CN1951932B - [N-(3',4'-methylenedioxy) phenylethyl] carboxamido benzoic acid derivatives, processes for their preparation and their use - Google Patents
[N-(3',4'-methylenedioxy) phenylethyl] carboxamido benzoic acid derivatives, processes for their preparation and their use Download PDFInfo
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Abstract
The invention discloses a compound (I) or stereomer or drug salt, wherein each group is defined in the introduction, which can be applied in the hepatitis drug.
Description
Technical field
The present invention relates to 2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoic acid derivative, its steric isomer and its pharmacologically acceptable salt, their preparation method and they are as medicine, particularly as the application of liver protection medicine.
Background technology
Hepatic diseases, particularly hepatitis are that the whole world is the most common, one of most important infectious diseases.The whole world has 3.5 hundred million people to suffer from hepatitis B approximately, and the patient who dies from every year has 2,000,000, ranks the 9th in the dead cause of disease in the whole world.The sickness rate of China's viral hepatitis occupies first place in the world, and about 80% hepatitis concentrates on China, has every year nearly 500,000 people to die from and the hepatitis diseases associated.For a long time, the treatment of hepatitis is a great problem of world the world of medicine always.
The Chinese and western drugs that is used for the treatment of hepatitis at present reaches kind more than 700, and wherein, what clinical application was maximum is Interferon, rabbit and nucleoside medicine.Interferon anti-reflecting virus has certain curative effect, but efficient is not high, side effect is more, cost an arm and a leg, so the only a few patient can adhere to using for a long time; The nucleoside medicine short term effect is good, but bounce-back rate height after the drug withdrawal, so late result still needs further checking.As seen, although it is various to treat the medicament categories of hepatitis at present, yet curative effect certainly and the little medicine of side effect also few in number.Therefore, the development novel structure, the sure novel liver of curative effect protects medicine very urgent.
Summary of the invention
The purpose of this invention is to provide a kind of new compound, it has brand-new structure, can reduce gpt and glutamic-oxal(o)acetic transaminase (ALT and AST), can become the medicine of treatment hepatic diseases; Another object of the present invention provides the method for preparation compound of the present invention; Another object of the present invention provides the medicinal compositions that contains compound of the present invention.In order to finish purpose of the present invention, the inventor is through discovering that the brand new compound of following general formula (I) has good liver-protecting activity.The present invention relates to compound or its steric isomer or its pharmacologically acceptable salt of general formula (I).
Wherein:
X is a nitrogen, oxygen or sulphur;
R1 is a hydrogen, monovalence or divalent-metal ion, or cationic nitrogenous, the C1-C8 alkyl, the C3-C6 alkenyl, the C3-C6 alkynyl, the C3-C6 cycloalkyl, the C3-C6 heterocyclic radical, the C6-C14 aryl, the C4-C12 heteroaryl, and the group that is connected to form by aryl or heteroaryl and above group, for example: C6-C14 aryl C1-C8 alkyl, C4-C12 heteroaryl C1-C8 alkyl, C6-C14 aryl C3-C6 heterocyclic radical, C4-C12 heteroaryl C3-C6 heterocyclic radical, C6-C14 aryl C3-C6 alkenyl, C4-C12 heteroaryl C3-C6 alkenyl, C6-C14 aryl C3-C6 alkynyl, C4-C12 heteroaryl C3-C6 alkynyl, C6-C14 aryl C3-C6 cycloalkyl or C4-C12 heteroaryl C3-C6 cycloalkyl, wherein said aryl or heteroaryl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C
1-C
4Alkyl etc.;
Perhaps, the R1-X base can form inferior amide compound together with the amido of 3 ', the 4 '-methylenedioxyphenyl ethamine that forms amide group;
R2, R3, R4 and R5 are selected from hydrogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, C3-C5 cycloalkyl, C2-C4 alkenyl, C3-C6 alkynyl, phenyl, halogen, nitro, hydroxyl and C1-C4 alkoxyl group independently of one another, wherein, R2, R3, R4, R5 arbitrarily can substituted positions on phenyl ring;
R6 is a hydrogen, C1-C8 alkyl, C1-C3 perfluoroalkyl, C3-C5 cycloalkyl or phenyl.
In above definition, except as otherwise noted, monovalence or divalent-metal ion are alkali metal cations as lithium ion (Li
+), sodium ion (Na+), potassium ion (K+) etc., or alkaline earth metal cation is as magnesium ion (Mg2+), calcium ion (Ca2+) etc.; Described cationic nitrogenous for example is selected from NH
4 +, tetramethylammonium, tetrabutylammonium, the acid positively charged ion of PROCAINE HCL, PHARMA GRADE, the acid positively charged ion of N-methylmorpholine, the acid positively charged ion of N-methyl piperidine, the acid positively charged ion of hexahydroaniline, the acid positively charged ion of phenylethylamine, the acid positively charged ion of aniline, the acid positively charged ion of Pyrrolidine, the acid positively charged ion of pyridine, the acid positively charged ion of ethamine, the acid positively charged ion of diethylamine, the acid positively charged ion of triethylamine etc.; Halogen is fluorine, chlorine, bromine or iodine; " C1-C8 alkyl " is meant the alkyl that contains 1-8 carbon atom, can be the straight or branched alkyl, can also comprise 1-3 two keys or triple bond, as: methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, isobutyl-, 4-butyl-2-alkynes, amyl group etc.; Heterocyclic radical is to contain 3-6 carbon atom and at least one heteroatoms for example saturated or unsaturated assorted monocycle or assorted many cyclic groups of nitrogen, oxygen or sulphur etc.; Aryl is the aromatic group that contains 6-14 carbon atom, for example phenyl, naphthyl, anthryl etc.; Heteroaryl is meant and contains 4-12 carbon atom and 1-4 identical or different heteroatomic aromatic group, described heteroatoms is nitrogen, oxygen or sulphur etc. for example, described heteroaryl for example: indyl, pyridyl, furyl, pyrryl, thienyl, pyrimidyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl etc.
Formula (I) compound can contain one or more asymmetric centers, can exist with the form of enantiomer or diastereomer.In addition, when formula (I) compound contains two key, can exist with the form of cis or trans-isomer(ide).The present invention includes formula (I) the compound form (form the form of mixtures of racemic modification compound and form form of mixtures suitable, the trans isomer compound) of above definition and the isomer monomer (monomeric compound of optically active compound and cis or trans-isomer(ide)) that separates.
The salt of formula (I) compound formation can be an alkali metal salt (as sodium salt or sylvite), alkaline earth salt (as calcium salt or magnesium salts) or the ammonium salt that is formed by ammonia or organic amine such as PROCAINE HCL, PHARMA GRADE, tetramethylammonium, tetrabutylammonium, diethylamine, triethylamine, N-methylmorpholine or N-methyl piperidine.
Wherein do not comprise following compounds:
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
N, N-(3 ', 4 ' methylene-dioxy) phenylethyl phthalic imidine
The preferred one group of compound of the present invention is general formula (II) compound or its steric isomer or its pharmacologically acceptable salt:
Wherein, X is a nitrogen, oxygen or sulphur;
The definition of R1, R2, R3, R4, R5 and R6 is as above described in the face of the definition of general formula (I);
Preferred R6 is a hydrogen, C1-C8 alkyl, C1-C3 perfluoroalkyl or C3-C5 cycloalkyl.
Wherein, the R1-X base can form inferior amide compound together with the amido of 3 ', the 4 '-methylenedioxyphenyl ethamine that forms amide group, i.e. general formula (III) compound or its steric isomer or its pharmacologically acceptable salt:
The definition of R1, R2, R3, R4 and R5 is as above described in the face of the definition of general formula (I);
Wherein, R2, R3, R4, R5 arbitrarily can substituted positions on phenyl ring.
The preferred one group of compound of the present invention is general formula (IV) compound or its steric isomer or its pharmacologically acceptable salt:
Wherein, X is a nitrogen, oxygen or sulphur, preferred nitrogen wherein, oxygen;
The definition of R1 is as above described in the face of the definition of general formula (I);
R6 is a hydrogen, C1-C8 alkyl, C1-C3 perfluoroalkyl or C3-C5 cycloalkyl;
Wherein, the R1-X base can form inferior amide compound together with the amido of 3 ', the 4 '-methylenedioxyphenyl ethamine that forms amide group, promptly logical formula V compound or its steric isomer or its pharmacologically acceptable salt:
At general formula (IV) with (V), R ' is hydrogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, C3-C5 cycloalkyl, C2-C4 alkenyl, C3-C6 alkynyl, phenyl, halogen, nitro, hydroxyl or C1-C4 alkoxyl group.
Particularly preferred compound is among the present invention:
The compound of general formula (IV) and logical formula V, wherein R1 is a hydrogen, the C1-C8 alkyl, piperazinyl, phenyl, phenyl C1-C8 alkyl, 3-indyl C1-C8 alkyl or 4-Phenylpiperazinyl, wherein said phenyl and 3-indyl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C1-C4 alkyl; R ' is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxyl or C1-C4 alkoxyl group; R6 is hydrogen or methyl.
Particularly preferred particular compound according to general formula of the present invention (I) compound is the compound for preparing among the embodiment.Specify the method for preparing general formula of the present invention (I) compound below with reference to drawings and Examples:
Method I:
Wherein:
M is alkali metal cation (Li for example among the formula VIa
+, Na
+, K
+Deng), alkaline earth metal cation (Mg for example
2+, Ca
2+Deng), the C1-C8 alkyl, the C3-C6 alkenyl, the C3-C6 alkynyl, the C3-C6 cycloalkyl, the C3-C6 heterocyclic radical, the C6-C14 aryl, and the group that is connected to form by aryl and above group, for example C6-C14 aryl C1-8 alkyl, C6-C14 aryl C3-C6 heterocyclic radical, C6-C14 aryl C3-C6 alkenyl, C6-C14 aryl C3-C6 alkynyl or C6-C14 aryl C3-C6 cycloalkyl, wherein said aryl optionally contains 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C
1-C
4Alkyl etc.;
The definition of R1, R2, R3, R4, R5 and R6 is as above described in the face of the definition of general formula (I).
Step 1
Make general formula VIa compound in the non-proton organic solvent of disturbance reponse not, in the presence of organic bases and chloroformyl ester or carbodiimide compound,, obtain general formula VIII compound with the reaction of general formula VII compound; Perhaps make the reaction of general formula VIa compound and thionyl chloride or oxalyl chloride, obtain chloride compounds, obtain general formula VIII compound with the reaction of general formula VII compound again.
Step 2
When M was metal ion, general formula VIII compound obtained general formula I V compound through acidifying, or when M was other groups that limited, general formula VIII compound obtained general formula (IV) compound through the mineral alkali hydrolysis in water or protic organic solvent.
Step 3
General formula I V compound in the presence of organic bases and chloroformyl ester or carbodiimide compound, obtains compound of Formula I with general formula compound R1-X-H reaction in the non-proton organic solvent of disturbance reponse not.When X is oxygen or sulphur, also should there be extra and the suitable organic bases of general formula compound R1-X-H consumption in the reaction system.
For preferred compound is that general formula (II) compound or its steric isomer also can synthesize by method II:
Method II:
Wherein: the definition of R1, R2, R3, R4, R5 and R6 is as above described in the face of the definition of general formula (II);
Step 1
General formula VII compound and general formula VIb compound be direct reaction in the non-proton organic solvent of water or any not disturbance reponse, obtains the general formula X compound, when carrying out in being reflected at water, also need add phase-transfer catalyst.
Step 2
General formula compound is in the non-proton organic solvent of disturbance reponse not, in the presence of organic bases and chloroformyl ester or carbodiimide compound, obtain general formula compound with general formula compound R1-X-H reaction, when X is oxygen or sulphur, also should there be extra and the suitable organic bases of general formula compound R1-X-H consumption in the reaction system.
For preferred compound is that general formula (III) compound or its steric isomer also can synthesize by method III:
Method comprises following three routes composition, and is specific as follows:
Wherein: the definition of R1, R2, R3, R4, R5 and R6 is as above described in the face of the definition of general formula (III);
R7 is a C1-C8 alkyl identical or inequality with R8, phenyl, phenyl C1-C8 alkyl, 3-indyl C1-C8 alkyl or 4-Phenylpiperazinyl, wherein said phenyl and 3-indyl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C1-C4 alkyl;
Route 1:
3 ', the compound of 4 '-methylenedioxyphenyl ethamine and general formula (VIb) exists under the organic bases, reaction makes or 3 ' in the non-proton organic solvent of disturbance reponse not, the compound of 4 '-methylenedioxyphenyl ethamine and general formula (VIb) exists under phase-transfer catalyst and the mineral alkali, and the Yu Shuizhong reaction makes.
Route 2:
The compound of 3 ', 4 '-methylenedioxyphenyl ethamine and general formula (VIc) exists under the organic bases, reacts to make in the non-proton organic solvent of disturbance reponse not and protic organic solvent.
Route 3:
The compound of general formula (XI) makes reacting in the non-proton organic solvent of disturbance reponse not in the presence of chloroformyl ester or carbodiimide and the organic bases.
In the preparation method of above-mentioned general formula I, general formula I I and general formula III, the non-proton organic solvent of described not disturbance reponse is selected from aromatic hydrocarbon, as: benzene,toluene,xylene and oil of mirbane etc., halohydrocarbon, as: methylene dichloride, chloroform, tetracol phenixin or 1,2-ethylene dichloride etc., ether solvent, as: ether, methyl tert-butyl ether, tetrahydrofuran (THF) or 1,4-dioxane etc.; Ketones solvent, as: acetone, 2-butanone etc.; Polar aprotic solvent, as: DMF, DMSO or N-Methyl pyrrolidone etc.; And the mixed solvent of above qualification solvent composition, as: methylene dichloride/DMF, benzene/DMF etc.Described phase-transfer catalyst is selected from tetramethyl ammonium chloride, Tetrabutyl amonium bromide and tetraethylammonium bromide.Described organic bases is pyridine, 4-N for example, N-lutidine, hexamethyldisilazane (HMDS) and tertiary amine molecule (as: triethylamine, tri-n-butylamine etc.), wherein preferred pyridine and triethylamine; Described carbodiimide compound is dicyclohexyl carbodiimide (DCC), di-isopropyl carbodiimide (DIC), carbonyl dimidazoles (Carbonyldiimidazole) for example, wherein preferred dicyclohexyl carbodiimide; The chloroformyl ester for example is chloroformyl isobutyl ester, chloroformyl ethyl ester, chloroformyl methyl esters, wherein preferred chloroformyl isobutyl ester.
At protic organic solvent described in the preparation method of above-mentioned general formula I and general formula III for example is the C1-C4 lower alkyl alcohol, as: methyl alcohol, ethanol, propyl alcohol, Virahol etc., wherein particular methanol, ethanol; Used mineral alkali is preferably NaOH, KOH, K
2CO
3, Na
2CO
3Or Ca (OH)
2, wherein preferred NaOH, K
2CO
3
At the not preferred toluene of non-proton organic solvent, methylene dichloride, the methylene dichloride/DMF of disturbance reponse described in above-mentioned general formula I preparation method's step 1, step 3 and general formula I I preparation method's step 2 and general formula III preparation method's the route 3;
At the not preferred acetone of non-proton organic solvent, the ether of disturbance reponse described in above-mentioned general formula I I preparation method's the step 1.
At the not preferred tetrahydrofuran (THF) of non-proton organic solvent, the acetone of disturbance reponse described in above-mentioned general formula III preparation method's route 1, the route 2.
The present invention also relates to a kind of pharmaceutical composition on the other hand, it comprise general formula (I) compound of at least a treatment effective dose and/or steric isomer or its pharmacologically acceptable salt for example with the additive salt of pharmaceutically acceptable acid, and pharmaceutically acceptable carrier.
The invention still further relates to above-mentioned compound of Formula I or its steric isomer or its pharmacologically acceptable salt medicine, especially as the purposes in the medicine that reduces gpt and glutamic-oxal(o)acetic transaminase (ALT and AST) at preparation treatment hepatic diseases.
General formula of the present invention (I) compound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc. for example, can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For tablet is made in the administration unit, the example of operable carrier well known in the art is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in the administration unit, the example of operable carrier well known in the art is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in the administration unit, the example of operable carrier well known in the art is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in the administration unit, effective constituent general formula (I) compound or its steric isomer or its pharmacologically acceptable salt are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard ' Yanming ' capsules for clearing or soft capsule.Also effective constituent general formula (I) compound or its steric isomer or its pharmacologically acceptable salt can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners commonly used, for example, water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The dosage of general formula of the present invention (I) compound or its steric isomer or its pharmacologically acceptable salt depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.The day oral administration dosage of the general formula of giving (I) compound be preferably 0.001-100mg/kg, more preferably 0.1-40mg/kg.
In order further to understand the present invention, the following examples and pharmacological evaluation are used for further specifying the present invention, but are not the meaning any limitation of the invention.
Embodiment
Embodiment 1
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-Sodium Benzoate
Tetra hydro Phthalic anhydride 20.02g is broad in 120mL acetone, under the stirring at room, drips (3 ', 4 ' methylene-dioxy) phenylethylamine 22.3g dripped off in 10 minutes, continued to stir 2 hours, precipitation is separated out gradually, filters, and the white solid that obtains is recrystallization (w/v:2g/mL) in 95% ethanol.Obtain 2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-phenylformic acid 38.0g, white, needle-shaped crystals.m.p.142-143℃
1HNMR(300MHz，CD
3OD，δppm)：2.76(t，2H，J＝6.9Hz，H-9)，3.45(t，2H，J＝6.9Hz，H-8)，5.83(s，2H，H-7’)，6.7-7.9(m，7H，Ar-H)
Ultimate analysis: theoretical value: C65.17%, H4.79%, N4.47%; Measured value: C65.23%, H4.69%, N4.60%
IR(KBr，cm
-1)：3307，3300-2500(br.)，1730，1628，1600，1577，1500，1489，1300，1248，1039，937，924，876，766，700
With 2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-phenylformic acid 939mg is dissolved in the 10mL methyl alcohol, adds aqueous sodium hydroxide solution (containing sodium hydroxide 120mg), be concentrated into dried, the vacuum drying, the gained solid with heat dehydrated alcohol wash, obtain required compound, white solid.
Embodiment 2
3-nitro-2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
3-nitrophthalic acid acid anhydride 0.989g is dissolved in the acetone, under the stirring at room, drips (3 ', 4 ' methylene-dioxy) phenylethylamine 0.99ml dripped off in 10 minutes, continued to stir 2 hours, precipitation is separated out gradually, filters, and the white solid that obtains is recrystallization in 95% ethanol.Obtain required compound 1.35g, faint yellow solid.m.p.168-169℃
1HNMR(300MHz，CD
3OD，δppm)：2.82(t，2H，J＝7.2Hz，H-9)，3.50(t，2H，J＝7.2Hz，H-8)，5.98(s，2H，H-7’)，6.74(m+s，3H，H-5’，H-6’，H-2’)，7.73-8.29(m，3H，H-4，H-5，H-6)。ESIMS：359(M+1)
Embodiment 3
6-methyl-2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
Method is with embodiment 2.Replace 3-nitrophthalic acid acid anhydride with 3-methylphthalic acid acid anhydride 0.908g.Use substituted ether acetone, filter, the white solid that obtains is recrystallization (w/v:2g/ml) in 80% ethanol.Obtain required compound 1.3g, white, needle-shaped crystals.m.p.113-115℃
1HNMR(300MHz，CD
3OD，δppm)：2..19(s，3H，CH
3-6)，2.82(t，2H，J＝7.5Hz，H-9)，3.48(t，2H，J＝7.5Hz，H-8)，5.83(s，2H，H-7’)，6.70(m+s，3H，H-5’，H-6’，H-2’)，7.24-7.80(m，3H，H-3，H-4，H-5)
ESIMS：328(M+1)
Embodiment 4
5-chloro-2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
4-chloro-2-carboxyl-Sodium Benzoate 0.996g adds chloroformyl isobutyl ester 0.7ml in the 6ml dry DMF, 0 ℃ was stirred 1 hour, be added dropwise to (3 ', 4 ' methylene-dioxy) phenylethylamine 0.9ml, rise to room temperature, continue to stir 10 hours, add frozen water, 1mo l/L hydrochloric acid is transferred about pH to 2, and (3 * 25ml) extract with methylene dichloride, organic phase is respectively with saturated common salt washing, anhydrous sodium sulfate drying.Be concentrated into driedly, gained solid recrystallization in sherwood oil/acetone gets required product 930mg.White solid.m.p.109-110℃
1HNMR(300MHz，CD
3OD，δppm)：2.82(t，2H，J＝6.9Hz，H-9)，3.49(t，2H，J＝6.9Hz，H-8)，5.89(s，2H，H-7’)，6.73(m+s，3H，H-5’，H-6’，H-2’)，7.31-7.95(m，3H，H-3，H-4，H-6)ESI?MS：348.4(M+1)，370.4(M+Na)
Embodiment 5
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl benzyl amine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-phenylformic acid 0.997g in the 6ml dry DMF, drip triethylamine 1.2ml, be cooled to 0-5 ℃, drip chloroformyl isobutyl ester 0.48ml, stirred 40 minutes, be added dropwise to benzylamine 0.41ml, rise to room temperature, continue to stir 3 hours, add frozen water, 1mol/L hydrochloric acid is transferred about pH to 2, (3 * 25ml) extract, and organic phase is respectively with saturated common salt washing, anhydrous sodium sulfate drying with methylene dichloride.Concentrate, add elutriation and go out white solid, filtration drying gets 1.23g.Recrystallization gets required product 1.05g in sherwood oil/acetone.White solid.m.p.136-137℃
1HNMR(300MHz，CDCl
3，δppm)：2.72(t，2H，J＝7.2Hz，H-9)，3.48(dd，2H，J＝6.9Hz，6.3Hz，H-8)，4.52(d，2H，J＝5.7Hz，Ph
CH 2 -)，5.90(s，2H，H-7’)，6.61-7.95(m，14H，Ar-H，CO
NH)ESI?MS：403(M+1)，425(M+Na)
Embodiment 6
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-benzanilide
Method is with embodiment 5.Replace benzyl amine with aniline.2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid is 0.996g.Gained solid recrystallization in sherwood oil/acetone gets required product 1.0g.White solid.m.p.191-192℃。
1HNMR(300MHz，CDCl
3，δppm)：2.74(t，2H，J＝6.9Hz，H-9)，3.57(m，2H，H-8)，5.90(s，2H，H-7’)，6.61-7.85(m，13H，Ar-H，7-CO
NH-)，9.33(s，1H，Ph
NHCO)
ESI?MS：389(M+1)，411(M+Na)
Embodiment 7
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N '-phenyl ethyl amine
Method is with embodiment 5.Replace benzyl amine with phenylethylamine.2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid is 0.982g.Gained solid recrystallization in sherwood oil/acetone gets required product 1.08g.White solid.m.p.156-157℃
1HNMR(300MHz，CDCl
3，δppm)：2.80(t，2H，J＝6.9Hz，H-9)，2.90(t，2H，J＝7.2Hz，Ph
CH 2 CH
2-)，3.48-3.65(m，4H，H-8，PhCH
2 CH 2 -)，5.90(s，2H，H-7’)，6.64-7.75(m，14H，Ar-H，CO
NH)
ESI?MS：417(M+1)，439(M+Na)
Embodiment 8
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N '-(3 "-indyl) ethylamine
Method is with embodiment 5.Replace benzyl amine with tryptamines.2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid is 0.983g.Gained solid recrystallization in sherwood oil/acetone gets required product 1.15g.White solid.m.p.140-141℃
1HNMR(300MHz，CD
3OD，δppm)：2.74(t，2H，J＝6.9Hz，H-9)，2.99(t，2H，J＝7.2Hz，Indole-
CH 2 CH
2-)，3.41(t，2H，J＝6.9Hz，H-8)，3.57(t，2H，J＝7.5Hz，Indole-CH
2 CH 2 -)，5.81(s，2H，H-7’)，6.66-7.56(m，13H，Ar-H)
ESI?MS：456.6(M+1)，478.6(M+Na)
Embodiment 9
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N '-(4 "-hydroxy phenyl) ethylamine
Method is with embodiment 5.Replace benzyl amine with tyrasamine.2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid is 0.994g.Gained solid recrystallization in sherwood oil/acetone gets required product 1.2g.White solid.m.p.120-121℃
1HNMR(300MHz，CD
3OD，δppm)：2.73(m，4H，H-9，Ph
CH 2 CH
2-)，3.44(m，4H，H-8，PhCH
2 CH 2 -)，5.81(s，2H，H-7’)，6.66-7.75(m，11H，Ar-H)
ESI?MS：433(M+1)，455(M+Na)
Embodiment 10
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl n-propyl amine
Method is with embodiment 5.Replace benzyl amine with n-propyl amine.2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid is 0.996g.Gained solid-20 ℃ of recrystallizations in sherwood oil/acetone get required product 0.98g.White solid.m.p.122-123℃。
1HNMR(300MHz，CDCl
3，δppm)：0.96(t，3H，J＝7.2Hz，
CH 3 CH
2CH
2-)，1.60(m，2H，CH
3 CH 2 CH
2-)，2.81(t，2H，J＝7.2Hz，H-9)，3.46(dd，2H，J＝6.9Hz，6.6Hz，CH
3CH
2 CH 2 -)，3.60(dd，2H，J＝6.9Hz，7.2Hz，H-8)，5.90(s，2H，H-7’)，6.65-7.65(m，9H，Ar-H，CO
NH)
ESI?MS：355(M+1)，377(M+Na)
Embodiment 11
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N ', N '-4 '-(4 "-fluorophenyl) piperazine
Method is with embodiment 5.Replace benzyl amine with 4-fluorophenyl piperazine.2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid is 0.99g.Gained solid recrystallization in sherwood oil/acetone gets required product 1.21g.White solid.m.p.142℃
1HNMR(300MHz，CDCl
3，δppm)：2.79(t，2H，J＝7.2Hz，H-9)，2.97(br.s，2H，Ar-N-
CH 2 )，3.13(br.s，2H，Ar-N-
CH 2 )，3.34(br.s，2H，Ar-N-CH
2 CH 2 -NCO)，3.58(br.s，2H，H-8)，3.86(br.s，2H，Ar-N-CH
2 CH 2 -NCO)，5.91(s，2H，H-7’)，6.66-7.84(m，12H，Ar-H，CO
NH)
ESI?MS：476(M+1)
Embodiment 12
3-methyl-N, N-(3 ', 4 ' methylene-dioxy) phenylethyl phthalic imidine
3-methylphthalic acid acid anhydride 135mg under the stirring at room, adds (3 ', 4 ' methylene-dioxy) phenylethylamine in methylene dichloride, and triethylamine, stirred 2 hours, the concentrated white solid that obtains, in silica gel column chromatography separate required product 211mg.White solid.m.p.128-130℃
1HNMR(300MHz，CDCl
3，δppm)：2..69(s，3H，CH
3-6)，2.89(t，2H，J＝7.5Hz，H-9)，3.84(t，2H，J＝7.5Hz，H-8)，5.93(s，2H，H-7’)，6.71(m+s，3H，H-5’，H-6’，H-2’)，7.26-7.86(m，3H，H-4，H-5，H-6)
Embodiment 13
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-peruscabin
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-phenylformic acid (500mg) is in the 5ml anhydrous methylene chloride,-the 10-0 ℃ following oxalyl chloride (0.28ml) that drips, and in 0 ℃ of following 1h that stirs, evaporated under reduced pressure with the anhydrous methylene chloride 2ml * 3 remaining oxalyl chloride of taking, adds the 5ml anhydrous methylene chloride, benzylalcohol 0.23ml, Et
3N (240mg), stirring at room 4h.With the dilution of 10ml methylene dichloride, successively with the 1N hydrochloric acid soln, saturated NaHCO
3Solution, brine washes, anhydrous sodium sulfate drying, silica gel column chromatography separate required product 0.57g.Faint yellow solid.m.p.49-51℃
1HNMR(300MHz，CDCl
3，δppm)：2.75(t，2H，J＝7.2Hz，H-9)，3.53(dd，2H，J＝6.9Hz，6.3Hz，H-8)，5.31(s，2H，J＝5.7Hz，Ph
CH 2 -)，5.94(s，2H，H-7’)，6.61-7.95(m，13H，Ar-H，CO
NH)
Embodiment 14
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid (4 "-methoxyl group)-the phenyl methyl ester
Method is with embodiment 13.With pmethoxybenzyl alcohol (332mg) replace benzylalcohol, silica gel column chromatography separate required product 0.603g.White solid.m.p.88-90℃
1HNMR(300MHz，CDCl
3，δppm)：2.75(t，2H，J＝6.9Hz，H-9)，3.52(dd，2H，J＝6.9Hz，6.3Hz，H-8)，3.79(s，3H，Ar-O-
CH 3 )，5.25(s，2H，J＝5.7Hz，Ar
CH 2 -)，5.92(s，2H，H-7’)，6.61-7.90(m，12H，Ar-H，CO
NH)
Embodiment 15
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-phenylformic acid phenyl propyl diester
Method is with embodiment 13.With phenylpropyl alcohol (0.33ml) replace benzylalcohol, silica gel column chromatography separate required product 0.64g.Faint yellow solid.m.p.45-47℃
1HNMR(300MHz，CDCl
3，δppm)：2.06(m，2H，PhCH
2 CH 2 CH
2-)，2.76(t，2H，J＝6.9Hz，H-9)，2.85(t，2H，J＝7.2Hz，Ph
CH 2 CH
2CH
2)，3.65(dd，2H，J＝7.2Hz，6.3Hz，H-8)，4.31(t，2H，J＝6.9Hz，PhCH
2CH
2 CH 2 -)，5.92(s，2H，H-7’)，6.66-7.86(m，13H，Ar-H，CO
NH)
Embodiment 16
3-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-methyl benzoate
M-phthalic acid mono-methyl 300mg is in 10ml methylene dichloride and 0.4ml DMF; under the nitrogen protection; drip oxalyl chloride 0.143ml; after stopping to emit bubble, continue to stir 45 minutes the ice bath cooling; add homopiperony lamine 0.55ml; rose to stirring at room 1 hour, reaction mixture is with the aqueous hydrochloric acid of 1mol/L, semi-saturation NaHCO
3Solution, brine washes, anhydrous sodium sulfate drying, silica gel column chromatography separate required product 0.18g.White solid.
m.p.130-132℃
1HNMR(400MHz，CDC?l
3，δppm)：2.85(t，2H，J＝7.2Hz，H-9)，3.60(q，2H，J＝7.2Hz，H-8)，3.90(s，3H，CH
3)，5.94(s，2H，H-7’)，6.74(m+s，3H，H-5’，H-6’，H-2’)，7.59(t，1H，J＝8Hz，H-4)，8.03-8.11(m，2H，H-5，H-6)，8.45(s，1H，H-2)
Embodiment 17
4-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-methyl benzoate
Method is with embodiment 16.Replace the m-phthalic acid mono-methyl with terephthalic acid monomethyl ester 700mg, silica gel column chromatography separate required product 730mg.m.p.158-160℃
1HNMR(400MHz，CDCl
3，δppm)：2.83(t，2H，J＝7.2Hz，H-9)，3.59(q，2H，J＝7.2Hz，H-8)，3.89(s，3H，CH
3)，5.94(s，2H，H-7’)，6.74(m+s，3H，H-5’，H-6’，H-2’)，7.94(d，2H，J＝8Hz，H-2，H-6)，8.05(d，2H，J＝8.4Hz，H-3，H-5)
Embodiment 18
3-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
3-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-methyl benzoate 150mg adds 1N aqueous sodium hydroxide solution 0.55ml in 2ml methyl alcohol, water 0.3ml, stirring at room 3 hours, transfer pH value about 2 with the 2mol/L aqueous hydrochloric acid, white precipitate generates, filter required product 0.105g.m.p.218-220℃
1HNMR(400MHz，CDCl
3，δppm)：2.86(t，2H，J＝7.2Hz，H-9)，3.61(q，2H，J＝7.2Hz，H-8)，5.93(s，2H，H-7’)，6.74(t+s，3H，H-5’，H-6’，H-2’)，7.59(t，1H，J＝8Hz，H-4)，8.03-8.11(m，2H，H-5，H-6)，8.48(s，1H，H-2)
Embodiment 19
4-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
Method is with embodiment 18.With 4-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-methyl benzoate 654mg replacement 3-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-methyl benzoate, get required product 453mg.m.p.234-236℃
1HNMR(400MHz，CDCl
3，δppm)：2.78(t，2H，J＝7.2Hz，H-9)，3.50(q，2H，J＝6.8Hz，H-8)，5.84(s，2H，H-7’)，6.67(m+s，3H，H-5’，H-6’，H-2’)，7.78(d，2H，J＝8.4Hz，H-2，H-6)，8.08(d，2H，J＝8.8Hz，H-3，H-5)
Embodiment 20
6-methyl-2-[N-methyl, N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
3-methylphthalic acid acid anhydride 6.48g is in the mixed solvent of 80mL acetone and ether, under the stirring at room, drip the N-methyl, N-(3 ', 4 ' methylene-dioxy) phenyl ethyl amine 6.94g dripped off in 10 minutes, continue to stir 12 hours, precipitation is separated out gradually, filters, and the white solid that obtains is recrystallization in 50% ethanol.Obtain required compound 8.3g, white solid.m.p.143-145℃
1HNMR(400MHz，CDCl
3，δppm)：2.14(s，3H，CH
3-6)，2..67(s，3H，CH
3-N)，2.83-2.92(m，2H，H-9)，3.57-3.77(m，2H，H-8)，5.84(s，2H，H-7’)，6.71(m+s，3H，H-5’，H-6’，H-2’)，7.32-7.86(m，3H，H-3，H-4，H-5)
Embodiment 21
The 2-[N-methyl, N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
Tetra hydro Phthalic anhydride 6.48g is in the mixed solvent of 80mL acetone and ether, under the stirring at room, drip the N-methyl, N-(3 ', 4 ' methylene-dioxy) phenyl ethyl amine 6.94g dripped off in 10 minutes, continue to stir 12 hours, precipitation is separated out gradually, filters, and the white solid that obtains is recrystallization in 50% ethanol.Obtain required compound 8.3g, white solid.
m.p.197-199℃
1HNMR(400MHz，CDCl
3，δppm)：2.64(t，1H，J＝7.6Hz，H-9)，2.67(s，3H，CH
3-N)，2.86(t，1H，J＝7.6Hz，H-9)，3.18(t，1H，J＝7.2Hz，H-8)，3.64(t，1H，J＝7.6Hz，H-8)，5.84(d，2H，H-7’)，6.34-8.02(m，7H，Ar-H)
Embodiment 22
5-trifluoromethyl-2-[N-methyl-N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
4-trifluoromethyl Tetra hydro Phthalic anhydride 1.86g is in the 10mL ether, under the stirring at room, drip the N-methyl, N-(3 ', 4 ' methylene-dioxy) phenyl ethyl amine 1.79g, dripped off in 10 minutes, and continued to stir 3 hours, precipitation is separated out gradually, filter, and wash twice with the 10mL ether, obtain required compound 2.9g, white solid.m.p.118-119℃
1HNMR(400MHz，CDCl
3，δppm)：2.65(s，3H，CH
3-N)，2.85(t，2H，J＝8.0Hz，H-9)，3.15(t，2H，J＝7.6Hz，H-8)，5.85(s，2H，H-7’)，6.65-6.73(m+s，3H，H-5’，H-6’，H-2’)，7.75-8.30(s+d+d，3H，H-3，H-4，H-6)
Embodiment 23
3-fluoro-2-[N-methyl-N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
3-difluorophthalic anhydride 1.56g under the stirring at room, drips the N-methyl in the 10mL ether, N-(3 ', 4 ' methylene-dioxy) phenyl ethyl amine 1.79g dripped off in 10 minutes, continued to stir 15 hours, concentrated, resistates 50% ethyl alcohol recrystallization obtains required compound 1.8g, white solid.m.p.175-176℃
1HNMR(400MHz，CDCl
3，δppm)：2.72(s，3H，CH
3-N)，2.85(m，2H，H-9)，3.65(m，2H，H-8)，5.84(s，2H，H-7’)，6.68-6.79(m+s，3H，H-5’，H-6’，H-2’)，7.35-7.85(d+dd+t，3H，H-4，H-5，H-6)
Test of pesticide effectiveness example
Experiment purpose
The The compounds of this invention that observation obtains through the foregoing description protects the liver the pharmacodynamics evaluation in vivo to the provide protection of mouse carbon tetrachloride acute liver damage to these compounds.
Test example 1.
1. experiment material is subjected to the The compounds of this invention that reagent thing: embodiment 1, embodiment 3, embodiment 4, embodiment 9 obtain.Time spent suspends with 0.5%CMC-Na.
Other drug and reagent: Biphenylylmethylcarbinol, dripping pill, Beijing consonance pharmaceutical factory product; Time spent suspends with 0.5%CMC-Na.Tetracol phenixin, analytical pure, Beijing northization fine chemicals limited liability company product.ALT and AST detection kit are the safe clinical reagent of Beijing northization company limited product.
Animal: the ICR mouse, male, body weight 18-20 gram is provided by dimension tonneau China laboratory animal technology company limited.
2.. method and result
1) principle: CCl
4Activate through liver cell pigment P450s, generate trichloromethyl free radical (CCl
3.), attack phospholipid molecule on the endoplasmic reticulum by hydrogen adsorption, cause the lipid peroxidation of film, and carry out covalent attachment with membrane lipid and protein macromolecule, cause the destruction of membrane structure and functional completeness.CCl
4. the activity of calcium pump on film also capable of inhibiting cell and the microsomal membrane makes Ca
2+Stream increases in the ion, thereby causes cytotoxic death.ALT, AST rising in the visible blood in the experimentation on animals, the visible liver inflammatory cell infiltration of pathologic finding, steatosis and hepatic necrosis.
2) method: laboratory animal is divided into normal control group, model group (CCl
40.2ml/20g), Biphenylylmethylcarbinol bulk drug positive controls, bifendate drop pill positive controls, given the test agent administration group (The compounds of this invention that embodiment 1, embodiment 3, embodiment 4, embodiment 9 obtain).Positive drug control group (200mg/kg) and each given the test agent administration group (200mg/kg) are gastric infusion 0.4ml/20g, and in modeling preceding 24 hours, 8 hours and administration in 1 hour, administration is 3 times altogether.Normal control group and tetracol phenixin model group give with the volume vehicle.Except that the normal control group, all the other respectively organize equal abdominal injection 0.14% tetracol phenixin olive oil solution, and volume 10ml/kg puts to death the preceding overnight fasting of animal.With the animal sacrificed by decapitation, get serum and do ALT, AST biochemical indicator mensuration after 36 hours.
3) result
The results are shown in Table 1.After intact animal gave 0.14% tetracol phenixin, serum alt, AST obviously raise.Given the test agent compound (The compounds of this invention that embodiment 1, embodiment 3, embodiment 4, embodiment 9 obtain) has significant protective effect to ALT and the AST rising that tetracol phenixin causes; and compare with positive Biphenylylmethylcarbinol bulk drug contrast medicine; AST raise, and to have better restraining effect, the The compounds of this invention that embodiment 3 obtains to have suitable for the bifendate drop pill positive control drug ALT and AST rising restraining effect.
Table 1 given the test agent causes the provide protection of chmice acute liver injury to tetracol phenixin
*P＜0.05,
* *Compare with the normal control group P＜0.001;
*P＜0.05,
*P＜0.01,
* *Compare with model group P＜0.001.
Test example 2.
1. experiment material
The The compounds of this invention that obtained by reagent thing: embodiment 3 and embodiment 12.Time spent is made into the solution of desired concn with 0.2% tween 80, faces with now joining.
Other drug and reagent: Biphenylylmethylcarbinol, dripping pill, Beijing consonance pharmaceutical factory product; Be made into desired concn with sterile purified water, face with now joining.Tetracol phenixin, analytical pure, Beijing northization fine chemicals limited liability company product.ALT and AST detection kit are the safe clinical reagent of Beijing northization company limited product.
Animal: Kunming mouse is provided by laboratory animal institute of Chinese Academy of Medical Sciences breeding field, the cleaning level.Experimental animal feeding is at barrier level Animal House.
2. method and result
1) method tetracol phenixin (being dissolved in Semen Maydis oil) consumption is the 0.14%10ml/kg abdominal injection, and animal fasting 16 hours behind injection tetracol phenixin hepatotoxicant gets that serum is ALT, the AST biochemical indicator is measured, and sacrificed by decapitation is weighed.
Laboratory animal is divided into the The compounds of this invention administration group (100mg/kg) that normal control group, model group (tetracol phenixin 0.2ml/20g), tetracol phenixin+Biphenylylmethylcarbinol group (200mg/kg), embodiment 3 obtain, the The compounds of this invention administration group (100mg/kg) that embodiment 12 obtains is gastric infusion 0.4ml/20g, modeling preceding 24 hours, 8 hours and administration in 1 hour, administration is 3 times altogether.
2) result
The results are shown in Table 2.The The compounds of this invention that embodiment 3 and embodiment 12 obtain all can reduce tetracol phenixin and cause chmice acute liver injury Serum ALT and AST level (all P＜0.001).Illustrate that the The compounds of this invention that embodiment 3 and embodiment 12 obtain causes the chmice acute liver injury all to have significant protective effect to tetracol phenixin, and obviously be better than the effect that the 200mg/kg Biphenylylmethylcarbinol reduces the AST level.
Table 2 given the test agent causes the provide protection of chmice acute liver injury to tetracol phenixin
* *Compare with the normal control group P＜0.001;
* *Compare with model group P＜0.001
Test example 3.
1. experiment material
The The compounds of this invention that obtained by reagent thing: embodiment 20 and embodiment 21.Time spent is made into the solution of desired concn with 0.2% tween 80, faces with now joining.
Other drug and reagent: Biphenylylmethylcarbinol, dripping pill, Beijing consonance pharmaceutical factory product; Be made into desired concn with sterile purified water, face with now joining.Tetracol phenixin, analytical pure, Beijing northization fine chemicals limited liability company product.ALT and AST detection kit are the safe clinical reagent of Beijing northization company limited product.
Animal: Kunming mouse is provided by laboratory animal institute of Chinese Academy of Medical Sciences breeding field, and the cleaning level is by Beijing Kelaibo Medicine Development Co., Ltd's product.Experimental animal feeding is at barrier level Animal House.
2. method and result
1) method tetracol phenixin (being dissolved in Semen Maydis oil) consumption is the 0.14%10ml/kg abdominal injection, and animal fasting 16 hours behind injection tetracol phenixin hepatotoxicant gets that serum is ALT, the AST biochemical indicator is measured, and sacrificed by decapitation is weighed.
Laboratory animal is divided into, the The compounds of this invention administration group (50mg/kg, 100mg/kg) that normal control group, model group (tetracol phenixin 0.2ml/20g), tetracol phenixin+Biphenylylmethylcarbinol group (200mg/kg), embodiment 20 obtain, the The compounds of this invention administration group (50mg/kg, 100mg/kg) that embodiment 21 obtains is gastric infusion 0.4ml/20g, modeling preceding 24 hours, 8 hours and administration in 1 hour, administration is 3 times altogether.
2) result
The results are shown in Table 3.The The compounds of this invention that embodiment 20 and embodiment 21 obtain all can reduce tetracol phenixin and cause chmice acute liver injury Serum ALT levels (all P＜0.001); Per three the dosage groups of two compounds all can reduce serum AST level (P＜0.05, P＜0.001), and dose-effect relationship is preferably arranged.Illustrate that the The compounds of this invention that embodiment 20 and embodiment 21 obtain causes the chmice acute liver injury all to have significant protective effect to tetracol phenixin, and obviously be better than the effect that the 200mg/kg Biphenylylmethylcarbinol reduces the AST level.
Table 3 given the test agent causes the provide protection of chmice acute liver injury to tetracol phenixin
*P＜0.05,
* *Compare with the normal control group P＜0.001;
*P＜0.05,
*P＜0.01,
* *Compare with model group P＜0.001.
Claims (25)
1. the compound or pharmaceutically acceptable salt thereof of a general formula (I):
Wherein:
X is a nitrogen, oxygen or sulphur;
R1 is selected from hydrogen, monovalence or divalent-metal ion, the C1-C8 alkyl, C3-C6 cycloalkyl, C6-C14 aryl, the C4-C12 heteroaryl, C6-C14 aryl C1-8 alkyl, C3-6 heterocyclic radical, C6-C14 aryl C3-6 heterocyclic radical and C4-C12 heteroaryl C1-8 alkyl, wherein said aryl or heteroaryl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C
1-C
4Alkyl;
Wherein said monovalence or divalent-metal ion are selected from Li
+, Na
+, K
+, Mg
2+And Ca
2+
Perhaps, the R1-X base forms inferior amide compound together with the amido that forms 3 ', 4 '-methylenedioxyphenyl ethamine of amide group;
R2, R3, R4 and R5 are selected from hydrogen, C1-C4 alkyl, C1-C 3 perfluoroalkyls, phenyl, halogen, nitro, hydroxyl and C1-C4 alkoxyl group independently of one another, and wherein, R2, R3, R4, R5 arbitrarily can substituted positions on phenyl ring;
R6 is a hydrogen, C1-C8 alkyl or C3-C5 cycloalkyl;
Wherein do not comprise following compounds:
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
N, N-(3 ', 4 ' methylene-dioxy) phenylethyl phthalic imidine
2. compound or pharmaceutically acceptable salt thereof as claimed in claim 1 is characterized in that described compound is selected from following general formula I I compound and compound of formula III:
Wherein, described in the definition such as claim 1 of each group;
Perhaps wherein the R1-X base forms inferior amide compound together with the amido that forms 3 ', 4 '-methylenedioxyphenyl ethamine of amide group, promptly forms general formula (III) compound:
Wherein, described in the definition such as claim 1 of each group.
3. compound or pharmaceutically acceptable salt thereof as claimed in claim 1 is characterized in that described compound is selected from following general formula I V compound and general formula V compound:
Wherein, described in the definition such as claim 1 of X, R1 and R6;
R ' is hydrogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, phenyl, halogen, nitro, hydroxyl or C1-C4 alkoxyl group;
Perhaps wherein the R1-X base forms inferior amide compound together with the amido that forms 3 ', 4 '-methylenedioxyphenyl ethamine of amide group, promptly forms logical formula V compound:
R ' is hydrogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, phenyl, halogen, nitro, hydroxyl or C1-C4 alkoxyl group.
4. compound or pharmaceutically acceptable salt thereof as claimed in claim 3 is characterized in that X is nitrogen or oxygen in general formula I V compound;
R1 is a hydrogen, C1-C8 alkyl, piperazinyl, phenyl, phenyl C1-C8 alkyl, 3-indyl C1-C8 alkyl or 4-Phenylpiperazinyl, wherein said phenyl and 3-indyl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C1-C4 alkyl;
R ' is hydrogen, C1-C4 alkyl, halogen, nitro, hydroxyl or C1-C4 alkoxyl group;
R6 is hydrogen or methyl.
5. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound is:
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-Sodium Benzoate
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido--3-nitrobenzoic acid
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido--6-tolyl acid
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido--5-chloro-benzoic acid
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl benzyl amine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-benzanilide
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N '-phenyl ethyl amine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N '-(3 "-indyl) ethylamine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N '-(4 "-hydroxy phenyl) ethylamine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl n-propyl amine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-benzoyl-N ', N '-4 '-(4 "-fluorophenyl) piperazine
3-methyl-N, N-(3 ', 4 ' methylene-dioxy) phenylethyl phthalic imidine
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-peruscabin
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid (4 "-methoxyl group)-the phenyl methyl ester
2-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] formamido-phenylformic acid phenyl propyl diester
3-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-methyl benzoate
4-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-methyl benzoate
3-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
4-[N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
6-methyl-2-[N-methyl, N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
The 2-[N-methyl, N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
5-trifluoromethyl-2-[N-methyl-N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
3-fluoro-2-[N-methyl-N-(3 ', 4 ' methylene-dioxy) phenylethyl] the formamido-phenylformic acid
6. a method for preparing general formula as claimed in claim 1 (I) compound comprises
(1) general formula VIa compound
In the non-proton organic solvent of disturbance reponse not, in the presence of organic bases and chloroformyl ester or carbodiimide compound, with general formula VII compound
Reaction obtains general formula VIII compound
Perhaps general formula VIa compound and thionyl chloride or oxalyl chloride
Reaction obtains chloride compounds, obtains general formula VIII compound with the reaction of general formula VII compound again;
In general formula VIa and general formula VIII, M is selected from monovalence or divalent-metal ion, the C1-C8 alkyl, C3-C6 cycloalkyl, C6-C14 aryl, the C4-C12 heteroaryl, C6-C14 aryl C1-8 alkyl, C3-C6 heterocyclic radical, C6-C14 aryl C3-C6 heterocyclic radical and C4-C12 heteroaryl C1-8 alkyl, wherein said aryl or heteroaryl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C
1-C
4Alkyl; Wherein said monovalence or divalent-metal ion are selected from Li
+, Na
+, K
+, Mg
2+And Ca
2+
(2) the formula VIII compound that obtains through step 1 when M is metal ion, obtains general formula I X compound through acidifying
Or when M was other groups that limited, general formula VIII compound obtained general formula I X compound through the mineral alkali hydrolysis in water or protic organic solvent;
(3) in general formula I X compound that step 2 obtains non-proton organic solvent at disturbance reponse not, in the presence of organic bases and chloroformyl ester or carbodiimide compound, obtain compound of Formula I with general formula compound R1-X-H reaction, when X is oxygen or sulphur, also should there be extra and the suitable organic bases of general formula compound R1-X-H consumption in the reaction system;
Wherein said organic bases is selected from pyridine, 4-N, N-lutidine, hexamethyldisilazane and tertiary amine molecule.
7. a method for preparing general formula as claimed in claim 2 (II) compound comprises
(1) general formula VII compound and general formula VIb compound
At water or do not react in the disturbance reponse non-proton organic solvent, obtain the general formula X compound
When in being reflected at water, carrying out, also need add phase-transfer catalyst;
(2) the general formula X compound is in the non-proton organic solvent of disturbance reponse not, in the presence of organic bases and chloroformyl ester or carbodiimide compound, obtain general formula (II) compound with general formula compound R1-X-H reaction, perhaps the reaction of general formula X compound and thionyl chloride or oxalyl chloride obtains chloride compounds, obtains general formula (II) compound with general formula compound R1-X-H reaction again; When X is oxygen or sulphur, also should there be extra and the suitable organic bases of general formula compound R1-X-H mole dosage in the reaction system;
Wherein said organic bases is selected from pyridine, 4-N, N-lutidine, hexamethyldisilazane and tertiary amine molecule.
8. a method for preparing general formula as claimed in claim 2 (III) compound comprises
3 ', 4 '-methylenedioxyphenyl ethamine
Exist under the condition of organic bases with the compound of general formula (VIb), in the non-proton organic solvent of disturbance reponse not and protic organic solvent, react and make, perhaps 3 ', the compound of 4 '-methylenedioxyphenyl ethamine and general formula (VIb) is under the condition that has phase-transfer catalyst and mineral alkali, and the Yu Shuizhong reaction makes; Perhaps comprise
The compound of 3 ', 4 '-methylenedioxyphenyl ethamine and general formula (VIc)
Exist under the organic bases, in the non-proton organic solvent of disturbance reponse not and protic organic solvent, react and make; Perhaps comprise
The compound of general formula (XI)
In the presence of chloroformyl ester or carbodiimide and organic bases, in non-proton organic solvent, react and make;
Wherein said organic bases is selected from pyridine, 4-N, N-lutidine, hexamethyldisilazane and tertiary amine molecule.
9. according to each method of claim 6-8, wherein said carbodiimide compound is selected from dicyclohexyl carbodiimide, di-isopropyl carbodiimide and carbonyl dimidazoles.
10. according to the method for claim 9, wherein said carbodiimide compound is a dicyclohexyl carbodiimide.
11. according to each method of claim 6-8, wherein said chloroformyl ester is selected from chloroformyl isobutyl ester, chloroformyl ethyl ester and chloroformyl methyl esters.
12. according to the method for claim 11, wherein said chloroformyl ester is the chloroformyl isobutyl ester.
13. according to each method among the claim 6-8, the non-proton organic solvent of wherein said not disturbance reponse is selected from aromatic hydrocarbon, halohydrocarbon, ether solvent, ketones solvent, the mixed solvent of polar aprotic solvent and above qualification solvent composition.
14. method according to claim 13, the non-proton organic solvent of wherein said not disturbance reponse is selected from benzene,toluene,xylene, oil of mirbane, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, ether, methyl tert-butyl ether, tetrahydrofuran (THF), 1,4-dioxane, acetone, 2-butanone, DMF, DMSO, N-Methyl pyrrolidone, methylene dichloride/DMF and benzene/DMF.
15. according to each method among the claim 6-8, wherein said protic solvent is selected from methyl alcohol, ethanol, propyl alcohol, Virahol and butanols.
16. according to each method among the claim 6-8, wherein said organic bases is selected from pyridine and triethylamine.
17. according to each method among the claim 6-8, wherein said phase-transfer catalyst is selected from tetramethyl ammonium chloride, Tetrabutyl amonium bromide and tetraethylammonium bromide.
18. according to each method among the claim 6-8, wherein said mineral alkali is selected from NaOH, KOH, K
2CO
3, Na
2CO
3And Ca (OH)
2
19., it is characterized in that described in the step 1 that the non-proton organic solvent of disturbance reponse is not acetone, ether or acetone mixed solvent according to the method for claim 7.
20. method according to Claim 8, the organic solvent that it is characterized in that described not disturbance reponse is tetrahydrofuran (THF), acetone or alcohol.
21. a medicinal compositions is characterized in that containing the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier of the following general formula (I) for the treatment of effective dose:
Wherein:
X is a nitrogen, oxygen or sulphur;
R1 is selected from hydrogen, monovalence or divalent-metal ion, the C1-C8 alkyl, C 3-C6 cycloalkyl, C6-C14 aryl, the C4-C12 heteroaryl, C6-C14 aryl C1-8 alkyl, C3-C6 heterocyclic radical, C6-C14 aryl C3-C6 heterocyclic radical and C4-C12 heteroaryl C1-8 alkyl, wherein said aryl or heteroaryl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C
1-C
4Alkyl;
Wherein said monovalence or divalent-metal ion are selected from Li
+, Na
+, K
+, Mg
2+And Ca
2+
Perhaps, the R1-X base forms inferior amide compound together with the amido that forms 3 ', 4 '-methylenedioxyphenyl ethamine of amide group;
R2, R3, R4 and R5 are selected from hydrogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, phenyl, halogen, nitro, hydroxyl and C1-C4 alkoxyl group independently of one another, and wherein, R2, R3, R4 and R5 arbitrarily can substituted positions on phenyl ring;
R6 is a hydrogen, C1-C8 alkyl or C3-C5 cycloalkyl.
22. the compound or pharmaceutically acceptable salt thereof of following general formula (I) is used for the treatment of purposes in the medicine of hepatic diseases in preparation
Wherein:
X is a nitrogen, oxygen or sulphur;
R1 is selected from hydrogen, monovalence or divalent-metal ion, the C1-C8 alkyl, C3-C6 cycloalkyl, C6-C14 aryl, the C4-C12 heteroaryl, C6-C14 aryl C1-8 alkyl, C3-C6 heterocyclic radical, C6-C14 aryl C3-C6 heterocyclic radical and C4-C12 heteroaryl C1-8 alkyl, wherein said aryl or heteroaryl optionally contain 1-3 substituting group, and described substituting group is selected from halogen, nitro, hydroxyl, C1-C4 alkoxyl group and C
1-C
4Alkyl;
Wherein said monovalence or divalent-metal ion are selected from Li
+, N
A+, K
+, Mg
2+And Ca
2+
Perhaps, the R1-X base forms inferior amide compound together with the amido that forms 3 ', 4 '-methylenedioxyphenyl ethamine of amide group;
R2, R3, R4 and R5 are selected from hydrogen, C1-C4 alkyl, C1-C3 perfluoroalkyl, phenyl, halogen, nitro, hydroxyl and C1-C4 alkoxyl group independently of one another, and wherein, R2, R3, R4, R5 arbitrarily can substituted positions on phenyl ring;
R6 is a hydrogen, C1-C8 alkyl or C3-C5 cycloalkyl.
23. according to the purposes of claim 22, wherein said medicine is used for the treatment of hepatitis.
24. according to the purposes of claim 23, wherein said medicine is used for the treatment of viral hepatitis.
25. according to the purposes of claim 24, wherein said medicine is used for the treatment of hepatitis B.
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| CN2005101094524A CN1951932B (en) | 2005-10-20 | 2005-10-20 | [N-(3',4'-methylenedioxy) phenylethyl] carboxamido benzoic acid derivatives, processes for their preparation and their use |
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| AU2013355220B2 (en) * | 2012-12-06 | 2018-08-02 | Baruch S. Blumberg Institute | Functionalized benzamide derivatives as antiviral agents against HBV infection |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6232475B1 (en) * | 1998-12-23 | 2001-05-15 | Bayer Aktiengesellschaft | Process for preparing fluorine-containing phenethylamines and novel fluorine-containing β-iminovinyl-and β-iminoethylbenzenes |
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2005
- 2005-10-20 CN CN2005101094524A patent/CN1951932B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6232475B1 (en) * | 1998-12-23 | 2001-05-15 | Bayer Aktiengesellschaft | Process for preparing fluorine-containing phenethylamines and novel fluorine-containing β-iminovinyl-and β-iminoethylbenzenes |
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| M. Rita Paleo, et al.A new synthesis of 4-aryl-2-benzazepine-1,5-diones.Tetrahedron letters34 14.1993,34(14),2369-2370. |
| M. Rita Paleo, et al.A new synthesis of 4-aryl-2-benzazepine-1,5-diones.Tetrahedron letters34 14.1993,34(14),2369-2370. * |
| Minoru Machida, et al.Photoreaction of phthalimides possessessing an ortho-methylphenyl group in their N-side chain. Synthesisoftetracyclic nitrogen heterocycles minoru machidea.heterocylcycles26 10.1987,26(10),2683-2690. |
| Minoru Machida, et al.Photoreaction of phthalimides possessessing an ortho-methylphenyl group in their N-side chain. Synthesisoftetracyclic nitrogen heterocycles minoru machidea.heterocylcycles26 10.1987,26(10),2683-2690. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2013355220B2 (en) * | 2012-12-06 | 2018-08-02 | Baruch S. Blumberg Institute | Functionalized benzamide derivatives as antiviral agents against HBV infection |
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