CN101928274B - Peperphentonamine derivative - Google Patents

Peperphentonamine derivative Download PDF

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CN101928274B
CN101928274B CN 200910016450 CN200910016450A CN101928274B CN 101928274 B CN101928274 B CN 101928274B CN 200910016450 CN200910016450 CN 200910016450 CN 200910016450 A CN200910016450 A CN 200910016450A CN 101928274 B CN101928274 B CN 101928274B
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ethyl
methyl
preparation
naphthalene
propylene
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CN101928274A (en
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万华印
李茹冰
万德夫
付岩霖
李若冰
万黎霞
李敏
李永贺
周力践
刘铁球
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Guangzhou Huasong Biotechnology Co ltd
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ZHONGWEI BIOTECHNOLOGY CO Ltd GUANGZHOU CITY
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Abstract

The invention belongs to the technical field of medicines and in particular relates to a peperphentonamine derivative shown in the general formula (I) and pharmaceutically acceptable salt and isomers thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, m and n are defined in the specification. The invention also relates to preparation methods of the compounds and application of the compounds in preparing the medicines for treating cardiovascular and cerebrovascular diseases.

Description

Peperphentonamine derivative
1, technical field
The invention belongs to medical technical field, be specifically related to Peperphentonamine derivative, its isomer and pharmacy acceptable salt thereof, the preparation method of these compounds, and the application of these compounds in the medicine of preparation Cardiovarscular.
2, background technology
Heart failure is the eventually end stage of cardiovascular diseases, and mortality ratio is high.Myocardial infarction and reperfusion injury of cardiac muscle are to cause major reason in heart failure.Experimental study both domestic and external shows that calcium antagonist and free-radical scavengers have the treatment myocardial infarction and to the effect of anti reperfusion injury.Yet most of calcium antagonists suppress myocardial contraction, reduce heart function, and clinical application is restricted.Free-radical scavengers is on not directly impact of heart function, and its clinical effectiveness not yet is identified.Principle of reatment in heart failure is cardiac stimulant, expansion blood vessel and diuresis.Cardiac tonic improves heart output by strengthening myocardial contraction, keeps the blood supply of the vitals such as the heart, brain, kidney; Expand blood vessel medicine and diuretic(s) by reducing cardiac load, cardioprotection function.Yet, the toxic side effects of all types of cardiac tonics such as cardiotonic glycoside, catecholamine, phosphodiesterase inhibitor (PDEI) is larger, because they are mainly by increasing intracellular calcium concentration, reach and strengthen the myocardial contraction effect of force, this just easily causes intracellular calcium overload, has arrhythogenic danger.Diuretic(s) Ceng Zuowei drug of first choice is used in heart failure, still easily causes the side effects such as electrolyte disturbance.
The phosphodiesterase inhibitor milrinone is with positive inotropic and vasorelaxation action, and its positive inotropic action can make cyclic monophosphate (cAMP) Enrichment in the myocardial cell, and intracellular Ca2+ increases, and myocardial contraction is strengthened, and cardiac output increases.But milrinone easily causes intracellular calcium overload, has arrhythogenic danger.
Calcium sensitizer is that a class can strengthen the myocardial cell to Ca 2+The medicine of susceptibility is not namely increasing Ca 2+The situation of normal physiological concentration under can make cardiac muscle produce stronger convergent force, to reach the purpose of cardiac stimulant, reduce because of Ca 2+Enrichment and cause the side effects such as irregular pulse and myocardial cell injury.Peperphentonamine hydrochloride is a kind of calcium sensitizer, can increase myocardial contraction albumen to Ca 2+Susceptibility, but do not increase Ca in the myocardial cell 2+Concentration; Do not suppress Na +, K +-ATP enzyme and phosphodiesterase (PDE) do not increase content of cAMP content, do not affect sarcoplasmic reticulum Ca yet 2+, Mg 2+-ATP enzyme.The Peperphentonamine hydrochloride structure is as follows:
Peperphentonamine hydrochloride
Yet, since the metabolism unstable of Xanthiphenyl ketamine, the curative effect decrease to some degree, and its meta-bolites also may have cytotoxicity; The plasma half-life of Peperphentonamine hydrochloride is shorter, need frequent drug administration to keep Plasma Concentration, but it is mainly injection, and long-term prescription may cause the injection site vascular lesion, has not only limited clinical application and has also brought certain risk for patient's medication; The exploitation better efficacy, the new drug of the treatment heart failure of successful, for heart failure patient provide safe, effective, quality controllable novel drugs become at present clinical in the urgent need to.
3, summary of the invention
The purpose of this invention is to provide the compound of better efficacy, long-acting, safe Cardiovarscular, had a stronger cardiac stimulant vasodilative effect, curative effect is obvious.
Technical scheme of the present invention is as follows:
The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt and isomer thereof:
Figure G2009100164509D00021
Wherein: R 1Represent hydrogen atom, carboxyl, amino, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, sulfonic acid amido, halogen atom, the C that is not substituted or is replaced by carboxyl, amino, nitro, cyano group, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl, halogen atom 1-6Alkyl, C 1-6Alkoxyl group, C 2-6Thiazolinyl, C 2-6Alkynyl, C 2-6Alkylamidoalkyl, aryl C 1-6Alkyl or heterocyclic radical C 1-6Alkyl;
R 2With R 3Independently represent respectively hydrogen atom, C 1-6Alkyl, C 1-6Alkoxyl group, perhaps R 2, R 3The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle;
R 4And R 5Independently represent respectively hydrogen atom, hydroxyl, halogen atom, C 1-6Alkyl, C 1-6Alkoxyl group, perhaps R 4, R 5The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle,
R 2With R 3When becoming ring, R 4And R 5Be chain group, R 4With R 5When becoming ring, R 2And R 3Be the chain group;
R 6Represent hydrogen atom, the C that is not substituted or is replaced by carboxyl, amino, nitro, cyano group, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl, halogen atom 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, aryl C 1-6Alkyl or heterocyclic radical C 1-6Alkyl;
R 7And R 8Independently represent respectively hydrogen atom, C 1-6Alkyl, perhaps R 7, R 8The Sauerstoffatom that is adjacent is connected and forms five yuan or hexa-member heterocycle;
M is 1,2,3 or 4;
N is 0,1,2 or 3.
Preferred compound is:
Wherein: R 1Represent hydrogen atom, carboxyl, amino, C 1-4Alkyl amine group, two (C 1-4Alkyl) amido, hydroxyl, formamyl, amino-sulfonyl, halogen atom, the C that is not substituted or is replaced by carboxyl, amino, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl, halogen atom 1-4Alkyl, C 1-4Alkoxyl group or C 2-4Alkylamidoalkyl;
R 2With R 3Independently represent respectively hydrogen atom, C 1-4Alkyl, perhaps R 2, R 3The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle;
R 4And R 5Independently represent respectively hydrogen atom, C 1-4Alkyl, perhaps R 4, R 5The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle,
R 2With R 3When becoming ring, R 4And R 5Be chain group, R 4With R 5When becoming ring, R 2And R 3Be the chain group;
R 6Represent hydrogen atom or C 1-4Alkyl;
R 7And R 8Independently represent respectively hydrogen atom, C 1-4Alkyl, perhaps R 7, R 8The Sauerstoffatom that is adjacent is connected and forms five yuan or six-ring;
M is 1,2,3 or 4;
N is 0,1,2 or 3.
Further preferred compound is:
Wherein: R 1Represent hydrogen atom, hydroxyl, methoxyl group, oxyethyl group, acetamido, amino, methylamino-;
R 2With R 3Independently represent respectively hydrogen atom, methyl, ethyl, perhaps R 2, R 3The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle;
R 4With R 5Independently represent respectively hydrogen atom, methyl, ethyl, perhaps R 4, R 5The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle,
R 2With R 3When becoming ring, R 4And R 5Be chain group, R 4With R 5When becoming ring, R 2And R 3Be the chain group;
R 6Represent methylidene;
R 7And R 8Independently represent hydrogen atom, methyl, ethyl, perhaps R respectively 7, R 8The Sauerstoffatom that the is adjacent formation five-membered ring that is connected;
M is 1; N is 1.
Further preferred compound is again:
Wherein: R 1Representation hydroxy, methoxyl group, formamido-, amino;
R 2With R 3Independently represent respectively hydrogen atom, methyl, perhaps R 2, R 3The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle;
R 4With R 5Independently represent respectively hydrogen atom, methyl, perhaps R 4, R 5The carbon atom that is adjacent is connected and forms phenyl ring or unsaturated hexa-member heterocycle,
R 2With R 3When becoming ring, R 4And R 5Be chain group, R 4With R 5When becoming ring, R 2And R 3Be the chain group;
R 6Represent methylidene;
R 7And R 8Difference independent represent methylidene, perhaps R 7, R 8The Sauerstoffatom that is adjacent is connected and forms 1,3-dioxole;
M is 1; N is 1.
" C of the present invention 1-6Alkyl " be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 3-amyl group, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention 1-6Alkoxyl group " be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy etc.Refer to that alkyl is connected to Sauerstoffatom with covalent linkage, such as methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, isopropoxy, tert.-butoxy, isobutoxy, isopentyloxy etc., ring propoxy-, cyclopentyloxy, cyclohexyloxy etc.
" C of the present invention 2-6Thiazolinyl " carbonatoms that refers to contain two keys is the straight or branched of 2-6 or the thiazolinyl of ring-type, for example can be vinyl; the 1-propenyl; 1-propyl group-2-alkene; 2-propenyl; 1-butylene base; 1-butyl-2-alkene, 1-butyl-3-alkene, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl isophthalic acid-propyl group-2-alkene, 2-methyl isophthalic acid-propyl group-2-alkene, the 1-pentenyl, 1-amyl group-2-alkene, 1-amyl group-3-alkene, 1-amyl group-4-alkene, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 3-methyl-1-butene base, 1-methyl isophthalic acid-butyl-2-alkene, 2-methyl-1-butene base-2-alkene, 3-methyl isophthalic acid-butyl-2-alkene, 1-methyl isophthalic acid-butyl-3-alkene, 2-methyl-1-butene base-3-alkene, 3-methyl isophthalic acid-butyl-3-alkene, the 1-hexenyl, 1-hexyl-2-alkene, 1-hexyl-3-alkene, 1-hexyl-4-alkene, 1-hexyl-5-alkene, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-1-pentene base-2-alkene, 2-methyl-1-pentene base-2-alkene, 3-methyl-1-pentene base-2-alkene, 4-methyl-1-pentene base-2-alkene, 1-methyl-1-pentene base 3-alkene, 2-methyl-1-pentene base-3-alkene, 3-methyl-1-pentene base-3-alkene, 4-methyl-1-pentene base-3-alkene, 1-methyl-1-pentene base-4-alkene, 2-methyl-1-pentene base-4-alkene, 3-methyl-1-pentene base-4-alkene, 4-methyl-1-pentene base-4-alkene, the cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl etc.
" C of the present invention 2-6Alkynyl " carbonatoms that refers to contain triple bond is the straight or branched of 2-6 or the alkynyl of ring-type, for example can be ethynyl; the 1-proyl; 1-propyl group-2-alkynes; ethyl acetylene base; 1-butyl-2-alkynes; 1-butyl-3-alkynes, the 1-pentynyl, 1-amyl group-2-alkynes, 1-amyl group-3-alkynes, 1-amyl group-4-alkynes, 3-methyl isophthalic acid-butynyl, 1-methyl isophthalic acid-butyl-2-alkynes, 1-methyl isophthalic acid-butyl-3-alkynes, 2-methyl-1-butene base-3-alkynes, 1-hexin base, 1-hexyl-2-alkynes, 1-hexyl-3-alkynes, 1-hexyl-4-alkynes, 1-hexyl-5-alkynes, 3-methyl-1-pentene alkynyl, 4-methyl-1-pentene alkynyl, 1-methyl-1-pentene base-2-alkynes, 4-methyl-1-pentene base-2-alkynes, 1-methyl-1-pentene base-3-alkynes, 2-methyl-1-pentene base-3-alkynes etc.
" aryl " of the present invention refer to aromatic ring such as phenyl, replacement phenyl (such as benzyl, styroyl) and thick and aromatic nucleus such as naphthyl etc.
" C of the present invention 2-6Alkyl amide " be acetamido, propionamido-, amide-based small, valeryl amido, hexanoyl amido etc.
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms or iodine atom.
" aromatic ring " of the present invention refer to aromatic ring such as phenyl, replacement phenyl (such as benzyl, styroyl) and thick and aromatic nucleus such as naphthyl etc.
" heterocycle " of the present invention refers to " the saturated or undersaturated single heterocycle of 3-8 unit " and " the saturated or undersaturated fused heterocycle of 8-14 unit "." the saturated or undersaturated single heterocycle of 3-8 unit " comprising: the single heterocycle of saturated or undersaturated 3-8 unit that contains 1-4 nitrogen-atoms in (1) ring, ethylenimine for example, the 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1, the 2-diazetidine, azete, 1, the 2-diazetine, the pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4, the 5-glyoxalidine, imidazolidine, pyrazoles, 4,5-pyrazoline, pyrazolidine, 1,2, the 3-triazole, 1,2,4-triazole, tetrazolium, pyridine, the 2-pyridone, the 4-pyridone, hydrogenated pyridine ketone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, the 3-triazine, 1,2,4-triazine, 1,3, the 5-triazine, 1,2,4,5-tetrazine, the nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, Isosorbide-5-Nitrae-diazacyclo heptantriene, the nitrogen heterocyclic octatetraene, Isosorbide-5-Nitrae-dihydro-1,4-diazacyclo sarohornene etc., preferred pyrroles, pyridine; (2) contain the single heterocycle of 1-2 Sauerstoffatom or sulphur atom saturated or undersaturated 3-8 unit in the ring, oxyethane for example, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, tetrahydrofuran (THF), thiophene, 2, the 5-dihydro-thiophene, tetramethylene sulfide, 1, the 3-dioxolane, 1, the 3-dioxole, 1, the 2-dithiole, 1, the 3-dithiolane, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, the 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, Isosorbide-5-Nitrae-oxathiin, Isosorbide-5-Nitrae-dioxane, 1, the 3-dioxane, 1, the 3-oxathiane, oxepin, the thia cycloheptatriene, Isosorbide-5-Nitrae-dioxane sarohornene etc., preferred furans, thiophene; (3) contain 1-2 Sauerstoffatom or sulphur atom and 1-3 the saturated or undersaturated 3-8 of nitrogen-atoms unit single heterocycle, for example oxaza propane oxazole in the ring, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2, the 3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4, the 5-thiazoline, isothiazole, 1,2,3-thiadiazoles, 1,2,4-thiadiazoles, 1,3, the 4-thiadiazoles, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 5,6-dihydro-4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1, the 4-thiazine, morpholine etc., preferred thiazole, 1,2, the 4-thiadiazoles, 1,3,4-thiadiazoles.Described " the saturated or undersaturated fused heterocycle of 8-14 unit " comprising: the first fused heterocycle of saturated or undersaturated 8-14 that contains 1-5 nitrogen-atoms in (1) ring, indoles for example, isoindole, carbazole, benzoglyoxaline, indazole, benzotriazole, imidazolidine also [4,5-c] pyridine, quinoline, isoquinoline 99.9, the 2-quinolinone, the 4-quinolinone, the 1-isoquinolines, acridine, phenanthridines, cinnolines, phthalazines, quinazoline, 3, the 4-dihydroquinazoline, quinoxaline, 1, the 2-dihydro-quinoxaline, 1, the 8-naphthyridines, 1, the 7-naphthyridines, 1, the 6-naphthyridines, 1, the 5-naphthyridines, 2, the 7-naphthyridines, 2,6-naphthyridines, purine, pteridine, azophenlyene etc., preferred benzoglyoxaline, quinoline; (2) contain the first fused heterocycle of saturated or undersaturated 8-14 of 1-2 Sauerstoffatom or sulphur atom in the ring, for example benzo [b] furans, different benzo [b] furans, dibenzo [b] furans, benzo [b] thiophene, benzo [c] thiophene, benzo [d] [1,3] dioxole, 2H-chromogen alkene, 2H-chromogen alkene-2-ketone, 4H-chromene, 4H-chromene-4-ketone, chroman etc., preferred benzo [b] furans, different benzo [b] furans, benzo [b] thiophene, benzo [c] thiophene; (3) contain the first fused heterocycle of saturated or undersaturated 8-14 of 1-2 Sauerstoffatom or sulphur atom and 1-3 nitrogen-atoms in the ring, for example benzoxazole, benzothiazole, 4H-1,3-benzoxazine, azophenlyene, thiodiphenylamine, 4,6-dihydro-1H-furo [3,4-d] imidazoles, 4,6-dihydro-1H-thieno-[3,4-d] imidazoles, 4,6-dihydro-1H-pyrrolo-[3,4-d] imidazoles, 4,5,6,7-tetrahydrochysene-1H-benzo [d] imidazoles etc., preferred benzoxazole, benzothiazole.
Further preferred compound is as follows:
Figure G2009100164509D00061
Figure G2009100164509D00071
The present invention also provides the preparation method of above-claimed cpd, and reaction equation is as follows, but is not limited only to following method:
Scheme one: R 2With R 3Cheng Huan, R 4And R 5During for the chain group:
Figure G2009100164509D00072
Reactions steps is:
The preparation of step 1 compd A
Add triphen phosphoranyl methylene radical ethyl formate (raw material 2) in the reaction flask of drying, benzene stirs and is warming up to backflow, then adds raw material 1 in batches, the insulated and stirred reaction.Reaction is finished, and is cooled to room temperature, filters, and filtrate decompression is steamed and desolventized, and the residuum re-crystallizing in ethyl acetate gets compd A.
The preparation of step 2 compd B
Under the nitrogen protection, add upper step gained compd A in the reaction flask of sealing, drying, toluene reduces temperature, slowly drips the 1M diisobutyl aluminium hydride of precooling.React complete after, carefully add cold 2N hydrochloric acid, after stirring in the impouring frozen water, minute oil-yielding stratum.Water layer is used dichloromethane extraction again, merges organic layer, washs through sodium hydrogen carbonate solution.The organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product, and re-crystallizing in ethyl acetate gets compd B.
The preparation of step 3 the compounds of this invention
In the reaction flask of drying, step gained compd B in the adding, after the stirring and dissolving, under nitrogen protection, cooling adds sodium cyanoborohydride, after the stirring, adds raw material 3 and toluene solution.Finish, stirring reaction, and then heat up the restir reaction.Stopped reaction, the lower 2N hydrochloric acid that slowly adds of ice bath cooling after the stirring, leaves standstill, and tells organic layer.Water layer is regulated pH alkalescence with sodium hydrogen carbonate solution after washing with ether, and ethyl acetate extraction merges organic layer, anhydrous sodium sulfate drying, and concentrating under reduced pressure adds ethyl acetate in residuum, and heated and stirred refluxed several minutes, cooled off, and got target compound I.
R in the reaction equation 1, R 6, R 7, R 8, m and n be as indicated above.
Scheme two, R 4With R 5Cheng Huan, R 2And R 3During for the chain group:
Figure G2009100164509D00081
Reactions steps is:
The preparation of step 1 Compound C
In the reaction flask of drying, add 4-chloro-pyridine carboxylic acid methyl esters and raw material 4, methylene dichloride, be heated with stirring to backflow, then under stirring, be added dropwise to triethylamine, drip and finish, the insulated and stirred reaction, reaction is finished, cooling, filter, with filtrate successively water, dilute hydrochloric acid solution, sodium hydrogen carbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, get Compound C with re-crystallizing in ethyl acetate.
The preparation of step 2 Compound D
Under the nitrogen protection, in the reaction flask of sealing, drying, add Compound C, toluene; reduce temperature, slowly drip the 1M diisobutyl aluminium hydride of precooling, react complete after; the cold HCl of careful adding in the impouring frozen water, divides oil-yielding stratum after stirring; water layer is used dichloromethane extraction again, merges organic layer, washs through sodium hydrogen carbonate solution; the organic layer anhydrous sodium sulfate drying; concentrating under reduced pressure gets crude product, and re-crystallizing in ethyl acetate gets Compound D.
The preparation of step 3 the compounds of this invention
In the reaction flask of drying, add raw material 5, dry toluene; after the stirring and dissolving, under nitrogen protection, cooling adds the cyclohexane solution of n-Butyl Lithium; continue to stir in room temperature, add Compound D and toluene, finish; then stirring reaction rises to the stirring at room reaction, and then heats up; the restir reaction, stopped reaction, the lower hydrochloric acid that slowly adds of ice bath cooling; after the stirred for several minute, leave standstill, tell organic layer; water layer is regulated pH alkalescence, ethyl acetate extraction with sodium hydrogen carbonate solution after washing with ether; merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure; in residuum, add ethyl acetate; heated and stirred refluxed several minutes, and cooling gets target compound II.
R in the reaction equation 1, R 6, R 7, R 8, m and n be as indicated above.
Pharmacy acceptable salt of the present invention comprises hydrochloride, vitriol, phosphoric acid salt, carbonate, hydrobromate, oxalate, succinate, maleate, mesylate, benzene sulfonate, tosilate, acetate, benzoate, fumarate, tartrate, malate, lactic acid salt, Citrate trianion etc.Be preferably hydrochloride, vitriol, phosphoric acid salt, carbonate, hydrobromate, oxalate, succinate, maleate.
Part of compounds of the present invention can exist with its isomeric forms, and the compounds of this invention comprises a two key, so its cis and trans-isomer(ide) and composition thereof all are included in the compound of the present invention.
The present invention finds by pharmacological research, when the compounds of this invention, its pharmacy acceptable salt or its isomer are used as the medicinal application of preparation Cardiovarscular, has obvious cardiac stimulant vasodilative effect, for experimental heart failure, myocardial ischemia and reperfusion injury of cardiac muscle all have good preventive and therapeutic effect.The compounds of this invention, its pharmacy acceptable salt and isomery physical efficiency thereof strengthen myocardial contraction, improve heart function, but do not increase [Ca in the myocardial cell 2+], even can also be to the overload of the cytosolic free calcium concentration in cardiomyocyte due to the anti reperfusion injury.For the heart of myocardial infarction or ischemia reperfusion injury, can increase blood supply of cardiac muscle, reduce myocardial oxygen consumption, strengthen resistance of oxidation, improve energy metabolism of myocardial, keep heart function.
Research of the present invention shows that from aspects such as heart physiological function, myocardium biochemistry and pathomorphism the compounds of this invention, its pharmacy acceptable salt or its isomer can be to resisting myocardial ischemia; Ischemic myocardium-reperfusion injury; can improve again the novel cardiac stimulant extension vascular agent of heart function; it increases myocardial contraction albumen to the susceptibility of calcium, does not but increase [Ca in the myocardial cell 2+], it is difficult for causing irregular pulse, is conducive to the treatment of multiple cardiovascular diseases.The compounds of this invention result for the treatment of is good simultaneously, and toxic side effects is lower.
The compounds of this invention, its pharmacy acceptable salt or its isomer can be made liquid drugs injection, the powder pin, and tablet or capsule etc. adopt respectively intravenous injection, and intramuscularly or oral method are used.The various preparations of making contain the compounds of this invention, its pharmacy acceptable salt or its isomer 1mg～1000mg as essential activeconstituents, such as 1mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 100mg etc.Consumption is 0.1-1.0mg/kg.
During the compounds of this invention administration, can be made into injection.Injection means the solution that the confession is injected in vivo, emulsion or the suspension that medicine is made and supplies to prepare or be diluted to the powder of solution or suspension or the sterile preparation of strong solution before use that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid mean that medicine makes for the sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid that are injected in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid for intravenous drip also claims intravenous infusion.Injectable sterile powder means that the sterile solution for suitable before use that medicine makes is mixed with settled solution or evenly sterilized powder or the aseptic block of suspension, injection after the available suitable solvent for injection preparation, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection mean that medicine makes for the aseptic strong solution of diluting before use for intravenous drip.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives according to the character of medicine, such as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for can be made into conventional solid preparation, such as tablet, capsule, pill, granule etc. when oral; Also can be made into oral liquid, such as oral solution, oral suspensions, syrup etc.Tablet means disc-shaped that medicine and suitable auxiliary materials and mixing compacting form or the solid preparation of special-shaped sheet, take oral ordinary tablet as main, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or is sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means that medicine evenly mixes with the auxiliary material that suits, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The compounds of this invention is compared with immediate prior art, has the following advantages:
(1) the compounds of this invention has the cardiac stimulant vasodilative effect, and Cardiovarscular has good curative effect;
(2) the compounds of this invention Stability Analysis of Structures is easy to quality control;
(3) the compounds of this invention metabolic stability has good pharmacokinetics, and meta-bolites is simple, has preferably security;
(4) the compounds of this invention is longer plasma half-life, need not frequent drug administration and can keep Plasma Concentration;
(5) the compounds of this invention LD 50Be worth greatlyr, safety range is wider;
(6) the compounds of this invention can not cause [Ca in the cell 2+] increase, toxic side effect is less;
(7) the compounds of this invention preparation technology is simple, and medicine purity is high, high, the steady quality of yield, is easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of the compounds of this invention by isolated activity experiment, but this should be interpreted as that the compounds of this invention only has following beneficial effect.
The cardiotonic experiment of experimental example 1 the compounds of this invention
Trial-product:
Peperphentonamine hydrochloride: structural formula such as background technology, self-control; Compound 1-16 and hydrochloride thereof, self-control.
Adopt guinea pig in vitro papillary muscle and heart muscle sample, observe the compounds of this invention to cardiac contractility, the impact of autorhymicity.
Shrinkability:
Convergent force before cavy right ventricle papillary muscle and the flesh administration of left room is respectively 52.5 ± 13.1mg and 369 ± 162mg.
Namely produce positive inotropic action in the 3min behind the adding Peperphentonamine hydrochloride, 20min reaches peak value after the administration, and effect continues 30min.
Add behind the compounds of this invention hydrochloride and namely produce positive inotropic action in the 1min, 12min reaches peak value after the administration, act on more than the lasting 50min, and along with the increase of drug level, peak time shortens more, and the time length prolongs more.
The positive inotropic action strength ratio Peperphentonamine hydrochloride of the compounds of this invention hydrochloride is better, and when the two reached close positive inotropic action intensity, Peperphentonamine hydrochloride made the 191 ± 10ms that is when shrinking before the administration extend to 205 ± 11ms; And the compounds of this invention makes and shrinks respectively 187 ± 11ms before the administration of time-histories, 185 ± 13ms, 182 ± 14m, 183 ± 14ms, 189 ± 11ms, 192 ± 14ms, 188 ± 10ms, 195 ± 16ms, 186 ± 8ms, 189 ± 13ms, 186 ± 11ms, 191 ± 12ms, 180 ± 10ms, 181 ± 8ms, 182 ± 11ms, 181 ± 9ms extends to 226 ± 10ms, 229 ± 12ms, 224 ± 15ms, 228 ± 11ms, 231 ± 10ms, 237 ± 15ms, 229 ± 13ms, 241 ± 11ms, 234 ± 11ms, 238 ± 10ms, 235 ± 9ms, 239 ± 12ms, 225 ± 11ms, 228 ± 10ms, 226 ± 9ms, 227 ± 12ms has stronger action intensity than Peperphentonamine hydrochloride.
Autorhymicity:
The experiment of bringing out the guinea pig papillary muscle autorhymicity with suprarenin shows: the increase suprarenin of the equal energy of the compounds of this invention and hydrochloride thereof and Peperphentonamine hydrochloride dose-dependently brings out the threshold concentration of autorhymicity, when drug level was 10 μ mol/L, Peperphentonamine hydrochloride was compared remarkable increase before making adrenergic threshold concentration and administration; And the compounds of this invention and hydrochloride thereof extremely significantly increase comparing before adrenergic threshold concentration and the administration; Illustrate that the compounds of this invention has more significant effect to the increase of adrenergic threshold concentration.The result is referring to table 1.
Table 1 the compounds of this invention is on the impact of guinea pig papillary muscle autorhymicity.
Figure G2009100164509D00121
Figure G2009100164509D00131
Experiment conclusion: table 1 experimental result shows: the increase suprarenin of the equal energy of the compounds of this invention and hydrochloride thereof and Peperphentonamine hydrochloride dose-dependently brings out the threshold concentration of autorhymicity, and the compounds of this invention and hydrochloride thereof have more significant effect to the increase of adrenergic threshold concentration than the hydrochloride of Xanthiphenyl ketamine, right room spontaneous frequency is slowed down, be that the right atrium autorhymicity reduces, useful to recovering normal sinus rhythm.
The acute toxicity test of experimental example 2 the compounds of this invention
Trial-product:
Peperphentonamine hydrochloride: structural formula such as background technology, self-control; The compounds of this invention 1-16, self-control.
Administration and observation: get body weight 18～22g mouse, be divided at random 5 groups, 10 every group, the dosage grouping administration by 92.0,119.6,155.5,202.1,262.8, the Intraperitoneal injection Xanthiphenyl ketamine is observed and the record per cent death loss respectively, calculates LD 50
LD 50＝log-1[Xm-I(∑p-0.5)]
Xm is the logarithm of maximal dose in the formula; P is the mortality ratio of each treated animal, with fractional representation (such as 80% writing 0.8); ∑ p is the summation (p1+p2+p3+p4+p5...) of each treated animal mortality ratio; I is the poor of two adjacent groups dosage (D) logarithmic value, gets the LD of Peperphentonamine hydrochloride 50147.8mg.
Determine LD after the trial test respectively according to same method 0And LD 100Determine afterwards dosage, record the LD of each compound of the present invention 50As shown in the table
The compounds of this invention is compared with Peperphentonamine hydrochloride, and medium lethal dose obviously increases, and the treatment window of the compounds of this invention is wider, has greatly improved security.
The pharmacokinetic of experimental example 3 the compounds of this invention
The compounds of this invention is in the research of SD Pharmacokinetics in Rat
Tested medicine and preparation:
Trial-product: prepared compound 2, compound 6, compound 10 and compound 15 in the embodiment of the invention.
Contrast medicine: Peperphentonamine hydrochloride, self-control.
Internal standard substance: Warfarin: white powder, purity are 99%, and lot number is 0072-8501, and medicine inspecting institute provides by Shanghai City.
The medicine preparation: preparation before the administration, be dissolved in the physiological saline, making its final concentration is 5mg/mL, is used for intravenous injection.
Experimental animal: male SD rat; Body weight 200～250 grams; Source: Shanghai Slac Experimental Animal Co., Ltd..
Experimentation on animals:
Administration: male SD rat is divided into 5 groups at random, and 3 every group, Bolos intravenous administration; Weighed body weight before the administration, quiet notes 10mg/kg administration.
Sample collecting: be designated as zero before the administration constantly, get blood 0.5mL at 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 24h after the administration in the heparinization centrifuge tube by the eye socket venous plexus respectively, the centrifugal 6min of 8000rpm separates upper plasma, frozenly delivers to LC-MS/MS in-20 ℃ and detects.
The foundation of LC-MS/MS assay method in the plasma sample:
Chromatographic condition: chromatographic column: Gemini C6-Phenyl (50mm * 4.6mm, 5 μ m); Moving phase: 0.1% formic acid-water-acetonitrile (5: 35: 60, v/v/v); Flow velocity: 1mL/min; Column temperature: 35-40 ℃; Sampling volume: 5 μ L; Splitting ratio: 1/5.
Mass spectrum condition: scan pattern: positive ion multiple-reaction monitoring (MRM); Ion source: electron spray(ES) (ESI); Atomizing gas: 8L/min; Gas curtain gas: 8L/min; Collision gas: 4L/min; Ionspray voltage: 4500v; Temperature: 400 ℃/500 ℃.
Typical curve and quality-control sample preparation: accurately take by weighing an amount of trial-product, be mixed with the storing solution that concentration is 2.60mg/mL with ultrapure water.Dilute to such an extent that a series of concentration be 25000,5000,2500,500,250 and the working fluid of 50ng/mL with methyl alcohol this storing solution.Get 100 μ L blood plasma, add respectively therein above-mentioned working fluid 20 μ L, can obtain concentration and be 5000,1000,500,100,50 and the calibration solution of 10ng/mL.Press same method, can make concentration and be 4000,800 and the quality-control sample solution of 20ng/mL.After the analysis, do color atlas and typical curve.
Sample treatment: get plasma sample 100 μ L, add therein the Warfarin acetonitrile solution of 20 μ L acetonitriles and 200 μ L 200ng/mL.With gains DL 1 minute, and with its under 15000rpm centrifugal 5 minutes.The supernatant liquor 100 μ L that obtain, and the supernatant liquor of 3 μ L is used for the analysis of LC/MS/MS sample introduction.
Results and discussions:
Administration concentration: the medicine of preparation is detected through HPLC, and and standard control, the concentration accuracy that obtains Bolos intravenous administration solution is 103.2%.
Data analysis: plasma drug level is lower than detectability (10ng/ml) person and is calculated as 0, and pharmacokinetic parameters is calculated by the non-compartment model in the WinnonlinProfessional 5.2 pharmacokinetics softwares.
Pharmacokinetics: curve when calculating pharmacokinetic parameters and doing medicine according to each time point blood plasma Chinese traditional medicine concentration.(t plasma half-life of each compound 1/2) see the following form, can be found out by the resulting transformation period data of table 3, in rat (quiet notes) experiment, obviously be longer than Peperphentonamine hydrochloride the plasma half-life of the compounds of this invention.
The transformation period (n=3) of table 3. part the compounds of this invention
Figure G2009100164509D00151
Owing to compare with Peperphentonamine hydrochloride, compound of the present invention has the transformation period that rises appreciably, thereby, in clinical application, show better treatment effect in heart failure, and can reduce administration number of times, alleviate patient's burden and misery.
By above-mentioned experimental result as seen, compare with Peperphentonamine hydrochloride, the compounds of this invention has better cardiac stimulant vasodilative effect, significantly improve guinea pig papillary muscle and left room myotility, significantly increase the threshold concentration that suprarenin brings out autorhymicity, the right room spontaneous frequency that significantly slows down, namely the right atrium autorhymicity reduces; In addition, the compounds of this invention is longer plasma half-life, need not Plasma Concentration and the compounds of this invention LD that frequent drug administration can be kept therapeutic dose 50Be worth greatlyr, safety range is wider, so but life-time service.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with pharmaceutically acceptable auxiliary material in following examples, perhaps reduces, increases.
Embodiment 1 (E)-N-[3-(6-hydroxyl-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) second Base]-preparation of methylamine
1, the preparation of 3-(6-methoxy methoxy base-naphthalene-1-yl)-2-methyl acrylate
In the reaction flask of drying, add triphen phosphoranyl methylene radical ethyl formate 10.4g (45mmol), benzene 100ml, stirring is warming up to backflow, then adds 6-methoxy methoxy base-naphthaldehyde 6.5g (30mmol) in batches, and insulated and stirred reaction 6h. reaction is finished, be cooled to room temperature, filter, filtrate decompression is steamed and is desolventized the residuum re-crystallizing in ethyl acetate, get solid 4.3g, yield: 52.1%.
2, the preparation of 3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene formaldehyde
Under the nitrogen protection; in the reaction flask of sealing, drying, add 3-(6-methoxy methoxy base-naphthalene-1-yl)-2-methyl acrylate 13.6g (0.05mol); toluene 100ml reduces temperature to-78 ℃, slowly drips the 1M diisobutyl aluminium hydride 65ml of precooling.React complete after, carefully add cold 2NHCl100ml, stir behind the 15min in the impouring 200ml frozen water minute oil-yielding stratum.Water layer extracts 2 times with methylene dichloride 200ml again, merges organic layer, washs through sodium hydrogen carbonate solution 50ml.The organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product, and re-crystallizing in ethyl acetate gets faint yellow solid 8.1g, yield: 67.1%.
3, (E)-N-[3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]- The preparation of methylamine
In the reaction flask of drying; add 3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene formaldehyde 10.9g (0.04mol); dry toluene 100ml; after the stirring and dissolving; under nitrogen protection, be cooled to below-15 ℃ and add sodium cyanoborohydride 3.8g, after the stirred for several minute; add N-methyl-homopiperony lamine hydrochloride 9.7g (0.045mol), and the solution of toluene 50ml.Finish, stirring reaction 3h, and then be warming up to 40 ℃, restir reaction 0.5h.Stopped reaction, the lower 2N hydrochloric acid 50ml that slowly adds of ice bath cooling after the stirred for several minute, leaves standstill, and tells organic layer.Water layer is regulated pH alkalescence with sodium hydrogen carbonate solution after washing with ether, and ethyl acetate 50ml extracts 3 times, merges organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure adds the 30ml ethyl acetate in residuum, and heated and stirred refluxed several minutes, cooling is separated out solid 7.6g, yield: 46.7%.
4, (E)-N-[3-(6-hydroxyl-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine Preparation
In reaction flask, add (E)-N-[3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine 4.9g (12mmol), 10%HCl-MeOH20ml, stirring and refluxing 50min, reaction solution are evaporated to do with ethyl acetate 40ml and extract united extraction liquid 4 times, the concentrated steaming desolventizes after dry, dehydrated alcohol-ethyl acetate crystallization gets solid 3.2g, yield 74.5%.
Molecular formula: C 23H 23NO 3
Molecular weight: 361.43
Ultimate analysis:
Measured value: C, 76.12%; H, 6.78%; N, 3.49%
Theoretical value: C, 76.43%; H, 6.41%; N, 3.88%
Mass spectrum: m/e 362 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.27(s，3H)，2.64～2.73(m，4H)，3.02(d，2H)，5.36(brs，1H)，6.07(s，2H)，6.19(m，1H)，6.56(d，1H)，6.73～6.85(m，3H)，7.1(dd，1H)，7.39(t，1H)，7.50(dd，1H)，7.61(dd，1H)，7.82(t，1H)，7.99(dd，1H)
Embodiment 2 (E)-N-[3-(6-methoxyl group-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) second Base]-preparation of methylamine
1, the preparation of 3-(6-methoxyl group-naphthalene-1-yl)-2-methyl acrylate
The step 1 of preparation method's reference example 1 is thrown 6-methoxyl group-naphthaldehyde 5.6g (30mmol), triphen phosphoranyl methylene radical ethyl formate 10.4g (45mmol).Get solid 4.0g, yield: 55.4%.
2, the preparation of 3-(6-methoxyl group-naphthalene-1-yl)-2-propylene formaldehyde
The step 2 of preparation method's reference example 1 is thrown 3-(6-methoxyl group-naphthalene-1-yl)-2-methyl acrylate 12.1g (50mmol).Get solid 7.5g, yield: 70.4%.
3, (E)-N-[3-(6-methoxyl group-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine Preparation
The step 3 of preparation method's reference example 1 is thrown 3-(6-methoxyl group-naphthalene-1-yl)-2-propylene formaldehyde 8.5g (0.04mol), N-methyl-homopiperony lamine hydrochloride 9.7g (0.045mol).Get solid 7.4g, yield: 49.6%.
Molecular formula: C 24H 25NO 3
Molecular weight: 375.46
Ultimate analysis:
Measured value: C, 76.45%; H, 6.97%; N, 3.36%
Theoretical value: C, 76.77%; H, 6.71%; N, 3.73%
Mass spectrum: m/e 376 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.07(s，3H)，2.26(s，3H)，2.64～2.72(m，4H)，3.05(d，2H)，6.09(s，2H)，6.21(m，1H)，6.59(d，1H)，6.75～6.86(m，3H)，7.25(brs，1H)，7.39(dd，1H)，7.45～7.50(m，2H)，7.71(t，1H)，7.86(dd，1H)，8.29(t，1H)
Embodiment 3 (E)-N-[3-(6-amino-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) second Base]-preparation of methylamine
1, the preparation of 3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-methyl acrylate
The step 1 of preparation method's reference example 1 is thrown 6-tertbutyloxycarbonyl amido-naphthaldehyde 8.1g (30mmol), triphen phosphoranyl methylene radical ethyl formate 10.4g (45mmol).Get solid 4.8g, yield: 48.6%.
2, the preparation of 3-(6-t-butoxycarbonylamino-naphthalene-1-yl)-2-propylene formaldehyde
The step 2 of preparation method's reference example 1 is thrown 3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-methyl acrylate 16.4g (50mmol).Get solid 9.7g, yield: 65.1%.
3, (E)-N-[3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) Ethyl]-preparation of methylamine
The step 3 of preparation method's reference example 1 is thrown 3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-propylene formaldehyde 11.9g (0.04mol), N-methyl-homopiperony lamine hydrochloride 9.7g (0.045mol).Get solid 7.8g, yield: 42.1%.
4, (E)-N-[3-(6-amino-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine Preparation
The step 4 of preparation method's reference example 1 is thrown (E)-N-[3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine 5.5g (12mmol).Get (E)-2-[4-(amido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine 2.9g, yield: 66.8%.
Molecular formula: C 24H 24N 2O 2
Molecular weight: 360.45
Ultimate analysis:
Measured value: C, 73.68%; H, 6.56%; N, 10.92%
Theoretical value: C, 73.97%; H, 6.21%; N, 11.25%
Mass spectrum: m/e 361 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.28(s，3H)，2.63～2.71(m，4H)，3.06(d，2H)，6.09(s，2H)，6.18(m，1H)，6.29(brs，2H)，6.61(d，1H)，6.72～6.85(m，3H)，7.39(dd，1H)，7.46～7.53(m，2H)，7.70(t，1H)，7.76(t，1H)，7.85(dd，1H)
Embodiment 4 (E)-N-[3-(6-acetamido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) Ethyl]-preparation of methylamine
1, the preparation of 3-(6-acetamido-naphthalene-1-yl)-2-methyl acrylate
The step 1 of preparation method's reference example 1 is thrown 6-acetamido-naphthaldehyde 6.4g (30mmol), triphen phosphoranyl methylene radical ethyl formate 10.4g (45mmol).Get solid 4.1g, yield: 50.8%.
2, the preparation of 3-(6-acetamido-naphthalene-1-yl)-2-propylene formaldehyde
The step 2 of preparation method's reference example 1 is thrown 3-(6-acetamido-naphthalene-1-yl)-2-methyl acrylate 13.5g (50mmol).Get solid 8.5g, yield: 71.3%.
3, (E)-N-[3-(6-acetamido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-first The preparation of amine
The step 3 of preparation method's reference example 1 is thrown 3-(6-acetamido-naphthalene-1-yl)-2-propylene formaldehyde 9.6g (0.04mol), N-methyl-homopiperony lamine hydrochloride 9.7g (0.045mol).Get solid 7.5g, yield: 46.7%.
Molecular formula: C 25H 26N 2O 3
Molecular weight: 402.49
Ultimate analysis:
Measured value: C, 74.18%; H, 6.92%; N, 6.67%
Theoretical value: C, 74.60%; H, 6.51%; N, 6.96%
Mass spectrum: m/e 403 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.02(s，3H)，2.29(s，3H)，2.66～2.72(m，4H)，3.06(dd，2H)，6.07(s，2H)，6.19(m，1H)，6.57(d，1H)，6.72～6.85(m，3H)，7.25(brs，1H)，7.39～7.55(m，3H)，7.71(t，1H)，7.86(d，1H)，8.29(t，1H)
Embodiment 5 (E)-N-[3-(6-hydroxyl-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine Preparation
1, (E)-N-[3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine Preparation
The step 3 of preparation method's reference example 1, add 3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene formaldehyde 10.9g (0.04mol), sodium cyanoborohydride 3.8g, N-methyl-(3,4-dimethoxy) phenylethylamine hydrochloride 10.4g (0.045mol).Get solid 8.2g, yield: 48.5%.
2, (E)-N-[3-(6-hydroxyl-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-preparation of methylamine
The step 4 of preparation method's reference example 1, drop into (E)-N-[3-(6-methoxy methoxy base-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine 5.1g (12mmol), 10%HCl-MeOH20ml.Get solid 3.4g, yield: 75.1%.
Molecular formula: C 24H 27NO 3
Molecular weight: 377.48
Ultimate analysis:
Measured value: C, 76.05%; H, 7.62%; N, 3.53%
Theoretical value: C, 76.36%; H, 7.21%; N, 3.71%
Mass spectrum: m/e 378 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.27(s，3H)，2.66～2.73(m，4H)，3.06(dd，2H)，3.83(s，6H)，5.38(brs，1H)，6.18(m，1H)，6.59(d，1H)，6.73～6.85(m，3H)，7.15(dd，1H)，7.42～7.50(m，2H)，7.61(dd，1H)，7.79(t，1H)，7.95(dd，1H)
Embodiment 6 (E)-N-[3-(6-methoxyl group-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-first The preparation of amine
The step 3 of preparation method's reference example 1 is thrown 3-(6-methoxyl group-naphthalene-1-yl)-2-propylene formaldehyde 8.5g (0.04mol), N-methyl-(3,4-dimethoxy) phenylethylamine hydrochloride 10.4g (0.045mol).Get solid 8.2g, yield: 52.1%.
Molecular formula: C 25H 29NO 3
Molecular weight: 391.5
Ultimate analysis:
Measured value: C, 76.32%; H, 7.86%; N, 3.19%
Theoretical value: C, 76.70%; H, 7.47%; N, 3.58%
Mass spectrum: m/e 392 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.25(s，3H)，2.66～2.72(m，4H)，3.04(dd，2H)，3.84(s，9H)，6.17(m，1H)，6.56(d，1H)，6.74～6.83(m，3H)，7.23(dd，1H)，7.38(t，1H)，7.50(dd，1H)，7.69(dd，1H)，7.82(t，1H)，7.94(dd，1H)
Embodiment 7 (E)-N-[3-(6-amino-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine Preparation
1, (E)-N-[3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]- The preparation of methylamine
The step 3 of preparation method's reference example 1 is thrown 3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-propylene formaldehyde 11.9g (0.04mol), N-methyl-(3,4-dimethoxy) phenylethylamine hydrochloride 9.7g (0.045mol).Get solid 8.7g, yield: 45.6%.
2, (E)-N-[3-(6-amino-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-preparation of methylamine
The step 4 of preparation method's reference example 1 is thrown (E)-N-[3-(6-tertbutyloxycarbonyl amido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine 5.7g (12mmol).Get (E)-2-[4-(amido) styryl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine 3.1g, yield: 68.0%.
Molecular formula: C 24H 28N 2O 2
Molecular weight: 376.49
Ultimate analysis:
Measured value: C, 76.19%; H, 7.87%; N, 7.13%
Theoretical value: C, 76.56%; H, 7.50%; N, 7.44%
Mass spectrum: m/e 377 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.29(s，3H)，2.68～2.75(m，4H)，3.06(dd，2H)，3.85(s，6H)，6.18(m，1H)，6.29(brs，2H)，6.58(d，1H)，6.75～6.84(m，3H)，7.39～7.52(m，3H)，7.69～7.78(t，2H)，7.86(dd，1H)
Embodiment 8 (E)-N-[3-(6-acetamido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]- The preparation of methylamine
The step 3 of preparation method's reference example 1 is thrown 3-(6-acetamido-naphthalene-1-yl)-2-propylene formaldehyde 9.6g (0.04mol), N-methyl-(3,4-dimethoxy) phenylethylamine hydrochloride 10.4g (0.045mol).Get solid 8.0g, yield: 47.8%.
Molecular formula: C 26H 30N 2O 3
Molecular weight: 418.53
Ultimate analysis:
Measured value: C, 74.26%; H, 7.63%; N, 6.35%
Theoretical value: C, 74.61%; H, 7.22%; N, 6.69%
Mass spectrum: m/e 419 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.04(s，3H)，2.26(s，3H)，2.66～2.70(m，4H)，3.03(dd，2H)，3.83(s，6H)，6.19(m，1H)，6.56(d，1H)，6.77～6.83(m，3H)，7.23(brs，1H)，7.39(dd，1H)，7.49(m，2H)，7.71(t，1H)，7.84(d，1H)，8.28(t，1H)
Embodiment 9 (E)-2-[4-(hydroxyl) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine The preparation of-4-amine
1,4-[N-methyl-2-(benzo [d] [1,3] dioxolane-5-yl) ethyl amido]-preparation of 2-pyridine carboxylic acid methyl esters
In the reaction flask of drying, add 4-chloro-pyridine carboxylic acid methyl esters 17.2g (0.1mol), N-methyl-homopiperony lamine hydrochloride 25.9g (0.12mol), methylene dichloride 100ml is heated with stirring to backflow, then is added dropwise to triethylamine 15ml under stirring, drip and finish, insulated and stirred reaction 5h, reaction is finished, cooling, filter. with filtrate successively water, dilute hydrochloric acid solution, sodium hydrogen carbonate solution, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure, get solid 14.9g with re-crystallizing in ethyl acetate, yield: 47.5%.
2,4-[N-methyl-2-(benzo [d] [1,3] dioxolane-5-yl) ethyl amido]-preparation of 2-pyridylaldehyde
Under the nitrogen protection; in sealing; add 4-[N-methyl-2-(benzo [d] [1 in the dry reaction flask; 3] dioxolane-5-yl) ethyl amido]-2-pyridine carboxylic acid methyl esters 15.7g (0.05mol); toluene 100ml; reduce temperature to-78 ℃; slowly drip the 1M diisobutyl aluminium hydride 65ml of precooling; react complete after; the cold 100ml 2N HCl of careful adding in the impouring 200ml frozen water, divides oil-yielding stratum behind the stirring 15min; water layer extracts 2 times with methylene dichloride 200ml again; merge organic layer, through sodium hydrogen carbonate solution 50ml washing, organic layer anhydrous sodium sulfate drying; concentrating under reduced pressure gets crude product; re-crystallizing in ethyl acetate gets faint yellow solid 9.1g, yield: 64.2%.
3, (E)-2-[4-(methoxy methoxy base) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine The preparation of-4-amine
In the reaction flask of drying; add triphenyl-(4-methoxy methoxy base-benzene-1-yl) methyl bromide phosphine 9.9g (0.02mol); dry toluene 75ml; after the stirring and dissolving; under nitrogen protection; be cooled to the cyclohexane solution 10ml that adds the 1.6mol/L n-Butyl Lithium below-30 ℃; after room temperature continues to stir 0.5h; add 4-[N-methyl-2-(benzo [d] [1; 3] dioxolane-5-yl) ethyl amido]-2-pyridylaldehyde 5.1g (0.018mol); solution with toluene 50ml; finish, then stirring reaction 1h rises to stirring at room reaction 1h; and then be warming up to 50 ℃; restir reaction 1h, stopped reaction, the lower 2N hydrochloric acid 50ml that slowly adds of ice bath cooling; after the stirred for several minute; leave standstill, tell organic layer, after water layer washs with ether; regulate pH alkalescence with sodium hydrogen carbonate solution; ethyl acetate 50ml extracts 3 times, merges organic layer, anhydrous sodium sulfate drying; concentrating under reduced pressure; add the 20ml ethyl acetate in residuum, heated and stirred refluxed several minutes, cooling; separate out solid 3.3g, yield: 43.5%.
4, (E)-2-[4-(hydroxyl) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine-4-amine Preparation
In reaction flask, add (E)-2-[4-(methoxy methoxy base) styryl] N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine-4-amine 5g (12mmol), 10%HCl-MeOH20ml, stirring and refluxing 50min, reaction solution is evaporated to dried, extract 4 times with ethyl acetate 40ml, united extraction liquid, dry rear concentrated the steaming desolventizes dehydrated alcohol-ethyl acetate crystallization, get solid 3.3g, yield 73.2%.
Molecular formula: C 23H 22N 2O 3
Molecular weight: 374.43
Ultimate analysis:
Measured value: C, 73.04%; H, 6.25%; N, 7.19%
Theoretical value: C, 73.38%; H, 5.92%; N, 7.48%
Mass spectrum: m/e 375 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.37(s，3H)，2.82(t，2H)，3.41(t，2H)，5.32(brs，1H)，6.07(s，2H)，6.59(m，2H)，6.65(m，2H)，6.73～6.83(m，3H)，7.20～7.26(m，1H)，7.56(d，1H)，7.86(dd，1H)
Embodiment 10 (E)-2-[4-(methoxyl group) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-the N-methyl- The preparation of pyridine-4-amine
The step 3 of preparation method's reference example 9, throw triphenyl-(4-methoxyl group-benzene-1-yl) methyl bromide phosphine 9.3g (0.02mol), 4-[N-methyl-2-(benzo [d] [1,3] dioxolane-5-yl) ethyl amido]-2-pyridylaldehyde 5.1g (0.018mol), get solid 3.6g, yield: 51.4%.
Molecular formula: C 24H 24N 2O 3
Molecular weight: 388.46
Ultimate analysis:
Measured value: C, 73.94%; H, 6.64%; N, 7.06%
Theoretical value: C, 74.21%; H, 6.23%; N, 7.21%
Mass spectrum: m/e 389 (M+1)
1H-NMR(600MHz，CDCl 3)：
δ2.36(s，3H)，2.84(t，2H)，3.40(t，2H)，3.83(s，3H)，6.09(s，2H)，6.59(m，2H)，6.73～6.83(m，3H)，6.94(m，2H)，7.20(m，1H)，7.56～7.62(m，3H)，7.86(dd，1H)
Embodiment 11 (E)-2-[4-(amido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyrrole The preparation of pyridine-4-amine
1, (E)-2-[4-(tertbutyloxycarbonyl amido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-the N-methyl- The preparation of pyridine-4-amine
The step 3 of preparation method's reference example 9, throw triphenyl-[4-(tertbutyloxycarbonyl amido)-benzene-1-yl] methyl bromide phosphine 11g (0.02mol), 4-[N-methyl-2-(benzo [d] [1,3] dioxolane-5-yl) ethyl amido]-2-pyridylaldehyde 5.1g (0.018mol), get solid 3.5g, yield: 41.1%.
2, (E)-2-[4-(amido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine-4-amine Preparation
The step 4 of preparation method's reference example 9, throw (E)-2-[4-(tertbutyloxycarbonyl amido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine-4-amine 5.7g (12mmol), get (E)-2-[4-(amido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-N-methyl-pyridine-4-amine 3.1g, yield: 68.3%.
Molecular formula: C 23H 23N 3O 3
Molecular weight: 373.45
Ultimate analysis:
Measured value: C, 73.68%; H, 6.56%; N, 10.92%
Theoretical value: C, 73.97%; H, 6.21%; N, 11.25%
Mass spectrum: m/e 374 (M+1)
1H-NMR(600MHz，CDCl 3)：δ2.38(s，3H)，2.81(t，2H)，3.40(t，2H)，6.08(s，2H)，6.27(brs，2H)，6.34(m，2H)，6.59(m，2H)，6.73～6.83(m，3H)，7.22(m，1H)，7.56～7.61(m，3H)，7.85(dd，1H)
Embodiment 12 (E)-2-[4-(acetamido) styryl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-the N-methyl The preparation of-pyridine-4-amine
The step 3 of preparation method's reference example 9, throw triphenyl-[4-(tertbutyloxycarbonyl amido)-benzene-1-yl] methyl bromide phosphine 8.8g (0.02mol), 4-[N-methyl-2-(benzo [d] [1,3] dioxolane-5-yl) ethyl amido]-2-pyridylaldehyde 5.1g (0.018mol), get solid 3.4g, yield: 45.4%.
Molecular formula: C 25H 25N 3O 3
Molecular weight: 415.48
Ultimate analysis:
Measured value: C, 71.95%; H, 6.46%; N, 9.82%
Theoretical value: C, 72.27%; H, 6.06%; N, 10.11%
Mass spectrum: m/e 416 (M+1)
1H-NMR(600MHz，CDCl 3)：δ2.04(s，3H)，2.37(s，3H)，2.81(t，2H)，3.40(t，2H)，6.08(s，2H)，6.59(m，2H)，6.73～6.83(m，3H)，7.23(m，2H)，7.56～7.61(m，3H)，7.86(m，3H)
Embodiment 13 (E)-2-[4-(hydroxyl) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine-4- The preparation of amine
1,4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-preparation of 2-pyridine carboxylic acid methyl esters
The step 1 of preparation method's reference example 9 adds 4-chloro-pyridine carboxylic acid methyl esters 17.2g (0.1mol), N-methyl-2-(3,4-dimethoxy benzene-1-yl) ethylamine hydrochloride 27.8g (0.12mol).Get solid 20.7g, yield: 52.2%.
2,4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-preparation of 2-pyridylaldehyde
The step 2 of preparation method's reference example 9 adds 4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-2-pyridine carboxylic acid methyl esters 16.5g (0.05mol).Get faint yellow solid 10.1g, yield: 67.1%.
3, (E)-2-[4-(methoxy methoxy base) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine-4-amine Preparation
The step 3 of preparation method's reference example 9, add triphenyl-(4-methoxy methoxy base-benzene-1-yl) methyl bromide phosphine 9.9g (0.02mol), 4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-2-pyridylaldehyde 5.4g (0.018mol).Get solid 3.7g, yield: 47.6%.
4, (E)-2-[4-(hydroxyl) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-preparation of N-methyl-pyridine-4-amine
The step 4 of preparation method's reference example 9, add (E)-2-[4-(methoxy methoxy base) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine-4-amine 5.2g (12mmol), 10%HCl-MeOH20ml.Get solid 3.5g, yield: 75.5%.
Molecular formula: C 24H 26N 2O 3
Molecular weight: 390.47
Ultimate analysis:
Measured value: C, 73.58%; H, 6.96%; N, 6.84%
Theoretical value: C, 73.82%; H, 6.71%; N, 7.17%
Mass spectrum: m/e 391 (M+1)
1H-NMR(600MHz，CDCl 3)：δ2.36(s，3H)，2.81(t，2H)，3.40(t，2H)，3.83(s，6H)，5.35(brs，1H)，6.58(m，2H)，6.64(m，2H)，6.72～6.81(m，3H)，7.20～7.25(m，1H)，7.55(d，1H)，7.86(dd，1H)
Embodiment 14 (E)-2-[4-(methoxyl group) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine The preparation of-4-amine
The step 3 of preparation method's reference example 9, throw triphenyl-(4-methoxyl group-benzene-1-yl) methyl bromide phosphine 9.3g (0.02mol), 4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-2-pyridylaldehyde 5.4g (0.018mol), get solid 3.8g, yield: 52.6%.
Molecular formula: C 25H 28N 2O 3
Molecular weight: 404.5
Ultimate analysis:
Measured value: C, 73.87%; H, 7.26%; N, 7.06%
Theoretical value: C, 74.23%; H, 6.98%; N, 6.93%
Mass spectrum: m/e 405 (M+1)
1H-NMR(600MHz，CDCl 3)：δ2.37(s，3H)，2.82(t，2H)，3.39(t，2H)，3.84(s，9H)，6.59(m，2H)，6.73～6.83(m，3H)，6.94(m，2H)，7.21(m，1H)，7.56～7.63(m，3H)，7.85(dd，1H)
Embodiment 15 (E)-2-[4-(amido) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine-4- The preparation of amine
1, (E)-2-[4-(tertbutyloxycarbonyl amido) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine The preparation of-4-amine
The step 3 of preparation method's reference example 9, throw triphenyl-[4-(tertbutyloxycarbonyl amido)-benzene-1-yl] methyl bromide phosphine 11g (0.02mol), 4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-2-pyridylaldehyde 5.4g (0.018mol), get solid 3.7g, yield: 42.1%.
2, (E)-2-[4-(amido) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-preparation of N-methyl-pyridine-4-amine
The step 4 of preparation method's reference example 9, throw (E)-2-[4-(tertbutyloxycarbonyl amido) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine-4-amine 5.2g (12mmol), get (E)-2-[4-(amido) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyridine-4-amine 3.3g, yield: 70.4%.
Molecular formula: C 24H 27N 3O 2
Molecular weight: 389.49
Ultimate analysis:
Measured value: C, 73.72%; H, 7.28%; N, 10.41%
Theoretical value: C, 74.01%; H, 6.99%; N, 10.79%
Mass spectrum: m/e 390 (M+1)
1H-NMR(600MHz，CDCl 3)：δ2.38(s，3H)，2.81(t，2H)，3.40(t，2H)，3.83(s，6H)，6.27(brs，2H)，6.35(m，2H)，6.59(m，2H)，6.73～6.83(m，3H)，7.56(dd，1H)，7.56～7.61(m，2H)，7.86(dd，1H)
Embodiment 16 (E)-2-[4-(acetamido) styryl]-N-[2-(3,4-dimethoxy-benzene-1-yl) ethyl]-N-methyl-pyrrole The preparation of pyridine-4-amine
The step 3 of preparation method's reference example 9, throw triphenyl-[4-(tertbutyloxycarbonyl amido)-benzene-1-yl] methyl bromide phosphine 8.8g (0.02mol), 4-[N-methyl-2-(3,4-dimethoxy-benzene-1-yl) ethyl amido]-2-pyridylaldehyde 5.4g (0.018mol), get solid 3.6g, yield: 46.2%.
Molecular formula: C 26H 29N 3O 3
Molecular weight: 431.53
Ultimate analysis:
Measured value: C, 72.13%; H, 6.98%; N, 9.45%
Theoretical value: C, 72.37%; H, 6.77%; N, 9.74%
Mass spectrum: m/e 432 (M+1)
1H-NMR(600MHz，CDCl 3)：δ2.05(s，3H)，2.38(s，3H)，2.82(t，2H)，3.39(t，2H)，3.83(s，6H)，6.58(m，2H)，6.73～6.84(m，3H)，7.22(m，3H)，7.56～7.61(m，3H)，7.86(dd，1H)
The preparation of embodiment 17 the compounds of this invention aqueous injections
1, prescription: prescription 1:
The hydrochloride 10g (in compound) of compound 1
Water for injection adds to 2000ml
Prepare altogether 1000
Prescription 2:
Compound 5 20g
Water for injection adds to 2000ml
Prepare altogether 1000
2, preparation technology: any one and auxiliary material in the compounds of this invention or derivatives thereof are dissolved dosing with water for injection, and filtration after charcoal absorption is processed, constant volume, smart worry, the inspection of semifinished product, embedding, sterilization, leak detection, lamp inspection, packing are made finished product.
The preparation of embodiment 18 the compounds of this invention sterile packaged preparations
1, the prescription prescription 1
Compound 2 30g
Methionin 170g
Prepare altogether 1000
Prescription 2
Compound 4 20g
Methionin 80g
Prepare altogether 1000
Prescription 3
Compound 9 hydrochloride 10g (in compound)
Methionin 190g
Prepare altogether 1000
Prescription 4
Compound 12 5g
Methionin 95g
Prepare altogether 1000
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing stock and adjunct (aseptic raw material can prepare with sterilization crystallization process, spray-drying process) by prescription, pulverize mixing, place the portioning machine packing, detect at any time loading amount; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 19 the compounds of this invention freeze-dried powders
1, prescription:
Prescription 1:
The hydrochloride 10g (in compound) of compound 3
N.F,USP MANNITOL 40g
EDTA-Na 2 2.5g
Water for injection adds to 1000ml
Prepare altogether 1000
Prescription 2:
Compound 6 20g
N.F,USP MANNITOL 80g
EDTA-Na 2 5g
Water for injection adds to 1000ml
Prepare altogether 1000
Prescription 3:
Compound 8 30g
N.F,USP MANNITOL 60g
Water for injection is an amount of
Prepare altogether 1000
Prescription 4:
Compound 14 40g
N.F,USP MANNITOL 90g
Water for injection is an amount of
Prepare altogether 1000
2, preparation technology: take by weighing supplementary material by prescription; There is the water for injection of dosing amount 80% to dissolve in N.F,USP MANNITOL, adds the EDTA-Na2 dissolving; Any one stirring and dissolving in the compounds of this invention or derivatives thereof is complete, measure the pH value, regulate pH to proper range with hydrochloric acid and the sodium hydroxide of 1mol/L, add water for injection to full dose, add the gac of dosing amount 0.05%, 30 ℃ of insulated and stirred 20min, filtering decarbonization, with 0.45 μ m filtering with microporous membrane, the inspection of semifinished product, liquid is with 0.22 μ m filtering with microporous membrane, check clarity, can, false add plug, freeze-drying, freeze-dry process is: 40mg; Specification freeze-dry process :-40 ℃ of pre-freeze 3h ,-40～-5 ℃ of low-temperature distillation 15h ,-5～30 ℃ of dry 4h that heat up, 30 ℃ of high temperature drying 2.5h; Freeze-drying is complete, and lid is rolled in tamponade, packing, full inspection.
The preparation of embodiment 20 the compounds of this invention capsules
1, the prescription prescription 1:
Compound 4 5g
Pregelatinized Starch 45g
Microcrystalline Cellulose 40g
Magnesium Stearate 1.5g
Silicon-dioxide 2g
Water is an amount of
Prepare altogether 1000
Prescription 2:
Compound 10 10g
Pregelatinized Starch 48g
Microcrystalline Cellulose 45g
Magnesium Stearate 1.5g
Silicon-dioxide 3g
Water is an amount of
Prepare altogether 1000
Prescription 3:
The hydrochloride 20g (in compound) of compound 13
Pregelatinized Starch 64g
Microcrystalline Cellulose 60g
Magnesium Stearate 2g
Silicon-dioxide 4g
Water is an amount of
Prepare altogether 1000
Prescription 4:
Compound or 16 30g
Pregelatinized Starch 60g
Microcrystalline Cellulose 65g
Magnesium Stearate 2.5g
Silicon-dioxide 5g
Water is an amount of
Prepare altogether 1000
2, preparation technology:
Raw material, auxiliary material are crossed respectively 100 mesh sieves, for subsequent use; With in the compounds of this invention or derivatives thereof any one, pregelatinized Starch, Microcrystalline Cellulose mix, it is an amount of to add entry, stirs, and makes suitable softwood, crosses 20 mesh sieves particle processed; Dry under 60 ℃ condition, dry good particle adds Magnesium Stearate, silicon-dioxide, crosses the whole grain of 18 mesh sieves, mixes; Sampling, the work in-process chemical examination; The loading amount of determining according to chemical examination incapsulates; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 21 the compounds of this invention tablets
1, prescription
Prescription 1:
The hydrochloride 10g (in compound) of compound 12
Starch 200g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 45g
50% aqueous ethanolic solution of 1%HPMC is an amount of
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare altogether 1000
Prescription 2:
Compound 7 20g
Starch 240g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 55g
50% aqueous ethanolic solution of 1%HPMC is an amount of
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare altogether 1000
Prescription 3:
The hydrochloride 10g (in compound) of compound 12
Starch 200g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 45g
50% aqueous ethanolic solution of 1%HPMC is an amount of
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare altogether 1000
Prescription 4:
Compound 9 20g
Starch 240g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 55g
50% aqueous ethanolic solution of 1%HPMC is an amount of
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare altogether 1000
2, preparation technology: take by weighing stock and adjunct according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed respectively 100 mesh sieves; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, add 50% aqueous ethanolic solution of 1%HPMC, stirred granulation 15 minutes; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.

Claims (8)

1. compound or the pharmacy acceptable salt shown in the general formula (I):
Figure FSB00000935905300011
Wherein:
R 1Represent hydrogen atom, hydroxyl, methoxyl group, oxyethyl group, kharophen, amino, methylamino-;
R 2, R 3The carbon atom that the is adjacent formation phenyl ring that is connected;
R 4With R 5Independently represent respectively hydrogen atom, methyl, ethyl;
R 6Represent methylidene;
R 7And R 8Independently represent hydrogen atom, methyl, ethyl, perhaps R respectively 7, R 8The Sauerstoffatom that the is adjacent formation five-membered ring that is connected;
M is 1;
N is 1.
2. compound as claimed in claim 1 or pharmacy acceptable salt:
Wherein:
R 1Representation hydroxy, methoxyl group, kharophen, amino;
R 2, R 3The carbon atom that the is adjacent formation phenyl ring that is connected;
R 4With R 5Independently represent respectively hydrogen atom, methyl;
R 6Represent methylidene;
R 7And R 8Difference independent represent methylidene, perhaps R 7, R 8The Sauerstoffatom that is adjacent is connected and forms 1,3-dioxole;
M is 1;
N is 1.
3. compound as claimed in claim 2 or pharmacy acceptable salt are selected from following compound:
(E)-N-[3-(6-methoxyl group-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine,
(E)-N-[3-(6-acetamido-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine,
(E)-N-[3-(6-hydroxyl-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine,
(E)-N-[3-(6-amino-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(benzo [d] [1,3] dioxolane-5-yl) ethyl]-methylamine,
(E)-N-[3-(6-hydroxyl-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine,
(E)-N-[3-(6-methoxyl group-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine,
(E)-N-[3-(6-amino-naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine,
(E)-N-[3-(6-acetylaminohydroxyphenylarsonic acid naphthalene-1-yl)-2-propylene-1-yl]-N-[2-(3,4-dimethoxy benzene-1-yl) ethyl]-methylamine.
4. such as claim 1-3 each described compound or pharmacy acceptable salt, wherein, its pharmacy acceptable salt is acid addition salt.
5. compound as claimed in claim 4 or pharmacy acceptable salt, wherein, its pharmacy acceptable salt is hydrochloride, vitriol, phosphoric acid salt, carbonate, hydrobromate, oxalate, succinate.
6. such as the pharmaceutical composition of each described compound of claim 1-3 or pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner, make pharmaceutically acceptable arbitrary formulation.
7. pharmaceutical composition as claimed in claim 6, per unit preparation contain the described compound of each claim of claim 1-3 or pharmacy acceptable salt 1mg-1000mg as essential activeconstituents.
8. the application in the medicine of preparation Cardiovarscular such as the described compound of each claim of claim 1-3 or pharmacy acceptable salt.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1049338A (en) * 1989-08-11 1991-02-20 中国医学科学院药物研究所 The preparation method of amino ketone compound
CN1396162A (en) * 2002-07-24 2003-02-12 广州市众为生物技术有限公司 Xanthiphenyl ketamine or its salt and its preparing process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1049338A (en) * 1989-08-11 1991-02-20 中国医学科学院药物研究所 The preparation method of amino ketone compound
CN1396162A (en) * 2002-07-24 2003-02-12 广州市众为生物技术有限公司 Xanthiphenyl ketamine or its salt and its preparing process

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