CN101450912B - Tetrahydronaphthalene substituted benzoic acid derivates - Google Patents

Tetrahydronaphthalene substituted benzoic acid derivates Download PDF

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CN101450912B
CN101450912B CN2008101768817A CN200810176881A CN101450912B CN 101450912 B CN101450912 B CN 101450912B CN 2008101768817 A CN2008101768817 A CN 2008101768817A CN 200810176881 A CN200810176881 A CN 200810176881A CN 101450912 B CN101450912 B CN 101450912B
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represent wasserstoffatoms
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ethyl
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CN101450912A (en
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黄振华
赵红宇
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Beijing Ao He Research Institute Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicine, in particular to tetraline substituted benzoic acid derivatives shown in the general formula (I), pharmaceutically acceptable salts or isomers thereof, wherein R<1>, R<2>, R<3>, R<4>, R<5>and R<6>are defined as the description. The invention also relates to a method for preparing the compounds, medical compositions containing the compounds, and application of the compounds in preparing medicines for treating and/or preventing infectious disease.

Description

The substituted benzoic acid derivative of tetraline
1, technical field
The invention belongs to medical technical field; Be specifically related to the substituted benzoic acid derivative of tetraline, its pharmacy acceptable salt or its isomer; The preparation method of these compounds; The pharmaceutical composition that contains these compounds, and these compounds are in the purposes that is used for preparing the medicine that treats and/or prevents infection.
2, background technology
Lipid acid is the important component part of cell biological film etc., so in vivo, the synthetic of lipid acid is necessary.Difference according to participating in fatty acid synthetase (FAS) can be divided into two types with the lipid acid route of synthesis, promptly is present in the intravital I type of Mammals lipid acid route of synthesis and is present in the II type lipid acid route of synthesis in bacterium and the plant.In I type lipid acid route of synthesis, the enzyme of participating in building-up reactions is made up of a polypeptied chain, and this chain has comprised all catalytic active centers that synthetic fatty acid is required; And in II type lipid acid route of synthesis, each step reaction all has an independent enzyme catalysis, and these enzymes have the specificity of height in the bacterium of different genera.Exactly because extensive existence and the difference on avtive spot weave construction of II type FAS enzyme in bacterium makes the enzyme of this approach of catalysis become comparatively ideal target spot, carries out the screening of antibacterials.In recent years, the medicine scholars of countries in the world have carried out a large amount of research to fatty acid sythetase inhibitor, and some suppressor factor show strong anti-microbial effect.
3, summary of the invention
Technical scheme of the present invention is following:
The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt or its isomer:
Figure G2008101768817D00011
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group;
R 2Represent Wasserstoffatoms, by halogen atom, hydroxyl, amino, carboxyl substituted or unsubstituted C 1-6Alkyl, C 1-6Alkoxyl group or C 1-6Alkyl sulphonyl;
R 3, R 4Independently represent Wasserstoffatoms, C respectively 1-6Alkyl or hydroxyl protecting group;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, C 2-6Alkenyl, C 2-6Alkynyl group or aryl.
Preferred compound is:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group;
R 2Represent Wasserstoffatoms, by halogen atom, hydroxyl, amino, carboxyl substituted or unsubstituted C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkyl sulphonyl;
R 3, R 4Independently represent Wasserstoffatoms, C respectively 1-4Alkyl or hydroxyl protecting group;
R 5Represent Wasserstoffatoms or C 1-4Alkyl;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from C 1-6Alkyl, C 1-6Alkoxyl group, C 3-8Naphthenic base, C 2-4Alkenyl, C 2-4Alkynyl group or aryl.
Further preferred compound is:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group;
R 2Represent Wasserstoffatoms, methyl, ethyl, trifluoromethyl, methylol, aminomethyl, ethyloic, methoxyl group, oxyethyl group or methyl sulphonyl;
R 3, R 4Independently represent Wasserstoffatoms respectively, methyl, ethyl or hydroxyl protecting group;
R 5Represent Wasserstoffatoms, methyl, ethyl or propyl group;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from methyl, ethyl, methoxyl group, oxyethyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl.
Further preferred compound is:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group;
R 2Represent Wasserstoffatoms, methyl, ethyl or trifluoromethyl;
R 3, R 4Independently represent Wasserstoffatoms respectively, methyl, ethyl or hydroxyl protecting group;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from methyl, methoxyl group or aryl.
Further preferred again compound is:
Wherein, R 1Represent Wasserstoffatoms;
R 2Represent Wasserstoffatoms, methyl, ethyl or trifluoromethyl;
R 3, R 4Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or 1～2 substituting group, wherein substituting group is selected from methyl, methoxyl group or aryl.
Further preferred once more compound is:
Wherein, R 1Represent Wasserstoffatoms;
R 2Represent Wasserstoffatoms, methyl or trifluoromethyl;
R 3, R 4Independently represent Wasserstoffatoms or methyl respectively;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or 1～2 substituting group, wherein substituting group is selected from methyl or methoxy.
Most preferred is:
Wherein, R 1Represent Wasserstoffatoms;
R 2Represent Wasserstoffatoms or methyl;
R 3, R 4Independently represent Wasserstoffatoms or methyl respectively;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or methyl.
Further preferred compound is following:
Chemical name: 2,4-dihydroxyl-3-[3-(1-oxo-1,2,3,4-tetralin-2-yl) propionamido-] phenylformic acid is called for short compound 7, and structural formula is following:
Figure G2008101768817D00031
Chemical name: 2,4-dihydroxyl-3-[3-(1-oxo-2-methyl isophthalic acid, 2,3,4-tetraline-2-yl) propionamido-] phenylformic acid is called for short compound 8, and structural formula is following:
Figure G2008101768817D00032
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention 1-6Alkyl " be can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc. by the alkyl that contains 1-6 carbon atom of straight or branched.
" C of the present invention 1-6Alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.
" C of the present invention 1-6Alkyl sulphonyl " comprise methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base etc.
" C of the present invention 3-8Naphthenic base " for cyclic contains the naphthenic base of 3-8 carbon atom, can be cyclopropyl, 1-methyl-2-methyl-propyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.
" C of the present invention 2-6Alkenyl " be the alkenyl of the straight or branched of 2-6 carbon atom, comprise vinyl, propenyl, pseudoallyl, crotonyl, pentenyl, hexenyl etc.
" C of the present invention 2-6Alkynyl group " be the alkynyl group of the straight or branched of 2-6 carbon atom, comprise ethynyl, proyl, different proyl, butynyl, pentynyl, hexyn etc.
" aryl " of the present invention is phenyl, benzyl etc.
" hydroxyl protecting group " of the present invention protection base for introducing and remove easily is selected from silicomethane fundamental mode protection base, acyl group type protection base, benzylic type protection base, ether type protection base, ester class protection base, sulphonate protection base; Concrete is t-butyldimethylsilyl, tertiary butyl dimethyl silanyl; Propionyl group, butyryl radicals, isobutyryl, valeryl, benzoyl-, toluyl; Benzyl; Methoxymethyl, 2-methoxyl group ethoxymethyl, first sulphomethyl ether, phenacyl, ring third methyl, allyl group; Acetic acid aryl ester, trimethylacetic acid aryl ester, phenylformic acid aryl ester; Methylsulfonic acid aryl ester, toluenesulphonic acids aryl ester.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methyl, methoxymethyl, first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl-, to bromobenzene formyl methyl, Alpha-Methyl phenacyl-, to methoxybenzoyl methyl, diacyl methyl, N phlhalimide ylmethyl, ethyl, 2; 2; 2-three chloroethyls, 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9; The 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2; 4; The 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, sec.-propyl dimetylsilyl, diphenyl methyl, phenyl dimetylsilyl, the S-tertiary butyl, S-phenyl, S-2-pyridyl, N-hydroxy piperidine base, N-succinimido, N phlhalimide base, N-benzotriazole base, O-acyl group oxime, 2; 4-dinitrobenzene sulfenyl, 2-alkyl-1; 3-oxazoline, 4-alkyl-5-oxo-1; 3-oxazolidine, 5-alkyl-4-oxo-1,3-diox, triethyltin alkyl, tri-n-butyl tin alkyl; N, N '-di-isopropyl hydrazides etc.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, like sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is like calcium salt, magnesium salts etc.; Other metal-salts are like aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is like ammonium salt; Organic alkali salt; Like uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-NMG salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) amido methane salt; Halogen acid salt is like hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is like nitrate salt, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulphonate is like mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is like benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is like acetate, malate, fumarate, SUMATRIPTAN SUCCINATE, Citrate trianion, tartrate, oxalate, PHENRAMINE MALEATE etc.; Amino acid salts is like glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.For fear of query, have one, two or three salt-forming cations, but this depends on the quantity and the said cationic valence mumber of carboxyl functional group.It is obvious that for the professional of this area, and the pharmacy acceptable salt of The compounds of this invention can make through ordinary method in the formation such as free carboxy place of this compound.Yet for the ease of in the preparation process, separating this salt, no matter whether it is pharmaceutically acceptable, not diffluent salt possibly be preferred in selected solvent.
Isomer according to the invention comprises that all differences are to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this was illustrated in three-dimensional this key of going up and will comes out from paper, and when a key was shade, this was illustrated in three-dimensional this key of going up and will returns in the paper.Said isomer can be through standard stripping technique and the abundant purity isomer of the synthetic acquisition of stereochemistry control.
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method, and reaction equation is following:
Figure G2008101768817D00051
Reactions step:
The preparation of embodiment 1 midbody 1
In reaction flask, throw an amount of raw material 1, add acetone and dissolve in right amount, add anhydrous K under the vigorous stirring 2CO 3, drip chloromethyl ether, the heating reflux reaction that slowly heats up, TLC detection reaction terminal point; Decompression adds THF dissolving residuum after steaming down and removing most of acetone, adds Pd/C, stirring reaction; Reaction finishes, and filters, and adds entry in the filtrating; Use ethyl acetate extraction then, merge organic phase, anhydrous MgSO behind water, saturated common salt solution washing 4Drying is steamed and is removed ETHYLE ACETATE, and the gained resistates is through silica gel column chromatography separating purification, and promptly midbody 1.
The preparation of embodiment 2 midbodys 2
In reaction flask, add midbody 1, methylene dichloride, triethylamine, lower the temperature after the stirring and dissolving, slowly drip then (Boc) 2The dichloromethane solution of O drips and finishes, the insulated and stirred reaction; Add entry in the reaction solution, divide water-yielding stratum, organic layer washs with 5% sodium hydrogen carbonate solution, saturated nacl aqueous solution respectively; Anhydrous magnesium sulfate drying; Remove solvent under reduced pressure, residuum is used ETHYLE ACETATE: the mixed solution recrystallization of methyl alcohol gets midbody 2.
The preparation of embodiment 3 midbodys 3
In-78 ℃, nitrogen protection adds midbody 2, THF down, stirs the cyclohexane solution that slowly drips n-Butyl Lithium down, drips and finishes; The insulated and stirred reaction, and then slowly add raw material 2 and THF, the insulated and stirred reaction, reaction finishes; Carefully add entry, slowly rise to room temperature after stirring slightly, remove organic solvent under reduced pressure, residuum is used ethyl acetate extraction; Merge organic layer, wash anhydrous magnesium sulfate drying with HCl solution, 5% sodium hydrogen carbonate solution, saturated nacl aqueous solution respectively; Remove solvent under reduced pressure, residuum is used ETHYLE ACETATE: the mixed solution recrystallization of sherwood oil gets midbody 3.
The preparation of embodiment 4 midbodys 4
In reaction flask, add raw material 3, toluene, add potassium tert.-butoxide then, after the stirring and dissolving, cooling slowly adds raw material 4, stirring reaction; The intensification stirring reaction, reaction finishes, and adds entry, tells organic layer, and half solvent of organic layer reclaim under reduced pressure changes in the reaction flask; Elevated temperature slowly drips the vitriol oil, and stirring reaction adds entry, under room temperature, transfers pH with strong aqua, tells organic layer; Water layer is used extracted in toluene, merges organic layer, washing, and drying reclaims solvent, and recrystallization gets midbody 4.
The preparation of embodiment 6 The compounds of this invention
In the exsiccant reaction flask, add midbody 4, DMF, chloroform, add O-(benzotriazole-1-yl)-N then, N, N '; N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU) is warming up to the refluxing and stirring reaction, slowly adds midbody 3 reinforced finishing in batches, the insulated and stirred reaction, and reaction finishes; Add entry, divide water-yielding stratum, the organic layer concentrating under reduced pressure, residuum is used dissolve with ethanol, drips the aqueous solution of Lithium Hydroxide MonoHydrate; Back flow reaction, reaction solution is evaporated to dried, and residuum is used dehydrated alcohol extraction, united extraction liquid; Move in the reaction flask, add 10%HCl-MeOH again, stirring and refluxing adds the frozen water crystallization and gets The compounds of this invention.
R in the above reaction equation 1, R 2, R 3, R 4, R 5, R 6The representative group such as preamble definition.
The present invention further requires to protect the pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner; For clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral prepns, injection or external preparation.Wherein contain the compound shown in the general formula (I) of physiology significant quantity.Described physiology significant quantity is for treating and/or preventing the amount of the compound shown in the necessary general formula of infection (I) or enough amounts, can change according to the factors such as type like patient's the bodily form and body weight, disease.
Significant quantity commonly used can be 0.01g, 0.025g, 0.05g, 0.075g, 0.1g, 0.125g, 0.25g, 0.3g, 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g etc. for to contain the arbitrary compound shown in the formula (I), its pharmacy acceptable salt or its isomer 0.01g～10g (by compound shown in the formula (I)) as essential active ingredient.What one of ordinary skill in the art will appreciate that is: this drug dose also depends on the mammiferous age, and situation and desire prevention are or/and the kind of treatment disease.
The present invention also comprises the pharmaceutical composition of above-mentioned arbitrary compound, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner; Can be mixed with clinically or pharmaceutically acceptable arbitrary formulation with mode known in the art, be applied to the patient who needs this treatment with oral, parenteral, rectum or through modes such as lung administrations.When being used for oral administration, can be made into conventional solid preparation, like tablet, capsule, pill, granule etc.; Also can be made into oral liquid, like oral solution, oral suspensions, syrup etc.When processing oral prepns, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When processing injection, can adopt the conventional method production in the existing pharmaceutical field, during the preparation injection, can not add additives, also can add suitable additives based on the character of medicine.Pharmaceutical composition of the present invention can also be processed external solid, semi-solid preparations such as ointment, ointment, gelifying agent, powder, rubber-emplastrum, cataplasma, patch; Liquid preparation for external application such as lotion, liniment, liniment.
The present invention also provides above-claimed cpd, its pharmacy acceptable salt or its isomer to treat and/or prevent the purposes of infectious disease medicament in preparation.Wherein The compounds of this invention all has good activity to the organism of wide range; Wherein these organisms comprise gram-negative organism such as escherichia coli, Klebsiella Pneumoniae, Salmonellas, wish and draw faecalis, Acinetobacter bauamnnii, moraxelle catarrhalis, hemophilus influenzae, Pseudomonas aeruginosa etc., and gram-positive organism such as streptococcus aureus, streptococcus pneumoniae, enterococcus faecalis and faecium etc.In addition, The compounds of this invention and other microbiotic do not have cross resistance, have good pharmacokinetic property, and medication is convenient, and preparation technology is simple, and medicine purity is high, high, the steady quality of yield, is easy to carry out large-scale commercial prodn.
Below further set forth the beneficial effect of The compounds of this invention, but should this be interpreted as that The compounds of this invention only has following beneficial effect through the in-vitro antibacterial experiment of part The compounds of this invention.
The antibacterial activity in vitro of experimental example The compounds of this invention
Supply the examination bacterial classification: streptococcus aureus, escherichia coli, purchase in public institution.
Trial-product: The compounds of this invention is as shown in the table, self-control (preparation method sees specific embodiment for details); The contrast medicine: Cefuroxime sodium (cefuroxime sodium for injection), commercial.
Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.
Experimental result and conclusion:
The compounds of this invention is to the anti-microbial activity of clinical isolates
Figure G2008101768817D00071
Visible by last table experimental result, to compare with Cefuroxime sodium, The compounds of this invention all has better antibacterial activity to clinical common isolated strains.
4, embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation of following examples 8-12 can be replaced with acceptable accessories, perhaps reduces, increases.
Embodiment 12, the preparation of 6-two (methoxy methoxy base) aniline
In reaction flask, drop into 9.3g (60mmol) 2-nitro-1, the 3-dihydroxy-benzene adds the 100ml acetone solution, adds anhydrous K under the vigorous stirring 2CO 315.0g (108mmol), drip chloromethyl ether 9ml (120mmol), the heating reflux reaction that slowly heats up, TLC detection reaction terminal point behind the 10min; After decompression is steamed down and removed most of acetone, add THF dissolving residuum 60ml, add 1g Pd/C, in the following 40 ℃ of stirring reaction 1h of 1Mpa hydrogen pressure; Reaction finishes, and filters, and adds entry 100ml in the filtrating; Use ETHYLE ACETATE 100ml * 3 extractions then, merge organic phase, anhydrous MgSO behind water, saturated common salt solution washing 4Drying is steamed and is removed ETHYLE ACETATE, and the gained resistates gets faint yellow oily thing 10.8g, productive rate 84.8% through silica gel column chromatography separating purification [V (sherwood oil): V (ETHYLE ACETATE)=4:1].
Embodiment 22, the preparation of 6-two (methoxy methoxy base)-1-tertbutyloxycarbonyl aniline
In reaction flask, add 2,6-two (methoxy methoxy base) aniline 10.7g (50mmol), methylene dichloride 120ml, triethylamine 8ml is cooled to 0 ℃ after the stirring and dissolving, slowly drip 14.2g (65mmol) then (Boc) 2The dichloromethane solution 20ml of O drips and finishes, insulated and stirred reaction 4h; Add 60ml water in the reaction solution, divide water-yielding stratum, organic layer washs with 5% sodium hydrogen carbonate solution, saturated nacl aqueous solution respectively; Anhydrous magnesium sulfate drying removes solvent under reduced pressure, and residuum is used ETHYLE ACETATE: the mixed solution recrystallization of methyl alcohol; Get 2,6-two (methoxy methoxy base)-1-tertbutyloxycarbonyl aniline 14.6g, yield: 93.1%.
Embodiment 32, the preparation of 4-two (methoxy methoxy base)-3-Methyl anthranilate
In-78 ℃, nitrogen protection adding 2 down, 6-two (methoxy methoxy base)-1-tertbutyloxycarbonyl aniline 12.45g (40mmol), THF 150ml; Stir the cyclohexane solution 22ml that slowly drips the n-Butyl Lithium of 2.5mol/L down, drip and finish, insulated and stirred reaction 0.5h; And then slowly add methyl-chloroformate 4.7g (50mmol) and THF 20ml, and insulated and stirred reaction 2h, reaction is finished; The careful 50ml water that adds slowly rises to room temperature after stirring slightly, removes organic solvent under reduced pressure; Residuum merges organic layer with ETHYLE ACETATE 50ml * 3 extractions, respectively with the HCl solution of 1N, sodium hydrogen carbonate solution, each 20ml washing of saturated nacl aqueous solution of 5%; Anhydrous magnesium sulfate drying removes solvent under reduced pressure, and residuum is used ETHYLE ACETATE: the mixed solution recrystallization of sherwood oil; Get 2,4-two (methoxy methoxy base)-3-Methyl anthranilate 9.2g, yield: 84.5%.
The preparation of embodiment 4 3-(1-oxo-1,2,3,4-tetralin-2-yl) propionic acid
In reaction flask, add 1-oxo tetraline 14.6g (100mmol), toluene 200ml adds potassium tert.-butoxide 11.8g (105mmol) then, after the stirring and dissolving, is cooled to about 10 ℃; Slowly add propylene cyanogen 6.4g (120mmol), stirring reaction 0.5h is warming up to 60 ℃, stirring reaction 6h, and reaction finishes; Add entry 100ml, tell organic layer, half solvent of organic layer reclaim under reduced pressure changes in the reaction flask, more than the elevated temperature to 80 ℃; Slowly drip vitriol oil 20ml, stirring reaction 1h adds entry 100ml, under room temperature, transfers PH5～5.5 with strong aqua; Tell organic layer, water layer is used extracted in toluene, merges organic layer, washing; Drying reclaims solvent, gets crystallization 12.8g, yield 58.6%.
The preparation of embodiment 5 3-(1-oxo-2-methyl isophthalic acid, 2,3,4-tetraline-2-yl) propionic acid
Preparing method's reference implementation example 4 of this compound is thrown 1-oxo tetraline 16g (100mmol), potassium tert.-butoxide 12.3g (110mmol); Propylene cyanogen 6.4g (120mmol) gets 3-(1-oxo-2-methyl isophthalic acid, 2; 3,4-tetraline-2-yl) propionic acid 11.3g, yield 48.7%.
Embodiment 62,4-dihydroxyl-3-[3-(1-oxo-1,2,3,4-tetralin-2-yl) propionamido-] phenylformic acid (being compound 7) Preparation
In the exsiccant reaction flask, add 3-(1-oxo-2-methyl isophthalic acid, 2,3,4-tetraline-2-yl) propionic acid 4.4g (20mmol); DMF10ml, chloroform 50ml adds O-(benzotriazole-1-yl)-N, N, N ' then; N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU) 7.7g (24mmol) is warming up to refluxing and stirring reaction 50min, slowly adds 2 in batches, 4-two (methoxy methoxy base)-3-Methyl anthranilate 5.4g (20mmol), reinforced finishing; Insulated and stirred reaction 2h, reaction finishes, and adds 100ml water, divides water-yielding stratum, the organic layer concentrating under reduced pressure; Residuum is used dissolve with ethanol, drips the 10ml aqueous solution of 2g Lithium Hydroxide MonoHydrate, back flow reaction 0.5h, and reaction solution is evaporated to dried; Residuum is with dehydrated alcohol extraction 40ml * 4 time, and united extraction liquid moves in the reaction flask, adds 10%HCl-MeOH25ml again; Stirring and refluxing 20min adds frozen water 100ml, separates out white solid 3.3g, yield 44.5%.Molecular formula: C 20H 19NO 6
Molecular weight: 369.37
Ultimate analysis: theoretical value: C, 65.03%; H, 5.18%; N, 3.79%
Measured value: C, 64.81%; H, 5.39%; N, 3.52%
Mass spectrum (m/e): 370 (M+1)
1H?NMR(300MHz，CDCl 3)：δ11.55(s，1H)，11.24(s，1H)，8.11(s，1H)，8.03(d，J＝7.5Hz，1H)，7.63(d，J＝9.0Hz，1H)，7.49(t，J＝7.5Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.25(d，J＝7.5Hz，1H)，6.52(d，J＝8.7Hz，1H)，3.06～3.04(m，2H)，2.98(m，1H)，2.61～2.56(m，2H)，2.18～1.98(m，4H)
Embodiment 72, and 4-dihydroxyl-3-[3-(1-oxo-2-methyl isophthalic acid, 2,3,4-tetraline-2-yl) propionamido-] phenylformic acid (is promptly changed Compound 8) preparation
Preparing method's reference implementation example 6 of this compound is thrown 3-(1-oxo-2-methyl isophthalic acid, 2; 3,4-tetraline-2-yl) propionic acid 4.6g (20mmol), 2; 4-two (methoxy methoxy base)-3-Methyl anthranilate 5.4g (20mmol) gets 3-(1-oxo-2-methyl isophthalic acid, 2; 3,4-tetraline-2-yl) propionic acid 3.1g, yield 40.7%.
Molecular formula: C 21H 21NO 6
Molecular weight: 383.39
Ultimate analysis: theoretical value: C, 65.79%; H, 5.52%; N, 3.65%
Measured value: C, 65.43%; H, 5.87%; N, 3.47%
Mass spectrum (m/e): 384 (M+1)
1H?NMR(300MHz，CDCl 3)：δ11.55(s，1H)，11.24(s，1H)，8.11(s，1H)，8.03(d，J＝7.5Hz，1H)，7.63(d，J＝9.0Hz，1H)，7.49(t，J＝7.5Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.25(d，J＝7.5Hz，1H)，6.52(d，J＝8.7Hz，1H)，3.06～3.04(m，2H)，2.61～2.56(m，2H)，2.18～1.98(m，4H)，1.27(s，3H)
With reference to above-mentioned preparation method, also prepared following compound:
Figure G2008101768817D00101
Figure G2008101768817D00121
Figure G2008101768817D00131
The preparation of embodiment 8 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Figure G2008101768817D00132
Prescription 2:
Figure G2008101768817D00133
Prescription 3:
Figure G2008101768817D00134
Prescription 3:
Figure G2008101768817D00135
Prescription 4:
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, the detection at any time loading amount; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 The compounds of this invention aqueous injections
1, prescription:
Prescription 1:
Figure G2008101768817D00137
Figure G2008101768817D00141
Prescription 2:
Figure G2008101768817D00142
2, preparation technology: the raw material in will writing out a prescription dissolves dosing with water for injection, handles after-filtration, constant volume, smart worry, the inspection of semifinished product, embedding, sterilization, leak detection, lamp inspection, packs and process finished product through charcoal absorption.
The preparation of embodiment 10 The compounds of this invention freeze-dried powders
1, prescription:
Prescription 1:
Figure G2008101768817D00143
Prescription 2:
Figure G2008101768817D00144
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, N.F,USP MANNITOL is added about 80% water for injection stirring and dissolving (Expex boils dissolving to be put cold), add the raw material stirring dissolving again; Regulate the appropriate pH value, benefit adds to the full amount of water for injection, and adds dosing amount 0.05% needle-use activated carbon absorption 15 minutes; Filtering decarbonization, smart filter, work in-process chemical examination; Can, lid is rolled in freeze-drying, tamponade.Step of freeze drying is :-40 ℃ of pre-freezes 5 hours, with on average per hour 1.5 ℃ heat up, be warming up to 2 ℃ and carry out low-temperature vacuum drying, the 35 ℃ of high-temperature vacuum dryings that are rapidly heated, vacuum degree control is below the 0.1mm mercury column.
The preparation of embodiment 11 The compounds of this invention tablets
1, prescription:
Prescription 1:
Figure G2008101768817D00145
Prescription 2:
Figure G2008101768817D00146
Prescription 3:
Figure G2008101768817D00152
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, Microcrystalline Cellulose, pregelatinized Starch (starch and hydroxypropylcellulose) are mixed, add mixer-granulator, it is an amount of to add entry (or 50% aqueous ethanolic solution of 1%HPMC), stirs 15 minutes, processes particle; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds Magnesium Stearate, carboxymethylstach sodium (or micropowder silica gel), and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 12 The compounds of this invention emulsifiable pastes
1, prescription:
Figure G2008101768817D00153
Prescription 2:
Figure G2008101768817D00154
2, preparation technology
The preparation technology of prescription 1: with raw material, mono-glycerides, stearyl alcohol, isopropyl myristate, heating and melting mixes, as oil phase, and glycerine, peregal-O, Bu Luoboer, water; Heating mixes, stirs, and 70 ℃ of insulations, 75 ℃ of insulations of oil phase slowly add aqueous phase with oil phase; Constantly stir, after adding, stop insulation, keep whipped state, cool to 40 ℃; Stop to stir, cool to room temperature, get emulsifiable paste, the aluminium foil pipe is distributed into finished product.
The preparation technology of prescription 2: card taking POP 940 adds an amount of water and is dipped into dissolving fully, adds ethyl p-hydroxybenzoate (using dissolve with ethanol), reenters glycerine, tween 80; Stirring and evenly mixing; Add raw material stirring mixing or dissolving, add the trolamine neutralization at last, the emulsifiable paste of water-soluble base.
Those skilled in the art will know or only use routine test just can confirm many embodiments that are equal to of concrete grammar described herein.The embodiment that is equal to is like this considered within the scope of the present invention, and is included in claims scope.

Claims (10)

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group, carboxyl-protecting group is selected from methyl, ethyl, allyl group or the tertiary butyl;
R 2Represent Wasserstoffatoms, C 1-6Alkyl, C 1-6Alkoxyl group or C 1-6Alkyl sulphonyl;
R 3, R 4Independently represent Wasserstoffatoms or C respectively 1-6Alkyl;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from C 1-6Alkyl, C 1-6Alkoxyl group or C 3-8Naphthenic base.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group, carboxyl-protecting group is selected from methyl, ethyl, allyl group or the tertiary butyl;
R 2Represent Wasserstoffatoms, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkyl sulphonyl;
R 3, R 4Independently represent Wasserstoffatoms or C respectively 1-4Alkyl;
R 5Represent Wasserstoffatoms or C 1-4Alkyl;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from C 1-6Alkyl, C 1-6Alkoxyl group or C 3-8Naphthenic base.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group, carboxyl-protecting group is selected from methyl, ethyl, allyl group or the tertiary butyl;
R 2Represent Wasserstoffatoms, methyl, ethyl, methoxyl group, oxyethyl group or methyl sulphonyl;
R 3, R 4Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R 5Represent Wasserstoffatoms, methyl, ethyl or propyl group;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from methyl, ethyl, methoxyl group, oxyethyl group, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms or carboxyl-protecting group, carboxyl-protecting group is selected from methyl, ethyl, allyl group or the tertiary butyl;
R 2Represent Wasserstoffatoms, methyl or ethyl;
R 3, R 4Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or 1～4 substituting group, wherein substituting group is selected from methyl or methoxy.
5. compound as claimed in claim 4 or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms;
R 2Represent Wasserstoffatoms, methyl or ethyl;
R 3, R 4Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or 1～2 substituting group, wherein substituting group is selected from methyl or methoxy.
6. compound as claimed in claim 5 or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms;
R 2Represent Wasserstoffatoms or methyl;
R 3, R 4Independently represent Wasserstoffatoms or methyl respectively;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or 1～2 substituting group, wherein substituting group is selected from methyl or methoxy.
7. compound as claimed in claim 6 or its pharmacy acceptable salt:
Wherein, R 1Represent Wasserstoffatoms;
R 2Represent Wasserstoffatoms or methyl;
R 3, R 4Independently represent Wasserstoffatoms or methyl respectively;
R 5Represent Wasserstoffatoms or methyl;
R 6Represent Wasserstoffatoms or methyl.
8. compound as claimed in claim 7 or its pharmacy acceptable salt, described compound is selected from:
2,4-dihydroxyl-3-[3-(1-oxo-1,2,3,4-tetralin-2-yl) propionamido-] phenylformic acid and
2,4-dihydroxyl-3-[3-(1-oxo-2-methyl isophthalic acid, 2,3,4-tetraline-2-yl) propionamido-] phenylformic acid.
9. a pharmaceutical composition contains the described compound of the arbitrary claim of claim 1～8 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner.
10. be used for preparing the application that treats and/or prevents infectious disease medicament like the described compound of the arbitrary claim of claim 1～8 or its pharmacy acceptable salt.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1038092A (en) * 1988-04-11 1989-12-20 阿勒根公司 The preparation method of the tetraline ester of phenol or benzoic acids
CN1370158A (en) * 1999-08-23 2002-09-18 史密丝克莱恩比彻姆公司 Fatty acid synthase inhibitors
WO2005016867A2 (en) * 2003-08-14 2005-02-24 Smithkline Beecham Corporation Anthranilic acid derivatives and their use as activators of the hm74a receptor
WO2006052555A2 (en) * 2004-11-04 2006-05-18 Merck & Co., Inc. Niacin receptor agonists, compositions containing such compounds and methods of treatment

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1038092A (en) * 1988-04-11 1989-12-20 阿勒根公司 The preparation method of the tetraline ester of phenol or benzoic acids
CN1370158A (en) * 1999-08-23 2002-09-18 史密丝克莱恩比彻姆公司 Fatty acid synthase inhibitors
WO2005016867A2 (en) * 2003-08-14 2005-02-24 Smithkline Beecham Corporation Anthranilic acid derivatives and their use as activators of the hm74a receptor
WO2006052555A2 (en) * 2004-11-04 2006-05-18 Merck & Co., Inc. Niacin receptor agonists, compositions containing such compounds and methods of treatment

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