CN1128029A - Thiazole derivatives as lipoxygenase inhibitors - Google Patents

Thiazole derivatives as lipoxygenase inhibitors Download PDF

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CN1128029A
CN1128029A CN94192895A CN94192895A CN1128029A CN 1128029 A CN1128029 A CN 1128029A CN 94192895 A CN94192895 A CN 94192895A CN 94192895 A CN94192895 A CN 94192895A CN 1128029 A CN1128029 A CN 1128029A
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thiazole
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T·G·C·伯德
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Zeneca Pharmaceuticals
Syngenta Ltd
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention concerns a thiazole derivative of formula (I) wherein Q is 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl or 2-oxo-1,2-dihydroquinolin-6-yl which bears on the nitrogen atom at the 1-position a (1-4C)alkyl substituent; X<1> is thio, sulphinyl or sulphonyl; Ar is thiazolediyl; R<1> is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R<2> and R<3> together form a group of the formula -A<2>-X<2>-A<3>- which together with the carbon atom to which A<2> and A<3> are attached define a ring having 5 or 6 ring atoms, wherein A<2> and A<3>, which may be the same or different, each is (1-3C)alkylene and X<2> is oxy, and which ring may bear one or two (1-4C)alkyl substituents; or a pharmaceutically-acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description

Thiazole derivative as lipoxidase inhibitor
The present invention relates to thiazole derivative, more particularly, relate to thiazole derivative as 5-lipoxygenase (hereinafter being called 5-LO) inhibitor.The invention still further relates to method of the described thiazole derivative of preparation and the new pharmaceutical composition that contains them.The present invention comprises that also described thiazole derivative for example wherein relates to the inflammatory of direct or indirect product of the catalytic arachidonic oxidizing reaction of 5-LO and/or the purposes aspect the allergic disease at the treatment various diseases, and the preparation that is used for the novel drugs of this purposes.
As mentioned above, thiazole derivative hereinafter described is the 5-LO inhibitor, the known oxidizing reaction that participates in conversion of arachidonic acid of described enzyme 5-LO, thus leukotrienes compounds produced through a cascade process, leukotrienes B for example with physiologically active 4(LTB 4) and peptide-lipoid leukotrienes compounds (leukotriene C for example 4(LTC 4) and leukotriene D 4(LTD 4)) and various meta-bolites.
The biosynthesizing contact of leukotrienes compounds and physiological characteristics are summarized in Trends in Pharmacological Sciences, 1986,7,100～103 by G.W.Taylor and S.R.Clarke.Leukotrienes compounds and meta-bolites thereof relate to the generation and the development of various diseases, for example various inflammatories and allergic disease be sacroiliitis (rheumatoid arthritis especially for example, osteoarthritis and gout), gastrointestinal tract inflammation (inflammatory bowel disease especially, ulcerative colitis and gastritis), dermatosis (psoriasis especially, eczema and dermatitis), ocular disorders (especially allergic conjunctivitis and uveitis) and respiratory disease (asthma especially, bronchitis and rhinallergosis), for example relate to various cardiovascular and cerebrovascular diseases (myocardial infarction for example, the formation of atherosclerotic plaque, hypertension, platelet aggregation, angina, apoplexy, reperfusion injury, blood vessel injury (comprising restenosis and peripheral vascular disease)) formation and development, for example relate to the formation of shock or damage illness, described illness for example is burn, toxanemia or postoperative shock or damage illness, for example various bone metabolism diseases are osteoporosis (comprising senile and postclimacteric osteoporosis) for example, Paget ' s disease, metastatic tumor of bone, hypercalcemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormality in the bone metabolism, these pathologies can be attended by rheumatoid arthritis and osteoarthritis.In addition, the leukotrienes compounds because it has the ability of regulating lymphocyte and leukocyte function as the transmission matter of inflammatory diseases.Arachidonic other physiologically active meta-bolitess for example prostanoid and thromboxan compounds are produced arachidonic effect by cyclooxygenase.
In european patent application the 0385662nd and No. 0420511, disclose some Hete rocyclic derivatives and had rejection 5-LO.Particularly, european patent application also relates to 5-LO inhibited Hete rocyclic derivatives for No. 0462812, and wherein disclosed Hete rocyclic derivatives has the following formula structure,
Figure A9419289500071
Ar wherein 2For containing the heteroatomic five-membered ring alkene part that is selected from nitrogen, oxygen and sulphur, for example pyrroles's two bases, furans two bases and thiophene two bases.Wherein disclosed particular compound comprises thiophene two radical derivatives: 4-methoxyl group-4-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl)-thiophene-2-yl] tetrahydropyrans (embodiment 7 wherein); (2S, 4R)-4-methoxyl group-2-methyl-4-[5-(1-methyl-2-sulfo--1,2,3,4-tetrahydroquinoline-6-base sulfenyl)-thiophene-2-yl] tetrahydropyrans (embodiment 12 wherein).
Not open wherein Ar in european patent application the 0462812nd 2Be to contain two compounds that are selected from the heteroatomic five-membered ring alkene part of nitrogen, oxygen and sulphur.Particularly not open wherein Ar 2Compound for thiazole two bases.
Find that disclosed some compound has bad automatic induction character in the european patent application the 0462812nd, promptly can cause the efficient of the described compound of various enzymes metabolisms of animal livers to improve this compound of warm-blooded animal repetitive administration.The result is that existing compound quantity reduces when repeat administration in the animal blood flow, this reduction is for example by the reduction of the peak concentration that is reached (Cmax), is for example bestowed by the animal of the area under a curve (AUC) of time mapping being measured by the concentration of compound after the administration in blood flow perhaps that the reduction of this compound number of times indicates.Compound 4-methoxyl group-4-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiophene-2-yl] tetrahydropyrans has bad automatic sensitivity.
Find that also disclosed some compound is an amorphism in No. the 0462812nd, the european patent application, for example, they perhaps separate as foams with oily or gluey formation.When the preparation of considering a large amount of this compounds, purifying, analysis, processing and preparation, these amorphism compounds are exactly bad.Compound (2S, 4R)-4-methoxyl group-2-methyl-4-[5-(1-methyl-2-sulfo--1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiophene-2-yl] tetrahydropyrans has the undesirable property as thickness oily matter.
The applicant has now found that some thiazole derivative is preferred 5-LO enzyme inhibitors, thereby is the biosynthetic inhibitor of leukotrienes.So these compounds are valuable as therapeutical agent treating aspect allergic conditions for example, psoriasis, asthma, cardiovascular and cerebrovascular disease, inflammatory and arthritis illness and/or the bone metabolism disease (only by or part by one or more leukotrienes compounds mediations).
The invention provides thiazole derivative or its pharmacologically acceptable salt of formula I: Wherein: Q is a 2-oxo-1,2,3,4-tetrahydroquinoline-6-base or 2-oxo-1, and 2-dihydroquinoline-6-base, described group has (1-4C) alkyl substituent on 1 nitrogen-atoms; X 1Be sulphur, sulfinyl or alkylsulfonyl; Ar is thiazole two bases; R 1Be (1-4C) alkyl, (3-4C) alkenyl or (3-4C) alkynyl, and R 2And R 3Can form formula-A together 2-X 2-A 3-group, this group and A 2And A 3The carbon atom that is connected constitutes a ring with 5 or 6 annular atomses, wherein A together 2And A 3Can be identical or different, their respectively do for oneself (1-3C) alkylidene group and X 2Be oxygen, and described ring can have one or two (1-4C) alkyl substituent,
In this manual, general term " alkyl " comprises straight chain and branched-chain alkyl.For example only refer to its straight chain implication specially when " propyl group " and relate to concrete alkyl, relate to concrete branched-chain alkyl and for example only refer to its side chain implication when " sec.-propyl " specially.Similarly regulation is applicable to other general terms.
Self-evidently in addition be, have only certain formula I compound as defined above and can exist with optically-active form or racemic form, comprise any optically-active or racemic form that suppresses the 5-LO performance that have in the definition then of the present invention owing to have one or more unsymmetrical carbons.The synthetic of optically-active form can be undertaken by standard technique of organic chemistry well known in the art, for example by being synthesized by the optically-active raw material or being undertaken by the resolution of racemic form.
Above the suitable meaning of mentioned general term comprise following meaning.
The suitable meaning of Q last existing (1-4C) alkyl substituent is for example methyl, ethyl or propyl group.
When if Ar is thiazole two base, its suitable meaning is for example 2, and 4-thiazole two is basic or 2,5-thiazole two bases.
If R 1During for (1-4C) alkyl, its suitable meaning is for example methyl, ethyl or propyl group; If R 1During for (3-4C) alkenyl, its suitable meaning is for example allyl group; And if R 1During for (3-4C) alkynyl, its suitable meaning is for example 2-propynyl.
If R 2And R 3Form formula-A together 2-X 2-A 3-group, this group and A 2And A 3Connect carbon atom and constitute a ring together, A that can be identical or different then with 5 or 6 annular atomses 2And A 3Suitable meaning when respectively doing for oneself (1-3C) alkylidene group is for example methylene radical, ethylene or trimethylene.The suitable meaning that can be present in (1-4C) alkyl substituent on described 5 or 6 yuan of rings comprises for example methyl and ethyl.
The suitable pharmacologically acceptable salt of The compounds of this invention is for for example having the acid salt of the The compounds of this invention of enough alkalescence, for example with the inorganic or organic acid acid salt that forms of hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or toxilic acid for example.In addition, suitable pharmacologically acceptable salt with enough tart The compounds of this invention be an alkali metal salt (for example sodium salt or sylvite), alkaline earth salt (for example calcium salt or magnesium salts), ammonium salt or with can provide the salt that acceptable cationic organic bases forms on the physiology, the salt that forms with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three (2-hydroxyethyl) amine for example.
Particular compound of the present invention comprises for example thiazole derivative or its pharmacologically acceptable salt of formula I, wherein variable group Q, X 1, Ar, R 1, R 2And R 3Have in these chapters and sections aforementioned or following disclosed meaning to concrete The compounds of this invention:
(a) Q is 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base;
(b) X 1Be sulphur or alkylsulfonyl;
(c) Ar is 2, and 4-thiazole two bases (have X on 2 1Group);
(d) Ar is 2, and 5-thiazole two bases (have X on 2 1Group):
(e) Ar is 2, and 5-thiazole two bases (have X on 5 1Group);
(f) R 1It is methyl; Or
(g) R 2And R 3Form formula-A together 2-X 2-A 3-group, this group and A 2And A 3Connect carbon atom and constitute a ring together, A wherein with 5 or 6 annular atomses 2Be methylene radical or ethylene, A 3Be ethylene and X 2Be oxygen, and this ring can have and is in X 2The methyl substituents of α position.
Preferred The compounds of this invention comprises thiazole derivative or its pharmacologically acceptable salt of formula I: wherein: Q is 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base; X 1Be sulphur or alkylsulfonyl; Ar is 2, and 5-thiazole two bases (have X on 2 1Group); R 1Be methyl, and R 2And R 3Form formula-A together 2-X 2-A 3-group, this group and A 2And A 3The carbon atom that is connected constitutes the ring with 6 annular atomses together, wherein A 2And A 3Ethylene and X respectively do for oneself 2Be oxygen, and this ring can have and is in X 2The methyl substituents of α position.
Further preferred The compounds of this invention comprises thiazole derivative or its pharmacologically acceptable salt of formula I: wherein: Q is 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base; X 1Be sulphur or alkylsulfonyl; Ar is 2, and 5-thiazole two bases (have X on 2 1Group); R 1Be methyl, and R 2And R 3Form formula-CH together 2CH 2OCH (CH 3) CH 2-group.
Particularly preferred The compounds of this invention is following formula I compound: (2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans.
Another aspect of the present invention that the applicant has now found that is that certain compound of the present invention does not have bad automatic sensitivity on sizable degree.Therefore described compound is valuable especially aspect various inflammatories for the treatment of warm-blooded animal and/or allergic disease, does not have the shortcoming that produces as automatic induced result because these compounds.So, for example,, then to do more complicated evaluation to pharmacology and toxicity data if testing compound has shown the automatic induction with quite big degree.In addition, automatically induction may indicate that this may produce adverse influence, for example the deleterious rising aspect the metabolic rate of any medicine of using jointly to generally the inducing of some enzymes.
Another aspect of the present invention that the applicant has found is that some compound of the present invention is a crystalline.Therefore, these compounds are valuable for the occasion that needs its preparation on a large scale.If material forms with crystalline state, then purifying, analysis and the processing to it will become easy.It is for example known that to remove the solvent residues thing from non-crystalline oily mater be difficult.In addition, the preparation of drug combination that comprises crystalline material is carried out according to a conventional method, and for example, described composition can be to be suitable for oral form, for example tablet or capsule; Or for example, be to be suitable for coming the form of administration by inhaling people's method, for example as the powder or the microcrystalline form of fine dispersion.If these materials form with oily, then can hinder selection to its preparation.
Comprising the thiazole derivative of formula I or the The compounds of this invention of its pharmacologically acceptable salt can prepare by any currently known methods that can be used for preparing compound relevant on the structure.Another feature of the present invention has provided described method, and these methods are to be illustrated by following representational example, wherein unless otherwise noted, and Q, X 1, Ar, R 1, R 2And R 3It is in all senses defined to have the front.
(a) with formula Q-X 1-H compound and the coupling of formula II compound suit to carry out in the presence of suitable alkali.
Figure A9419289500131
Wherein Z is one can be by the metathetical group.
Suitable can be by metathetical group Z: for example halogen or sulfonyloxy, for example fluorine, chlorine, bromine, iodine, mesyloxy or toluene-4-sulfonyloxy.
The alkali that is suitable for coupled reaction is: for example basic metal or alkaline earth metal carbonate, (1-4C) alkoxide, oxyhydroxide or hydride, for example yellow soda ash, salt of wormwood, sodium ethylate, butanols potassium, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride KH; Or organo-metallic alkali, for example (1-4C) lithium alkylide, for example n-Butyl Lithium.Described coupled reaction suits at suitable inert solvent or thinner N for example, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone, methyl-sulphoxide, acetone, 1, in 2-glycol dimethyl ether or the tetrahydrofuran (THF) at for example 10～150 ℃, suit or near 100 ℃ temperature range in carry out.
Described reaction can suit for example to carry out under the existence of metal catalyst (for example palladium (O) or copper (I), for example four (triphenyl phosphine) palladium, cuprous chloride or cuprous bromide) at suitable catalyzer.
Formula Q-X 1The starting raw material of-H and formula II can make with the standard method in the organic chemistry.The preparation of described starting raw material is described in the appended non-limiting example.Other essential starting raw materials are by making with the similar method of illustrational method, and these methods are within organic chemist's ordinary skill.
(b) make formula Q-Z compound and the coupling of formula III compound, carry out under the existence of suitable defined suitable alkali in the above, wherein Z is that the front is defined can be by the metathetical group.
Figure A9419289500141
In the suitable defined in the above suitable inert solvent of described coupled reaction, for example 10～150 ℃, suit or near 100 ℃ temperature range in carry out.Described reaction can be carried out in the presence of the catalyzer that suits as defined above aptly.
The starting raw material of formula Q-Z and formula III can obtain by the standard method in the organic chemistry.Other essential starting raw materials make by being similar to illustrational method, and these methods are in organic chemist's ordinary skill.The disclosure that No. the 0420511st, european patent application is particularly related to the preparation of suitable starting raw material.
(c) with formula Q-X 1The organometallic reagent coupling of-Z compound and formula IV, wherein Z be as the front is defined can be by the metathetical group, perhaps if X1 is a sulphur, then Z can be formula Q-X 1-group,
Figure A9419289500142
Wherein M is basic metal or alkaline-earth metal for example lithium or calcium, and perhaps M represents the magnesium halide part in the conventional Grignard reagent.
In suitable defined in the above suitable inert solvent of described coupled reaction or the thinner, for example-80～+ 50 ℃, suit to the temperature range of envrionment temperature, to carry out at-80 ℃.
Formula Q-X 1The preparation of the starting raw material of-Z and formula IV can be undertaken by the standard method in the organic chemistry.Other essential starting raw materials are that illustrational method obtains by being similar to, and these methods are within organic chemist's ordinary skill.The disclosure of foregoing european patent application is particularly related to the preparation of suitable starting raw material.
(d) be that the front is defined can be by the formula R of metathetical group with Z wherein 1-Z alkylation formula V compound carries out under the existence of the suitable defined suitable alkali in front of this alkylation.
Figure A9419289500151
In described the alkylated reaction suitable defined in front suitable inert solvent or thinner, for example-20～+ 70 ℃, suit or near the temperature range of envrionment temperature in carry out.
The starting raw material of formula V can make by the standard method in the organic chemistry.Other essential starting raw materials are to make by the method that is similar to described in front european patent application illustrated.
(e), make Q wherein on described available nitrogen-atoms, have the formula I alkylation of hydrogen atom for making Q wherein has alkyl substituent on available nitrogen-atoms formula I compound.
Suitable alkylating agent is for for example being used for as known in the art any reagent of the available nitrogen-atoms of alkylation, for example, alkylogen, for example (1-4C) alkyl chloride, (1-4C) alkyl bromide or (1-4C) alkyl iodide, these alkylating agents are to react in the presence of the suitable defined alkali in front.Described alkylated reaction is preferably at suitable inert solvent or thinner (N for example, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, acetone, 1,2-glycol dimethyl ether or tetrahydrofuran (THF)) in, for example 10～150 ℃, suit or near the temperature range of envrionment temperature under carry out.
(f) for preparing wherein X 1Be the formula I compound of sulfinyl or alkylsulfonyl, oxidation is X wherein 1Formula I compound for sulphur.
Suitable oxygenant is for example to be used for known in the art any reagent that the oxidation sulfenyl becomes sulfinyl and/or alkylsulfonyl, for example hydrogen peroxide, peracid (for example 3-chlorine peroxybenzoic acid or peracetic acid), alkali metal persulphate (for example permonosulphuric acid potassium), chromium trioxide or the gaseous oxygen in the presence of platinum.Described oxidizing reaction is generally carried out under gentle as far as possible condition, and uses the oxygenant of required stoichiometric amount, so that reduce snperoxiaized danger and to the infringement of other functional groups.In general, described reaction is in The suitable solvent or thinner (for example methylene dichloride, chloroform, acetone, tetrahydrofuran (THF) or t-butyl methyl ether), for example in envrionment temperature or the temperature range near envrionment temperature, promptly carries out in 15～35 ℃ of temperature ranges.If need have the compound of sulfinyl, then also can use relatively mild oxygenant, for example sodium metaperiodate or potassium suit for example to carry out in acetate or the ethanol at polar solvent.Should be appreciated that if need contain the formula I compound of alkylsulfonyl, then can prepare by corresponding sulfinyl compound of oxidation and corresponding sulfur-based compound.
If need the pharmacologically acceptable salt of formula I new compound, then can be for example by described compound and the acid or the alkali reaction that suit are made.If need the optically-active form of formula I compound, then can be by adopting a kind of optically-active starting raw material to carry out a kind of aforesaid operations or obtaining by the racemic modification that adopts ordinary method to split described compound.
As previously mentioned, formula I compound is the 5-LO enzyme inhibitors.This inhibiting effect can prove with following one or more standard methods:
A) external test system, it is included in before Calcium ionophore A 23187 attacks, testing compound is incubated with the human blood of heparinization, pass through then by Carey and Forder described specificity radioimmunoassay (F.Carey and R.A.Forder, Prostaglandins, Leukotrienes Med., 1986,22,57; Prostaglandins, 1984,28,666; Brit.J.Pharmacol.1985,84,34P) measure the restraining effect of the indirect measurement of amount of LTB4 to 5-LO, described radioimmunoassay comprises use protein-LTB 4The yoke zoarium, the latter is made by the method (Prostaglandins, 1983,26 (4), 605～613) of using Young et alia.Testing compound can used specificity radioimmunoassay method thromboxan B to the influence of cyclooxygenase (described cyclooxygenase has participated in arachidonic another kind of pathways metabolism and produced prostanoid, thromboxan compounds and relevant meta-bolites) 2(TxB 2) (by Carey and the described method of Forder, document as mentioned above) time measures.This test provide hemocyte and proteinic in the presence of testing compound to the indication of the effect of 5-LO and cyclooxygenase.This feasible inhibiting selectivity that can estimate 5-LO or cyclooxygenase.
B) isolated measuring system, it is above-mentioned test variant a), comprise one group of rat is used testing compound (Orally administered with suspension usually, this suspension is to produce), collects blood, heparinization, attacks and radioimmunoassay LTB with A 23187 when the dimethyl sulfoxide solution with testing compound is added in the carboxymethyl cellulose 4And TxB 2This test provides the indication as the bioavailability of the testing compound of 5-LO or cyclooxygenase-2 inhibitors.
C) system in the body, comprise measurement to the Orally administered testing compound of one group of male rat to LTB 4The effect of release, this LTB 4Be to bring out by the zymosan in the air bag that in the subcutis of every rat back of the body, produces.With rat anesthesia, and by injection sterile air (20ml) formation air bag.After 3 days, inject air (10ml) equally once more.After initial air is injected 6 days, use testing compound (Orally administered as suspension usually, this suspension is to produce) when the dimethyl sulfoxide solution with testing compound is added in the Vltra tears, follows intracapsular injection zymosan (physiological salt liquid of the suspension of 1ml 1%).After 3 hours, kill rat, air bag physiological saline lavation is with the LTB in the above-mentioned specificity radioimmunoassay mensuration washings 4This test provides in the inflammatory environment the inhibiting indication to 5-LO.
Although the pharmacological properties of formula I compound, just according to expectation is such, changes with structural changes, and generally speaking, formula I compound has the 5-LO restraining effect at least a above-mentioned test a)～c) when following concentration or dosage:
Test a): IC 50(LTB 4) concentration range for example is 0.01～40 μ M
IC 50(TxB 2) concentration range for example is 40～200 μ M;
Test b): oral ED 50(LTB 4) concentration range for example is 0.1～100mg/kg;
Test c): oral ED 50(LTB 4) concentration range for example is 0.1～100mg/kg.
When formula I compound when using, at test b times over its MID or concentration) and/or c) in do not have tangible toxicity or other unsuitable effects.
Therefore, for example compound (2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans resists LTB in test a) 4IC 50Be 0.06 μ M, and at test c) in resist LTB 4IC 50Be approximately 0.2mg/kg.
These compounds are to show the The compounds of this invention of 5-LO with respect to the selection rejection of cyclooxygenase, described selection inhibition is expected to give the curative properties of improvement, for example, usually with cyclooxygenase-2 inhibitors reducing or eliminating of the relevant gastrointestinal side effect of INDOMETHACIN for example.
Another feature of the present invention has provided a kind of pharmaceutical composition, and this pharmaceutical composition comprises thiazole derivative or its pharmacologically acceptable salt of formula I, and pharmaceutically acceptable diluent or carrier.
Described composition can be for being suitable for Orally administered form, for example tablet, capsule, the aqueous solution or oily solution, suspension or emulsion; Be suitable for the form of topical application, for example creme, ointment, gelifying agent or water or oily solution or suspension; Be suitable for the form of nasal administration, for example smell agent, nasal spray or nasal drop; Be suitable for the form of sheath usefulness or rectal administration, for example suppository; Be suitable for by inhaling the form that people's method is used, for example pulvis of fine dispersion, for example dry powder doses, microcrystalline form or liquid aerosol; Be suitable for the form that hypogloeeis or cheek are used, for example tablet or capsule; Or (comprise in intravenously, subcutaneous, intramuscular, the blood vessel or infusion the is used) form that is suitable for that parenteral uses, for example aseptic water or oily solution or suspension.In a word, above-mentioned composition can adopt conventional excipients to prepare in the usual way.
The consumption of activeconstituents (be the thiazole derivative of formula I, or its pharmacologically acceptable salt) promptly combines the amount that produces the single dose form with one or more vehicle, inevitablely change with host who is treated and concrete route of administration.For example, the preparation that human oral is used generally contains for example active agents of 0.5mg to 2g and the mixed with excipients of sufficient quantity, and the vehicle of described sufficient quantity is meant and accounts for about 5～about 98% of whole composition weights.Dosage unit form generally contains about 1mg to about 500mg activeconstituents.
Further aspect of the present invention has provided thiazole derivative or its pharmacologically acceptable salt of the formula I that is used for the method for human or animal body being treated by therapeutics.
The present invention comprises that also treatment wholly or in part by the disease of one or more leukotrienes compounds mediations or the method for medical conditions, comprises the above-mentioned activeconstituents of the warm-blooded animal of the described treatment of needs being used significant quantity.The present invention also provides the purposes aspect this activeconstituents is used for the disease of leukotrienes mediation or medical conditions in preparation the novel drugs.
The treatment of formula I compound or prevention will change with the character of illness and severity, animal or patient's age and sex and route of administration according to known medicine principle with the size of dosage.As mentioned above, the disease that formula I compound can be used for treating has, for example the bone metabolism illness and the disease of allergy and inflammatory, this illness and disease are completely or partially arachidonic owing to what cause because of linear (5-LO is catalytic) approach, and the effect of the meta-bolites of the leukotrienes compounds that is particularly produced by the 5-LO mediation causes.Such just as previously mentioned, this illness comprises for example sacroiliitis (rheumatoid arthritis especially of for example various inflammatories and allergic disease, osteoarthritis and gout), gastrointestinal tract inflammation (inflammatory bowel disease especially, ulcerative colitis and gastritis), dermatosis (psoriasis especially, eczema and dermatitis), ocular disorders (especially allergic conjunctivitis and uveitis) and respiratory disease (asthma especially, bronchitis and rhinallergosis), for example relate to various cardiovascular and cerebrovascular diseases (myocardial infarction for example, the formation of atherosclerotic plaque, hypertension, platelet aggregation, angina, apoplexy, reperfusion injury, blood vessel injury (comprising restenosis and peripheral vascular disease)) formation and development, for example relate to the formation of shock or damage illness, described illness for example is burn, toxanemia or postoperative shock or damage illness, for example various bone metabolism diseases are osteoporosis (comprising senile and postclimacteric osteoporosis) for example, Paget ' s disease, metastatic tumor of bone, hypercalcemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormality in the bone metabolism, these pathologies can be attended by rheumatoid arthritis and osteoarthritis.
When formula I compound was used for the treatment of or prevents purpose, the per daily dose of its general administration was in for example 0.5mg～75mg/kg weight range, in case of necessity with the fractionated dose administration.If adopt the parenteral approach, the general lower dosage of administration.Therefore, for example for intravenous administration, the general dosage that adopts is in the scope of for example 0.5mg～30mg/kg body weight.Equally, for passing through the inhalation administration, the dosage that is adopted is in the scope of for example 0.5mg～25mg/kg body weight.
Although formula I compound is used for warm-blooded animal (comprising the people) mainly as therapeutical agent, they also can be used to suppress the 5-LO enzyme at any time because of needs.Therefore, they can be used as the pharmacology standard substance and are used to set up new biological test and are used to seek new pharmacological reagent.
Based on of the effect of described compound to the leukotrienes generation; formula I compound has some cytoprotection; for example they can be used to reduce or suppress to suppress certain disadvantageous gi tract effect, for example INDOMETHACIN, acetylsalicylic acid, Ibuprofen BP/EP, sulindac, TOL and piroxicam of anti-inflammatory agent (NSAIA) of the on-steroidal of cyclooxygenase.In addition, can cause needs to produce the reduction of amount of the NSAIA reagent of result of treatment with the NSAIA administration in the 5-LO inhibitor of formula I, thereby reduce issuable side effect.Another feature of the present invention has provided a kind of pharmaceutical composition, defined its pharmacologically acceptable salt of thiazole derivative or front that comprises formula I, and with it in conjunction with or non-steroidal anti-inflammatory agents (for example above-mentioned anti-inflammatory agent) and the pharmaceutically acceptable diluent or the carrier of the inhibition cyclooxygenase of fusion.
The cytoprotection of formula I compound can for example be confirmed in the standard laboratory model, and described model has for the provide protection of rat gastrointestinal tract because of INDOMETHACIN inductive or alcohol induced ulcer.
The present composition can also contain one or more known treatment or preventives that the disease of being treated is had value.Therefore, for example known anticoagulant, hypolipidemia agent, hypotensive agent, beta-adrenergic resistance preparation or vasodilator also can be present in the pharmaceutical composition of the present invention that is used for the treatment of heart or vascular disease or illness, equally, for example, antihistaminic, steroidal (for example beclomethasone dipropionate), Sodium Cromoglicate, phosphodiesterase inhibitor or beta-adrenergic energizer also can be present in the pharmaceutical composition of the present invention that is used for the treatment of tuberculosis or illness.
The present invention describes with following non-limiting examples now, wherein unless otherwise noted:
(i) evaporation is undertaken by rotary evaporation under vacuum, and post-processing operation is carried out after removing by filter residual solid;
(ii) operation is at room temperature, promptly for example carries out under the argon gas atmosphere in 18～25 ℃ of scopes, at rare gas element;
(iii) column chromatography (being undertaken by dodging the formula method) and medium pressure liquid chromatography method (MPLC) are from E.Merck, Darmstadt carries out on Merck Kieselgelsilica (Art.9385) that Germany obtains or Merck Lichroprep RP-18 (Art.9303) reverse phase silica gel;
(iv) productive rate only provides for explanation, their of course not accessible maximum values;
(v) the final product of formula I has gratifying trace analysis result, and its structure is proved conclusively with nucleus magnetic resonance (NMR) and mass-spectrometric technique; Unless otherwise noted, use the CDCl of the final product of formula I 3Measured in solution NMR spectroscopic data, chemical displacement value is measured with the δ scale; Used following abbreviation: s, unimodal; D, doublet; T, triplet; M, multiplet;
(vi) intermediate is not generally identified fully, and its purity is analyzed by tlc, far infrared (IR) or NMR and estimated;
(vii) fusing point is not calibrated, measures on automatic fusing point instrument of Mettler SP62 or oil bath device; The fusing point of the final product of formula I is for example being measured behind ethanol, methyl alcohol, acetone, ether or hexane or its crystalline mixture with conventional organic solvent; With
(viii) used following abbreviation:
NMP N-methylpyrrolidin-2-ketone;
The THF tetrahydrofuran (THF);
DMF N, dinethylformamide.
Embodiment 1
With 6-sulfydryl-1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-2-ketone (0.166g) joins in the mixture of 4-(2-diuril azoles-5-yl)-4-methoxyl group tetrahydropyrans (0.2g), salt of wormwood (0.13g) and NMP (2ml).Mixture is stirred and be heated to 100 ℃, under this temperature, kept 3 hours.Mixture is cooled to envrionment temperature, and is allocated between ethyl acetate and the water.Organic phase salt water washing, drying (MgSO 4), and the evaporation.Resistates carries out purifying with the sherwood oil (b.p.40～60 ℃) and the mixture of ethyl acetate that column chromatography adopted 1: 1 as eluent.Thereby make 4-methoxyl group-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans (0.25g); M.p.114～115 ℃ (using ethyl alcohol recrystallization);
NMR spectrum 1.97-2.01 (m, 4H), 2.69 (m, 2H), 2.94 (m, 2H), 3.05 (s,
3H)，3.38(s，3H)，3.7-3.8(m，4H)，7.02-7.04(d，1H)，7.45(s，1H)，
7.46-7.47(d，1H)，7.55-7.58(m，1H).
As the 6-sulfydryl-1-methyl isophthalic acid of starting raw material, 2,3,4-tetrahydroquinoline-2-ketone is following making:
The mixture of concentrated hydrochloric acid (5) and water (5ml) is added to two-(1-methyl-2-oxo-1,2,3, the 4-tetrahydroquinoline-6-yl) disulphide (embodiment 7 of european patent application No.0462812 that stirring; 38.4g), triphenyl phosphine (29g) and 1, in the mixture of 4-diox (300ml).This mixture was stirred 30 minutes at ambient temperature, and it is only about half of that evaporation concentration reduces its volume.Resistates is allocated in ethyl acetate and the 0.5 N aqueous sodium hydroxide solution.Water washs with ether, and adding diluted hydrochloric acid aqueous solution then, to be acidified to the pH value be 2.This acidic mixture ethyl acetate extraction.Organic phase drying (MgSO 4) and evaporation.Remaining oily matter is dissolved in the ether, adds hexane.Thereby obtain 6-sulfydryl-1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-2-ketone is solid (35.5g, 92%), it must not be further purified when using.
4-(2-diuril azoles-5-yl)-4-methoxyl group tetrahydropyrans as starting raw material can followingly make:
Saturated Sodium Nitrite (6.9 g) aqueous solution is added drop-wise in the solution that is stirring of concentrated hydrochloric acid (50ml) of the thiazolamine (10g) that is cooled to 0 ℃.Mixture was stirred 75 minutes at 0 ℃.Add cuprous chloride (9.9g) in batches, during temperature of reaction is remained on 0 ℃, mixture was stirred 2.5 hours.Add 10N aqueous sodium hydroxide solution this mixture that neutralizes.And mixture is allocated in ether and the water.Organic phase salt water washing, dry (MgSO 4) and evaporation.Resistates distillation method purifying.Thereby obtain 2-diuril azoles (3.95g, b.p.68 ℃/68mmHg).
(the 2.5M hexane solution 1.8ml) joins in the ether (5ml) that is cooled to-78 ℃ simultaneously with ether (4ml) solution of 2-diuril azoles (0.5g) and n-Butyl Lithium.This mixture is stirred and be warmed to-20 ℃.Drip ether (5ml) solution of tetrahydrofuran (THF)-4-ketone (0.42g).Mixture was stirred 1 hour, and be warmed to 0 ℃, be warmed to envrionment temperature then.Mixture is allocated in ether and the saturated aqueous ammonium chloride.Organic phase salt water washing, dry (MgSO 4) and evaporation.Resistates carries out purifying with the sherwood oil (b.p.40～60 ℃) and the mixture of ethyl acetate that column chromatography adopted 1: 1 as eluent.Thereby make 4-(2-diuril azoles-5-yl)-4-hydroxy tetrahydro pyrans (0.25g, 27%), m.p.94 ℃.
Sodium hydride [0.045g (remove mineral oil dispersion agent then make)] is joined in THF (1.5ml) solution of 4-(2-diuril azoles-5-yl)-4-hydroxy tetrahydro pyrans (0.2g), and this mixture was stirred 1 hour at ambient temperature.Add methyl-iodide (0.17ml), and mixture was stirred 12 hours at ambient temperature.With the mixture evaporation, resistates is assigned in ether and the salt solution, organic phase drying (MgSO 4) and evaporation.Resistates carries out purifying through the sherwood oil (b.p.40～60 ℃) and the mixture of ethyl acetate that column chromatography adopted 1: 1 as eluent.Thereby make 4-(2-diuril azoles-5-yl)-4-methoxyl group tetrahydropyrans (0.2g, 94%), be oily matter.
Embodiment 2
3-chlorine peroxybenzoic acid (0.141g) is joined 4-methoxyl group-4-[2-of stirring (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] in methylene dichloride (1.5ml) solution of tetrahydropyrans (0.08g).Mixture was stirred 5 hours at ambient temperature.Add saturated sodium hydrogen carbonate solution, with the mixture ethyl acetate extraction.Organic phase salt water washing, dry (MgSO 4) and evaporation.Thereby make 4-methoxyl group-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base alkylsulfonyl) thiazole-5-yl] tetrahydropyrans (0.071g); M.p.163～164 ℃ (using ethyl alcohol recrystallization);
NMR spectrum 2.03-2.05 (m, 4H), 2.70 (m, 2H), 3.0 (m, 2H), 3.1 (s,
3H)，3.38(s，3H)，3.78-3.81(m，4H)，7.12(d，1H)，7.73(s，1H)，7.9
(m，1H)，7.98-8.0?1(m，1H).
Embodiment 3
Adopt and embodiment 1 described similar method, make 6-sulfydryl-1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-2-ketone is with (2S 4R)-4-(2-diuril azoles-5-yl)-4-methoxyl group-reaction of 2-methyl tetrahydropyrans, makes (2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methoxyl group-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans, productive rate 95% is foams;
NMR spectrum 1.16-1.18 (d, 3H), 1.54-1.57 (m, 1H), 1.81-2.02 (m, 3H),
2.67-2.71(m，2H)，2.92-2.96(m，2H)，3.04(s，3H)，3.38(s，3H)，
3.77-3.82(m，3H)，7.02-7.04(d，1H)，7.42(s，1H)，7.46(m，1H)，7.56(m，1H).
As starting raw material (2S, 4R)-4-(2-diuril azoles-5-yl)-4-methoxyl group-2-methyl tetrahydropyrans is following making:
(the 2.5M hexane solution 1.8ml) joins in the ether (5ml) that is cooled to-78 ℃ simultaneously with ether (4ml) solution of 2-diuril azoles (0.5g) and n-Butyl Lithium in 10 minutes.This mixture was stirred 3.5 hours, and be warmed to-20 ℃.This mixture is cooled to-78 ℃ again, adds (2S)-2-methyl Tetrahydro-pyran-4-one [european patent application No.0385662 (embodiment 20); 0.43g] ether (4ml) solution.This mixture is stirred, and be warmed to-10 ℃.Add 5% aqueous ammonium chloride solution, the mixture extracted with diethyl ether.Organic phase salt water washing, drying (MgSO 4) and evaporation.Resistates is made the eluent purifying through the sherwood oil (b.p.40～60 ℃) and the mixture of ethyl acetate that column chromatography adopted 1: 1.Thereby obtain (2S, 4R)-4-(2-diuril azoles-5-yl)-4-hydroxy-2-methyl tetrahydropyrans (0.11g, 13%), be oily matter.
(0.127g 5.27mmol) is added in THF (2.5ml) solution of resulting 4-hydroxy-2-methyl tetrahydropyrans, and this mixture was stirred 1 hour at ambient temperature with sodium hydride.This mixture is cooled to 0 ℃, adds methyl-iodide (0.33ml).This mixture was stirred 2.5 hours at ambient temperature.Evaporating mixture is allocated in resistates in ether and the salt solution.Organic phase drying (MgSO 4) and evaporation.Resistates is carried out purifying with sherwood oil (b.p.40～60 ℃) and the ethyl acetate mixture that column chromatography adopted 1: 1 as eluent.Thereby make (2S, 4R)-4-(2-diuril azoles-5-yl)-4-methoxyl group-2-methyl-tetrahydropyrans (0.268g, 71%), be oily matter, produce crystallization through placing.
Embodiment 4
Employing is similar to embodiment 2 described methods, will (2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans be oxidized to (2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base alkylsulfonyl) thiazole-5-yl] tetrahydropyrans, productive rate 98% is foams;
NMR spectrum 1.18-1.20 (d, 3H), 1.61-1.65 (m, 1H), 1.94-2.10 (m, 3H),
2.68-2.72(m，2H)，2.98-3.02(m，2H)，3.09(s，3H)，3.38(s，3H)，
3.81-3.87(m，3H)，7.11-7.13(d，1H)，7.71(s，1H)，7.89-7.90(m，1H)，
7.98-8.01(m，1H).
Embodiment 5
Salt of wormwood (15.5g) is added to 6-sulfydryl-1-methyl isophthalic acid, 2,3, in NMP (140ml) solution of 4-tetrahydroquinoline-2-ketone (19.7g), and this mixture stirred 10 minutes at ambient temperature.Add that (2S 4R)-4-(2-diuril azoles-5-yl)-4-methoxyl group-2-methyl-tetrahydropyrans (25.2 g), and stirs this mixture and is heated to 100 ℃, keeps 2 hours under this temperature.This mixture is cooled to envrionment temperature, and is distributed between ether and the water.Organic phase water and salt water washing, dry (MgSO 4) and evaporation.Resistates obtains crystalline solid with the ether development.Thereby make (2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans (37.5g, 91%), m.p.78～79 ℃ (by the ether recrystallization).
As starting raw material (2S, 4R)-4-(2-diuril azoles-5-yl)-4-methoxyl group-2-methyl tetrahydropyrans is following making:
In 30 minutes, (the 2.5M hexane solution 57.5ml) is added drop-wise in THF (180ml) solution of the Diisopropylamine that is cooled to-78 ℃ with n-Butyl Lithium.This mixture was stirred 1 hour at-78 ℃.The reaction vessel lucifuge to wherein dripped 2-diuril azoles (15.0g) in 20 minutes, keeps the temperature of reaction mixture to be lower than-70 ℃ simultaneously.This mixture was stirred 1.5 hours at-78 ℃.In 20 minutes, add (2S)-2-methyl Tetrahydro-pyran-4-one (12.9g).Stir this mixture, and be warmed to-25 ℃ rapidly, obtain a kind of homogeneous solution.This mixture is cooled to-70 ℃ again, and under this temperature, stirred 1 hour.Add 5% aqueous ammonium chloride solution, the mixture extracted with diethyl ether.Organic solution salt water washing, dry (MgSO 4), and evaporation.Thereby make (2S, 4R)-4-(2-diuril azoles-5-yl)-4-hydroxy-2-methyl tetrahydropyrans and corresponding (2S, 4S)-1: 4 the mixture (29.4g) of isomer.The gained mixture is dissolved in the ether (250ml), solution is cooled to 0 ℃.Add dense (25%V/V) aqueous sulfuric acid, and stir the mixture, be warmed to envrionment temperature.This mixture was stirred 16 hours at ambient temperature, and mixture is neutralized to pH3 with ethyl acetate (750ml) dilution by adding sodium bicarbonate.Organic solution salt water washing, dry (MgSO 4) and evaporation obtain (2S, 4R)-4-(2-diuril azoles-5-yl)-4-hydroxy-2-methyl tetrahydropyrans and corresponding (2S, 4S)-9: 1 the mixture (26g) of isomer.This material adopts sherwood oil (b.p.40～60 ℃) and 1: 1 mixture of ethyl acetate to carry out purifying as eluent with column chromatography.Thereby make (2S, 4R)-4-(2-diuril azoles-5-yl)-4-hydroxy-2-methyl tetrahydropyrans (21g, 79%).
In 15 minutes, with sodium hydride (60% mineral oil dispersion, 14.5g, 0.36mol) gradation be added to be cooled to 0 ℃ (2S, 4R)-THF (150ml) solution of 4-(2-diuril azoles-5-yl)-4-hydroxy-2-methyl tetrahydropyrans (42.15g) in.This mixture was stirred 45 minutes at 0 ℃.Drip methyl-iodide (22.5ml), stir this mixture and in 2 hours, be warmed to envrionment temperature.This mixture is cooled to 0 ℃ again, adds salt brine solution.This mixture ethyl acetate extraction.Organic solution salt water washing, drying (MgSO 4) and evaporation.Resistates adopts sherwood oil (b.p.40～60 ℃) and 7: 3 mixtures of ethyl acetate to make the eluent purifying through column chromatography.Thereby make (2S, 4R)-4-(2-diuril azoles-5-yl)-4-methoxyl group-2-methyl tetrahydropyrans (40.9g, 91%), m.p.40～42 ℃.
Embodiment 6
Employing is similar to embodiment 1 described method, and different is the potassiumiodide that adds catalytic amount (0.01g), makes 6-sulfydryl-1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-2-ketone and 4-(2-diuril azoles-5-yl)-4-methoxyl group-2, the reaction of 2-dimethyl tetrahydro pyrans makes 4-methoxyl group-2,2-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans, productive rate is 80%, is foams;
NMR spectrum 1.2 (s, 3H), 1.4 (s, 3H), 1.6-1.75 (m, 2H), 1.9-2.0 (m,
2H)，2.70(m，2H)，2.95(m，2H)，3.02(s，3H)，3.4(s，3H)，3.65(m，
1H)，3.95(m，1H)，7.03(m，1H)，7.42(s，1H)，7.46(m，1H)，7.55(m，
1H).
As 4-(2-diuril azoles-5-the yl)-4-methoxyl group-2 of starting raw material, 2-dimethyl tetrahydro pyrans is prepared as follows:
With ether (8ml) solution of 2-diuril azoles (0.75g) and n-Butyl Lithium (the 1.4M hexane solution, 4.5ml) simultaneously but join respectively in the ether (8ml) that is cooled to-80 ℃.This mixture was stirred 10 minutes at-75 ℃, be warmed to-30 ℃ then.This mixture is cooled to-80 ℃ again, and adds 2, ether (5ml) solution of 2-dimethyl tetrahydro pyrans-4-ketone (0.76g).Stir the mixture, and be warmed to-30 ℃.This mixture is poured in the mixture of ice and saturated aqueous ammonium chloride.Organic solution salt water washing, drying (MgSO 4) and evaporation.Resistates adopts the mixture (10: 3) of hexane and ethyl acetate to make the eluent purifying with column chromatography.Thereby make 4-(2-diuril azoles-5-yl)-4-hydroxyl-2,2-dimethyl tetrahydro pyrans (0.67g, 46%) is oily matter;
NMR spectrum 1.2 (s, 3H), 1.45 (s, 3H), 1.8-2.15 (m, 4H), 3.75 (m,
1H)，4.1(m，1H)，7.38(s，1H).
Employing is similar to the method for preparation described in the final stage of embodiment 3 parts, that relate to starting raw material, different is to replace THF to make reaction solvent with DMF, with prepared 4-hydroxyl-2,2-dimethyl tetrahydro pyrans methylates, make 4-(2-diuril azoles-5-yl)-4-methoxyl group-2,2-dimethyl tetrahydro pyrans, productive rate 79% is oily matter.
Embodiment 7
With sodium hydride (60% mineral oil dispersion, 0.06g) join the 4-hydroxyl-2 that is stirring that has been cooled to 0 ℃, 6-dimethyl-4-[2-(1-methyl-2-oxo-1,2 in batches, 3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] in DMF (2ml) solution of tetrahydropyrans (0.27g).Mixture was stirred 30 minutes at 0 ℃.Add methyl-iodide (0.2ml).This mixture is warmed to envrionment temperature, and stirred 16 hours.This mixture is distributed in ethyl acetate and the saturated aqueous ammonium chloride.Organic solution salt water washing, drying (MgSO 4) and evaporation.Adopt the mixture that increases polar hexane and ethyl acetate gradually to carry out purifying with column chromatography resistates as eluent.Thereby make 4-methoxyl group-2,6-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans (0.063g), be jelly;
NMR spectrum 1.15 (d, 3H), 1.4 (d, 3H), 1.65 (m, 2H), 1.9-2.1 (m, 2H),
2.70(m，2H)，2.95(m，2H)，3.05(s，3H)，3.37(s，3H)，4.1(m，2H)，
7.03(m，1H)，7.40(s，1H)，7.47(m，1H)，7.55(m，1H).
As the 4-hydroxyl-2 of starting raw material, 6-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans is prepared as follows:
The method of the preparation that repetition is described first section of embodiment 6 parts, relate to starting raw material, different is 2,6-dimethyl tetrahydro pyrans-4-ketone replaces 2,2-dimethyl tetrahydro pyrans-4-ketone.Thereby make 4-(2-diuril azoles-5-yl)-4-hydroxyl-2,6-dimethyl tetrahydro pyrans, productive rate 77%.
NMR spectrum 1.2 (s, 3H), 1.5 (s, 3H), 1.7-2.0 (m, 3H), 2.16 (m, 2H),
4.2(m，2H)，7.38(s，1H).
With 6-sulfydryl-1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-2-ketone (0.32g), 4-(2-diuril azoles-5-yl)-4-hydroxyl-2, the mixture of 6-dimethyl tetrahydro pyrans (0.3 g), salt of wormwood (0.33g), potassiumiodide (0.01g) and DMF (3ml) stirs and is heated to 100 ℃, keeps under this temperature 4 hours.This mixture is cooled to envrionment temperature, and is allocated in acetate ethanol and the saturated aqueous ammonium chloride.Organic solution salt water washing, drying (MgSO 4) and evaporation.Resistates increases the polar hexane gradually with the column chromatography employing and ethyl acetate mixture is made the eluent purifying.Thereby make 4-hydroxyl-2,6-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans (0.26 g, 53%), be foams;
NMR spectrum 1.2 (s, 3H), 1.5 (s, 3H), 1.7-1.9 (m, 3H), 2.15 (m, 1H),
2.66(m，1H)，2.95(m，2H)，3.39(s，3H)，4.18(m，2H)，7.0(d，1H)，
7.5(m，2H)，7.55(m，1H).
Embodiment 8
Employing is similar to embodiment 1 described method, and different is to have added triphenyl phosphine (0.04g), makes 6-sulfydryl-1-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-2-ketone (0.153g) and (2S, 4R)-4-(5-bromo thiazole-2-yl)-4-methoxyl group-2-methyl-tetrahydropyrans (0.23g) reaction, make (2S, 4R)-4-methoxyl group-2-methyl-4-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazol-2-yl]-tetrahydropyrans, productive rate 72% is foams;
NMR spectrum 1.15-1.20 (d, 3H), 1.60 (m, 1H), 1.90-2.05 (m, 3H),
2.65-2.75(m，2H)，2.90-3.00(m，2H)，3.05(s，3H)，3.4(s，3H)，
3.75-3.85(m，3H)，7.05(d，1H)，7.4(s，1H)，7.45(m，1H)，7.55
(m，1H).
As starting raw material (2S, 4R)-4-(5-bromo thiazole-2-yl)-4-methoxyl group-2-methyl-tetrahydropyrans is following obtaining:
With 2, ether (3ml) drips of solution of 5-two bromo thiazoles (2g, J.Chem.Soc., Perkin Trans.I, 1992,215～219) is added to and is cooled to-100 ℃ n-Butyl Lithium, and (hexane solution of 2.5 M is in ether 3.7ml) (80ml) solution.This mixture was stirred 5 minutes, add (2S)-2-methyl Tetrahydro-pyran-4-one (0.845g), the temperature that keeps reaction mixture simultaneously is at-100 ℃.This mixture was stirred 45 minutes, and make reaction terminating with the aqueous solution of 5% ammonium chloride.The salt water washing is used in extracted with diethyl ether 2 times of this mixture, dry (MgSO 4), filter and evaporation.This oily matter adopts 1: 1 the sherwood oil and the mixture of ethyl acetate to make the eluent purifying with column chromatography.Thereby make buttery (2S, 4S)-and (2S, 4R)-mixture (1.177g, 46%) of 4-(5-bromo thiazole-2-yl)-4-hydroxy-2-methyl tetrahydropyrans.
Gained mixture (1g) is dissolved in the ether (15ml), and solution is cooled to 0 ℃.Add dense (30%V/V) aqueous sulfuric acid (10ml), this mixture is stirred, and be warmed to envrionment temperature.This mixture was stirred 16 hours at ambient temperature.Mixture is by adding the sodium bicarbonate neutralization, and with extracted with diethyl ether 3 times, uses the salt water washing, drying (MgSO 4), filter and evaporation.This oily matter adopts 1: 1 the sherwood oil and the mixture of ethyl acetate to make the eluent purifying with column chromatography.Thereby make (2S, 4R)-4-(5-bromo thiazole-2-yl)-4-hydroxy-2-methyl tetrahydropyrans, be solid (0.707g, 70%).
With sodium hydride (60% mineral oil dispersion, 0.045g, 0.0018mol) join be cooled to 0 ℃ (2S, 4R)-THF (2.5ml) solution of 4-(5-bromo thiazole-2-yl)-4-hydroxy-2-methyl tetrahydropyrans (0.25g) in.This mixture was stirred 45 minutes at 0 ℃.Drip methyl-iodide (0.13ml) and, in 2 hours, be warmed to envrionment temperature this mixture stirring.Add salt brine solution, organic solution ethyl acetate extraction, dry (MgSO 4), filter and evaporation.This oily matter adopts 1: 2 the sherwood oil and the mixture of ethyl acetate to make the eluent purifying with column chromatography.Thereby make (2S, 4R)-4-(5-bromo thiazole-2-yl)-4-methoxyl group-2-methyl tetrahydropyrans, be oily matter (0.233g, 89%).
Embodiment 9
The following describes be used for the treatment of or prevent that human body is used, contain the formula I compound or pharmaceutically acceptable salt thereof representational pharmaceutical dosage forms of (hereinafter claiming compounds X): (a) tablet I mg/ sheet
Compounds X 100
Lactose Ph.Eur 182.75
Croscarmellose?sodium 12.0
Corn starch paste (5%w/v paste) 2.25
Magnesium Stearate 3.0 (b) tablet II mg/ sheet
Compounds X 50
Lactose Ph.Eur 223.75
Croscarmellose?sodium 6.0
W-Gum 15.0
Polyvinylpyrrolidone (5%w/v paste) 2.25
Magnesium Stearate 3.0 (c) tablet III mg/ sheet
Compounds X 1.0
Lactose Ph.Eur 93.25
Croscarmellose?sodium 4.0
Corn starch paste (5%w/v paste) 0.75
Magnesium Stearate 1.0 (d) capsule mg/ capsule
Compounds X 10
Lactose Ph.Eur 488.5
Magnesium Stearate 1.5 (e) injection I (50mg/ml)
Compounds X 5.0%w/v
1M sodium hydroxide solution 15.0%v/v
0.1M hydrochloric acid
(transferring to pH 7.6)
Poly(oxyethylene glycol) 400 4.5%w/v
Water for injection adds to 100% (f) injection II (10mg/ml)
Compounds X 1.0%w/v
Sodium phosphate BP 3.6%w/v
0.1M sodium hydroxide solution 15.0%v/v
Water for injection adds to 100% (g) injection III (1mg/ml is buffered to pH6)
Compounds X 0.1%w/v
Sodium phosphate BP 2.26%w/v
Citric acid 0.38%w/v
Poly(oxyethylene glycol) 400 3.5%w/v
Water for injection adds to 100% (h) aerosol I mg/ml
Compounds X 10.0
Sorbitan trioleate 13.5
Trichloromonofluoromethane 910.0
Refrigerant 12 490.0 (i) aerosol II mg/ml
Compounds X 0.2
Sorbitan trioleate 0.27
Trichloromonofluoromethane 70.0
Refrigerant 12 280.0
Dichloro tetrafluoro ethane 1094.0 (j) aerosol III mg/ml
Compounds X 2.5
Sorbitan trioleate 3.38
Trichloromonofluoromethane 67.5
Refrigerant 12 1086.0
Dichloro tetrafluoro ethane 191.6 (k) aerosol IV mg/ml
Compounds X 2.5
Soybean lecithin 2.7
Trichloromonofluoromethane 67.5
Refrigerant 12 1086.0
Dichloro tetrafluoro ethane 191.6 is annotated:
Above-mentioned preparation can make with known ordinary method in the pharmaceutical field.Tablet (a)～(c) can be with the conventional means bag with enteric coating, the dressing aerosol (h)～(k) of for example making cellulose acetate salt phthalate can use with aerosol dispersion agent standard, dosing, and suspension agent sorbitan trioleate and soybean lecithin can for example sorbitan monooleate, dehydrated sorbitol mono-fatty acid ester-sorbitan dioleate, Spheron MD 30/70, Unigly GO 102S or oleic acid replace with other suspension agents.

Claims (8)

1. the thiazole derivative of formula I or its pharmacologically acceptable salt: Wherein: Q is a 2-oxo-1,2,3,4-tetrahydroquinoline-6-base or 2-oxo-1, and 2-dihydroquinoline-6-base, described group has (1-4C) alkyl substituent on 1 nitrogen-atoms; X 1Be sulphur, sulfinyl or alkylsulfonyl; Ar is thiazole two bases; R 1Be (1-4C) alkyl, (3-4C) alkenyl or (3-4C) alkynyl, and R 2And R 3Can form formula-A together 2-X 2-A 3-group, this group and A 2And A 3The carbon atom that is connected constitutes a ring with 5 or 6 annular atomses, wherein A together 2And A 3Can be identical or different, their respectively do for oneself (1-3C) alkylidene group and X 2Be oxygen, and described ring can have one or two (1-4C) alkyl substituent.
2. the thiazole derivative of the described formula 1 of claim 1 or its pharmacologically acceptable salt, wherein Q is a 2-oxo-1,2,3,4-tetrahydroquinoline-6-base or 2-oxo-1,2-dihydroquinoline-6-base, described group has (1-4C) alkyl substituent on 1 nitrogen-atoms; X 1Be sulphur, sulfinyl or alkylsulfonyl; Ar is 2, and 5-thiazole two bases (have X on 2 1Group); R 1Be (1-4C) alkyl, (3-4C) alkenyl or (3-4C) alkynyl; And R 2And R 3Form formula-A together 2-X 2-A 3-group, this group and A 2And A 3The carbon atom that is connected constitutes a ring with 5 or 6 annular atomses, wherein A together 2And A 3Can be identical or different, their respectively do for oneself (1-3C) alkylidene group and X 2Be oxygen, and described ring can have one or two (1-4C) alkyl substituent.
3. the thiazole derivative of the described formula I of claim 1 or its pharmacologically acceptable salt: wherein: Q is 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base; X 1Be sulphur or alkylsulfonyl; Ar is 2, and 5-thiazole two bases (have X on 2 1Group); R 1Be methyl, and R 2And R 3Form formula-A together 2-X 2-A 3-group, this group and A 2And A 3The carbon atom that is connected constitutes the ring with 6 annular atomses together, wherein A 2And A 3Ethylene and X respectively do for oneself 2Be oxygen, and this ring can be in X 2The α position on have methyl substituents.
4. the thiazole derivative of the described formula I of claim 1 or its pharmacologically acceptable salt: wherein: Q is 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base; X 1Be sulphur or alkylsulfonyl; Ar is 2, and 5-thiazole two bases (have X on 2 1Group); R 1Be methyl, and R 2And R 3Form formula-CH together 2CH 2OCH (CH 3) CH 2-group.
5. the thiazole derivative of the described formula I of claim 1, this compound is:
(2S, 4R)-4-methoxyl group-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-base sulfenyl) thiazole-5-yl] tetrahydropyrans or its pharmacologically acceptable salt.
6. the thiazole derivative of the formula I of preparation claim 1 to 5 described in any one or the method for its pharmacologically acceptable salt, this method comprises:
(a) make formula Q-X 1-H compound and the coupling of formula II compound:
Figure A9419289500041
Wherein Z is can be by the metathetical group;
(b) make formula Q-Z compound (wherein Z for can by the metathetical group) and the coupling of formula III compound:
Figure A9419289500042
(c) make formula Q-X 1(wherein Z can perhaps be worked as X by the metathetical group to-Z compound 1During for sulphur, Z can be formula Q-X 1-group) with the organometallic reagent coupling of formula IV, Wherein M is basic metal or alkaline-earth metal, or M represents the magnesium halide part of conventional Grignard reagent;
(d) using wherein, Z is can be by the formula R of metathetical group 1-Z alkylation formula V compound;
(e), make Q wherein on described available nitrogen-atoms, have the formula I alkylation of hydrogen atom for preparing Q wherein has alkyl substituent on available nitrogen-atoms formula I compound; Or
(f) for preparing wherein X 1Be the formula I compound of sulfinyl or alkylsulfonyl, oxidation is X wherein 1Formula I compound for sulphur;
And if need the pharmacologically acceptable salt of formula I new compound, then can make by making described compound and the acid or the alkali reaction that suit according to a conventional method, and if need the optically-active form of formula I compound, then can be by adopting a kind of optically-active starting raw material to carry out a kind of aforesaid operations or obtaining by the racemic modification that adopts ordinary method to split described compound.
7. pharmaceutical composition, it comprises as the thiazole derivative of the formula I described in the claim 1 to 5 any one or its pharmacologically acceptable salt and blended pharmaceutically acceptable diluent or carrier with it.
8. the thiazole derivative of the formula I described in any one or its pharmacologically acceptable salt are used for application aspect the novel drugs of the disease of leukotrienes mediation or medical conditions in the claim 1 to 5 in preparation.
CN94192895A 1993-07-27 1994-07-21 Thiazole derivatives as lipoxygenase inhibitors Pending CN1128029A (en)

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