CN1186492A - Imidazo [1, 2-alpha] pyridine derivatives - Google Patents

Imidazo [1, 2-alpha] pyridine derivatives Download PDF

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CN1186492A
CN1186492A CN96194403A CN96194403A CN1186492A CN 1186492 A CN1186492 A CN 1186492A CN 96194403 A CN96194403 A CN 96194403A CN 96194403 A CN96194403 A CN 96194403A CN 1186492 A CN1186492 A CN 1186492A
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compound
formula
represent
alkyl
methyl
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P·J·贝斯威克
I·B·坎贝尔
A·内勒
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority claimed from GBGB9506965.4A external-priority patent/GB9506965D0/en
Priority claimed from GBGB9512099.4A external-priority patent/GB9512099D0/en
Priority claimed from GBGB9516117.0A external-priority patent/GB9516117D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of CN1186492A publication Critical patent/CN1186492A/en
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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
    • 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: R<0> represents halogen; R<1> and R<2> 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 R<3> 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

Imidazo [1,2-a] pyridine derivate
The present invention relates to imidazo [1,2-a] pyridine derivate, its preparation technology, the medical composition that contains this derivative and medical usage thereof.
Found that recently cyclo-oxygenase (COX) exists with two kinds of isoforming types, i.e. COX-1 and COX-2.COX-1 is corresponding to the original constitutive enzyme of confirming, and COX-2 can be rapidly and easily induced by many agents, comprising mitogen, intracellular toxin, hormone, division of cytoplasm element and somatomedin.The existing physiological role of the prostaglandin(PG) that effect produced by COX also has the pathology effect.People believe that generally COX-1 is responsible for such as important physiological function such as stomach and intestine completeness maintaining and kidney blood flow.Otherwise induction type COX-2 then is considered to and will be responsible for the pathology effect of prostaglandin(PG), and in this case, this enzyme takes place to induce rapidly, so that agents such as inflammatory agent, hormone, somatomedin and division of cytoplasm element are responded.Therefore, the selective depressant of COX-2 can have anti-inflammatory, bring down a fever and the pain relieving performance, and the potential side effect of not getting in touch with the COX-1 inhibitory phase.We have been found that now one group of novel cpd is the potent double selective depressant of COX-2.
Therefore, the invention provides formula (I) compound and pharmaceutically acceptable derivative thereof, R wherein 0Represent halogen;
R 1And R 2Be independently selected from H, halogen, C 1-4Alkyl, the C that has one or more fluorine atoms to replace 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Hydroxyalkyl, SC 1-4Alkyl, C (O) H or C (O) C 1-4Alkyl; With
R 3Represent C 1-4Alkyl.
So-called pharmaceutically acceptable derivative, mean any pharmaceutically acceptable salt, solvate or the ester of formula (I) compound, the perhaps salt of this type of ester or solvate perhaps can (directly or indirectly) when to the acceptor administration provide any other compound of formula (I) compound or its effective metabolite or residue.
What know is, for medicinal use, the salt of above indication will be physiologically acceptable salt, but other salt can find purposes aspect the preparation of acceptable salt on formula (I) compound and physiology thereof.
The suitable drug acceptable salt of formula (I) compound comprises with mineral acid or organic acid, better is the acid salt that mineral acid generates, example hydrochloric acid salt, hydrobromate and vitriol.
This term of halogen is used for representing fluorine, chlorine, bromine or iodine.
" alkyl " this term as the integral part of a group or a group, means straight chain or cladodification alkyl group, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl or tertiary butyl groups.
Substituent R 1And R 2Can as 5-, 6-, 7-or the 8-position of the pyridine ring of following defined, formula (I):
Be preferably R 1In the 8-position; And R 2In the 7-position, or work as R 1When being other group except that H, in 5-, 6-or 7-position.Be more preferably R 1In the 8-position; And R 2In the 7-position, or work as R 1Be C 1-4During alkyl (as methyl), in 5-or 7-position.
Be preferably R 0Represent fluorine.
Be preferably R 1Represent H, chlorine, bromine, C 1-4Alkyl (as methyl), methyl that 1～3 fluorine atom replaces is arranged (as CH 2F or CF 3), C 1-4Hydroxyalkyl is (as CH 2OH or CH (OH) CH 3), SC 1-4Alkyl is (as SCH 3), C (O) H or C (O) C 1-4Alkyl is (as C (O) CH 3).Be more preferably R 1Represent H, chlorine, bromine, methyl, CH 2F, CF 3, SCH 3, C (O) H or C (O) CH 3That best is R 1Represent C (O) CH 3
Be preferably R 2Represent H, chlorine, bromine or C 1-4Alkyl (as methyl).Be more preferably R 2Represent H, bromine or methyl.
Be preferably R 3Represent methylidene.
Within the scope of the present invention, provide one group of general formula (I) compound (A group), wherein: R 0Represent fluorine; R 1Represent H, chlorine, bromine, C 1-4Alkyl (as methyl), methyl that 1～3 fluorine atom replaces is arranged (as CH 2F or CF 3), C 1-4Hydroxyalkyl is (as CH 2OH or CH (OH) CH 3), SC 1-4Alkyl is (as SCH 3), C (O) H or C (O) C 1-4Alkyl is (as C (O) CH 3); R 2Represent H, chlorine, bromine or C 1-4Alkyl (as methyl); And R 3Represent methylidene.
In the A class range, provide group's compound, wherein: R 0Represent fluorine; R 1Represent H, chlorine, bromine, methyl, CH 2F, CF 3, SCH 3, C (O) H or C (O) CH 3R 2Represent H, bromine or methyl; And R 3Represent methylidene.
Within the scope of the present invention, provide another group general formula (I) compound (B group), wherein: R 0Represent fluorine; R 1In the 8-position, and represent H, chlorine, bromine, C 1-4Alkyl (as methyl), methyl that 1～3 fluorine atom replaces is arranged (as CH 2F or CF 3), C 1-4Hydroxyalkyl is (as CH 2OH or CH (OH) CH 3), SC 1-4Alkyl is (as SCH 3), C (O) H or C (O) C 1-4Alkyl is (as C (O) CH 3); R 2In the 7-position, or work as R 1When being other group except that H,, and represent H, chlorine, bromine or C in 5-, 6-or 7-position 1-4Alkyl (as methyl); And R 3Represent methylidene.
In the B class range, provide group's compound, wherein: R 0Represent fluorine; R 1At 8, and represent H, chlorine, bromine, methyl, CH 2F, CF 3, SCH 3, C (O) H or C (O) CH 3R 2In the 7-position, or work as R 1In 5-or 7-position, and represent H, bromine or methyl when being methyl; And R 3Represent methylidene.
Within the scope of the present invention, provide another group of general formula (I) compound (C group), wherein: R 0Represent fluorine; R 1In the 8-position, and represent H, chlorine, bromine, C 1-4Alkyl (as methyl), methyl that 1-3 fluorine atom replace is arranged (as CH 2F or CF 3), C 1-4Hydroxyalkyl is (as CH 2OH or CH (OH) CH 3), SC 1-4Alkyl is (as SCH 3), C (O) H or C (O) C 1-4Alkyl is (as C (O) CH 3); R 2Represent H; And R 3Represent methylidene.
In the C class range, provide group's compound, wherein: R 0Represent fluorine; R 1In the 8-position, and represent H, chlorine, bromine, methyl, CH 2F, CF 3, CH (OH) CH 3, SCH 3, C (O) H or C (O) CH 3R 2Represent H; And R 3Represent methylidene.
In above-mentioned each group (with each better group) compound scope, good especially compound group is R wherein 1Represent C (O) CH 3Those compounds.
It being understood that the present invention contains all isomer that can accept derivative on formula (I) compound and the medicine thereof, comprise all rotamerism forms, tautomeric form and optical siomerism form, and composition thereof (as racemic mixture).
Better compound of the present invention is:
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine;
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole is [1,2-a] pyridine also;
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-trifluoromethyl imidazoles is [1,2-a] pyridine also;
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-7-Methylimidazole is [1,2-a] pyridine also;
8-chloro-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine;
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-first sulfanilyl-imidazo [1,2-a] pyridine;
8-bromo-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine;
8-methyl fluoride-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine;
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-7,8-dimethyl-imidazo [1,2-a] pyridine;
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-formaldehyde;
5-bromo-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole is [1,2-a] pyridine also;
6-bromo-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole is [1,2-a] pyridine also;
[3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-yl] methyl alcohol;
(±) 1-[3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-yl] second-1-alcohol;
And pharmaceutically acceptable derivative.
A kind of good especially compound of the present invention is:
8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine; And pharmaceutically acceptable derivative.
The compounds of this invention is the potent and selective depressant of COX-2.This activity has more by them to COX-2 comparison COX-1, and highly selective inhibition ability illustrates.
In view of its selective COX-2-2 suppresses active, The compounds of this invention can be used for human body and veterinary drug, especially can be used for treating pain, heating and the inflammation of various illness and disease.Such illness and disease are technical well-known, comprising: the rheumatosis heating; The symptom that interrelates with influenza or other viral infection such as flu; Low back and cervical pain; Headache; Toothache; Sprain and strain; Myositis; Neurodynia; Synovitis; Sacroiliitis; Comprise rheumatoid arthritis; Degenerative joint disease comprises osteoarthritis; Gout and ankylosing spondylitis; Tendonitis; Bursitis; The illness relevant with skin is as psoriasis, eczema, burn and dermatitis; Injured, what injured and surgery and dental operation caused as sports is injured.
The compounds of this invention also can be used for the treatment of other and suppress relevant illness with the selectivity of COX-2.
For example, The compounds of this invention transformation capable of inhibiting cell, tumour change and the metastatic tumo(u)r growth, therefore, can be used for treating some Cancerous disease, as colorectal carcinoma.
The compounds of this invention also can prevent neuronal damage by suppressing neurone free-radical generating (thereby inhibited oxidation stress produces), thereby can be used for treating apoplexy, epilepsy and epileptic seizures (comprising epilepsy grand mal, petit mal epilepsy, myoclonus epilepsy and partial seizure).
The compounds of this invention also can suppress the smooth muscle contraction that the class prostate gland brings out, thereby can be used for treating dysmenorrhoea and drought product.
The compounds of this invention can suppress inflammatory process, thereby can be used for treating asthma, allergic rhinitis and respiratory distress syndrome; Gastrointestinal disorder, for example inflammatory bowel, ChronShi disease, gastritis, irritable intestine syndrome and ulcerative colitis; And the inflammation in the following disease: vascular disease, migraine, periarteritis tubercle, thyroiditis, aplastic anemia, Hodgkin, scleroderma, type i diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet Cotard, polymyositis, oulitis, conjunctivitis and myocardial ischemia.
The compounds of this invention also can be used for treating illness in eye, for example retinitis, retinopathy, uveitis, and ocular tissue's acute injury.
The compounds of this invention also can be used for the imbalance of treatment understanding, for example dull-witted, degenerative dementia (comprising senile dementia, presenile dementia, Pick's disease, Huntington Chorea, Parkinson's disease and Creutz Fil spy-jacob's syndrome) especially, and vascular dementia (comprising multi-infarct dementia), and with following relevant dementia: the occupying property damage of encephalic space, wound, infect and related disorders (comprise HIV infect), metabolism, toxin, anoxic and vitamin deficiency arranged; With with the aging slight understanding damage that interrelates, especially relevant amnesia with the age.
According to a further aspect of the present invention, we provide formula (I) compound or its pharmaceutically acceptable derivative that can be used for human body or veterinary drug.
According to another aspect of the present invention, we provide formula (I) compound or its pharmaceutically acceptable derivative that can be used for treating the illness relevant with the inhibition of COX-2 selectivity.
According to further aspect of the present invention, we provide treatment to suffer from the COX-2 selectivity to suppress the human body of relevant illness or the method for animal target, comprise formula (I) compound or pharmaceutically acceptable derivative to a certain significant quantity of described object administration.
According to another aspect of the present invention, we provide formula (I) compound or its pharmaceutically acceptable derivative to be used to make the purposes of inflammatory conditions treatment with therapeutical agent.
According to further again aspect of the present invention, the method that we provide a kind of treatment to suffer from the human body or the animal target of inflammatory conditions, this method comprise formula (I) compound of a certain significant quantity of described object administration or its pharmaceutically acceptable derivative.
It being understood that all treatments of mentioning, unless expressly stated otherwise,, otherwise both comprised the treatment that has symptom, also comprise prophylactic treatment.
What also will know is that The compounds of this invention can advantageously be used in combination with one or more other therapeutical agents.The example that is suitable for auxiliary therapeutical agent comprises anodyne, and for example glycine antagonistic, sodium channel inhibitor (as lamotrigine), Substance P antagonistic are (as NK 1Antagonistic), Paracetamol (paracetamol) or phenacetin; The matrix metal proteinase inhibitor; Nitric oxide synthase (NOS) inhibitor (as iNOS or nNOS inhibitor); The release of tumor necrosis factor alpha or function inhibitor; Antybody therapy (as mab treatment); Stimulant comprises caffeine; H 2-antagonist is as ranitidine (ranitidine); Antacid, for example aluminium hydroxide or magnesium hydroxide; Carminative is as Simethicone (simethicone); Decongestant is as phyenlephrinium, norephedrine, pseudo-ephedrine, hazol (vasoconstrictor), suprarenin, naphazoline, wooden first azoles quinoline, eventin or left-handed desoxyephedrine; Anti-tussive agents is as morphine monomethyl ether, hydrocodone, carmiphen, pentoxiverin or dextramethorphan; Hydragog(ue); Perhaps calmness or non-sedative antihistamine agent.It being understood that the purposes of cover type of the present invention (I) compound or its pharmaceutically acceptable derivative and one or more other therapeutical agent combinations.
Formula (I) compound and pharmaceutically acceptable derivative thereof are easily with the medical composition form administration.Therefore, another aspect of the present invention, we provide a kind of medical composition that comprises formula (I) compound or its pharmaceutically acceptable derivative, is suitable for human body or veterinary drug.Such composition can be the form of mixtures with one or more physiologically acceptable carriers or vehicle, uses and be provided with usual manner easily.
Formula (I) compound and pharmaceutically acceptable derivative thereof can prepare can be with any applicable pattern administration.For example, they can prepare can topical or through inhalation, or be more preferably per os, through skin or non-through enteral administration.This medical composition can be a kind of like this form: it can realize the controlled release of formula (I) compound and pharmaceutically acceptable derivative thereof.
For oral administration, this medical composition can be got following form, for example, and with usual way and tablet (comprising sublingual tablet), capsule, pulvis, solution, syrup or the suspension liquor that can accept the vehicle preparation.
For percutaneous dosing, this medical composition can be a kind of form through the skin patch, and is for example a kind of through skin ionotherapy patch.
Through enteral administration, this medical composition can be used as a kind of injection or a kind of continuous infusion agent (as in intravenously, intravascular or through subcutaneous) provides for non-.This based composition can be got the forms such as suspension liquor, solution or emulsion agent in oil base or the aqueous based carrier, and can contain formulation adjuvant, as suspension agent, stablizer and/or dispersion agent.For administrated by injection, these compositions can be got the dosage unit dosage form, or as a kind of multiple doses preparation, better add a kind of sanitas.
In addition, through enteral administration, this effective constituent can also be powder type for non-, for reconstructing with a kind of suitable carrier.
The compounds of this invention also can be prepared becomes a kind of deposition (long-acting) preparation.Long-acting prescription like this can or be used through the intramuscular injection administration with (for example through subcutaneous or through intramuscular) implantation.Therefore, for example, The compounds of this invention can be with suitable polymer materials or hydrophobic material preparation (for example, becoming a kind of a kind of emulsion of accepting in the oil), or the spent ion exchange resin preparation, or preparation becomes indissoluble derivative slightly, for example becomes difficulty soluble salt slightly.
As previously discussed, The compounds of this invention also can be used for and other therapeutical agent combination.Therefore, one further aspect, the invention provides a kind of combination, wherein comprise formula (I) compound or its pharmaceutically acceptable derivative and a kind of further therapeutical agent.
The combination of above indication can be supplied with the form of medicine prescription easily and use, and therefore, comprising the medicine prescription that can accept carrier or vehicle on above institute's combinations of definitions and the medicine is further aspect of the present invention.Each integral part of this type of combination can or with the medicine prescription of independent or combination in order or administration simultaneously.
When a kind of formula (I) compound or its pharmaceutically acceptable derivative and second kind were used in combination the effective therapeutical agent of illness of the same race, the dosage of every kind of compound can be different from the dosage when respectively this compound uses separately.Suitable dose will be that this gate technique skilled person understands easily.
The suggestion per daily dose that formula (I) compound is used for human body therapy is 0.01mg/kg～500mg/kg, 0.05mg/kg～100mg/kg for example, and as 0.1mg/kg～50mg/kg, these can conveniently be divided into 1～4 dosed administration.Used accurate dosage will depend on patient's age and illness, also depend on route of administration.Therefore, the per daily dose such as 0.25mg/kg～10mg/kg may be applicable to the general administration.
Formula (I) compound and pharmaceutically acceptable derivative thereof can prepare with the technical known any method of the compound that similar structures is arranged.
The suitable preparation method of formula (I) compound and pharmaceutically acceptable derivative thereof is described below.In formula subsequently, R 0～R 3Except as otherwise noted otherwise all as being defined in the following formula (I), and Lg represents a leavings group, as sulfonate radical (for example methanesulfonate) or halogen (as bromine).
Therefore, according to first kind of technology (A), formula (I) compound can be by making formula (II) compound or its protected derivative
Figure A9619440300121
Prepare with formula (III) compound or its protected derivatives reaction. This is reflected in for example a kind of polar solvent of a kind of solvent (as acetonitrile or Virahol), high temperature as under refluxing and randomly a kind of alkali for example alkali metal hydrocarbonate or carbonate (as salt of wormwood) in the presence of, can carry out easily.
Suitable atom or the group of leaving away about Lg in the formula (II), can consult a lot of organic chemistry standard textbooks, for example, Jerry March work " Advanced Organic Chemistry " (Advanced Organic Chemistry) the 4th edition (Wiley 1992) the 357th page table 10.10.The people who is familiar with this gate technique will know that more than the selection of specific leavings group may be depended on R in the reaction 0-R 3Implication (thereby depending on desirable formula (1) compound) and the reaction conditions that is adopted.
According to another kind of technology (B), formula (I) compound can be by making formula (IV) compound or its protected derivative
Figure A9619440300131
Prepare with a kind of oxidant reaction.This oxidation (is referred to as Oxone with a kind of single persulfuric acid phosphate compounds such as peroxide one vitriolate of tartar TM) just can carry out easily, and reaction is for example to carry out between-78 ℃～normal temperature in the alcohol solution (as methanol aqueous solution) at a kind of solvent.
According to another kind of technology (C), formula (I) compound can be by utilizing the preparation that is converted mutually of other formula (I) compound as precursor.
Therefore, for example, its R 1Or R 2Represent formula (I) compound of chlorine, bromine or iodine, can be from its R 1Or R 2Represent corresponding (I) compound of H to prepare by handling with a kind of suitable halogenating agent (being chlorizating agent, bromizating agent or iodinating agent).The halogenating agent that is suitable for comprises corresponding N-halo succinimide.This reaction is carried out in for example a kind of halohydrocarbon of a kind of solvent (as chloroform) He under the normal temperature easily.
Its R 1Or R 2The C that representative has one or more fluorine atoms to replace 1-4The formula of alkyl (I) compound can be from its R 1Or R 2Represent corresponding C 1-4The formula of hydroxyalkyl (I) compound prepares by handling with a kind of suitable fluorine source.The fluorine source that is suitable for comprises such as three fluoridizes diethylin sulphur.This reaction easily a kind of solvent for example halohydrocarbon (as methylene dichloride) in the presence of carry out as-78 ℃ at low temperature.
Its R 1Or R 2Represent formula (I) compound of C (O) H, can be from its R 1Or R 2Represent CH 2The corresponding of OH (I) compound prepares by oxidation.The oxygenant that is suitable for comprises such as Manganse Dioxide (IV).This oxidation easily a kind of solvent for example halohydrocarbon (as chloroform) in the presence of carry out at high temperature (as reflux).
Its R 1Or R 2Represent C 1-4Hydroxyalkyl and its hydroxyl be connected to that with carbon that pyridine ring links to each other on formula (I) compound, can pass through its R 1Or R 2Represent the also original preparation of formula (I) compound of corresponding aldehydes or ketones.The reductive agent that is suitable for comprises hydride reducer, for example diisobutylaluminium hydride.This reduction in the presence of for example a kind of halohydrocarbon of a kind of solvent (as methylene dichloride), is carried out as-78 ℃ at low temperature easily.
Will know that as the skilled person of this gate technique any one stage in the above technology has necessity or it is desirable to protect one or more sensitive groups in the molecule, to prevent undesirable side reaction.
Therefore, the another kind of preparation technology (D) of formula (I) compound comprises the protected derivative deprotection that makes formula (I) compound.
The blocking group that uses in formula (I) compound can use in normal way.For example, see also Theodora W.Green work " blocking group in the organic synthesis " (ProtectiveGroups in Organic Synthesis) second edition (John Wiley ﹠amp; Sons.1991) those described in, this book has also been described the removal methods of this type of group.
Formula (II) compound can prepare with usual way from the formula V compound.
Therefore, on behalf of formula (II) compound of halogen, its Lg can prepare by handling with a kind of halogenating agent for example a kind of chlorinated solvent of a kind of solvent at low temperatures from the formula V compound.For example, represent at Lg under the situation of bromine, this reaction easily in the presence of a kind of strong acid (as Hydrogen bromide-acetic acid solution) with a kind of bromizating agent for example bromine carry out.
Its Lg represents formula (II) compound of sulfonate radical can be from the formula V compound earlier by being oxidized to corresponding alpha-alcohol ketone, handling with a kind of sulphonating agent and prepare then.The oxygenant that is suitable for comprises such as Pb (OAc) 4, dimethyl ethylene oxide and F A Davis, J.Org.Chem., 1984,49 (17), those described in 3284.The sulphonating agent that is suitable for comprises for example SULPHURYL CHLORIDE (as methylsulfonyl chloride) of sulfonic acid halide.This sulfonylation in the presence of for example a kind of amine of a kind of alkali (as triethylamine), carries out in for example a kind of halohydrocarbon of a kind of solvent easily.
The formula V compound can prepare by handling with for example a kind of-sulfinic acid sodium of a kind of basic metal-sulfinate from formula (VI) compound.This reaction is for example at high temperature carried out in the dimethyl sulfoxide (DMSO) at a kind of polar solvent easily.
Figure A9619440300151
Formula (III) compound or known compound, perhaps can use those literature method preparations described in following document: for example, J A Turner, J.Org.Chem., 1983,48,3401; M Malinowski, Bull.Soc.Chim.Belg., 1988,97.51; W O Siegl, J.Het.Chem., 1981,18,1613-18; Or FTrecourt et al, J.Chem.Soc, Perkin Trans.1 1990,9.2409-2415.
Formula (VI) compound or known compound, perhaps can use those literature method preparations described in following document: for example, N Seko et al, Chem.Pharm.Bull., 1991,39, (3), 651-7, or I Lalazori et al, J.Med.Chem.1971,14,1138-40.
Formula (IV) compound or its protected derivative can utilize the general chemistry method, for example herein to the described class quasi-chemical method preparation of formula (I) compound.
Above-described some intermediate is a novel cpd, and it being understood that all new intermediates here all constitute further aspect of the present invention.Formula (II) and compound (IV) are key intermediates, and represent particular aspects of the present invention.
The compounds of this invention is isolating easily after being refined into free alkali form.Can accept acid salt on the medicine of The compounds of this invention can prepare with usual way.
The solvate of The compounds of this invention (as hydrate) can form during the refining program of one of above-mentioned processing step.
Following example explanation the present invention, but do not limit the present invention in any way.Temperature is all with ℃ representing.Dodging anxious chromatography carries out with Merck 9385 silicon-dioxide.Tlc (Tlc) is carried out on silica plate.Nucleus magnetic resonance (NMR) carries out on Brucker 300Mhz spectrometer, uses CDCl 3As solvent.Chemical shift is represented with δ ppm, uses the tetramethyl-silicomethane as the reference of chemical shift interpolation.Use following shortenings: Et=ethyl, s=singlet, d=two-wire attitude, t=triplet state, the multi-thread attitude of m=.
Intermediate 1
2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone
The mixture of 2-(4-fluorophenyl)-1-(4-fluorophenyl) ethyl ketone 1 (3g) and methyl-sulfinic acid sodium (1.58g) is in anhydrous dimethyl sulphoxide (10ml), under nitrogen, 105-110 ℃ of heating 18 hours.In refrigerative reaction mixture impouring water (500ml), the mixture ethyl acetate extraction.The organic extract that merges is adsorbed on the silicon-dioxide, and with dodging anxious chromatography purification, with ethyl acetate: hexane (1: 1) wash-out provides white solid title compound (2.1g).m.p.115-116° 1Ref：I?Lalazori?et?al，J.Med?Chem.1971，14，1138-40。
Intermediate 2
2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone
The solution of 2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (1.6g) in methylene dichloride (30ml) and Glacial acetic acid (15ml) is cooled to 0 ℃, handles with 48% Hydrogen bromide (3).Add the solution of bromine (875mg) in acetate (2ml), continue to stir 4 hours.This mixture is with methylene dichloride (35ml) dilution, and the solution with water washing, provides yellow solid shape title compound (2.0g) after concentrating at drying.m.p.124-126℃
Intermediate 3
3-(trifluoromethyl) pyridine-2-amine
2-chloro-3-(trifluoromethyl) pyridine (5g), cupric iodide (1) (5g) and the mixture of liquefied ammonia (50ml) in autoclave in 80 ℃ (internal temperature) heating 28 hours.Refrigerative reaction mixture methyl alcohol/chloroform (1/1,250ml) furnishing soup compound, filtration.Filtrate absorbs on the silicon-dioxide, with dodging anxious chromatography purification, with ethyl acetate/hexane (1/1) wash-out, obtains white solid title compound (1.4g).M.p.71-72 ° of MH +=163T1c SiO 2, Rf 0.50 (ethyl acetate/hexane (1/1)) detects UV/KMnO 4
Intermediate 4
2-(4-fluorophenyl)-1-(4-first sulfanilyl-phenyl) ethyl ketone
2-(4-fluorophenyl)-1-(4-fluorophenyl) ethyl ketone (10.0g), sodium methyl mercaptide (3.0g) and dimethyl sulfoxide (DMSO) (10ml) heated 8 hours at～100 ℃ under nitrogen.The refrigerative mixture add in the water (250ml), stir 10 minutes, filter.Resulting solid provides white solid title compound (5.0g) with Virahol (100ml) crystallization 2 times.m.p.143-144℃
Intermediate 5
2-bromo-2-(4-fluorophenyl)-1-(4-first sulfanilyl-phenyl) ethyl ketone
2-(4-fluorophenyl)-1-(4-first sulfanilyl-phenyl)-ethyl ketone (4.8g) uses the method for acetate (6ml) solution of dripping bromine (2.6g) to handle in methylene dichloride (75ml) and acetate (30ml), at 0 ℃ of solution that contains 48%HBr (15).This solution 0 ℃ stir 10 minutes, stirring at room 3 hours, with methylene dichloride (100ml) dilution, water (2 * 100ml) washings.Dry (MgSO 4) organic phase evaporation, residue provides white solid title compound (4.5g) with diethyl ether (30ml) development.m.p.117-119℃。Tlc SiO 2(Et 2O: hexane=1: 1) Rf0.6 detects UV/KMnO 4, Virahol.
Intermediate 6
3-(4-fluorophenyl)-2-(4-first sulfanilyl-phenyl)-imidazo [1,2-a] pyridine
2-bromo-2-(4-fluorophenyl)-1-(4-first sulfanilyl-phenyl) ethyl ketone (4.0g) and the solution of 2-aminopyridine (1.2g) in acetonitrile (25ml) were at room temperature placed 16 hours refluxed under nitrogen 2 hours.Solution evaporation, residue (is added in CH with dodging anxious column chromatography purifying with the diethyl ether wash-out 2Cl 2In), provide white solid title compound (1.6g).M.p.115-118 ℃ of Tlc SiO 2(Et 2O) Rf 0.5, ultraviolet detection, Virahol.
Intermediate 7
8-chloro-3-(4-fluorophenyl)-2-(4-first sulfanilyl-phenyl)-imidazo [1,2-a] pyridine
(1.6M 0.35ml) is added drop-wise in tetrahydrofuran (THF) (2ml) solution of 3-(4-fluorophenyl)-2-(4-first sulfanilyl-phenyl)-imidazo [1,2-a] pyridine (167mg) the n-Butyl Lithium hexane solution, drips under nitrogen at-78 ℃.This solution stirred 1 hour at-78 ℃, with tetrahydrofuran (THF) (0.25ml) solution-treated of hexachloroethane (142mg).Allow this solution go back up to room temperature, add water (2ml) with 30 fens clock times.(2 * 5ml) extract mixture, dry (MgSO with ethyl acetate 4) extraction liquid evaporation, provide butteriness solid title compound (180mg).m.p.148-149℃MH +＝369
Intermediate 8
3-first sulfanilyl-pyridine-2-amine
2,2-dimethyl-N-pyridine-2-base propionic acid amide 2(890mg) solution in anhydrous tetrahydro furan (30ml) is cooled to-78 ℃, and (6.25ml 1.6M) handles with n-butyllithium solution.This solution stirred 4 hours at 0 ℃, added tetrahydrofuran (THF) (5ml) solution of dimethyl disulphide (235mg), continued to stir 30 minutes in room temperature.Add 2N hydrochloric acid (1ml), solution for vacuum concentration.The mixture reflux of residue and 2N hydrochloric acid (15ml) 4 hours.The refrigerative reaction mixture is by adding solid carbonic acid potassium furnishing alkalescence.Alkaline mixt extracts with ethyl acetate (15ml), organic extract liquid drying (Na 2SO 4), absorb on the silicon-dioxide.With dodging anxious chromatography purification,, obtain colorless oil title compound (490mg) with ethyl acetate/hexanaphthene (1/1) wash-out.MH +=141Tlc, SiO 2, Rf0.48, (ethyl acetate/hexanaphthene (1/1)) ultraviolet detection, KMn0 4 2Ref:J A Turner J.Org.Chem. 1983,48,3401
Intermediate 9
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-carboxylate methyl ester
The anhydrous acetonitrile reflux of 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (700mg) and 2-amino-nicotinic acid methyl esters (287mg) spends the night.Reaction mixture is concentrated on the silicon-dioxide, and with dodging anxious chromatography purification, with ethyl acetate: hexanaphthene (5: 1) wash-out obtains yellow solid shape title compound (176mg).MH +=425Tlc, SiO 2, Rf0.21 (ethyl acetate: ultraviolet detection hexanaphthene=5: 1).
Intermediate 10
8-acetyl-3-(4-fluorophenyl)-2-(4-first sulfanilyl-phenyl)-imidazo [1,2-a] pyridine
At-78 ℃, under nitrogen, dropping n-Butyl Lithium hexane solution in tetrahydrofuran (THF) (3ml) solution of 3-(4-fluorophenyl)-2-(4-first sulfanilyl-phenyl)-imidazo [1,2-a] pyridine (250mg) (1.6M, 0.5ml).This solution stirred 1 hour at-78 ℃, with tetrahydrofuran (THF) (0.25ml) solution-treated of N-methyl-N-methoxyl group ethanamide (90mg).Allow solution go back up to room temperature, add water (10ml) with 60 fens clock times.(2 * 5ml) extract mixture, dry (MgSO with ethyl acetate 4) extraction liquid evaporation.Residue silicagel column purifying, use hexane: diethyl ether (3: 1) wash-out provides butteriness solid title compound (130mg).MH +=377Tlc SiO 2(Et 2O) Rf0.9 ultraviolet detection.
Example 1
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine
2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (233mg) spends the night with the anhydrous acetonitrile reflux of 2-aminopyridine (59mg).Reaction mixture is adsorbed onto on the silicon-dioxide,, uses eluent ethyl acetate, provide butteriness solid title compound (100mg) with dodging anxious chromatography purification.MH +＝367.2m.p.198-200°
Example 2
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole is [1,2-a] pyridine also
2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (233mg) spends the night with anhydrous acetonitrile (10ml) reflux of 2-amino-3-picoline (68mg).Reaction mixture is adsorbed onto on the silicon-dioxide,,, provides light brown solid state title compound (61mg) with methylene chloride (19: 1) wash-out with dodging anxious chromatography purification.MH +＝381m.p.180-182°
Example 3
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-trifluoromethyl imidazoles is [1,2-a] pyridine also
2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (742mg) spends the night with the 3-5-flumethiazine-solution reflux of 2-amine (324mg) in the anhydrous acetonitrile that contains salt of wormwood (276mg).Reaction mixture is concentrated on the silicon-dioxide, with dodging anxious chromatography purification, uses eluent ethyl acetate, provides a kind of yellow solid.Be further purified with the propan-2-ol recrystallization, obtain yellow crystal shape title compound (210mg).M.p.260-261 ° of analysis: measured value: C, 57.7; H, 3.0; N, 6.2; S, 7.3C 21H 14F 4N 2O 2S theoretical value: C, 58.1; H, 3.25; N, 6.45; S, 7.4%MH +=435Tlc, SiO 2, Rf0.25, (ethyl acetate) ultraviolet detection
Example 4
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-7-Methylimidazole is [1,2-a] pyridine also
Acetonitrile (10ml) the solution reflux of 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (233mg) and 2-amino-4-picoline (68mg) 18 hours.The refrigerative reaction mixture is absorbed on the silicon-dioxide, with dodging anxious chromatography purification, with ethyl acetate/hexane (1/1) wash-out, obtains beige solid shape title compound (105mg).M.p.194-196 ° of MH +=381Tlc, SiO 2, Rf0.26, (ethyl acetate/hexane (2/1)) ultraviolet detection
Example 5
8-chloro-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine
8-chloro-3-(4-fluorophenyl)-2-(4-first sulfanilyl-the phenyl)-suspension Oxone of imidazo [1,2-a] pyridine (150mg) in methyl alcohol (8ml) and water (2ml) TM(561mg) handle, stirring at room 2 hours.Resulting suspension water (50ml) is handled, with ethyl acetate (2 * 50ml) extractions.Dry (MgSO 4) extraction liquid evaporation, resulting solid was handled 10 minutes with boiling Virahol (8ml), provided white solid title compound (85mg) through cooling, after filtering.M.p.242-244 ° of Tlc SiO 2(Et 2O) RF 0.5 ultraviolet detection, KMnO 4MH +=401
Example 6
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-first sulfanilyl-imidazo [1,2-a] pyridine
3-first sulfanilyl-pyridine-2-amine (140mg) spends the night with acetonitrile (15ml) the solution reflux of 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (371mg).The refrigerative reaction mixture absorbs on the silicon-dioxide, with dodging anxious chromatography purification and with ethyl acetate/hexanaphthene (1/1) wash-out, obtaining white solid title compound (179mg).M.p.224-226 ℃ of MH +=413Tlc, SiO 2, Rf0.60 (ethyl acetate/hexanaphthene (1/1)), ultraviolet detection/KMnO 4
Example 7
8-bromo-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine
3-bromopyridine-2-amine 3(173mg) acetonitrile (15ml) the solution reflux with 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (371mg) spends the night.During cool to room temperature, crystallization and filter to isolate white solid title compound (241mg) from solution.M.p 266-268 ° MH +=446 analyze: measured value: C, 53.5; H, 3.0; N, 6.2; F, 4.3; S, 7.1C 20H 14BrFN 2O 2S theoretical value: C, 53.9; H, 3.2; N, 6.3; F, 4.3; S, 7.2%Tlc, SiO 2, Rf0.61 (ethyl acetate/hexanaphthene (2/1)) ultraviolet detection, KMnO 4 3Ref:M.Malinowski, Bull.Soc.Chim.Belg.1988,97,51
Example 8
8-methyl fluoride-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine
Methylene dichloride (10ml) solution of 3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-methyl alcohol (200mg) adds at-78 ℃ of refrigerative three with 5 fens clock times and fluoridizes in methylene dichloride (4ml) solution of diethylin sulphur (0.067ml).Allow solution in 30 minutes, go back up to room temperature.Carefully add water (15ml) while stirring, with organic phase separation, dry (Na 2SO 4) and absorb on the silicon-dioxide.With dodging anxious chromatography purification, with ethyl acetate/hexanaphthene (1/1) wash-out, obtain the white solid title compound, use propan-2-ol (10ml) crystallization process to be further purified again, obtain white crystals (85mg).M.p.221-222 ° of MH +=399 analyze: measured value: C, 63.1; H, 3.9; N, 6.8, F, 9.4; S, 8.1C 21H 16F 2N 2O 2S theoretical value: C, 63.3; H, 4.05; N, 7.1, F; 9.5:S, 8.05%
Example 9
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-7,8-dimethyl-imidazo [1,2-a] pyridine
3,4-lutidine-2-amine 4(122mg) spend the night with the solution reflux of 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (371mg) in the acetonitrile that contains salt of wormwood (138mg) (15ml).The refrigerative mixture absorbs on the silicon-dioxide, with dodging anxious chromatography purification and with ethyl acetate/hexanaphthene (1/1) wash-out, obtaining the white solid title compound.With propan-2-ol (10ml) crystallization, obtain white crystals (136mg).M.p.228-230 ° of MH +=395 analyze: measured value: C, 66.6; H, 4.7; N, 6.9; F, 4.8; S, 8.2C 22H 19N 2FO 2S theoretical value: C, 67.0; H, 4.85; N, 7:1; F, 4.8; S8.1% 4Ref:W O Siegl, J Het.Chem.1981,18,1613-18
Example 10
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-formaldehyde
Chloroform (50ml) the solution reflux of [3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-methyl alcohol (500mg) and Manganse Dioxide (IV) are (1.32g)] 16 hours.The refrigerative reaction mixture filters, and filtrate is concentrated on the silicon-dioxide.With dodging anxious chromatography purification,, obtain glassy yellow solid state title compound (315mg) with ethyl acetate/hexanaphthene (4/1) wash-out.MH +=395 analyze: measured value: C, 63.71; H, 3.55; N, 6.89; S, 8.07; C 21H 15FN 2O 3S theoretical value: C, 63.95; H, 3.83; N, 7.10; S, 8.13%.
Example 11
5-bromo-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole is [1,2-a] pyridine also
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole also chloroform (20ml) solution of [1,2-a] pyridine (380mg) uses a collection of adding of solid N-bromine succinimide (178mg) to handle at normal temperatures, and resulting solution stirring is spent the night.Add water (50ml), with organic phase collection, dry (Na 2SO 4) and absorb on the silicon-dioxide.With dodging anxious chromatography purification,, obtain white solid title compound (106mg) with cyclohexane/ethyl acetate (1/1) wash-out.M.p.277-279 ° of (decomposition) MH +=461Tlc, SiO 2, Rf 0.22 (ethyl acetate/hexanaphthene (1/1)) ultraviolet detection, KMnO 4
Example 12
8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine
8-acetyl-3-(4-fluorophenyl)-2-(4-first sulfanilyl-the phenyl)-suspension Oxone of imidazo [1,2-a] pyridine (130mg) in methyl alcohol (8ml) and water (2ml) TM(436mg) handle, and at room temperature stirred 3 hours.Resulting suspension water (50ml) is handled, with ethyl acetate (50ml) extraction.Dry (MgSO 4) extraction liquid evaporation, resulting solid was handled 10 minutes with boiling Virahol (3ml), cooling, filtered, and provided white solid title compound (85mg).M.p.236-237 ° of Tlc SiO 2(Et 2O) Rf0.5 ultraviolet detection, KMnO 4MH +=401
Example 13
6-bromo-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)-8-Methylimidazole is [1,2-a] pyridine also
The mixture of 1-amino-4-bromo-2-picoline (500mg), 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (1.0g) and acetonitrile (10ml) is in refluxed under nitrogen 20 hours, evaporation.Residue diethyl ether (20ml) development 5 minutes, cooling, filtration.Repeat this program, provide the Powdered title compound of beige (580mg).MH +=461Tlc SiO 2(Et 2O) Rf0.6 ultraviolet detection, KMnO 4
Example 14
8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine
3-acetyl-2-aminopyridine 5(2.50g) spend the night with the solution reflux of 2-bromo-2-(4-fluorophenyl)-1-(4-methylsulfonyl phenyl) ethyl ketone (6.82g) in the acetonitrile that contains sodium bicarbonate (2.31g) (125ml).The mixture heat filtering, filtrate placement is cooled to room temperature.From solution, separate out the title compound crystallization, filter to isolate a kind of yellow solid (3.58g).Tlc SiO 2Rf 0.34 (ethyl acetate/hexane, 1.3: 1) ultraviolet detection, iodine 1H NMR 3.04 (3H, s, CH 3SO 2-), 3.16 (3H, s, CH 3CO-), 6.90 (1H, t, J=7.0Hz, H-6), 7.31 (2H, t, J=8.8Hz) ﹠amp; 7.45 (2H, dd, J=5.2Hz, 8.8Hz)-C 6H 4F-, 7.85 (2H, d, J=8.4Hz) ﹠amp; 7.91 (2H, d, J=8.4Hz)-C 6H 4SO 2, 7.93 (1H, dd, J=1.1,7.0Hz, H-7), 8.02 (1H, dd, J=1.1,7.0Hz, H-5). 5Ref:F.Trecourt et al.J.Chem.Soc., Perkin Trans.1 1990,9,2409-2415
Example 15
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-methyl alcohol
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1, the 2-a] pyridine-solution of 8-carboxylate methyl ester (1.85g) in anhydrous tetrahydro furan (130ml) is cooled to-78 ℃, with diisobutylaluminium hydride (17.4m1; 1.0M dichloromethane solution) handle.Finish in case add, make mixture go back up to 25 ℃ immediately, and continue to stir 2 hours.Add methyl alcohol (80ml), mixture is concentrated on the silicon-dioxide.With dodging anxious chromatography purification,, obtain white foam shape title compound (1.54g) with methylene dichloride/ethanol/ammonia (100/8/1) wash-out.MH +=397Tlc (SiO 2) Rf 0.28 (methylene dichloride/ethanol/ammonia, 100/8/1) ultraviolet detection
Example 16
(±) 1-[3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine-8-yl] second-1-alcohol
3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1, the 2-a] pyridine-solution of 8-methyl alcohol (204mg) in anhydrous methylene chloride (10ml) is cooled to-78 ℃.Drip diisobutylaluminium hydride solution (1.0M dichloromethane solution 1ml), this mixture went back up to normal temperature in 30 minutes.Disposable interpolation methyl alcohol (10ml) continues to stir 30 minutes again.Reaction mixture absorbs on the silicon-dioxide, with dodging anxious chromatography purification, with eluent ethyl acetate, obtains white solid title compound (120mg).M.p.201-203 ° of T.l.c.SiO 2Rf0.45 (ethyl acetate) ultraviolet detection.
Example 17 tablets
A) The compounds of this invention 5.0mg
Lactose 95.0mg
Microcrystalline Cellulose 90.0mg
Cross-linking polyethylene pyrrolidone 8.0mg
Magnesium Stearate 2.0mg
Compressing tablet weight 200.0mg
The compounds of this invention, Microcrystalline Cellulose, lactose and cross-linking polyethylene pyrrolidone sieve with 500 μ m sieve, with being suitable for the mixing machine fusion.Magnesium Stearate sieves with 250 μ m sieve, again with the fusion of effective constituent adulterant.Adulterant is pressed into tablet with suitable tabletting machine.
B) The compounds of this invention 5.0mg
Lactose 165.0mg
Pre-gelatinized starch 20.0mg
Cross-linking polyethylene pyrrolidone 8.0mg
Magnesium Stearate 2.0mg
Compressing tablet weight 200.0mg
The compounds of this invention, lactose and pre-gelatinized starch are blended together, the water granulation.With the wet stock drying, pulverize.Magnesium Stearate and cross-linking polyethylene pyrrolidone sieve with 250 μ m sieve, with this particle fusion.Resulting adulterant is pressed into tablet with suitable tabletting machine.
Example 18 capsules
A) The compounds of this invention 5.0mg
Lactose 193.0mg
Magnesium Stearate 2.0mg
Charge weitght 200.0mg
The compounds of this invention and lactose sieve with 500 μ m mesh sieves, are blended together, and use Magnesium Stearate (crossing 250 μ m sieve) lubricated again.Adulterant is loaded in the hard gelatin capsule of suitable size.
B) The compounds of this invention 5.0mg
Lactose 177.0mg
Polyvinylpyrolidone (PVP) 8.0mg
Cross-linking polyethylene pyrrolidone 8.0mg
Magnesium Stearate 2.0mg
Charge weitght 200.0mg
The compounds of this invention and lactose are blended together, with the granulation of Polyvinylpyrolidone (PVP) solution.With the wet stock drying, pulverize.Magnesium Stearate and cross-linking polyethylene pyrrolidone sieve with 250 μ m sieve, and with this particle fusion.Resulting adulterant is loaded in the hard gelatin capsule of suitable size.
Example 19 syrups
A) The compounds of this invention 5.0mg
Vltra tears 45.0mg
Nipasol 1.5mg
Butoben 0.75mg
Soluble saccharin 5.0mg
Sorbitol solution 1.0mg
It is an amount of to be suitable for buffer reagent
It is an amount of to be suitable for strong smelly correctives
Purified water is to 10ml
Vltra tears is dispersed in a hot purified water with the hydroxybenzoate class, makes solution be cooled to normal temperature.In this mixing solutions in bulk, add soluble saccharin, rectify smelly correctives and sorbitol solution.The compounds of this invention is dissolved in a surplus water, adds in this mixing solutions in bulk again.Can add suitable buffer reagent, so that pH is controlled in the zone of maximum stable.Solution is transferred to final volume, is filtered, is loaded in the suitable container.
Example 20 injection prescriptions
% (weight/volume)
The compounds of this invention 1.0
(British Pharmacopoeia) water for injection to 100.00
Can add sodium-chlor and adjust the isotonicity of this solution, and utilize diluted acid or diluted alkaline or pass through to add suitable buffer reagent salt, pH regulator is had maximum stable and/or helps its dissolved pH value to The compounds of this invention.Also can comprise oxidation inhibitor and metal-chelating salt.Make the solution clarification, water adds to final volume, redeterminates and adjust the pH value in case of necessity, with formula (I) compound that 10mg/ml is provided.
This solution can be packaged into the form of being convenient to inject, and for example, can also is sealed in ampoule, phial or the syringe.Ampoule, phial or syringe can carry out sterile filling (for example, this solution can be sterilized with filtration method, and is filled in the aseptic ampoule) and/or carry out terminal sterilization (can accept one of sterilising cycle as heating in autoclave) under aseptic condition.This solution can be packed under the inert nitrogen atmosphere.
Be preferably, this filled with solution in ampoule, by melting glass capsulation and carrying out terminal sterilization.
Further aseptic prescription prepares in a similar manner, wherein contains 0.5,2.0 and 5% (weight/volume) formula (I) compound, thereby provides 5,20 and 50mg/ml formula (I) compound respectively.
Biological data
To the inhibition activity of human body COX-1 and COX-2, be in the COS cell that with cDNA it has stably been carried out human body COX-1 and human body COX-2 transfection, to estimate.Tested preceding 24 hours, and utilized following program, make the COS cell from being used for the 175cm of its growth 2Transfer in the flask on the 24 porocyte culture plates.(1 flask that reaches the symphysis state contains and has an appointment 1 * 10 from symphysis cell flask 7Individual cell) take out substratum in, the Dulbecco that has promptly added following ingredients improves Eagle's medium (DMEM): heat inactivation foetal calf serum (10% (volume ratio)), penicillin (100U/ml), Streptomycin sulphate (100 μ g/ml) and geneticin (600 μ g/ml).In this flask, add the salt solution (PBS) of 10ml phosphate buffered, with washed cell.Remove after the PBS, cell is removed trypsinase then with 20 seconds of 10ml trypsinase rinsing, and this flask was placed a thermostat container (37 ℃) 1～2 minute, opens until cell is loose.Then, flask is taken out from thermostat container, cell is suspended in the 10ml fresh culture again.The content of this flask is transferred in the 250ml sterile chamber, made the volume of this substratum add to 100ml subsequently.With transfer pipet shift-in 1ml cell suspending liquid in each hole of 4 * 24 porocyte culture plates.Then these culture plates place a thermostat container (37 ℃, 95% air/5%CO 2) in spend the night.If use more than 1 flask, be redistributed in 24 well culture plates after then earlier cell being merged.
After cultivating all night, substratum is taken off from 24 porocyte culture plates fully, replace the fresh DMEM of 250 μ l (37 ℃).Test compound is mixed with required experimental concentration among 250 * DMSO, adds in each hole with the volume of 1 μ l.Then, each plate is slowly mixed by rotation, then thermostat container (37 ℃, 95% air/5%CO 2) the middle placement 1 hour.After this incubation period, in every hole, add 10 μ l arachidonic acids (750 μ M) immediately, making the arachidonic acid ultimate density is 30 μ M.Then each plate was cultivated 15 minutes, after this substratum is taken out from each hole of this plate, measuring PGE with the enzyme immunologic test 2(PGE 2) be stored in-20 ℃ before the level.The inhibition drug effect of test compound is expressed as IC 50Value, it is defined as the PGE that this compound makes these cells 2Burst size suppresses 50% required concentration.The inhibition selectivity ratios of COX-1 and COX-2 is the IC by more separately 50Value is calculated.
For The compounds of this invention, obtained following COX-2 and COX-1 and suppressed IC 50Value:
Instance number COX-2：1C 50(nM) ??COX-1：1C 60(nM)
????1 ????428 ????＞100,000
????2 ????54 ????＞10,445
????3 ????144 ????＞100,000
????4 ????159 ????＞100,000
????5 ????38 ????＞100,000
????6 ????212 ????＞100,000
????7 ????71 ????＞100,000
????8 ????38 ????＞100,000
????9 ????38 ????＞100,000
????10 ????476 ????＞100,000
????11 ????18 ????6,295
????12 ????142 ????＞100,000
????13 ????275 ????＞100,000
????15 ????750 ????＞100,000
????16 ????650 ????＞100,000

Claims (19)

1. formula (I) compound and pharmaceutically acceptable derivative thereof
Figure A9619440300021
R in the formula 0Represent halogen;
R 1And R 2Be independently selected from H, halogen, C 1-4Alkyl, the C that has one or more fluorine atoms to replace 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Hydroxyalkyl, SC 1-4Alkyl, C (O) H or C (O) C 1-4Alkyl; With
R 3Represent C 1-4Alkyl.
2. the compound described in the claim 1, wherein R 3Represent methylidene.
3. the compound described in the claim 1 or 2, wherein R 0Represent fluorine.
4. any one described compound, wherein R in the claim 1～3 1Represent H, chlorine, bromine, C 1-4Alkyl (as methyl), methyl that 1～3 fluorine atom replaces is arranged (as CH 2F or CF 3), C 1-4Hydroxyalkyl is (as CH 2OH or CH (OH) CH 3), SC 1-4Alkyl is (as SCH 3), C (O) H or C (O) C 1-4Alkyl is (as C (O) CH 3).
5. any one described compound, wherein R in the claim 1-4 2Represent H, chlorine, bromine or C 1-4Alkyl (as methyl).
6. any one described compound, wherein R in the claim 1～5 0Represent fluorine; R 1Represent H, chlorine, bromine, C 1-4Alkyl (as methyl), methyl that 1～3 fluorine atom replaces is arranged (as CH 2F or CF 3), C 1-4Hydroxyalkyl is (as CH 2OH or CH (OH) CH 3), SC 1-4Alkyl is (as SCH 3), C (O) H or C (O) C 1-4Alkyl is (as C (O) CH 3); R 2Represent H, chlorine, bromine or C 1-4Alkyl (as methyl); And R 3Represent methylidene.
7. any one described compound, wherein R in the claim 1～6 0Represent fluorine; R 1Represent H, chlorine, bromine, methyl, CH 2F, CF 3, SCH 3, C (O) H or C (O) CH 3R 2Represent H, bromine or methyl; And R 3Represent methylidene.
8. any one described compound, wherein R in the claim 1～7 1At 8; And R 2At 7, or work as R 1When being other group except that H at 5,6 or 7.
9. any one described compound, wherein R in the claim 1～8 1At 8; And R 2At 7, or work as R 1Be C 1-4During alkyl (as methyl) at 5 or 7.
10. any one described compound, wherein R in the claim 1～9 1Represent C (O) CH 3
11. 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl) imidazo [1,2-a] pyridine and pharmaceutically acceptable derivative thereof.
12. any one described compound in the claim 1～11, its Chinese style (I) compound is hydrochloride, hydrobromate or sulphate form.
13. the preparation technology of any one defined formula (I) compound and pharmaceutically acceptable derivative thereof in the claim 1～12 comprises:
(A) make formula (II) compound or its protected derivative Lg represents a leavings group in the formula, with formula (III) compound or the reaction of its receptor derivative
Figure A9619440300032
Or
(B) make formula (IV) compound or its protected derivative
Figure A9619440300033
With a kind of oxidant reaction; Or
(C) the another kind of compound of a kind of compound of formula (I) and formula (I) transforms mutually; Or
(D) make the protected derivative deprotection of formula (I) compound;
And make randomly that any one prepared formula (I) compound changes into its pharmaceutically acceptable derivative in the technology (A)～(D).
14. a medical composition wherein comprises any one defined formula (I) compound or its pharmaceutically acceptable derivative in the claim 1～12, and fusion one or more physiologically acceptable carrier or vehicle.
15. be used for human body or veterinary drug, any one defined formula (I) compound of claim 1～12 or its pharmaceutically acceptable derivative.
16. be used for the treatment of a kind of illness of suppress transmitting by the COX-2 selectivity, any one defined formula (I) compound or its pharmaceutically acceptable derivative in the claim 1～12.
17. a treatment suffers from a kind of human body of the illness transmitted or method of animal target of being suppressed by the COX-2 selectivity, comprise to a certain significant quantity of described object administration, defined formula (I) compound or its pharmaceutically acceptable derivative in the claim 1～12.
18. any one defined formula (I) compound or its pharmaceutically acceptable derivative are used to make a kind of purposes for the treatment of the therapeutical agent of inflammatory diseases in the claim 1～12.
19. a treatment suffers from the method for the human body or the animal target of inflammatory diseases, this method comprise to a certain significant quantity of described object administration, any one defined formula (I) compound or its pharmaceutically acceptable derivative in the claim 1～12.
CN96194403A 1995-04-04 1996-04-02 Imidazo [1, 2-alpha] pyridine derivatives Pending CN1186492A (en)

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