CN101654435B - N-benzyl quinoline carboxylic acid compound, combination and preparation method thereof - Google Patents
N-benzyl quinoline carboxylic acid compound, combination and preparation method thereof Download PDFInfo
- Publication number
- CN101654435B CN101654435B CN200910011915.1A CN200910011915A CN101654435B CN 101654435 B CN101654435 B CN 101654435B CN 200910011915 A CN200910011915 A CN 200910011915A CN 101654435 B CN101654435 B CN 101654435B
- Authority
- CN
- China
- Prior art keywords
- dihydroquinoline
- nitrae
- isosorbide
- oxo
- acetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to an N- benzyl quinoline carboxylic acid compound and derivatives, tautomer and salt for medical purposes, pharmaceutically acceptable solvent and combination thereof containing the derivatives, the tautomer, the salt and the pharmaceutically acceptable solvent. The invention relates to quinoline carboxylic acid compound in general formula I and derivant, tautomer, salt for medical purposes, solvate for medical purposes and combination thereof containing the derivatives, the tautomer, the salt and the pharmaceutically acceptable solvent. The invention also relates to a preparation method of the above compounds, combination containing the compounds, applications of the compounds and the combination thereof, and intermediate compound II for preparing the compound I. The invention has simple preparation method, and the prepared compound or combination thereof in the general formula I can be used for treating and/or preventing diabetes syndrome.
Description
Technical field
The present invention relates to N-benzyl quinoline carboxylic acid compound, composition and method of making the same, the pharmaceutically useful composition and method of making the same that is specifically related to N-benzyl quinoline carboxylic acid compound and derivative thereof, tautomer, pharmaceutically useful salt, pharmaceutically useful solvate and contains them, and the purposes of these compounds in medicine.The invention still further relates to the method for the pharmaceutically useful composition of preparing above-claimed cpd and derivative thereof, analogue, tautomer, pharmaceutically useful salt, pharmaceutically useful solvate and containing them.
background technology
Diabetes are metabolic troubles of a kind of multi-pathogenesis, and feature is chronic hyperglycemia, sugar, fat and the protein metabolism disorder of following the defect because of insulin secretion effect to cause.
The treatment of diabetes itself can well be treated by controlling the level of blood sugar in patient body.Yet patient tends to occur some so-called long-term complications, i.e. diabetic complications in the process of long-term treatment diabetes.
The origin cause of formation that generally believes at present diabetic complication makes the body accumulation of sorbyl alcohol relevant [Drug of the Future 1998,23 (5): 521-529] with polyvalent alcohol metabolic pathway activity is hyperfunction.
When blood sugar concentration maintains normal physiological level, aldose reductase (Aldose Reductase, ALR2) is not activated.Physiological situation in hyperglycemia, hexokinase is by saturated, this is activated polyvalent alcohol path, the activity that sorbyl alcohol generates sorbito dehy drogenase when increasing does not increase and proportional increase with the activity of aldose reductase, sorbyl alcohol is again because the impact of self polarity factor makes it to be difficult for by cytolemma, so caused and accumulated in cell.
Experimentation on animalies and clinical study show in a large number, and it is abnormal that aldose reductase inhibitor can effectively improve diabetic subject's polyvalent alcohol metabolic pathway, thereby reach the object of prevention and treatment diabetic complication.
N-benzyl quinoline carboxylic acid compound, composition have good aldose reductase inhibition activity, yet there are no the relevant report of N-benzyl quinoline carboxylic acid compound, composition and method of making the same in prior art.
The object of the present invention is to provide a kind of new compound of general formula I, it has the effect that suppresses aldose reductase and the purposes for the treatment of diabetic syndrome (comprising diabetes cardio cerebrovascular affection, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy etc.).The present invention also provides the intermediate of the preparation compound of Formula I representing as general formula I I.
summary of the invention
The N-benzyl quinoline carboxylic acid compound that provides general formula I to represent is provided, and derivative, tautomer, pharmaceutically useful salt, pharmaceutically useful solvate and the pharmaceutically useful composition and the method thereof that contain them.The mixture that the present invention provides as above material is simultaneously in suitable carrier, solvent, thinner and the pharmaceutical composition of preparing normally used other combination of media of this compounds.
Compound general formula provided by the invention is as follows:
Wherein:
K is the integer of 0-4;
Each R
1independent is the (C of hydrogen atom, replacement or unsubstituted straight or branched
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkenyl group, (C
1-C
6) alkoxyl group, ring (C
3-C
7) alkoxyl group, aryl, aryl oxide, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heterocyclic radical alkyl, heteroaralkyl, heteroaryl oxygen, assorted aralkoxy, heterocyclic radical alkyl oxygen, acyl group, acyl group oxygen, amide group, one alkylamino, dialkyl amido, arylamino, aryl alkyl amino, alkoxy carbonyl, aryl carbonyl oxygen, aromatic alkoxy carbonyl, heterocycle alkoxy carbonyl, heteroaryl oxygen carbonyl, assorted aromatic alkoxy carbonyl, hydroxyl, hydroxyalkyl, aminoalkyl group, one alkylamino alkyl, dialkyl aminoalkyl, alkoxyalkyl, aryl oxide alkyl, sweet-smelling alkoxy alkyl, alkoxycarbonyl amino, aryl carbonyl oxygen is amino, aryl alkyl carbonyl oxygen is amino, halogen, fully halogenated alkyl, nitro, cyano group, methylene-dioxy,
X is Sauerstoffatom or sulphur atom or CH
2group;
N is the integer of 0-3;
M is the integer of 0-5;
Each R
2independent is the (C of hydrogen atom, replacement or unsubstituted straight or branched
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkenyl group, (C
1-C
6) alkoxyl group, ring (C
3-C
7) alkoxyl group, aryl, aryl oxide, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heterocyclic radical alkyl, heteroaralkyl, heteroaryl oxygen, assorted aralkoxy, heterocyclic radical alkyl oxygen, halogen, methylene-dioxy, acyl group, acyl group oxygen, amide group, one alkylamino, dialkyl amido, arylamino, aryl alkyl amino, alkoxy carbonyl, aryl carbonyl oxygen, aromatic alkoxy carbonyl, heterocycle alkoxy carbonyl, heteroaryl oxygen carbonyl, assorted aromatic alkoxy carbonyl, hydroxyl, hydroxyalkyl, aminoalkyl group, one alkylamino alkyl, dialkyl aminoalkyl, alkoxyalkyl, aryl oxide alkyl, sweet-smelling alkoxy alkyl, alkoxycarbonyl amino, aryl carbonyl oxygen is amino, aryl alkyl carbonyl oxygen is amino, halogen, fully halogenated alkyl, nitro, cyano group, hydroxyl,
C ring is cycloaliphatic ring, heterocycle, aromatic ring or fragrant heterocycle.
This invention also comprises the preparation method of formula I compound as defined above:
(1) preparation of 2-(6-methyl isophthalic acid-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 6-methyl-2,3-dihydro-4 (1H)-quinolinone is raw material, carry out N-alkylation reaction with benzyl chloride and obtain 1-benzyl-6-methyl-2,3-dihydro-4 (1H) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(6-methyl isophthalic acid-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid.
(2) preparation of 2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 6-fluoro-2,3-dihydro-4 (1H)-quinolinone is raw material, carry out N-alkylation reaction with benzyl chloride and obtain 1-benzyl-6-fluoro-2,3-dihydro-4 (1H) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid.
(3) preparation of 2-(6-methoxyl group-1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is raw material, carry out N-alkylation reaction with benzyl chloride and obtain 1-benzyl-6-methoxyl group-2,3-dihydro-4 (1H) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(6-methoxyl group-1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid.
(4) 2-(1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 2,3-dihydro-4 (1H)-quinolinone is raw material, carries out N-alkylation reaction and obtains 1-benzyl-2,3-dihydro-4 (1H) quinolinone with benzyl chloride, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid.
Optional pharmacy acceptable salt or the solvate that forms the formula I compound obtaining.
As pharmaceutical salts of the present invention, be defined as follows, but be not limited to this: the salt of carboxylic moiety, if an alkali metal salt is as Li, Na and K salt; Alkaline earth salt is as Ca and Mg salt; Organic alkali salt, as Methionin, arginine, guanidine, diethanolamine, choline, Trometamol etc.; The ammonium salt of ammonium or replacement and aluminium salt.Salt can be acid salt, its include but not limited to vitriol, nitrate, phosphoric acid salt, perchlorate, borate, hydrohalogen, acetate, tartrate, maleate, Citrate trianion, succinate, palmitate, mesylate, benzoate, salicylate, benzene sulfonate, ascorbate salt, glycerophosphate, ketoglutarate etc.Pharmaceutically useful solvate can be hydrate, or contains other recrystallisation solvents as alcohol.
Compound of Formula I or its pharmacy acceptable salt or solvate, they are selected from:
2-(6-methyl isophthalic acid-phenmethyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
2-[6-methyl isophthalic acid-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2,4 dichloro benzene base) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-(the fluoro-1-phenmethyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
The fluoro-1-of 2-[6-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2,4 dichloro benzene base) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-(6-methoxyl group-1-phenmethyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
2-[6-methoxyl group-1-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2,4 dichloro benzene base) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-(1-phenmethyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
2-[1-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2,4 dichloro benzene base) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
Another aspect of the present invention comprises a kind of pharmaceutical composition, the compound that it contains at least one general formula I, using and derivative, analogue, tautomer, polymorphic form, pharmaceutically useful salt, pharmaceutically useful solvated compounds as activeconstituents, and pharmaceutically useful carrier, thinner etc.
The pharmaceutical composition that contains the compounds of this invention can be prepared by ordinary method, and for example, at Remington:the Science and Practice of Pharmacy, 19th Ed., describes in 1995.Said composition can be that conventional formulation is as capsule, tablet, powder, solution, suspension, syrup, aerosol or topical form.They can contain suitable solid or liquid vehicle, or form injection solution or suspension in suitable sterile media.Said composition can contain the active compound of 5-20%, preferred 0.5-10% weight, and surplus is pharmaceutically useful carrier, excipient, thinner, solvent etc.
Compound or its pharmaceutically useful salt that typical composition contains formula I, and pharmaceutically useful excipient, it can be carrier or thinner, or is diluted by carrier, or is wrapped in carrier, it can be the form of capsule, pouch, paper or other container.When carrier is used as thinner, it can be solid, semisolid or liquid substance, and it can be as carrier, excipient or the medium of active compound.This active compound can with container for example the form of the particulate solid in pouch be absorbed.Some applicable carriers are water, salts solution, alcohol, polyoxyethylene glycol, poly-hydroxyl-oxethyl Viscotrol C, peanut oil, coconut palm pulls oil, gelatin, lactose, terra alba, sucrose cyclodextrin, amylose starch, Magnesium Stearate (magnesium sterate), talcum, gelatin, agar, pectin, gum arabic, stearic acid or cellulosic lower alkyl ether, silicic acid, lipid acid, fatty acid amine, fatty mono glyceride and triglyceride, season becomes tetrol fatty acid ester, polyoxyethylene, hydroxy-methyl cellulose and polyvinylpyrrolidone.Similarly, carrier or thinner can comprise any slow-release material known in the art, and as glyceryl monostearate or distearin, it uses separately or mixes with wax.In preparation, can also comprise wetting agent, emulsifying agent, suspensoid, sanitas, sweeting agent or sweetener.Can prepare preparation of the present invention by methods known in the art, so that quick, the lasting or delayed release after delivery of active ingredients patient to be provided.
This pharmaceutical composition can be aseptic, and if need can with assistant agent, emulsifying agent, buffer reagent and (or) tinting material etc. mixes, as long as it does not react with active compound.
Can be with any administration, as long as it is sent to active medicine suitable or required reactive site effectively, for example oral, nasal cavity, Jing Pi， lung, or administered parenterally, for example in rectum, reservoir, subcutaneous, intravenously, urethra, in intramuscular, nose, ophthalmic solution or ointment, preferably pass through oral administration.
If solid carrier is for oral administration, said preparation can be pressed into tablet, or in incapsulating with powder or bead form, or make lozenge or lozenge.If use liquid vehicle, said preparation can be syrup, emulsion, soft gelatin capsule or aseptic parenteral solution, as water-based or non-aqueous liquid suspension or solution.
For intranasal administration, said preparation can contain dissolving or be suspended in the formula I compound in liquid vehicle, especially aqueous carrier, as aerosol administration.This carrier can contain additive, comprises that solubilizing agent is as propylene glycol, tensio-active agent, and absorption enhancer is as Yelkin TTS (phosphatide phenol choline) or cyclodextrin, or sanitas is as parabens.
For administered parenterally, particularly suitable is injection solution or suspension, preferably the aqueous solution of active compound solvent in polyhydroxylated Viscotrol C.
Tablet, drageeing or the capsule with talcum and/or carbohydrate carrier or tackiness agent etc. are particularly suitable for oral administration.Preferably, the carrier of tablet, drageeing or capsule comprises lactose, W-Gum and/or yam starch.When using while adding sugar carrier, can use syrup or the agent of indulging in.
The typical tablet that can prepare by conventional pressed disc technique can contain:
Core: active compound (free cpds or its salt) 5.0mg
Colloid silica (KCrOSil) 1.5mg
Micro-& Mierocrystalline cellulose (AVicel) 70.0mg
Modified cellulose gum (Ac-Di-Sol) 7.5mg
Magnesium Stearate appropriate (ad.)
The about 9.0mg of coatings: HPMC
* the about 0.9mg of Mywacett 9-40T
* phenolic group monoglyceride is as film-coated softening agent
Preparation method of the present invention is simple, the compound of the general formula I of preparation or its composition is used for the treatment of and/or prevent diabetes syndromes (comprising diabetes cardio cerebrovascular affection, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy etc.).
Fig. 1 is the origin cause of formation and the polyvalent alcohol metabolic map of diabetic complication
By the following examples, explain in detail the present invention, these embodiment just illustrate, and are never in order to limit the scope of the invention.
embodiment:
Embodiment 1
The preparation of 2-(6-methyl isophthalic acid-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
Method according to following flow process 1 is prepared title compound
Flow process 1
(i) preparation of 3-(4-toluidine) propionic acid
To join in 250mL round-bottomed bottle monomethylaniline 21.4g (0.2mol), ethyl propenoate 22.0g (0.22mol) and Glacial acetic acid 1.0mL, be warming up under reflux conditions stirring reaction 15 hours.The remaining ethyl propenoate of pressure reducing and steaming after completion of the reaction, to the aqueous sodium hydroxide solution 100mL that adds 20% in reaction solution, is warming up under reflux conditions stirring reaction 30 minutes.After reaction finishes, reaction solution is chilled to room temperature, adds equal-volume water.Ethyl acetate 180ml (60mL * 3) extracts, water is first adjusted to PH6-7 with concentrated hydrochloric acid, with glacial acetic acid, adjust pH value 5 left and right again, it is muddy that water layer becomes, with ethyl acetate 270ml (90ml * 3), extract, merge organic layer, with saturated aqueous common salt 100ml (50ml * 2) washing, separate organic layer anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate, is fully dried to obtain yellow solid 32.2g, yield 90.0%, mp 80-82 ℃.
(ii) 6-methyl-2, the preparation of 3-dihydro-4 (1H)-quinolinone
200g polyphosphoric acid is joined in 250mL three-necked bottle, be warming up to after 120 ℃, lower minute of agitation condition
Criticize and add 3-(4-toluidine) propionic acid 10g (0.056mol), be warming up to 135 ℃ of stirring reactions 45 minutes.Stirring is transferred and is chilled to 30-40 ℃, and reaction solution is poured in 200g trash ice, with saturated potassium hydroxide aqueous solution, adjusts pH value 10 left and right.Stirring is transferred cold analysis and is gone out yellow solid, and suction filtration is used sherwood oil recrystallization, is dried and obtains yellow solid 6.9g, yield 77.0%, mp 83-84 ℃.
(iii) 1-benzyl-6-methyl-2, the preparation of 3-dihydro-4 (1H) quinolinone
By 8.0g (0.05mol) 6-methyl-2,3-dihydro-4 (1H)-quinolinone, the benzyl chloride of 18.9g (0.15mol), the salt of wormwood of 13.8g (0.1mol), the potassiumiodide of 8.3g (0.05mol), the anhydrous methanol of 40ml joins in the round-bottomed flask of 250ml, be warming up under reflux conditions stirring reaction 8 hours, stopped reaction, is slightly chilled to room temperature, reaction solution is joined in the water of 300ml, fully stir, have a large amount of yellow solids to separate out, suction filtration, vacuum-drying obtains 12.0g, yield 94.5%.If (do not have solid just to separate out and extract by ethyl acetate, merge organic phase, saturated common salt water washing, separates organic layer anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate obtains brown oil, and purifying, does not calculate and is directly used in the next step by theoretical yield.)
(iv) preparation of 2-(6-methyl isophthalic acid-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 1)
By 1-benzyl-6-methyl-2 of upper step reaction gained, 3-dihydro-4 (1H) quinolinone 2.51g (0.01mol) are dissolved in the ethanol of 20ml, 45 ℃ of temperature controls, add 20% NaOH solution 10ml, stirring reaction 10 minutes, add 50% aqueous glyoxylic acid 5.92g (0.03mol), react 4 hours, after reaction finishes, reaction solution is poured in the water of 50ml, the ethyl acetate of 90ml (30ml * 3) is extracted, water is adjusted to PH=2 left and right with concentrated hydrochloric acid, there is light yellow floss to separate out, suction filtration, vacuum-drying, recrystallizing methanol obtains the light yellow cotton-shaped solid of 2.31g, two-step reaction total recovery 75.4%, mp 204-206 ℃.
IR(cm
-1)3429.1，2918.1，2550.5，1724.0，1632.3，1548.4，1496.8，1397.8，1330.3，1300.6，1232.4，1184.7，809.8，698.2.
1H-NMR(DMSO-d
6)δ2.36(3H，s，-CH
3)，3.41(2H，s，-CH
2-)，5.52(2H，s，-CH
2-)，7.19(2H，d，2，6’-ArH)，7.26(1H，t，4’-ArH)，7.33(2H，t，3’，5’-ArH)，7.43(1H，dd，7-ArH)，7.49(1H，d，8-ArH)，7.98(1H，s，5-ArH)，8.25(1H，s，olefinic-H)，12.34(1H，s，-COOH).
The method of describing according to embodiment 1 is prepared following compounds 2-11 (table 1) similarly to replace accordingly benzyl chloride
Structural formula and the physicochemical constant of table 1 embodiment 2-11
Embodiment 12
The preparation of 2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 12)
Method according to following flow process 2 is prepared title compound
Flow process 2
(i) preparation of 3-(4-fluoroanilino) propionic acid
Fluoroaniline 16.65g (0.15mol), ethyl propenoate 16.5g (0.165mol) and Glacial acetic acid 1.0mL are joined in 250mL round-bottomed bottle, be warming up under reflux conditions, stirring reaction 15 hours.The remaining ethyl propenoate of pressure reducing and steaming after completion of the reaction, to the aqueous sodium hydroxide solution 100mL that adds 20% in reaction solution, is warming up under reflux conditions stirring reaction 30 minutes.After reaction finishes, reaction solution is chilled to room temperature, adds equal-volume water; Ethyl acetate 150ml (50mL * 3) extracts, water is first adjusted to PH6-7 with concentrated hydrochloric acid, with glacial acetic acid, adjust pH value 5 left and right again, it is muddy that water layer becomes, with ethyl acetate 180ml (60ml * 3), extract, merge organic layer, with saturated aqueous common salt 100ml (50ml * 2) washing, separate organic layer anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate is fully dried to obtain yellow solid 22.8g, yield 83.2%.
(ii) 6-is fluoro-2, the preparation of 3-dihydro-4 (1H)-quinolinone
200g polyphosphoric acid is joined in 250mL three-necked bottle, be warming up to after 120 ℃, under agitation condition, add after 3-(4-fluoroanilino) propionic acid 10g (0.056mol) in batches, be warming up to 135 ℃ of stirring reactions 45 minutes.Stirring is transferred and is chilled to 30-40 ℃, and reaction solution is poured in 200g trash ice, with saturated potassium hydroxide aqueous solution, adjusts pH value 10 left and right.Stirring is transferred cold analysis and is gone out yellow solid, and suction filtration is dried and obtains yellow solid 7.1g, yield 78.9%, mp 69-71 ℃.
(iii) 1-benzyl-6-is fluoro-2, the preparation of 3-dihydro-4 (1H) quinolinone
By 1.0g (0.006mol) 6-fluoro-2, 3-dihydro-4 (1H)-quinolinone, the benzyl chloride of 2.3g (0.018mol), the salt of wormwood of 1.66g (0.012mol), the potassiumiodide of 1.0g (0.006mol), the anhydrous methanol of 15ml joins in the round-bottomed flask of 50ml, be warming up under reflux conditions stirring reaction 12 hours, stopped reaction, slightly be chilled to room temperature, reaction solution is joined in the water of 80ml, fully stir, there is brown oil to separate out, by the ethyl acetate of 90ml (30ml * 3), extract, merge organic phase, saturated aqueous common salt 40ml (20ml * 2) washing, separate organic layer, anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate obtains brown oil, and purifying, does not calculate and is directly used in the next step by theoretical yield.
(iv) preparation of 2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 12)
By the 1-benzyl-6-fluoro-2 of upper step reaction gained, 3-dihydro-4 (1H) quinolinone is dissolved in the ethanol of 20ml, 45 ℃ of temperature controls, add 20% NaOH solution 6ml, stirring reaction 10 minutes, add 50% aqueous glyoxylic acid 3.55g (0.024mol), react 4 hours, after reaction finishes, reaction solution is poured in the water of 50ml, the ethyl acetate of 90ml (30ml * 3) is extracted, water is adjusted to PH=2 left and right with concentrated hydrochloric acid, there is light yellow floss to separate out, suction filtration, vacuum-drying, recrystallizing methanol obtains the light yellow cotton-shaped solid of 0.66g, two-step reaction total recovery 35.0%, mp 212-215 ℃.
IR(cm
-1)2925.4，2607.4，1718.9，1620.6，1539.9，1497.9，1385.1，1332.9，1255.4，1234.7，1172.2，820.3.
1H-NMR(DMSO-d
6)δ3.43[2H，s，-CH
2-]，5.57[2H，s，-CH
2-]，7.23[2H，d，2’，6’-ArH]，7.33[3H，m，3’，4’，5’-ArH]，7.55[1H，m，7-ArH]，7.70[1H，dd，8-ArH]，7.84[1H，dd，5-ArH，8.33[1H，s，olefinic-H]，12.25[1H，s，-COOH].
The method of describing according to embodiment 14 is prepared following compounds 13-22 (table 2) similarly to replace accordingly benzyl chloride
Structural formula and the physics and chemistry of table 2 embodiment 13-22 are normal
Embodiment 23
The preparation of 2-(6-methoxyl group-1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 27)
Method according to following flow process 3 is prepared title compound
Flow process 3
(i) preparation of 3-(4-anisole amido) propionic acid
P-nethoxyaniline 18.45g (0.15mol), ethyl propenoate 16.5g (0.165mol) and Glacial acetic acid 1.0mL are joined in 250mL round-bottomed bottle, 50 ℃, stirring reaction 15 hours.The remaining ethyl propenoate of pressure reducing and steaming after completion of the reaction, to the aqueous sodium hydroxide solution 100mL that adds 20% in reaction solution, is warming up under reflux conditions stirring reaction 30 minutes.After reaction finishes, reaction solution is chilled to room temperature, adds equal-volume water.Ethyl acetate 150ml (50mL * 3) extracts, and water is first adjusted to PH6-7 with concentrated hydrochloric acid, more slowly adjusts pH value with glacial acetic acid, when PH is 6-5.4, there is a large amount of grey flosss to separate out, suction filtration, vacuum-drying, obtain gray solid 17.0g, yield 68.4%, mp 75-76 ℃.
(ii) 6-methoxyl group-2, the preparation of 3-dihydro-4 (1H)-quinolinone
200g polyphosphoric acid is joined in 250mL three-necked bottle, be warming up to after 120 ℃, under agitation condition, add after 3-(4-anisole amido) propionic acid 10g (0.056mol) in batches, be warming up to 135 ℃ of stirring reactions 45 minutes.Stirring is transferred and is chilled to 30-40 ℃, and reaction solution is poured in 200g trash ice, with saturated potassium hydroxide aqueous solution, adjusts pH value 10 left and right.Stirring is transferred cold analysis and is gone out yellow solid, and suction filtration is dried and obtains yellow solid 7.5g, yield 82.6%, mp 110-111 ℃.
(iii) 1-benzyl-6-methoxyl group-2, (compound 23-1) preparation of 3-dihydro-4 (1H) quinolinone
By 1.0g (0.0056mol) 6-methoxyl group-2, 3-dihydro-4 (1H)-quinolinone, the benzyl chloride of 2.1g (0.0167mol), the salt of wormwood of 1.6g (0.0112mol), the potassiumiodide of 1.0g (0.006mol), the anhydrous methanol of 15ml joins in the round-bottomed flask of 50ml, be warming up under reflux conditions stirring reaction 8 hours, react complete, slightly be chilled to room temperature, reaction solution is joined in the water of 80ml, fully stir, there is brown oil to separate out, by the ethyl acetate of 90ml (30ml * 3), extract, merge organic phase, saturated aqueous common salt 40ml (20ml * 2) washing, separate organic layer anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate obtains brown oil, adopts column chromatography (petroleum: acetic ether=10: 0～1) obtain yellow crystals 0.6g, yield 40.0%, mp 90-93 ℃.
1H-NMR(CDCl
3)δ2.65[2H，t，-CH
2-]，3.54[2H，t，-CH
2-]，3.68[3H，s，-OCH
3]，4.58[2H，s，-CH
2-]，6.78[1H，d，8-ArH]，7.00[1H，dd，7-ArH]，7.20[1H，d，5-ArH]，7.32[5H，m，2’，3’，4’，5’，6’-ArH].
(iv) preparation of 2-(6-methoxyl group-1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 23)
By 1-benzyl-6-methoxyl group-2 of 0.6g (0.002mol), 3-dihydro-4 (1H) quinolinone is dissolved in the ethanol of 20ml, 45 ℃ of temperature controls, add 20% NaOH solution 10ml, stirring reaction 10 minutes, add 50% aqueous glyoxylic acid 1.2g (0.008mol), react 6 hours, after reaction finishes, reaction solution is poured in the water of 50ml, the ethyl acetate of 90ml (30ml * 3) is extracted, water is adjusted to PH=2 left and right with concentrated hydrochloric acid, there is lightpink floss to separate out, suction filtration, vacuum-drying, recrystallizing methanol obtains the cotton-shaped solid of pink colour of 0.46g, yield 61.3%, mp 203-206 ℃.
IR(cm
-1)3430.9，2913.1，1722.2，1625.7，1544.9，1497.0，1400.8，1385.7，1333.1，1300.6，1231.4，1185.0，816.1，697.1.
1H-NMR(DMSO-d
6)δ3.43[2H，s，-
CH 2 COOH]，3.81[3H，s，-OCH
3]，5.54[2H，s，-CH
2-]，7.27[6H，m，7，2’，3’，4’，5’，6’-ArH]，7.58[2H，q，5，8-ArH]，8.26[1H，s，olefinnic-H]，12.33[1H，s，-COOH].
The method of describing according to embodiment 27 is prepared following 1-substituted benzyl-6-methoxyl group-2,3-dihydro-4 (1H) quinolinone midbody compound 24-1～33-1 (table 3) and target compound 24-33 (table 4) similarly to replace accordingly benzyl chloride
Structural formula and the physicochemical constant of table 3 embodiment 24-1～33-1
The structural formula of table 4 embodiment 24～33 and physicochemical constant
Embodiment 34
The preparation of 2-(1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 34)
Method according to following flow process 4 is prepared title compound
Flow process 4
(i) preparation of 3-anilino propionic acid
Aniline 46.5g (0.5mol), the ethyl propenoate 55.0g (0.55mol) and the Glacial acetic acid 3.0mL that heavily steam are joined in 1000mL round-bottomed bottle, be warming up under reflux conditions stirring reaction 17 hours.Water pump decompression pumps remaining ethyl propenoate after completion of the reaction, to the aqueous sodium hydroxide solution 300mL that adds 20% in reaction solution, is warming up under reflux conditions stirring reaction 50 minutes.After reaction finishes, reaction solution is chilled to room temperature, adds equal-volume water.Ethyl acetate 300ml (100mL * 3) extracts, and water is adjusted pH value 5 left and right with glacial acetic acid, and it is muddy that water layer becomes, with 450ml (150ml * 3), extract, merge organic layer, with saturated aqueous common salt 100ml (50ml * 2) washing, separate organic layer anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate is fully dried to obtain standing curing yellow solid 56.9g, the yield 69.0% of becoming of oily matter.Mp 60-61 ℃ (document mp 58-60 ℃)
(ii) 2, the preparation of 3-dihydro-4 (1H)-quinolinone
1000g polyphosphoric acid is joined in 1000mL three-necked bottle, be warming up to after 120 ℃, under agitation condition, add after 3-anilino propionic acid 56.0g in batches, be warming up to 135 ℃ of stirring reactions 45 minutes.After completion of the reaction reaction solution is poured in 300g trash ice, with saturated potassium hydroxide aqueous solution, adjusted pH value 10 left and right.Stirring is transferred and is chilled to 30-40 ℃, is extracted with ethyl acetate (100ml * 3), merges organic layer, with saturated aqueous common salt (80mL * 2), is washed till neutrality, with anhydrous sodium sulfate drying, reclaims dry red-brown oily matter 47g, the yield 80% of obtaining of ethyl acetate.Mp 41-43 ℃ (document: mp43-44.5 ℃).
(iii) 1-benzyl-2, the preparation of 3-dihydro-4 (1H) quinolinones (compound 34-1)
By 1.0g (0.068mol) 2, 3-dihydro-4 (1H)-quinolinone, the benzyl chloride of 2.58g (0.0204mol), the salt of wormwood of 1.88g (0.0136mol), the potassiumiodide of 1.13g (0.068mol), the anhydrous methanol of 15ml joins in the round-bottomed flask of 50ml, be warming up under reflux conditions stirring reaction 24 hours, react complete, slightly be chilled to room temperature, reaction solution is joined in the water of 80ml, fully stir, there is brown oil to separate out, by the ethyl acetate of 90ml (30ml * 3), extract, merge organic phase, saturated aqueous common salt 40ml (20ml * 2) washing, separate organic layer anhydrous sodium sulfate drying.Elimination siccative, reclaim under reduced pressure ethyl acetate obtains brown oil, adopts column chromatography (petroleum: acetic ether=10: 0～1) obtain yellowish green solid 1.38g, yield 86.25%, mp 118-120 ℃.
1H-NMR(CDCl
3)δ2.75[2H，t，-CH
2-]，3.60[2H，t，-CH
2-]，4.57[2H，s，-CH
2-]，6.72[2H，m，6，8-ArH]，7.35[6H，m，7，2’，3’，4’，5’，6’-ArH]，7.92[1H，dd，5-ArH]
(iv) preparation of 2-(1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid (compound 34)
By 1-benzyl-2 of 1.38g (5.8mmol), 3-dihydro-4 (1H) quinolinone is dissolved in the ethanol of 20ml, 45 ℃ of temperature controls, add 20% NaOH solution 5ml, stirring reaction 10 minutes, adds 50% aqueous glyoxylic acid 3.43g (0.0232mol), reacts 24 hours, after reaction finishes, reaction solution is poured in the water of 50ml, the ethyl acetate of 90ml (30ml * 3) is extracted, and water is adjusted to PH=2 left and right with concentrated hydrochloric acid, there is canescence floss to separate out, suction filtration, vacuum-drying, obtains pale solid 0.63g, yield 36.9%, mp 193-197 ℃.
IR(cm
-1)3439.4，3062.6，1749.8，1615.6，1555.2，1527.9，1456.3，1385.8，1332.9，1237.3，763.0，698.0.
1H-NMR(DMSO-d
6)δ3.42[2H，s，-CH
2COOH]，5.54[2H，s，-CH
2-]，7.31[6H，m，7，2’，3’，4’，5’，6’-ArH]，7.60[2H，m，6，8-ArH]，8.20[1H，d，5-ArH]，8.30[1H，s，olefinnic-H]，12.23[1H，s，-COOH].
The method of describing according to embodiment 34 is prepared following 1-substituted benzyl-2,3-dihydro-4 (1H) quinolinone midbody compound 35-1～44-1 (table 5) compound 35-44 (table 6) similarly to replace accordingly benzyl chloride
Structural formula and the physicochemical constant of table 5 embodiment 35-1～44-1
The structural formula of table 6 embodiment 35～44 and physicochemical constant
The experiment of aldose reductase (Aldose Reductase) inhibitor screening
One. experimental principle
Aldose reductase in rat eye lens tissue, take DL-Glycerose as substrate detection aldose reductase activity.Observe sample the activity of enzyme is suppressed, with the inhibition of assess sample.The positive reference compound adopting is Epalrestat.
Two. test method
In 200uL reaction system, contain aldose reductase, 0.1M potassium phosphate buffer (PH7.0), and sample, be both and set up blank (not containing enzyme and sample) and negative control group (not containing sample), 37 ℃ of reaction 10min, add NADPH (Roche, 10621692001) and DL-Glycerose (SIGMA, G-5001), 37 ℃ of reaction 20min, 340nm measures OD value.According to OD value, calculate inhibiting rate, inhibiting rate=[1-(OD sample-OD is blank)/(OD feminine gender-OD is blank)] * 100.During primary dcreening operation, the single concentration of each sample is established two multiple holes, the sample determination IC50 value that inhibiting rate is greater than 50%, and six concentration of each sample gradient dilution, each concentration is established two multiple holes.According to inhibiting rate, the 4Parameter Logistic Model in application Xlfit software calculates IC50. epalrestat molecular weight 319.4 IC
50=0.075 μ mol/L.
Claims (6)
1. following compound or its pharmacy acceptable salt:
2-(6-methyl isophthalic acid-phenmethyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
2-[6-methyl isophthalic acid-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2,4-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methyl isophthalic acid-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
The fluoro-1-of 2-[6-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2,4-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
The fluoro-1-of 2-[6-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-(6-methoxyl group-1-phenmethyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
2-[6-methoxyl group-1-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2,4-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[6-methoxyl group-1-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-(1-phenmethyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
2-[1-(4-aminomethyl phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-p-methoxy-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2-fluorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(3-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-chloro-phenyl-) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2,4 dichloro benzene base) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(2-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-bromophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid
2-[1-(4-tert-butyl-phenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl] acetic acid.
2. a method of preparing compound described in claim 1, the method comprises:
(1)
the preparation of 2-(6-methyl isophthalic acid-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 6-methyl-2,3-dihydro-4 (1
h)-quinolinone is raw material, carries out with benzyl chloride
n-alkylation reaction obtains 1-benzyl-6-methyl-2,3-dihydro-4 (1
h) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(6-methyl isophthalic acid-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid;
(2)
the preparation of 2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
Fluoro-2 with 6-, 3-dihydro-4 (1
h)-quinolinone is raw material, carries out with benzyl chloride
nit is fluoro-2 that-alkylation reaction obtains 1-benzyl-6-, 3-dihydro-4 (1
h) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(the fluoro-1-benzyl-4-of 6-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid;
(3)
the preparation of 2-(6-methoxyl group-1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 6-methoxyl group-2,3-dihydro-4 (1
h)-quinolinone is raw material, carries out with benzyl chloride
n-alkylation reaction obtains 1-benzyl-6-methoxyl group-2,3-dihydro-4 (1
h) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(6-methoxyl group-1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid;
(4) 2-(1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid
With 2,3-dihydro-4 (1
h)-quinolinone is raw material, carries out with benzyl chloride
n-alkylation reaction obtains 1-benzyl-2,3-dihydro-4 (1
h) quinolinone, then carry out Claisen-Schmidt condensation reaction with oxoethanoic acid and obtain 2-(1-benzyl-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-yl) acetic acid.
3. a medicinal compositions, it comprises described in claim 1 compound or its pharmacy acceptable salt and pharmaceutically acceptable auxiliary material, diluent or carrier.
4. compound claimed in claim 1 or its pharmacy acceptable salt are treated the purposes in diabetes complicated disease drug in preparation.
5. the preparation method of a medicinal compositions as claimed in claim 3, it is characterized in that: compound claimed in claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable auxiliary material, diluent or carrier are mixed, wherein contain the active compound of 5-20% weight.
6. purposes according to claim 4, is characterized in that: described diabetic complication is diabetes cardio cerebrovascular affection, diabetic nephropathy, diabetic neuropathy or diabetic retinopathy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910011915.1A CN101654435B (en) | 2009-06-09 | 2009-06-09 | N-benzyl quinoline carboxylic acid compound, combination and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910011915.1A CN101654435B (en) | 2009-06-09 | 2009-06-09 | N-benzyl quinoline carboxylic acid compound, combination and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101654435A CN101654435A (en) | 2010-02-24 |
| CN101654435B true CN101654435B (en) | 2014-01-29 |
Family
ID=41708920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910011915.1A Expired - Fee Related CN101654435B (en) | 2009-06-09 | 2009-06-09 | N-benzyl quinoline carboxylic acid compound, combination and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101654435B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565602B (en) * | 2016-10-28 | 2020-09-08 | 常州市阳光药业有限公司 | Preparation method of 4-chloro-6-fluoroquinoline |
| CN111533729B (en) * | 2020-05-07 | 2022-07-26 | 盐城工学院 | Tetrazole-substituted quinolinone derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060128689A1 (en) * | 2004-11-24 | 2006-06-15 | Arthur Gomtsyan | Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof |
| CN101058558A (en) * | 2007-05-28 | 2007-10-24 | 沈阳药科大学 | 4-Oxy-1(4H)-quinoline carboxylic acids compound and composition with aldose reductase inhibition activity and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102004004972B3 (en) * | 2004-01-31 | 2005-09-15 | Aventis Pharma Deutschland Gmbh | Heterocyclic substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments |
| EP2522670A1 (en) * | 2004-04-07 | 2012-11-14 | Takeda Pharmaceutical Company Limited | Heterocyclic CRF receptor antagonists |
| CN101429160B (en) * | 2007-11-06 | 2011-10-19 | 上海药明康德新药开发有限公司 | Synthesis method of 1-R-4-amino-1,2,3,4-tetrahydroquinoline |
-
2009
- 2009-06-09 CN CN200910011915.1A patent/CN101654435B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060128689A1 (en) * | 2004-11-24 | 2006-06-15 | Arthur Gomtsyan | Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof |
| CN101058558A (en) * | 2007-05-28 | 2007-10-24 | 沈阳药科大学 | 4-Oxy-1(4H)-quinoline carboxylic acids compound and composition with aldose reductase inhibition activity and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 1,2,3,4-四氢喹啉-4-酮衍生物的线性及非线性光学性质;吴伟兵 等;《化学学报》;20081231;第66卷(第14期);第1700-1706页 * |
| 吴伟兵 等.1,2,3,4-四氢喹啉-4-酮衍生物的线性及非线性光学性质.《化学学报》.2008,第66卷(第14期),第1700-1706页. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101654435A (en) | 2010-02-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5002077B2 (en) | Novel 3-hydroxy-5-arylisothiazole derivatives | |
| CN101058558B (en) | 4-Oxy-1(4H)-quinoline carboxylic acids compound and composition with aldose reductase inhibition activity and preparation method thereof | |
| US20120184563A1 (en) | Composition for external application comprising aripiprazole and organic acid as active ingredients | |
| CN102766099B (en) | There is compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity | |
| CN103391932B (en) | For suppressing the heterogeneous ring compound of PASK | |
| CN106748922A (en) | The new sulfone acid derivative of one class, its preparation method and its purposes as medicine | |
| CN101654435B (en) | N-benzyl quinoline carboxylic acid compound, combination and preparation method thereof | |
| CN103102322B (en) | Oxazole compounds and preparation method thereof, medical composition and its use | |
| WO2007046544A1 (en) | Preparation for external application comprising salt of mast cell degranulation inhibitor having carboxyl group with organic amine | |
| CN101429183B (en) | 2H-1-benzopyran-2-ketone compounds with alpha-glucosidase inhibit activity, its composition and preparation method thereof | |
| CN104245696A (en) | Compounds as inhibitors of diacylglycerol O-acyltransferase type 1 enzyme | |
| CN101580496A (en) | 5-substituted phenyl-3-isoxazole carboxylic acid and ester compounds, compositions and preparation method thereof | |
| CN101580495A (en) | 5-substituted phenyl-3-isoxazole carboxylic acid and ester compounds, compositions and preparation method thereof | |
| CN102382036A (en) | Phenoxyacetic acid compound, preparation method thereof and drug application | |
| AU2020287549A1 (en) | Therapeutic for gout or hyperuricemia | |
| US20240173296A1 (en) | Pharmaceutical composition of (s)-ketorolac and preparation method therefor | |
| CN105407884A (en) | Methods for reducing triglyceride, total cholesterol and low density lipoprotein blood levels | |
| CN102382037B (en) | Phenylpropionic acid compound and method for making thereof and pharmaceutical use | |
| CN105541752B (en) | The preparation method of the acetogenin of 2 (imino group of 4 oxothiazoiium quinoline 2) thiazole 4 and application | |
| JP6732351B1 (en) | Isoquercitrin composition | |
| CN101492461B (en) | Benzimidazole derivative containing alkoxyl oxygen alkyl ethyl substituted pyridine-tetrahydrochysene isoxazole | |
| CN110183349B (en) | Oxalyl hydrazone derivative and preparation method and application thereof | |
| CN113896688A (en) | Application of triazolethione derivative in preparation of novel coronavirus inhibitor | |
| CN108358856B (en) | It is a kind of prevent and treat peptic ulcer drug with and its preparation method and application | |
| CN117924252A (en) | Quinazoline-carbazole skeleton derivative and antidiabetic activity thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140129 Termination date: 20180609 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |