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salts may also be included. The solution is clarified, made up to final volume with water and the pH remeasured and adjusted if necessaly, to provide 10mg/ml of the compound of formula (I).
The solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes. The ampoules, vials or syringes may be aseptically filled (e.g. the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e.g. by CA 022l6809 l997-09-29 W O 96/31~09 ~CT~EP96/01438 heali,~g in an ~l~t~ol~ve using one of the acce~,taL,le cycles). The solution may be packed Llnder an inert ~ll"os,~l ,er~ of nitrogen.
r~ ~rer~bly the soll ~tion is filled into ampoules, sealed by fusion of the glass and terminaily sterilised.
Further sterile formulations are ~lepared in a similar manner containing 0.5, 2.0 and 5% w/v of the co",,,~ound of formula (I), so as to provide respectively 5, 20 and 50mg/ml of the c4",,l~0und of formula (I).
Biolo~ical Data Inhibitory activity against human COX-1 and COX-2 was assessed in COS cells which have been stably l,;ansrected with cDNA for human COX-1 and huma COX-2. 24 Hours prior to experiment, COS cells were l,ansrerred from the 175cm2 flasks in whi~h they were grown, onto 24-well cell culture plates using the following procedure. The incubation medium, being Dulbecco's modified eagles medium (DME~M) to which had been added heat inactivated foetal calf serum (10%v/v), penicillin (100U Iml), streptomycin (10011g/ml) and geneticin (600~g/ml), was removed from a flask of confluent cells (1 flask at confluency contains approximately 1x10' cells). 10ml of phosphate buffered saline (PBS) was added to the flask to wash the cells. Having removed the PBS, cells were rinsed in 10ml trypsin for 20 seconds, after which the trypsin was removed and the flask placed in an inc~h~tor (37~) for 1-2 minutes until cells became loose.The flask was then removed from the inc~h~tor and cells resuspended in 10ml of fresh incubation medium. The conlenls of the flask was transferred to a 250ml sterile conlai"er and the volume of incubation medium subsequently made up to 100ml. 1ml cell suspension was pipetted into each well of 4x24-well cell culture plates. The plates were then placed in an incubator (37~C, 95%
air/5% CO2) overnight. If more than 1 flask was used, the cells were combined before being dispensed into the 24-well plates.
Following the overnight incubation, the incubation medium was completely , 30 removed from the 24-well cell culture plates and replaced with 250111 fresh DMEM (37~C). Test compounds were made up to 250x the required test concentration in DM~O and were added to the wells in a volume of 1~L1. Plates were then mixed gently by swirling and then placed in an incubator for 1 hour (37~C, 95% air/5% C02). Following the incubation period, 10111 of arachidonic acid (750~1M) was added to each well to give a final aracl .i ~' . ,ic acid conce"l~lion of 3011M. Plates were then ina Ih:~ted for 15 minutes, after which the inc~ Ih~tion medium was removed from each well of the plates and stored at -20~C, prior to ~leter",i"dlion of prost~ ,din E2 (PGE2) levels using enzyme immunoassay. The inhibitory potency of the test compounds was expressed as an IC50 value, which is defined as the conce, lll dlion of the compound required to inhibit the PGE2 release from the cells by 50%. The selectivity ratio of inhibition of COX-1 versus COX-2 was calculated by con,~arir,g respective IC50 values.
The following IC50 values for inhibition of COX-2 and COX-1 were obtained for compounds of the invention:
. . .
Example l~Jo~COX-2: lC~0~nM)COX-1,. IC~OlnM~
428 >100,000 2 54 >10,445 3 144 >100,000 4 159 >100,000 38 >100,000 6 212 >100,000 7 71 >100,000 8 38 >100,000 9 38 >100,000 476 >100,000 11 18 6,295 12 142 >100,000 13 275 >100,000 750 >100,000 16 650 >100,000 -
Claims (19)
1. Compounds of formula (I) and pharmaceutically acceptable derivatives thereof in which:
R0 represents halogen;
R1 and R2 are independently selected from H, halogen, C1-4alkyl, C1-4alkyl substituted by one or more fluorine atoms, C1-4alkoxy, C1-4hydroxyalkyl, SC1-4alkyl, C(O)H or C(O)C1-4alkyl; and R3 represents C1-4alkyl.
R0 represents halogen;
R1 and R2 are independently selected from H, halogen, C1-4alkyl, C1-4alkyl substituted by one or more fluorine atoms, C1-4alkoxy, C1-4hydroxyalkyl, SC1-4alkyl, C(O)H or C(O)C1-4alkyl; and R3 represents C1-4alkyl.
2. Compounds as claimed in claim 1 wherein R3 represents methyl.
3. Compounds as claimed in claim 1 or 2 wherein R0 represents fluorine.
4. Compounds as claimed in any one of claims 1 to 3 wherein R1 represents H, chlorine, bromine, C1-4alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2F or CF3), C1-4hydroxyalkyl (e.g. CH2OH or CH(OH)CH3), SC1-4alkyl(e.g. SCH3), C(O)H or C(O)C1-4alkyl (e.g. C(O)CH3).
5. Compounds as claimed in any one of claims 1 to 4 wherein R2 represents H, chlorine, bromine or C1-4 alkyl (e.g. methyl).
6. Compounds as claimed in any one of claims 1 to 5 wherein R0 represents fluorine; R1 represents H, chlorine, bromine, C1-4alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2F or CF3), C1-4hydroxyalkyl (e.g. CH2OH or CH(OH)CH3), SC1-4alkyl (e.g. SCH3), C(O)H or C(O)C1-4alkyl (e.g. C(O)CH3); R2 represents H, chlorine, bromine, or C1-4alkyl (e.g. methyl);
and R3 represents methyl.
and R3 represents methyl.
7. Compounds as claimed in any one of claims 1 to 6 wherein R0 represents fluorine; R1 represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(O)CH3; R2 represents H, bromine or methyl; and R3 represents methyl.
8. Compounds as claimed in any one of claims 1 to 7 wherein R1 is at the 8-position; and R2 is at the 7-position or, when R1 is other than H, the 5-, 6- or 7-position.
9. Compounds as claimed in any one of claims 1 to 8 wherein R1 is at the 8-position; and R2 is at the 7-position or, when R1 is C1-4alkyl (e.g. methyl), the 5-or 7-position.
10. Compounds as claimed in any one of claims 1 to 9 wherein R1 represents C(O)CH3.
11. 8-Acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine and pharmaceutically acceptable derivatives thereof.
12. Compounds as clamed in any of claims 1 to 11 wherein the compound of formula (I) is in the form of a hydrochloride, hydrobromide or sulphate.
13. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 12, which comprises:
(A) reacting a compound of formula (II) or a protected derivative thereof wherein Lg represents a leaving group, with a compound of formula (III) or a protected derivative thereof; or (B) reacting a compound of formula (IV) or a protected derivative thereof with an oxidising agent; or (C) interconversion of a compound of formula (I) into another compound of formula (I); or (D) deprotecting a protected derivative of compound of formula (I);
and optionally converting compounds of formula (I) prepared by any one of processes (A) to (D) into pharmaceutically acceptable derivatives thereof.
(A) reacting a compound of formula (II) or a protected derivative thereof wherein Lg represents a leaving group, with a compound of formula (III) or a protected derivative thereof; or (B) reacting a compound of formula (IV) or a protected derivative thereof with an oxidising agent; or (C) interconversion of a compound of formula (I) into another compound of formula (I); or (D) deprotecting a protected derivative of compound of formula (I);
and optionally converting compounds of formula (I) prepared by any one of processes (A) to (D) into pharmaceutically acceptable derivatives thereof.
14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 in admixture with one or more physiologically acceptable carriers or excipients.
15. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 for use in human or veterinary medicine.
16. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 for use in the treatment of a condition which is mediated by selective inhibition of COX-2
17. A method of treating a human or animal subject suffering from a condition which is mediated by selective inhibition of COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative as defined in any one of Claims 1 to12.
18. The use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12 for the manufacture of a therapeutic agent for the treatment of inflammatory disorders.
19. A method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 12.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9506965.4A GB9506965D0 (en) | 1995-04-04 | 1995-04-04 | Chemical compounds |
| GB9506965.4 | 1995-04-04 | ||
| GBGB9512099.4A GB9512099D0 (en) | 1995-06-14 | 1995-06-14 | Chemical compounds |
| GB9512099.4 | 1995-06-14 | ||
| GBGB9516117.0A GB9516117D0 (en) | 1995-08-05 | 1995-08-05 | Chemical compounds |
| GB9516117.0 | 1995-08-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2216809A1 true CA2216809A1 (en) | 1996-10-10 |
Family
ID=27267657
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002216809A Abandoned CA2216809A1 (en) | 1995-04-04 | 1996-04-02 | Imidazo[1,2-a]pyridine derivatives |
Country Status (17)
| Country | Link |
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| EP (1) | EP0819127A1 (en) |
| JP (1) | JPH11501049A (en) |
| KR (1) | KR19980703559A (en) |
| CN (1) | CN1186492A (en) |
| AU (1) | AU5276696A (en) |
| BG (1) | BG101934A (en) |
| CA (1) | CA2216809A1 (en) |
| CZ (1) | CZ313397A3 (en) |
| EA (1) | EA199700209A1 (en) |
| HU (1) | HUP9801602A3 (en) |
| IS (1) | IS4570A (en) |
| NO (1) | NO974595L (en) |
| NZ (1) | NZ304886A (en) |
| PL (1) | PL322623A1 (en) |
| SK (1) | SK133297A3 (en) |
| TR (1) | TR199701105T1 (en) |
| WO (1) | WO1996031509A1 (en) |
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| FR2764292B1 (en) * | 1997-06-10 | 2000-12-29 | Innothera Lab Sa | USE OF DICETONIC TETRACYCLE DERIVATIVES, NOVEL COMPOUNDS OBTAINED AND THEIR APPLICATION IN THERAPEUTICS |
| US6525053B1 (en) | 1997-08-22 | 2003-02-25 | Abbott Laboratories | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| US6307047B1 (en) | 1997-08-22 | 2001-10-23 | Abbott Laboratories | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| ATE245649T1 (en) * | 1997-09-05 | 2003-08-15 | Glaxo Group Ltd | 2,3-DIARYL-PYRAZOLO(1,5-B)PYRIDAZINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS CYCLOOXYGENASE 2 (COX-2) INHIBITORS |
| FR2770131A1 (en) * | 1997-10-27 | 1999-04-30 | Union Pharma Scient Appl | Analgesic combinations of a cyclooxygenase-2 inhibitor and acetaminophen or an opiate having synergistic activity |
| FR2771005B1 (en) * | 1997-11-18 | 2002-06-07 | Union Pharma Scient Appl | NEW PHARMACEUTICAL ASSOCIATION WITH ANALGESIC ACTIVITY |
| GB9810920D0 (en) * | 1998-05-21 | 1998-07-22 | Merck Sharp & Dohme | Therapeutic use |
| ES2140354B1 (en) * | 1998-08-03 | 2000-11-01 | S A L V A T Lab Sa | IMIDAZO (1,2A) AZINAS SUBSTITUTED AS SELECTIVE INHIBITORS OF COX-2. |
| TW587079B (en) * | 1998-09-25 | 2004-05-11 | Almirall Prodesfarma Ag | 2-phenylpyran-4-one derivatives |
| CN1263755C (en) * | 1998-11-03 | 2006-07-12 | 葛兰素集团有限公司 | Pyrazolopyridine derivatives as selective COX-2 inhibitors |
| ATE261444T1 (en) * | 1999-02-27 | 2004-03-15 | Glaxo Group Ltd | PYRAZOLOPYRIDINES |
| GB9930358D0 (en) * | 1999-12-22 | 2000-02-09 | Glaxo Group Ltd | Process for the preparation of chemical compounds |
| RU2002119574A (en) | 1999-12-23 | 2004-01-10 | Нитромед, Инк. (Us) | Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions based on them and methods for their use |
| GB0002312D0 (en) * | 2000-02-01 | 2000-03-22 | Glaxo Group Ltd | Medicaments |
| PE20011333A1 (en) | 2000-03-16 | 2002-01-16 | Almirall Prodesfarma Ag | DERIVATIVES OF 2-FENYLPYRAN-4-ONA AS INHIBITORS OF CYCLOOXYGENASE 2 |
| PE20020146A1 (en) * | 2000-07-13 | 2002-03-31 | Upjohn Co | OPHTHALMIC FORMULATION INCLUDING A CYCLOOXYGENASE-2 (COX-2) INHIBITOR |
| JP2004510705A (en) | 2000-07-20 | 2004-04-08 | ラウラス エイエス | Method |
| PE20020506A1 (en) | 2000-08-22 | 2002-07-09 | Glaxo Group Ltd | PIRAZOLE DERIVATIVES FUSED AS PROTEIN KINASE INHIBITORS |
| GB0025449D0 (en) * | 2000-10-17 | 2000-11-29 | Glaxo Group Ltd | Chemical compounds |
| AU2002239344A1 (en) | 2000-12-15 | 2002-06-24 | Glaxo Group Limited | Pyrazolopyridines |
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| WO2002078700A1 (en) | 2001-03-30 | 2002-10-10 | Smithkline Beecham Corporation | Pyralopyridines, process for their preparation and use as therapteutic compounds |
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| DE60212949T2 (en) | 2001-04-10 | 2007-01-04 | Smithkline Beecham Corp. | ANTIVIRAL PYRAZOLOPYRIDINE COMPOUNDS |
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| EP1432712B1 (en) | 2001-10-05 | 2006-05-17 | SmithKline Beecham Corporation | Imidazo-pyridine derivatives for use in the treatment of herpes viral infection |
| GB0124934D0 (en) | 2001-10-17 | 2001-12-05 | Glaxo Group 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 |
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| GB0217757D0 (en) | 2002-07-31 | 2002-09-11 | Glaxo Group Ltd | Novel compounds |
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| GB0318814D0 (en) | 2003-08-11 | 2003-09-10 | Smithkline Beecham Corp | Novel compounds |
| WO2006041855A2 (en) | 2004-10-04 | 2006-04-20 | Nitromed, Inc. | Compositions and methods using apocynin compounds and nitric oxide donors |
| WO2007016677A2 (en) | 2005-08-02 | 2007-02-08 | Nitromed, Inc. | Nitric oxide enhancing antimicrobial compounds, compositions and methods of use |
| AU2007243765A1 (en) | 2006-03-29 | 2007-11-08 | Nicox S.A. | Nitric oxide enhancing prostaglandin compounds, compositions and methods of use |
| CN101600718B (en) | 2006-11-06 | 2013-07-03 | 特雷罗药物股份有限公司 | Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors |
| US9416132B2 (en) | 2011-07-21 | 2016-08-16 | Tolero Pharmaceuticals, Inc. | Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors |
| EP3292213A1 (en) | 2015-05-04 | 2018-03-14 | Academisch Medisch Centrum | Biomarkers for the detection of aspirin insensitivity |
| CA3127502A1 (en) | 2019-02-12 | 2020-08-20 | Sumitomo Dainippon Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
| IL305573A (en) | 2021-03-15 | 2023-10-01 | Saul Yedgar | HYALURONIC ACID-CONJUGATED DIPALMITOYL PHOSPHATIDYL ETHANOLAMINE IN COMBINATION WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) FOR TREATING OR ALLEVIATING INFLAMMATORY DISEASES |
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1996
- 1996-04-02 JP JP8529971A patent/JPH11501049A/en active Pending
- 1996-04-02 NZ NZ304886A patent/NZ304886A/en unknown
- 1996-04-02 SK SK1332-97A patent/SK133297A3/en unknown
- 1996-04-02 EP EP96909164A patent/EP0819127A1/en not_active Withdrawn
- 1996-04-02 KR KR1019970706963A patent/KR19980703559A/en not_active Application Discontinuation
- 1996-04-02 WO PCT/EP1996/001438 patent/WO1996031509A1/en not_active Application Discontinuation
- 1996-04-02 CN CN96194403A patent/CN1186492A/en active Pending
- 1996-04-02 CZ CZ973133A patent/CZ313397A3/en unknown
- 1996-04-02 PL PL96322623A patent/PL322623A1/en unknown
- 1996-04-02 TR TR97/01105T patent/TR199701105T1/en unknown
- 1996-04-02 HU HU9801602A patent/HUP9801602A3/en unknown
- 1996-04-02 AU AU52766/96A patent/AU5276696A/en not_active Abandoned
- 1996-04-02 EA EA199700209A patent/EA199700209A1/en unknown
- 1996-04-02 CA CA002216809A patent/CA2216809A1/en not_active Abandoned
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1997
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- 1997-09-30 BG BG101934A patent/BG101934A/en unknown
- 1997-10-03 NO NO974595A patent/NO974595L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9707379A (en) | 1997-11-29 |
| EA199700209A1 (en) | 1998-04-30 |
| PL322623A1 (en) | 1998-02-02 |
| BG101934A (en) | 1999-04-30 |
| JPH11501049A (en) | 1999-01-26 |
| IS4570A (en) | 1997-09-25 |
| HUP9801602A3 (en) | 1999-01-28 |
| NO974595L (en) | 1997-12-03 |
| NO974595D0 (en) | 1997-10-03 |
| KR19980703559A (en) | 1998-11-05 |
| NZ304886A (en) | 1998-11-25 |
| AU5276696A (en) | 1996-10-23 |
| TR199701105T1 (en) | 1998-02-21 |
| CZ313397A3 (en) | 1998-03-18 |
| CN1186492A (en) | 1998-07-01 |
| SK133297A3 (en) | 1998-07-08 |
| HUP9801602A2 (en) | 1998-11-30 |
| WO1996031509A1 (en) | 1996-10-10 |
| EP0819127A1 (en) | 1998-01-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |