CN100386326C - 1-methylolimidazole [1,2-alpha] quinoxaline compound and its application - Google Patents
1-methylolimidazole [1,2-alpha] quinoxaline compound and its application Download PDFInfo
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- CN100386326C CN100386326C CNB2003101018786A CN200310101878A CN100386326C CN 100386326 C CN100386326 C CN 100386326C CN B2003101018786 A CNB2003101018786 A CN B2003101018786A CN 200310101878 A CN200310101878 A CN 200310101878A CN 100386326 C CN100386326 C CN 100386326C
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Abstract
The present invention relates to a substituted 1-hydroxymethylimidazole and [1, 2-a] quinoxaline compound with a general formula I or medicinal salt thereof. The definition of each group in the formula is given in the specification. The present invention discloses the compound, the medicinal composition thereof, and the application of the medicinal composition as an adenosine receptor antagonist in the prevention or the treatment of depression, cognitive defect, renal failure, asthma, acute respiratory distress syndrome, arrhythmia, sudden cardiac arrest, etc.
Description
Invention field
The present invention relates to also [1,2-a] quinoxaline compounds of 1-hydroxy methylimidazole, its preparation method contains their medicinal compositions and as adenosine A
1The purposes of receptor antagonist aspect illnesss such as prevention or treatment depression, cognitive defect, renal failure, asthma, acute respiratory distress disease, heart disorder, sudden cardiac arrest.
Background technology
Adenosine is a kind of important neurotransmitter and/or neuroregulator, discharges, causes that by suppressing some neurotransmitter the neurone hyperpolarization reduces modes such as neuronal excitability and the transmission of change aixs cylinder and suppresses the neurotransmission function.Selective adenosine A
1Receptor antagonist has been developed illnesss such as being used for the treatment of depression, cognitive defect, renal failure, heart disorder, sudden cardiac arrest.Adenosine receptor antagonists also can be used for treating allergic inflammation reaction and asthma.Studies show that adenosine A
1Receptor antagonist can block because smooth muscle contraction (the Nyce ﹠amp that respiratory distress syndrome (ivrds) causes; Metzger DNA anti senseTherapy for Asthma in an Animal Model.Nature 1997,385:721).
U.S.Pat.No.6,124,287 and Eur.J.Med.Chem.1998,33,943-955 described imidazoles or 1-Methylimidazole also [1,2-a] quinoxaline-4-aminated compounds be the potent antagonist of Adenosine Receptors.This compounds side effect incidence is low.But the poor solubility of this compounds is difficult to find suitable dissolution with solvents administration.
As everyone knows, change medicinal compound into salt and can improve solubleness to a certain extent, but for this compounds, even become salt, the improvement of solubleness is also limited.Therefore need alternate manner
The invention summary
The objective of the invention is searching and developmental function in adenosine A
1The non-xanthine organic micromolecule compound of acceptor is used for illnesss such as prevention or treatment depression, cognitive defect, renal failure, asthma, acute respiratory distress disease, heart disorder, sudden cardiac arrest.
We surprisingly find, introduce methylol 1 of imidazo [1,2-a] quinoxaline and can significantly improve its solvability.The choice of Solvent scope is broadened, and it all is favourable bringing into play drug effect and carry out various researchs for medicine.Our synthetic 1-hydroxy methylimidazole also [1,2-a] quinoxaline compounds solvability and imidazoles or 1-Methylimidazole also [1,2-a] quinoxaline-4-aminated compounds compare and improve a lot.And still keep high-affinity to Adenosine Receptors.
The present invention has now found that the compound of following general formula I has high-affinity for Adenosine Receptors, and therefore formula I compound of the present invention can be used for prevention or treats illnesss such as depression, cognitive defect, renal failure, asthma, acute respiratory distress disease, heart disorder, sudden cardiac arrest.
First aspect present invention relates to formula I compound or pharmaceutically acceptable salt thereof:
Wherein:
R
1Be alkyl, cycloalkyl, aryl or heterocyclic radical; Described alkyl also can be replaced by aryl, list or disubstituted amido or heterocyclic radical, and wherein An Ji substituting group is selected from alkyl or cycloalkyl, and wherein heterocyclic radical can also be replaced by alkyl, and wherein alkyl can also be replaced by aryl; Described heterocyclic radical can be replaced by alkyl.
R
2Be substituting groups such as hydrogen or halogen, alkyl or haloalkyl; N is 1 or 2, when n is 2, and two R
2Can be different, also can be symmetric double substituting groups such as dihalo, dialkyl group or dihalo alkyl.
R is H or hydroxyl protecting group.
As required, gained formula I compound can change its pharmaceutical salts into suitable medicinal acid.
The present invention relates to pharmaceutical composition on the other hand, comprising at least a formula I compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier or vehicle.
Further aspect of the present invention relates at least a formula I compound or pharmaceutically acceptable salt thereof is used for preventing or treat the medicine of illnesss such as depression, cognitive defect, renal failure, acute respiratory distress disease, heart disorder, sudden cardiac arrest in preparation purposes.
The invention still further relates to the method for illnesss such as prevention or treatment depression, cognitive defect, renal failure, asthma, acute respiratory distress disease, heart disorder, sudden cardiac arrest, it comprises the patient that at least a formula I compound or pharmaceutically acceptable salt thereof that will prevent and/or treat effective dose gives to prevent and/or treat prevention or treats illnesss such as depression, cognitive defect, renal failure, asthma, acute respiratory distress disease, heart disorder, sudden cardiac arrest.
Detailed Description Of The Invention
First aspect present invention relates to formula I compound or pharmaceutically acceptable salt thereof:
Wherein:
R
1Be alkyl, cycloalkyl, aryl or heterocyclic radical; Described alkyl also can be replaced by aryl, list or disubstituted amido or heterocyclic radical, and wherein An Ji substituting group is selected from alkyl or cycloalkyl, and wherein heterocyclic radical can also be replaced by alkyl, and wherein alkyl can also be replaced by aryl; Described heterocyclic radical can be replaced by alkyl.
R
2Be substituting groups such as hydrogen or halogen, alkyl or haloalkyl; N is 1 or 2, when n is 2, and two R
2Can be different, also can be symmetric double substituting groups such as dihalo, dialkyl group or dihalo alkyl.
R is H or hydroxyl protecting group.
In the above-mentioned definition, alkyl is meant C
1～C
8The straight or branched alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl etc.; Preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl, neo-pentyl, n-hexyl, n-octyl etc.
Cycloalkyl is meant C
3～C
6Cycloalkyl, for example cyclopropyl, cyclobutyl, methyl cyclopropyl, cyclopentyl, methyl cyclobutyl, ethyl cyclopropyl, dimethyl cyclopropyl, cyclohexyl, methylcyclopentyl etc., preferred cyclopentyl, cyclohexyl etc.
Above-mentioned aryl is meant C
6～C
10Aryl, for example phenyl, tolyl, xylyl, naphthyl etc., preferred phenyl.
Above-mentioned heterocyclic radical is meant the nitrogenous of 5 yuan or 6 yuan or contains the saturated heterocyclyl of oxygen and nitrogen, for example pyrrolidyl (Pyrrolidine base), piperazinyl, piperidyl, morpholinyl etc., preferred pyrrolidyl, piperazinyl, morpholinyl etc.
Above-mentioned halogen is meant fluorine, chlorine, bromine and iodine.
Above-mentioned substituted alkyl is meant the alkyl of the above-mentioned definition of group (aryl, alkyl or cycloalkyl list or dibasic amino, the heterocyclic radical) replacement with above-mentioned definition.
The above-mentioned heterocyclic radical that is replaced by alkyl is meant the heterocyclic radical of the above-mentioned definition that is replaced by the alkyl of above-mentioned definition.
Above-mentioned haloalkyl is meant by above-mentioned halogen list replacement, two replacements, three and replaces or polysubstituted abovementioned alkyls.
Above-mentioned hydroxyl protecting group is meant and is conventionally used as to hydroxyl protecting group; can pass through such as hydrogenation; the group that can form ehter bond or ester bond etc. that hydrolysis etc. are sloughed with hydroxyl; methyl for example; the tertiary butyl; allyl group; benzyl; trityl; by the trityl of replacements such as methoxyl group; trimethyl silyl; t-butyldimethylsilyl; THP trtrahydropyranyl; tetrahydrofuran base; tetrahydrochysene sulfo-pyranyl; thienyl; formaldehyde acetal; the pimelinketone acetal; methylthiomethyl; acetoxyl group; benzoyloxy; adjacent; between; the p-nitrophenyl methanoyl; methanoyl; trifluoroacetyl oxygen base; the chloroethene acyloxy; the methoxyl group acetoxyl group; the phenoxy group acetoxyl group; methoxycarbonyl; ethoxycarbonyl; isobutyl boc; carbobenzoxy-(Cbz); 2; 2; the 2-trichloro-ethoxycarbonyl; 2; 2; 2-tribromo ethoxycarbonyl; p-nitrophenyl oxygen carbonyl; phenylcarbamoyl; the benzyl thiocarbonyl group; new pentane acyloxy; 3-benzoyl acetoxyl group; the benzoyl formyl radical; the amber acyloxy; cautious each acyloxy; adjacent carbobenzoxy-(Cbz) benzoyl; 3-phenylpropyl alcohol acyloxy; nitro; tolysulfonyl oxygen base; 2; 4-2,4-dinitrophenoxy sulfonyloxy; the alkoxyl group ethanoyl; methoxymethyl; the 1-ethoxyethyl group; the benzoyl methyl; trimethyl silyl; triethylsilyl; β-trimethylsilylethoxymethyl; the benzoyloxy carbonyl, and other conventional hydroxyl protecting groups etc.
Above-claimed cpd, derivative and salt can form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges described activeconstituents in vivo after the metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.
According to preferred implementation of the present invention, unsubstituted alkyl is methyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl, n-hexyl, n-octyl etc.; The alkyl that is replaced by aryl, alkyl or cycloalkyl list or dibasic amino, heterocyclic radical is benzyl, 3-dimethylamino-2,2-dimethyl propyl, 3-hexamethylene aminopropyl, 2-(morpholine-4-yl) ethyl, 3-(morpholine-4-yl) propyl group, (1-ethyl Pyrrolidine-2-yl) methyl, 2-(Pyrrolidine-4-yl) ethyl etc.; Substituted heterocyclic radical is 2,2,6,6-tetramethyl piperidine-4-base, 1-benzyl piepridine-4-base etc.; Haloalkyl is a trifluoromethyl etc.
According to the present invention, the compound below formula I compound or pharmaceutically acceptable salt thereof of the present invention is preferred:
N-sec.-propyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-n-propyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-normal-butyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-n-octylcyclam-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-phenyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-benzyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-1-methyl alcohol also
N-(3-dimethylamino-2,2-dimethyl propyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2-(morpholine-4-yl) ethyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-(morpholine-4-yl) propyl group)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2,2,6,6-tetramethyl piperidine-4-yl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-normal-butyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-benzyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-n-pentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-(3-dimethylamino-2,2-dimethyl propyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2-(morpholine-4-yl) ethyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2,2,6,6-tetramethyl piperidine-4-yl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-(morpholine-4-yl) propyl group)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-normal-butyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-benzyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-n-propyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-isobutyl--7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-normal-butyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-benzyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-n-hexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(3-dimethylamino-2,2-dimethyl propyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(2-(Pyrrolidine-4-yl) ethyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(2-(morpholine-4-yl) ethyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(3-(morpholine-4-yl) propyl group)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(2,2,6,6-tetramethyl piperidine-4-yl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-[(1-ethyl Pyrrolidine-2-yl) methyl]-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(1-benzyl piepridine-4-yl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preferably, compound is selected from:
N-cyclopentyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also.
According to the present invention, the pharmacologically acceptable salt of The compounds of this invention comprises its inorganic or organic acid salt, comprising but be not limited to: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, oxalate, pivalate, adipate, alginate, oxyacetate, lactic acid salt, pyruvate salt, glycollate, Citrate trianion, tartrate, malonate, succinate, maleate, fumarate, trifluoroacetate, picrate, aspartate, gluconate, benzoate, salicylate, para-aminosalicylic acid salt, ascorbate salt, mesylate, esilate, benzene sulfonate, tosilate and embonate etc.
In addition, contain in above-mentioned protecting group under the situation of acidity or basic group, above-claimed cpd also can form the form of pharmacologically acceptable salt with atoxic alkali or acid.The example of acid comprises above-mentioned mineral acid or organic acid.The example of base addition salt form is basic metal or alkaline earth salts such as sodium, potassium, calcium salt, and the salt that forms with the acceptable amine of pharmacy, and described amine is such as ammonia, alkylamine, aniline and basic aminoacids, such as arginine and Methionin etc.
Can be according to the synthetic formula I compound or pharmaceutically acceptable salt thereof of the present invention of method well known in the art.
Therefore specifically, because compound of Formula I has 3 rings, can set up two other rings from any ring wherein.Concrete, can be from phenyl ring, first synthesizing quinoxaline ring and then structure imidazole ring; In addition, also can first synthesis of phenyl imidazoles, build quinoxaline ring etc. then.
Synthetic route 1:
Can adopt with the quinoxaline is the synthetic compound of the present invention of method that imidazole ring is taken on the basis.From for example 2,3-dihalo substituted quinoxaline (IV) sets out, protect hydroxyl 1 with for example 1-amino-3-tetrahydro-pyran oxy-2-propyl alcohol 3-amino-1-such as (III), reactions such as 2-propylene glycol compound obtain 2-(beta-hydroxy-gamma-tetrahydro-pyran oxy propyl group amino)-3-halo substituted quinoxaline that logical formula V is represented; Hydroxyl among the oxidation 2-(beta-hydroxy-gamma-tetrahydro-pyran oxy propyl group amino) obtains 2-(β-oxo-γ-tetrahydro-pyran oxy propyl group amino)-3-halo substituted quinoxaline that general formula (VI) is represented then; Cyclization afterwards forms imidazo quinoxaline compounds (VII); The last reaction with the precursor amine that constitutes the 3-substituted amido obtains target compound (I), and target compound (I) can also be converted into its pharmacologically acceptable salt with acid-respons as required.
Substep is described below:
Generate the reaction of (III): can react in the presence of acid catalyst such as tosic acid, sulfuric acid, methylsulfonic acid etc. with R-GLYCIDOL and dihydropyrane, obtain epoxypropyl-THP trtrahydropyranyl ether (II), then epoxy group(ing) ammonia being separated open loop can obtain.The reaction that generates epoxypropyl-THP trtrahydropyranyl ether (II) can be carried out having under solvent or the solvent-free condition, under the situation of using solvent, exceeding by the solubilizing reaction mixture, the amount of solvent can be selected arbitrarily, solvent can use strong polarity, weak polar solvent or non-polar solvent, preferably as methyl alcohol, ethanol, Virahol, propyl carbinol, dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMA), methyl-sulphoxide (DMSO), tetrahydrofuran (THF) (THF), acetone, ether, methylene dichloride, chloroform, tetracol phenixin, pentamethylene, hexanaphthene, normal hexane, benzene, toluene, dimethylbenzene etc., preferred polar aprotic solvent such as DMF, DMA, DMSO, THF, acetone, ether, methylene dichloride, chloroform etc.; Temperature of reaction can be selected arbitrarily, for example be lower than room temperature as-50 ℃ of reflux temperatures to reaction mixture as more than+80 ℃, preferred 0 ℃ of reflux temperature to reaction mixture is as+80 ℃, more preferably room temperature (about+25 ℃) to the reflux temperature that is lower than reaction mixture as about+60 ℃.The condition of ammonolysis reaction for example can be at ammoniacal liquor-methyl alcohol, ammoniacal liquor-ethanol, NH
3-methyl alcohol, NH
3-ethanol, NH
3Carry out among-the THF etc.; Low-grade fever can not be heated or add in reaction, condition be ammonia non-volatile and the reaction carry out only slow.As long as can slough in the reaction of back step, the protective material of above-mentioned hydroxyl also can use other group, various hydroxyl protecting groups as previously described etc.Above-mentioned reaction can be isolated by conventional separation means and be carried out dropping into the next step behind the purifying through chromatography, distillation etc. after respectively going on foot reaction product, also can directly enter the next step with crude product, can also do not separated, adopt the mode of so-called " treating different things alike " to carry out.
Generate the reaction of (V): 2; 3-dihalo quinoxaline derivatives (IV) is protected hydroxyl 1 with above-mentioned 1-amino-3-tetrahydro-pyran oxy-2-propyl alcohol 3-amino-1-such as (III); 2-propylene glycol compound etc. reacts in the presence of alkaline catalysts, obtains 2-(beta-hydroxy-gamma-tetrahydro-pyran oxy propyl group amino)-3-halo substituted quinoxaline that logical formula V is represented.2,3-dihalo quinoxaline derivatives (IV) can use same halogen atom, also can be different, for example can adopt commercially available various 2,3-dichloro-quinoxaline or 2,3-two bromo quinoxalines, the Fluka that this compounds can be familiar with from for example this area, catalogues such as Aldrich obtain.Employed alkaline catalysts is by mineral alkali in the reaction, as alkali metallic sodium, potassium, alkaline earth metals calcium etc., basic metal or alkaline earth metal hydride sodium hydride, hydrolith etc., alkali metal hydroxide sodium hydroxide, potassium hydroxide etc., alkaline earth metal hydroxides such as calcium hydroxide; Organic bases is as quaternary ammonium salt tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide etc.; Tertiary amine such as Trimethylamine 99, triethylamine, pyridine, right-Dimethylamino pyridine (DMAP); Heterocyclic amine such as piperazine, piperidines, morpholine etc.Preferred organic amine, more preferably tertiary amine such as triethylamine, DMAP etc.Solvent can use strong polarity, weak polar solvent or non-polar solvent, as DMF, DMA, DMSO, THF, acetone, ether, methylene dichloride, chloroform, tetracol phenixin, pentamethylene, hexanaphthene, normal hexane, benzene,toluene,xylene etc., preferred polar aprotic solvent such as acetone, ether, THF, methylene dichloride, chloroform etc.; Temperature of reaction can be selected arbitrarily, and for example the reflux temperature from the room temperature to the reaction mixture preferably carries out under heating, more preferably arrives about the reflux temperature of reaction mixture at about 40 ℃.
Generate the reaction of (VI): compound (V) alcohol obtains compound (VI) ketone through peroxidation.Reaction can adopt conventional various oxygenants to carry out, for example dichromate (sodium salt, sylvite etc.), dichromate-sulfuric acid, chloro-chromic acid-pyridine, chromic anhydride, chromic anhydride-pyridine, Manganse Dioxide, permanganate etc.Solvent can use non-proton strong polarity, weak polar solvent or non-polar solvent, as DMF, DMA, DMSO, THF, acetone, ether, methylene dichloride, chloroform, tetracol phenixin, pentamethylene, hexanaphthene, normal hexane, benzene,toluene,xylene etc., preferred polar aprotic solvent such as acetone, ether, THF, methylene dichloride, chloroform etc.Temperature of reaction can be selected arbitrarily, can heat or not heat and carry out, and is too violent for fear of reaction, preferably do not heat or only adds low-grade fever and react.
Generate the reaction of tricyclic compound (VII): the protecting group that compound (VI) ketone is sloughed hydroxyl, cyclization simultaneously, and the halogen of 3 of quinoxalines is oxidized to ketone, form imidazo quinoxaline compounds (VII).The deprotection base can adopt the conventional method of sloughing protecting group such as trifluoroacetic acid, trifluoroacetic anhydride (TFAA), hydrogenation etc.Solvent can use strong polarity, weak polar solvent or non-polar solvent, as DMF, DMA, DMSO, THF, acetone, ether, methylene dichloride, chloroform, tetracol phenixin, pentamethylene, hexanaphthene, normal hexane, benzene,toluene,xylene etc., preferred polar aprotic solvent such as acetone, ether, THF, methylene dichloride, chloroform etc.; Temperature of reaction can be selected arbitrarily, and for example the reflux temperature from the room temperature to the reaction mixture preferably carries out under heating, more preferably arrives about the reflux temperature of reaction mixture at about 40 ℃.
Generate the reaction of target compound (I): compound (VII) obtains target compound (I) with the precursor amine reaction that constitutes the 3-substituted amido.Be reflected under the existence of acid or alkaline catalysts and carry out acid catalyst such as tosic acid, sulfuric acid, methylsulfonic acid etc.Solvent can use strong polarity, weak polar solvent or non-polar solvent, as DMF, DMA, DMSO, THF, acetone, ether, methylene dichloride, chloroform, tetracol phenixin, pentamethylene, hexanaphthene, normal hexane, benzene,toluene,xylene etc., preferred polar aprotic solvent such as acetone, ether, THF, methylene dichloride, chloroform etc.; Temperature of reaction can be selected arbitrarily, and for example the reflux temperature from the room temperature to the reaction mixture preferably carries out under heating, more preferably arrives about the reflux temperature of reaction mixture at about 40 ℃.
Target compound (I) can also be converted into its pharmacologically acceptable salt with acid-respons as required.Methylol also can be added protecting group or prodrugization as required.Halogen definition in the above-claimed cpd is the same, can be halogen atoms such as chlorine, bromine, iodine.
Synthetic route 2
Also can adopt first synthesis of phenyl imidazoles to build the synthetic The compounds of this invention of mode of quinoxaline ring then.Concrete, for example can make by R
21-halo-2-oil of mirbane that replaces and hydroxy methylimidazole reaction obtain 1-(α-nitro-R that general formula (VIII) is represented
2Substituted-phenyl)-(wherein the raw material hydroxy methylimidazole can use commercially available prod (for example can obtain the hydrochloride of hydroxy methylimidazole from Aldrich) or synthetic according to following route to the 5-hydroxy methylimidazole: L-fructose and the reaction of ammoniacal liquor formaldehyde solution, obtain the picrate of hydroxy methylimidazole then with the picric acid reaction, acidifying again, alkalization obtains then); Methylol is protected with for example ethanoyl etc., obtain the hydroxymethyl protection shown in the general formula (IX) 1-(α-nitro-R
2Substituted-phenyl)-5-protects hydroxy methylimidazole; With reduction nitros such as hydrazine hydrates, obtain the 1-(alpha-amino group-R shown in the general formula (X) afterwards
2Substituted-phenyl)-5-protects hydroxy methylimidazole; Under effects such as cyclization agent such as carbonyl dimidazoles (CDI), cyclization forms imidazo quinoxaline compounds (XI) then; The last reaction with the precursor amine that constitutes the 3-substituted amido obtains target compound (I), and target compound (I) can also be converted into its pharmacologically acceptable salt with acid-respons as required.Halogen definition in the above-claimed cpd is the same, can be halogen atoms such as fluorine, chlorine, bromine, iodine.
Generate the reaction of (VIII): R
21-halo-2-oil of mirbane that replaces and hydroxy methylimidazole reaction obtain 1-(α-nitro-R that general formula (VIII) is represented
2Substituted-phenyl)-the 5-hydroxy methylimidazole.Be reflected under the existence of acidity or basic catalyst and carry out, employed alkaline catalysts is by mineral alkali in the reaction, as alkali metallic sodium, potassium, alkaline earth metals calcium, strontium, barium etc., basic metal or alkaline earth metal hydride sodium hydride, potassium hydride KH, hydrolith etc., alkali metal hydroxide sodium hydroxide, potassium hydroxide etc., alkaline earth metal hydroxides such as calcium hydroxide, hydrated barta etc.; Basic metal carbonic acid thing yellow soda ash, salt of wormwood etc., organic bases is as quaternary ammonium hydroxide tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide etc.; Tertiary amine such as Trimethylamine 99, triethylamine, pyridine, right-Dimethylamino pyridine (DMAP); Heterocyclic amine such as piperazine, piperidines, morpholine etc.Solvent can use strong polarity, weak polar solvent or non-polar solvent, as acetonitrile, DMF, DMA, DMSO, THF, acetone, ether, methylene dichloride, chloroform, tetracol phenixin, pentamethylene, hexanaphthene, normal hexane, benzene,toluene,xylene etc., preferred polar aprotic solvent such as acetone, acetonitrile, THF, chloroform etc.; Temperature of reaction can be selected arbitrarily, and for example the reflux temperature from the room temperature to the reaction mixture preferably carries out under heating, more preferably arrives about the reflux temperature of reaction mixture at about 40 ℃.
Generate the reaction of (X): the nitroreduction in the general formula (IX) obtains the 1-(alpha-amino group-R shown in the general formula (X)
2Substituted-phenyl)-5-protects hydroxy methylimidazole.Nitroreduction can adopt the catalytic hydrogenation method, alkali metal borohydride reduction method such as sodium borohydride, POTASSIUM BOROHYDRIDE etc., metal and low price salt reduction method such as iron powder, zinc powder or tin protochloride etc., the mixture of sulfide and sulphur or polysulfide reduction method such as sulphur powder, ammonium sulfide, sodium sulphite etc., the hydrazine hydrate reduction method.Preferred catalytic hydride process and hydrazine hydrate reduction method.During catalytic hydrogenation, be reflected at 5% or catalyzer such as 10%Pd/C, Raney's nickel carry out under existing.Solvent can use polar aprotic solvent such as methyl alcohol, ethanol etc.Temperature of reaction can be selected arbitrarily, for example the reflux temperature from the room temperature to the reaction mixture.
Generate the reaction of imidazo quinoxaline compounds (XI): the 1-(alpha-amino group-R shown in the general formula (X)
2Substituted-phenyl)-and 5-protection hydroxy methylimidazole is under cyclization agent effect, and cyclization forms imidazo quinoxaline compounds (XI).The cyclization agent can be used carbonyl dimidazoles, phosgene, triphosgene, formic acid and alkyl ester thereof etc.Solvent can use high boiling weak polar solvent or non-polar solvent, as ortho position, a position or para-dichlorobenzene, phenyl ether, dimethyl benzene etc.Temperature of reaction can be selected arbitrarily, and for example the reflux temperature from the room temperature to the reaction mixture preferably carries out under heating, more preferably arrives about the reflux temperature of reaction mixture at about 100 ℃.
According to the present invention, medicinal compositions of the present invention comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention and one or more the suitable pharmaceutically acceptable carrier or pharmaceutical excipients of effective dose.Pharmaceutically acceptable carrier here or pharmaceutical excipient are meant the various pharmaceutical excipients that are used for preparation etc., include but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum protein, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, sodium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, tween, sapn etc., water, salt or ionogen are as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, Crospovidone, starch and starch derivative such as hydroxyethylamyle, carboxymethyl starch or its salt etc., cellulose substances, as methylcellulose gum, carboxymethyl cellulose (sodium), cross-linked carboxymethyl cellulose (sodium), hydroxypropylcellulose, HPMC etc., polyoxyethylene glycol, polyacrylic ester, beeswax, polyethylene-polyoxypropylene block polymer, lanolin, laurocapram etc.
Compound as herein described or its pharmaceutically acceptable addition salt or hydrate can utilize various route of administration or mode to be released into the patient.The route of administration that is fit to includes but not limited to suction, transdermal, oral, rectum, in mucous membrane, intestines and administered parenterally, administered parenterally comprises intramuscular, subcutaneous and intravenous injection.
Term used herein " administration " comprises that all directly arrive the means at its predictive role position with indirect release compound.
Compound as herein described or its pharmaceutically acceptable derivates can be individually dosed or with other The compounds of this invention Combined Preparation, and/or with the form administration of other known Adenosine Receptors A1 antagonist combination.
Active compound of the present invention can form administration own, perhaps with the pharmaceutical compositions administration, and wherein active compound and one or more pharmaceutically acceptable carriers, vehicle or mixing diluents.Pharmaceutical composition is normally prepared in the usual way used according to the present invention, uses acceptable carrier on one or more physiology, comprises vehicle and auxiliary agent, and they help active compound is processed into can be at the preparation that pharmaceutically uses.Appropriate formulations depends on selected route of administration, can make according to general knowledge well known in the art.
Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows when having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.
The compounds of this invention also can be prepared and be used for administered parenterally or transdermal administration or mucosal.Perhaps adopt the mode administration of suppository or implants.
It will be understood by those skilled in the art that on the basis of The compounds of this invention, can adopt suitable drug delivery system (DDS), to obtain more favourable effect.
The selection of administering mode and effective dose will be especially according to the disease of being treated and different.In the limit of power that is chosen in those skilled in the art of administering mode and dosage.
The unit dosage of The compounds of this invention will contain 0.01 to 99 weight % active substance usually, be more typically 0.05 to 50 weight % active substance, more preferably 0.1 to 10 weight % active substance.For instance, unit dosage can contain 0.01mg to 500mg compound, is more typically 0.05mg to 100mg, and for example between 0.10mg and 50mg, dosage is generally 100mg to 200mg.
Each dose unit or each oral administration preferably contain 0.01 to 250mg (about administered parenterally, preferably containing 0.01 to 50mg) general formula (I) compound or its pharmaceutically acceptable derivates.
Compound of the present invention will be according to the amount administration that required result of treatment effectively is provided.Provide the necessary concentration of required result of treatment will be especially according to clear and definite character, patient's age, body weight and the severity of disease of disease and different.
Usually, the dosage of The compounds of this invention will be in the scope of 0.001mg/kg to 100mg/kg body weight, more preferably 0.005mg/kg to 10mg/kg body weight, particularly 0.01mg/kg to 5mg/kg body weight.
Pharmaceutically acceptable The compounds of this invention normally will according to every day dosage to curee's administration.About adult patients, this for example can be that the oral dosage of structure (I) compound or its pharmacy acceptable salt is between 1mg and 500mg, preferably between 1mg and 250mg, perhaps intravenously, subcutaneous or intramuscular dosage are between 0.1mg and 100mg, preferably between 0.1mg and 25mg, calculate according to free cpds, compound divides 1 to 4 administration every day.Thereby, about the general population of body weight 70kg, The compounds of this invention typical every day dosage will be in the scope of 7mg to 1750mg.
But, the frequency of the size of dosage and administration is decided by the doctor who treats this patient the most at last and judges.
Embodiment
The following examples are used for illustrating the present invention, but the present invention is not constituted any limitation.
Embodiment 1:N-cyclopentyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
1.1. with 2,3-R-GLYCIDOL 29g (0.392mol), 3,4-dihydropyrane 61g (0.726mol), p-methyl benzenesulfonic acid pyridinium salt 10g (0.04mol) and methylene dichloride 300ml add in the 500ml round-bottomed flask, stir, and are warming up to 30 ℃.TLC following response progress.React after 60 hours stopped reaction.Be chilled to room temperature, the 400ml anhydrous diethyl ether is added in the reaction mixture.With semi-saturation sodium chloride solution washing (3 * 200ml).Tell organic layer, use anhydrous sodium sulfate drying.Filter, the solvent evaporate to dryness is got faint yellow oily thing 35.2g.Yield is 56.8%.Crude product can directly feed intake without purifying.Can carry out purifying by silica gel column chromatography, eluent: sherwood oil: ethyl acetate=3: 1 obtains colourless liquid 19.4g.Yield is 31.3%.
Add in the 2000ml round-bottomed flask 1.2. will react 1.1 crude product 35.2g (0.223mol), 25～28% ammoniacal liquor 500ml and dehydrated alcohol 500ml, stir, be warming up to 40 ℃.React after 30 hours stopped reaction.Reaction solution is concentrated into the Ex-all of second alcohol and water.The resistates purification by silica gel column chromatography.Eluent: trichloromethane: methyl alcohol: ammoniacal liquor=3: 1: 0.04.Get faint yellow oily thing 35g, yield is about 90%.
MS (+Q1): 198.2 (M+Na peaks), 176.2 (M+1 peaks).
1.3. with 2,3,6,7-tetrachloro quinoxaline 15g (56mmol), 2-(3-amino-2-hydroxyl propoxy-) tetrahydropyrans 16g (91.4mmol), triethylamine 15ml and trichloromethane 100ml add in the 250ml eggplant type bottle, stir and are warming up to backflow.TLC detection reaction process.Need to reflux 60 hours.Stop heating, be cooled to room temperature, filter the filtrate evaporate to dryness.The resistates purification by silica gel column chromatography.Eluent: sherwood oil: ethyl acetate=1: 1.Obtain yellow oil 15.9g.
Fusing point: 114～116 ℃.
1.4. methylene dichloride 150ml and pyridine 16ml (198mmol) are added in the 500ml three-necked bottle, stir, be cooled to 10 ℃ with frozen water.Beginning adds chromium trioxide 9.9g (99mmol) in batches, maintains the temperature at below 15 ℃.Behind reinforced the finishing, stirred 15 minutes in 15 ℃.Begin to drip 1-(3,6,7-three chloro-quinoxalines-2-amino)-3-(tetrahydropyrans-2-oxygen)-2-propanol solution (5g (12.3mmol)+30ml methylene dichloride).Dropwised in 15 minutes.Rise to room temperature reaction.TLC detection reaction process.Termination reaction after 1 hour.In reaction solution impouring Erlenmeyer flask, resistates cleans (3 * 80ml) with trichloromethane.Reaction solution washs (3 * 120ml) with 5% sodium hydroxide solution.Tell organic layer, use anhydrous sodium sulfate drying.Filter, evaporate to dryness, resistates passes through purification by silica gel column chromatography.Eluent: sherwood oil: ethyl acetate=3: 1.Get product 2.95g.Yield is 59.3%.
1.5. with 1-(3,6,7-three chloro-quinoxalines-2-amino)-and 3-(tetrahydropyrans-2-oxygen) acetone 2.95g (7.3mmol), trifluoroacetic anhydride 15ml, trifluoroacetic acid 0.5ml and trichloromethane 25ml add in the 100ml eggplant type bottle, stirs and be warming up to backflow, reacted 72 hours.Stop heating, be chilled to room temperature.Evaporated under reduced pressure adds the 40ml trichloromethane, stirs 2 hours.Suction filtration then, filter cake washs with trichloromethane, oven dry.Get white-yellowish solid 2.0g.Yield is 97.0%.
MS (Q): 281.9 (M-1 peaks), 284.0 (M+1 peaks).
1H-NMR(δ)：12.18(1H，S，H-N)，8.03(1H，S，2-ArH)，7.79(1H，S，9-ArH)，7.58(1H，S，6-ArH)，6.08(2H，S，CH
2)，4.90(1H，S，H-O)。
1.6. with 7,8-two chloro-1-methylol-5H-imidazo [1,2-a] quinoxaline-4-ketone 0.5g (1.8mmol), hexamethyl silane diamines 5ml (21.7mmol), tosic acid 0.06g (0.32mmol) and cyclopentamine 6ml add in the 25ml eggplant-shape bottle, stir.120 ℃ of reacting by heating.TLC detection reaction process.Termination reaction after 60 hours.Evaporated under reduced pressure.With methylene dichloride 20ml dissolving resistates, stir, remove by filter insolubles.With the methylene dichloride evaporate to dryness.Resistates carries out column chromatography.Get faint yellow solid 64mg, yield: 10.4%.
Fusing point: 240-242 ℃.
MS(+Q)：351.2(M+1)，353.1(M+3)。
1H-NMR(δ)：8.52(1H，s，ArH)，7.83(1H，t，NH)，7.75(1H，s，ArH)，7.56(1H，s，ArH)，5.87(1H，t，OH)，4.93(2H，d，CH
2)，4.56(1H，m，CH)，2.09-1.57(8H，m，4CH
2)。
Embodiment 2:N-cyclopentyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
2.1. imidazoles-5-methyl alcohol 9.3g (0.095mol), o-fluoronitrobenzene 9.5g (0.068mol), triethylamine 10ml (0.069mol) and acetonitrile 150ml are added in the 250ml eggplant-shape bottle.Stirring is warming up to backflow.TLC detection reaction process.Reacted 30 hours, stopped reaction is chilled to room temperature.Freezing placement is spent the night, and separates out solid, and suction filtration gets yellow solid 7.8g.With the filtrate decompression evaporate to dryness, the resistates silica gel column chromatography separates.Eluent: ethyl acetate: methyl alcohol=10: 1.Get yellow solid 2.4g.Altogether product 10.2g, yield is 68%.
Fusing point is 150～152 ℃.
MS (+Q): 219.9 (M+1 peaks), 202.0 (M-H
2The O peak).
2.2. with 1-(2-nitrophenyl) imidazoles-5-methyl alcohol 4,8g (21.9mmol) and triethylamine 5ml add in the 250ml eggplant-shape bottle, stir.Be cooled to 0 ℃, drip diacetyl oxide, finish.Insulation reaction 2 hours rises to room temperature, reacts 30 hours.In reaction solution impouring 600ml frozen water, stirred 20 minutes, with dichloromethane extraction (4 * 100ml).Dichloromethane layer washs (4 * 100ml) with saturated sodium-chloride.Dry.The evaporated under reduced pressure solvent.The resistates silica gel column chromatography.Eluent: ethyl acetate: methyl alcohol=15: 1.Get yellow solid 4.26g.Yield is 74.5%.
Fusing point is 90～92 ℃.
MS (+Q): 284.0 (M+Na peaks), 262.0 (M+1 peaks), 202.1 (M-H
2The O peak).
2.3. hydrazine hydrate 3.8g (65.1mmol), anhydrous methanol 32ml and Raney-Ni 1g are added in the 100ml three-necked bottle stirring at room.Slowly drip the solution that 1-(2-nitrophenyl) imidazoles-5-methanol acetic acid ester 3.4g (13.0mmol) and methyl alcohol 16ml form.Dropwised in 20 minutes.Interior temperature is below 30 ℃.The reaction solution color becomes yellow by purple.TLC detection reaction process, termination reaction after 20 minutes.Filter.The filtrate evaporate to dryness.The resistates silica gel column chromatography.Eluent: ethyl acetate: methyl alcohol=15: 1.Get white-yellowish solid 1.78g.Yield is 59.3%.
Fusing point is 102～104 ℃.
MS (FAB): 232.0 (M+1 peaks), 172.1 (M-CH
3The COO peak).
2.4. 1-(2-aminophenyl) imidazoles-5-methanol acetic acid ester 2.0g (8.66mmol), carbonyl dimidazoles 1.62g (10mmol) and dichlorobenzene 70ml are added in the three-necked bottle, and logical nitrogen stirs.After 1 hour, be heated to 180 ℃.TLC detection reaction process, termination reaction after 5 hours.Be chilled to room temperature, separate out solid.Freezing placement is spent the night.Suction filtration is used the washing with acetone solid, gets yellow solid 1.58g.Yield is 70.8%.Fusing point is 134～136 ℃.
MS (EI): 257.1 (M
+The peak), 214.1 (M-CH
3The CO peak).
2.5. with 4-oxo-4,5-glyoxalidine also [1,2-a] quinoxaline-4-amine acetic ester 0.5g (1.9mmol), hexamethyl silane diamines 5ml (21.7mmol), tosic acid 0.06g (0.32mmol) and cyclopentamine 6ml add in the 25ml eggplant-shape bottle, stirs 120 ℃ of reacting by heating.TLC detection reaction process.Termination reaction after 60 hours.Evaporated under reduced pressure.With methylene dichloride 20ml dissolving resistates, stir, remove by filter insolubles.With the methylene dichloride evaporate to dryness.Resistates carries out column chromatography.Get faint yellow solid 188mg, yield: 34.2%.
Fusing point: 170-172 ℃.
MS(+Q)：283.1(M+1)。
1H-NMR(δ)：8.44(1H，s，ArH)，8.08(1H，dd，ArH)，7.58(1H，dd，NH)，7.42(1H，dd，ArH)，7.38(1H，td，ArH)，7.26(1H，td，ArH)，5.34(1H，t，OH)，4.65(2H，d，CH
2)，4.58(1H，m，CH)，1.58-2.03(8H，m，4CH
2)
Embodiment 3:N-n-propyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be Tri N-Propyl Amine.
Fusing point: 226-228 ℃.
MS(+Q)：324.9(M+1)，327.0(M+3)。
1H-NMR(δ)：8.52(1H，s，ArH)，7.75(1H，s，ArH)，7.56(1H，s，ArH)，4.93(2H，s，CH
2)，3.50(2H，t，CH
2)，1.68(2H，m，CH
2)，0.93(3H，t，CH
3)
Embodiment 4:N-isobutyl--7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be isobutylamine.
Fusing point: 210-212 ℃.
MS(+Q)：339.1(M+1)，341.0(M+3)。
1H-NMR(δ)：8.52(1H，s，ArH)，8.03{1H，t，NH}，7.75(1H，s，ArH)，7.56(1H，s，ArH)，5.84(1H，t，OH)，4.93(2H，d，CH
2)，3.38(2H，d，CH
2)，2.08(1H，m，CH)，0.92(6H，d，2CH
3)
Embodiment 5:N-normal-butyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be n-Butyl Amine 99.
Fusing point: 206-208 ℃.
MS(+Q)：339.2(M+1)，341.3(M+3)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.74(1H，s，ArH)，7.56(1H，s，ArH)，4.93(2H，s，CH
2)，3.54(2H，t，CH
2)，1.65(2H，m，CH
2)，1.37(2H，m，CH
2)，0.93(3H，t，CH
3)
Embodiment 6:N-cyclohexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be hexahydroaniline.
Fusing point: 258-260 ℃.
MS(+Q)：365.3(M+1)，367.2(M+3)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.76(1H，s，ArH)，7.56(1H，s，ArH)，4.93(2H，s，CH
2)，4.13(1H，m，CH)，1.98-1.15(10H，m，5CH
2)
Embodiment 7:N-benzyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be benzylamine.
Fusing point: 212-214 ℃.
MS(+Q)：373.0(M+1)，375.0(M+3)。
1H-NMR(δ)：8.52(1H，s，ArH)，7.75(1H，s，ArH)，7.59(1H，s，ArH)，7.43-7.19(5H，m，5ArH)，4.94(2H，s，CH
2)，4.75(2H，s，CH
2)
Embodiment 8:N-n-hexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be normal hexyl Amine.
Fusing point: 148-150 ℃.
MS(+Q)：367.0(M+1)，369.0(M+3)。
1H-NMR(δ)：8.50(1H，s，ArH)，7.72(1H，s，ArH)，7.56(1H，s，ArH)，4.92(2H，s，CH
2)，3.52(2H，m，CH
2)，1.65(2H，m，CH
2)，1.30(4H，m，2CH
2)，0.86(3H，t，CH
3)
Embodiment 9:N-(3-dimethylamino-2,2-dimethyl propylene amino)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 3-dimethylamino-2, the 2-dimethyl propylamine.
Fusing point: 154-156 ℃.
MS(+Q)：396.1(M+1)，398.0(M+3)。
1H-NMR(δ)：8.50(1H，s，ArH)，7.75(1H，s，ArH)，7.57(1H，s，ArH)，4.92(2H，s，CH
2)，3.49(2H，s，CH
2)，2.30(8H，s，2CH
3，CH
2)，0.96(6H，s，2CH
3)
Embodiment 10:N-(3-hexamethylene aminopropyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be the amino propylamine of 3-hexamethylene.
Fusing point: 152-154 ℃.
MS(+Q)：422.3(M+1)，424.2(M+3)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.73(1H，s，ArH)，7.56(1H，s，ArH)，4.92(2H，s，CH
2)，3.59(2H，t，CH
2)，2.60(2H，t，CH
2)，2.29(2H，m，CH
2)，1.83-1.75，1.18-0.98(10H，m，5CH
2)，1.54(H，m，CH)
Embodiment 11:N-(2-(Pyrrolidine-4-yl) ethyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 2-(Pyrrolidine-4-yl) ethamine.
Fusing point: 194-196 ℃.
MS(+Q)：380.2(M+1)，382.0(M+3)。
1H-NMR (δ): 8.50 (1H, s, ArH), 7.74 (1H, s, ArH), 7.56 (1H, s, ArH), 4.92 (2H, s, CH
2), 3.65 (2H, t, CH
2), 2.60 (2H, t, CH
2), 1.69 (4H, m, 2CH
2), the hydrogen peak of two methylene radical is that solvent peak is covered in addition.
Embodiment 12:N-(2-(morpholine-4-yl) ethyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 2-(morpholine-4-yl) ethamine.
Fusing point: 184-186 ℃.
1H-NMR(δ)：8.52(1H，s，ArH)，7.76(1H，s，ArH)，7.58(1H，s，ArH)，4.93(2H，s，CH
2)，3.65(2H，t，CH
2)，3.57(4H，t，2CH
2)，2.60(2H，t，CH
2)，2.50(4H，t，2CH
2)
Embodiment 13:N-(3-(morpholine-4-yl) propyl group)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 3-(morpholine-4-yl) propylamine.
Fusing point: 192-194 ℃.
MS(+Q)：410.2(M+1)，412.2(M+3)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.73(1H，s，ArH)，7.57(1H，s，ArH)，4.92(2H，s，CH
2)，3.63(4H，t，2CH
2)，3.58(2H，t，CH
2)，3.41(6H，m，3CH
2)，1.81(2H，m，CH
2)
Embodiment 14:N-(2,2,6,6-tetramethyl piperidine-4-yl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 2,2,6,6-tetramethyl piperidine-4-amine.
Fusing point: 246-248 ℃.
MS(EI)：421.0(M
+)，423.0(M+2)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.71(1H，s，ArH)，7.57(1H，s，ArH)，4.93(2H，s，CH
2)，4.66(H，m，CH)，1.80(2H，d，CH
2)，1.25(6H，s，2CH
3)，1.09(8H，m，CH
2，2CH
3)
Embodiment 15:N-[(1-ethyl Pyrrolidine-2-yl) methyl]-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 1-ethyl Pyrrolidine-2-methylamine.
Fusing point: 206-208 ℃.
MS(+Q)：394.3(M+1)，396.2(M+3)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.71(1H，s，ArH)，7.57(1H，s，ArH)，4.93(2H，s，CH
2)，1.61-3.79(11H，m，CH，5CH
2)，1.09(3H，t，CH
3)
Embodiment 16:N-(1-benzyl piepridine-4-yl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 1 method, is used R
1NH
2Be 1-benzyl piepridine-4-amine.
Fusing point: 204-206 ℃.
MS(+Q)：456.3(M+1)，458.3(M+3)。
1H-NMR(δ)：8.51(1H，s，ArH)，7.77(1H，s，ArH)，7.57(1H，s，ArH)，7.33(6H，m，5ArH，NH)，4.93(2H，s，CH
2)，4.15(H，m，CH)，3.49(2H，s，CH
2)，2.84(2H，d，CH
2)，2.08(2H，t，CH
2)，1.88(2H，d，CH
2)，1.74(2H，m，CH
2)
Embodiment 17:N-isobutyl--7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
Prepare this compound by embodiment 1 method, just with 2,3-two chloro-7,2,3,7 in the 8-dimethyl quinoxaline alternative embodiment 1.3,8-tetrachloro quinoxaline, used R
1NH
2Be isobutylamine.
Fusing point: 246-248 ℃.
MS(+Q)：299.1(M+1)。
1H-NMR (δ): 7.17 (1H, s, ArH), 7.10 (1H, s, NH), 7.07 (1H, s, ArH), 6.90 (1H, s, ArH), 3.24 (2H, d, CH
2), 3.16 (2H, s, CH
2), 2.25 (3H, s, CH
3), 2.21 (3H, s, CH
3), 2.25-221 (1H, broad peak, OH), 1.98 (1H, m, CH), 0.95 (6H, d, 2CH
3)
Embodiment 18:N-normal-butyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be n-Butyl Amine 99.
Fusing point: 232-234 ℃.
MS(EI)：298.1(M
+)。
Embodiment 19:N-cyclopentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be cyclopentamine.
Fusing point: 240-242 ℃.
MS(+Q)：311.3(M+1)。
1H-NMR(δ)：8.04(1H，s，ArH)，7.46(1H，s，ArH)，7.41(1H，s，ArH)，7.16(1H，d，NH)，5.66(1H，t，OH)，4.96(2H，d，CH
2)，4.51(1H，m，CH)，2.34(3H，s，CH
3)，2.31(3H，s，CH
3)，2.09-1.58(8H，m，4CH
2)
Embodiment 20:N-cyclohexyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be hexahydroaniline.
Fusing point: 202-204 ℃.
MS(EI)：324.0(M
+)。
Embodiment 21:N-benzyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be benzylamine.
Fusing point: 144-146 ℃.
MS(+Q)：333.0(M+1)。
1H-NMR(δ)：8.05(1H，s，ArH)，7.87(1H，d，NH)，7.20-7.51(7H，m，7ArH)，4.97(2H，s，CH
2)，4.74(2H，s，CH
2)，2.34(3H，s，CH
3)，2.29(3H，s，CH
3)
Embodiment 22:N-n-pentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be n-amylamine.
Fusing point: 164-166 ℃.
MS(+Q)：313.5(M+1)。
1H-NMR(δ)：8.04(1H，s，ArH)，7.46(1H，s，ArH)，7.41(1H，s，ArH)，7.16(1H，d，NH)，4.95(2H，s，CH
2)，3.50(2H，m，CH
2)，2.34(3H，s，CH
3)，2.31(3H，s，CH
3)，1.65(2H，m，CH
2)，1.34(4H，m，2CH
2)，0.88(3H，t，CH
3)
Embodiment 23:N-(3-dimethylamino-2,2-dimethyl propyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be 3-dimethylamino-2, the 2-dimethyl propylamine.
Fusing point: 136-138 ℃.
1H-NMR(δ)：8.04(1H，s，ArH)，7.48(1H，s，ArH)，7.41(1H，s，ArH)，4.95(2H，s，CH
2)，3.46(2H，s，CH
2)，2.34(3H，s，CH
3)，2.31(3H，s，CH
3)，2.29(6H，s，2CH
3)，2.27(2H，s，CH
2)，0.96(6H，s，2CH
3)
Embodiment 24:N-(3-hexamethylene aminopropyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be the amino propylamine of 3-hexamethylene.
Fusing point: 178-180 ℃.
1H-NMR(δ)：8.03(1H，s，ArH)，7.47(1H，s，ArH)，7.39(1H，s，ArH)，4.95(2H，s，CH
2)，3.56(2H，t，CH
2)，2.60(2H，t，CH
2)，2.34(3H，s，CH
3)，2.30(3H，s，CH
3)，1.83-1.74，1.17-0.98(10H，m，5CH
2)，1.66(2H，m，CH
2)，1.54(H，m，CH)
Embodiment 25:N-(2-(morpholine-4-yl) ethyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be 2-(morpholine-4-yl) ethamine.
Fusing point: 128-130 ℃.
1H-NMR(δ)：8.04(1H，s，ArH)，7.48(1H，s，ArH)，7.40(1H，s，ArH)，4.96(2H，s，CH
2)，3.63(2H，t，CH
2)，3.58(4H，t，2CH
2)，2.60(2H，t，CH
2)，2.50(4H，t，2CH
2)，2.34(3H，s，CH
3)，2.30(3H，s，CH
3)
Embodiment 26:N-(2,2,6,6-tetramethyl piperidine-4-yl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be 2,2,6,6-tetramethyl piperidine-4-amine.
Fusing point: 238-240 ℃.
1H-NMR(δ)：8.04(1H，s，ArH)，7.48(1H，s，ArH)，7.37(1H，s，ArH)，4.96(2H，s，CH
2)，4.62(H，m，CH)，2.34(3H，s，CH
3)，2.30(3H，s，CH
3)，1.85(2H，t，CH
2)，1.27(8H，m，2CH
3，CH
2)，1.08(6H，s，2CH
3)
Embodiment 27:N-(3-(morpholine-4-yl) propyl group)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 17 methods, is used R
1NH
2Be 3-(morpholine-4-yl) propylamine.
Fusing point: 162-164 ℃.
1H-NMR(δ)：8.02(1H，s，ArH)，7.47(1H，s，ArH)，7.37(1H，s，ArH)，4.95(2H，s，CH
2)，3.63(4H，t，2CH
2)，3.56(2H，t，CH
2)，2.41(6H，t，3CH
2)，2.33(3H，s，CH
3)，2.30(3H，s，CH
3)，1.81(2H，m，CH
2)
Embodiment 28:N-sec.-propyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be Isopropylamine.
Fusing point: 162-164 ℃.
1H-NMR(δ)：8.02(1H，s，ArH)，7.47(1H，s，ArH)，7.37(1H，s，ArH)，4.95(2H，s，CH
2)，3.63(4H，t，2CH
2)，3.56(2H，t，CH
2)，2.41(6H，t，3CH
2)，2.33(3H，s，CH
3)，2.30(3H，s，CH
3)，1.81(2H，m，CH
2)
Embodiment 29:N-n-propyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be Tri N-Propyl Amine.
Fusing point: 140-142 ℃.
MS(+Q)：257.2(M+1)
Embodiment 30:N-isobutyl--1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be isobutylamine.
Fusing point: 162-164 ℃.
MS(+Q)：271.4(M+1)。
1H-NMR (δ): 8.45 (1H, s, ArH), 8.08 (1H, dd, J=8Hz, ArH), 7.66 (1H, t, J=8Hz, NH), 7.56 (1H, dd, ArH), 7.37 (1H, td, ArH), 7.26 (1H, td, ArH), 5.34 (1H, broad peak, OH), 4.65 (2H, s, CH
2), 2.09 (1H, m, CH), 0.93 (6H, d, 2CH
3)
Embodiment 31:N-normal-butyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be n-Butyl Amine 99.
Fusing point: 146-148 ℃.
MS(+Q)：270.9(M+1)
Embodiment 32:N-cyclohexyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be hexahydroaniline.
Fusing point: 190-192 ℃.
1H-NMR(δ)：8.27(1H，d，ArH)，7.60(1H，d，ArH)，7.51(1H，s，ArH)，7.40(1H，td，ArH)，7.29(1H，td，ArH)，4.96(2H，s，CH
2)，4.14(1H，m，CH)，1.15-1.96(10H，m，5CH
2)
Embodiment 33:N-n-octylcyclam-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be n-octyl amine.
Fusing point: 96-98 ℃.
MS(+Q)：327.3(M+1)
Embodiment 34:N-phenyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be aniline.
Fusing point: 222-224 ℃.
MS(+Q)：291.0(M+1)
Embodiment 35:N-benzyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be benzylamine.
Fusing point: 160-162 ℃.
MS(+Q)：305.2(M+1)
Embodiment 36:N-(3-dimethylamino-2,2-dimethyl propyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be 3-dimethylamino-2, the 2-dimethyl propylamine.
Fusing point: 106-108 ℃.
MS(+Q)：328.1(M+1)
Embodiment 37:N-(3-hexamethylene aminopropyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be the amino propylamine of 3-hexamethylene.
Fusing point: 84-86 ℃.
MS(+Q)：354.0(M+1)
Embodiment 38:N-(2-(morpholine-4-yl) ethyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be 2-(morpholine-4-yl) ethamine.
Fusing point: 146-148 ℃.
MS(+Q)：328.3(M+1)。
1H-NMR(δ)：8.39(1H，s，ArH)，8.06(1H，dd，ArH)，7.58(1H，dd，ArH)，7.40(1H，td，ArH)，7.29(1H，td，ArH)，4.63(2H，s，CH
2)，3.67(2H，t，CH
2)，3.58(4H，t，2CH
2)，2.62(2H，t，CH
2)，2.50(4H，t，2CH
2)
Embodiment 39:N-(3-(morpholine-4-yl) propyl group)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be 3-(morpholine-4-yl) propylamine.
Fusing point: 136-138 ℃.
1H-NMR(δ)：8.27(1H，d，ArH)，7.57(1H，d，ArH)，7.52(1H，s，ArH)，7.40(1H，td，ArH)，7.28(1H，td，ArH)，4.96(2H，s，CH
2)，3.64(4H，t，2CH
2)，3.60(2H，t，CH
2)，2.42(2H，t，CH
2)，2.40(4H，t，2CH
2)，1.82(2H，t，CH
2)
Embodiment 40:N-(2,2,6,6-tetramethyl piperidine-4-yl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 2 methods, is used R
1NH
2Be 2,2,6,6-tetramethyl piperidine-4-amine.
Fusing point: 154-156 ℃.
1H-NMR(δ)：8.28(1H，d，ArH)，7.57(1H，d，ArH)，7.53(1H，s，ArH)，7.41(1H，td，ArH)，7.29(1H，td，ArH)，4.97(2H，s，CH
2)，4.70(1H，m，CH)，1.86(2H，d，CH
2)，1.29(6H，s，CH
3)，1.11(6H，s，2CH
3)，1.05(2H，d，CH
2)
Embodiment 41:N-isobutyl--7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Prepare this compound by embodiment 2 methods, just with the o-fluoronitrobenzene in the 4-fluoro-3-nitro-trifluoromethyl toluene alternative embodiment 2.1, used R
1NH
2Be isobutylamine.
Fusing point: 192-194 ℃.
MS(+Q)：339.1(M+1)。
1H-NMR(δ)：8.54(1H，s，ArH)，8.31(1H，d，ArH)，7.81(1H，s，ArH)，7.56(1H，d，ArH)，4.65(2H，s，CH
2)，2.43(2H，d，CH
2)，2.10(1H，m，CH)，0.93(6H，d，2CH
3)
Embodiment 42:N-normal-butyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 41 methods, is used R
1NH
2Be n-Butyl Amine 99.
Fusing point: 178-180 ℃.
MS(+Q)：339.1(M+1)。
1H-NMR(δ)：8.53(1H，s，ArH)，8.31(1H，d，ArH)，7.81(1H，s，ArH)，7.56(1H，d，ArH)，4.65(2H，s，CH
2)，3.55(2H，t，CH
2)，1.65(2H，m，CH
2)，1.38(2H，m，CH
2)，0.92(3H，d，CH
3)
Embodiment 43:N-cyclopentyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 41 methods, is used R
1NH
2Be cyclopentamine.
Fusing point: 218-220 ℃.
MS(+Q)：351.1(M+1)。
1H-NMR(δ)：8.53(1H，s，ArH)，8.32(1H，d，ArH)，7.82(1H，s，ArH)，7.58(1H，d，ArH)，4.65(2H，s，CH
2)，4.60(H，m，CH)，2.09-1.55(8H，m，4CH
2)
Embodiment 44:N-benzyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 41 methods, is used R
1NH
2Be cyclopentamine.
Fusing point: 176-178 ℃.
1H-NMR(δ)：8.56(1H，s，ArH)，8.32(1H，d，ArH)，7.80(1H，s，ArH)，7.58(1H，d，ArH)，7.44-7.21(5H，m，5ArH)，4.77(2H，s，CH
2)，4.66(2H，s，CH
2)
Embodiment 45:N-(3-hexamethylene aminopropyl)-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
Preparing this compound by embodiment 41 methods, is used R
1NH
2Be cyclopentamine.Oily matter.
MS(+Q)：351.1(M+1)。
1H-NMR (δ): 8.53 (1H, s, ArH), 8.30 (1H, d, ArH), 7.80 (1H, s, ArH), 7.56 (1H, d, ArH), 4.66 (2H, s, CH
2), 3.06 (2H, t, CH
2), 2.61 (2H, t, CH
2), 2.32 (1H, broad peak, OH), 1.83-1.75,1.18-0.98 (10H, m, 5CH
2), 1.65 (2H, m, CH
2), 1.54 (1H, m, CH)
Experimental example 1: dissolving contrast experiment
Embodiment 2 compound 4.0mg are put into test tube 1, and the Compound I RFI-165 (N-cyclopentyl-1-Methylimidazole is [1,2-a] quinoxaline-4-amine also, and is synthetic according to US Pat.6124287) that gets 4.0mg puts into test tube 2.Get the 1.0mL dimethyl sulfoxide (DMSO) and add two test tubes respectively, with sample dissolution.Slowly add distilled water then in test tube respectively, test tube 2 occurs muddy when adding 0.9mL distilled water.Test tube 1 occurs muddy after adding 2.1mL distilled water.
Experimental example 2: the avidity to adenosine A 1 receptor of The compounds of this invention
Illustrate by the extracorporeal receptor competitive binding experiment.
The extraction of membranin
Wistar rat broken end is got brain, in ice bath with full brain by 1: 10 (w/v) homogenate under 1000g, 4 ℃ of conditions centrifugal 10 minutes.Get supernatant liquor centrifugal 20 minutes at 13000g.Get precipitation and suspend again, 37 ℃ of water bath heat preservations 30 minutes with reaction solution 10ml.20000g is centrifugal 10 minutes under 4 ℃ of conditions.Getting precipitation uses an amount of reaction solution resuspended again.Measure protein concentration with examining horse light blue method.It is standby that protein liquid is diluted to desired concn (2mg/ml).
The experiment of radioligand competition combination rate
Use DMSO to dissolve tested medicine, and dilute desired concn with the Tris-HCl of pH7.4; Membranin concentration is 30 μ g/ pipes; Nonstandard part R-PIA strength of solution 30 μ mol.L
-1Total reaction volume is 300 μ L.Add in the total binding pipe reaction solution 100 μ L, isotropic substance [
3H]-DPCPX solution 100 μ L and membranin 100 μ L; Add in the non-special pipe nonstandard part R-PIA solution 100 μ L, isotropic substance [
3H]-DPCPX solution 100 μ L and membranin 100 μ L; Add in the medication tube medicine 100 μ L, isotropic substance [
3H]-DPCPX solution 100 μ L and membranin 100 μ L.Measure the inhibition percentage (IP) of compound.As shown in table 1.Use the nonlinear curve method to measure IC to wherein suppressing percentage at the compound more than 90% then
50Value goes out the Ki value according to the Cheng-Prusoff Equation for Calculating.As shown in table 2.
Table 1
Table 2
Claims (4)
1. the compound shown in the general formula I or its pharmaceutically useful salt:
Wherein:
R
1Be alkyl, cycloalkyl, aryl or heterocyclic radical;
Described alkyl also can be replaced by aryl, list or disubstituted amido or heterocyclic radical,
Wherein, the substituting group of described amino is selected from alkyl or cycloalkyl, described heterocycle
Base can also be replaced by alkyl, and this alkyl can also be replaced by aryl;
Described heterocyclic radical can be replaced by alkyl;
R
2Be hydrogen or halogen, alkyl or haloalkyl; N is 1 or 2, when n is 2, and two R
2Can be different, also can be symmetric dihalo, dialkyl group or dihalo alkyl;
R is H or the hydroxyl protecting group that can form ehter bond or ester bond with hydroxyl.
2. according to the compound of claim 1, compound is selected from:
N-sec.-propyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-n-propyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-normal-butyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-n-octylcyclam-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-phenyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-benzyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-dimethylamino-2,2-dimethyl propyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2-(morpholine-4-yl) ethyl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-(morpholine-4-yl) propyl group)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2,2,6,6-tetramethyl piperidine-4-yl)-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-normal-butyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-benzyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-n-pentyl-7,8-dimethyl-1-hydroxy methylimidazole be [1,2-a] quinoxaline-4-amine also
N-(3-dimethylamino-2,2-dimethyl propyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2-(morpholine-4-yl) ethyl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(2,2,6,6-tetramethyl piperidine-4-yl)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-(morpholine-4-yl) propyl group)-7,8-dimethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-isobutyl--7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-normal-butyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-benzyl-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7-Trifluoromethyl-1-hydroxy methylimidazole is [1,2-a] quinoxaline-4-amine also
N-n-propyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-isobutyl--7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-normal-butyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-cyclopentyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-cyclohexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-benzyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-n-hexyl-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(3-dimethylamino-2,2-dimethyl propyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(3-hexamethylene aminopropyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(2-(Pyrrolidine-4-yl) ethyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(2-(morpholine-4-yl) ethyl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(3-(morpholine-4-yl) propyl group)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(2,2,6,6-tetramethyl piperidine-4-yl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-[(1-ethyl Pyrrolidine-2-yl) methyl]-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also
N-(1-benzyl piepridine-4-yl)-7,8-two chloro-1-hydroxy methylimidazoles are [1,2-a] quinoxaline-4-amine also.
3. pharmaceutical composition comprises the claim 1 for the treatment of effective dose or 2 compound and pharmaceutically acceptable carrier or vehicle.
4. claim 1 or 2 compound are used for preventing and/or treating the application of the medicine of depression, cognitive defect, renal failure, asthma, acute respiratory distress disease, heart disorder, sudden cardiac arrest in preparation.
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| WO2022166548A1 (en) * | 2021-02-03 | 2022-08-11 | 苏州欧康维视生物科技有限公司 | Salt form and crystal form of pyrazole substituted imidazo[1,2- a]quinoxaline derivative |
| CN114621232B (en) * | 2022-03-31 | 2023-03-14 | 苏州欧康维视生物科技有限公司 | Preparation method and application of Syk and VEGFR2 double-target-point inhibitor |
Citations (3)
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|---|---|---|---|---|
| CN1120336A (en) * | 1993-03-31 | 1996-04-10 | Basf公司 | Imidazoloquinoxalinone derivatives as eaa antagonists |
| CN1159807A (en) * | 1994-09-30 | 1997-09-17 | 巴斯福股份公司 | New heterocyclic substituted imidazoloquinoxalinones their preparation and their use |
| US6124287A (en) * | 1995-11-24 | 2000-09-26 | Biomedica Foscama Industria Chimicofarmaceutica S.P.A. | Imidazo[1,2-a]quinoxalin-4-amines active as adenosine antagonists, process for their preparation and pharmaceutical compositions thereof |
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Patent Citations (3)
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|---|---|---|---|---|
| CN1120336A (en) * | 1993-03-31 | 1996-04-10 | Basf公司 | Imidazoloquinoxalinone derivatives as eaa antagonists |
| CN1159807A (en) * | 1994-09-30 | 1997-09-17 | 巴斯福股份公司 | New heterocyclic substituted imidazoloquinoxalinones their preparation and their use |
| US6124287A (en) * | 1995-11-24 | 2000-09-26 | Biomedica Foscama Industria Chimicofarmaceutica S.P.A. | Imidazo[1,2-a]quinoxalin-4-amines active as adenosine antagonists, process for their preparation and pharmaceutical compositions thereof |
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| Imidazo[1,2-a]quinoxalin-4-amines:A novel class ofnonxanthine A1-adenosine receptor antagonists. Stefano Ceccarelli et al.Eur.J.Med.Chem.,Vol.33 . 1998 * |
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