CN100335468C - Diaryl amidine compound, its production, medicinal composition and use - Google Patents
Diaryl amidine compound, its production, medicinal composition and use Download PDFInfo
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- CN100335468C CN100335468C CNB2004100600609A CN200410060060A CN100335468C CN 100335468 C CN100335468 C CN 100335468C CN B2004100600609 A CNB2004100600609 A CN B2004100600609A CN 200410060060 A CN200410060060 A CN 200410060060A CN 100335468 C CN100335468 C CN 100335468C
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- benzimidoyl
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Abstract
The present invention discloses a novel-structure substituted diaryl amidine compound, medicinal acid salt thereof and a preparation and purification method of the compound and the medicinal acid salt thereof, which contains the medicinal compositions thereof. The compound has 5-hydroxytryptamine reuptake inhibition activity, shows strong anti-depression effect in an animal experiment and is capable of treating depression and other kinds of psychoneurotic system disease relevant to 5-hydroxytryptamine in vivo.
Description
Technical field
The present invention relates to new diaryl amidine compound, its preparation method contains their pharmaceutical composition, and as medicine, especially as the purposes of antidepressant drug.
Background technology
In the at present clinical medicine that is used for the treatment of dysthymia disorders, serotonin reuptake inhibitor (SSRIs) is most important, most popular medicine.Its representative has fluoxetine [Fluoxetine sees USP 4018895 (1977), Ger.pat.2500110 (1975), USP 4314081 (1982)]; Paroxetine [Paroxetine, Ger.pat.2404113 (1974), USP3912743 (1975), USP 4007196 (1977)]; Sertraline [USP 4536518 (1985) for Sertraline, EP30081 (1981)]; Citalopram [USP 4136193 (1979) for Citalopram, Ger.pat.2657013 (1977)]; And fluvoxamine [Fluvaxamine, Neth.pat.Apple 7503310 (1975), USP 4085225 (1978)].Serotonin reuptake inhibitor anti-depressant therapy effect affirms that toxic side effect is less, and security and tolerance are better, uses on a large scale in worldwide.But still there is serious deficiency in above-mentioned several drugs, needs further to improve curative effect, reduces toxic side effects incidence and drug withdrawal rate, particularly solves onset hysteresis problem.New better with suppress serotonin reuptake transporter as the development of the new drug of treatment target spot still in actively developing.
United States Patent (USP) (US 2002123489) also relates to a class Benzamine derivatives, it is said that this compounds has δ-opiate receptor regulating effect (agonist or antagonist).Though this patent is applied for the molecular structure of the benzamidine analog derivative protected and also has diaryl amidine structure and piperazine ring that specifying has carboxyl or thiocarboxyl group on the benzyl phenyl ring, or carboxylicesters, carbothioic acid ester, acid amides, thioamides.Substituted diaryl amidine compound molecular structure involved in the present invention is different with it, does not replace on the benzyl phenyl ring, or other replacement that is different from carboxyl and carboxylic acid derivative is arranged, and phenyl ring can also be a hetero-aromatic ring.None is identical for the whole compounds announced of United States Patent (USP) (US 2002123489) and the whole compounds that the present invention relates to.
The preparation method of the substituted diaryl amidine compound that the present invention relates to and the salt of pharmaceutically acceptable acid thereof also is different from the preparation method of the benzamidine compounds that United States Patent (USP) (US 2002123489) relates to.
In addition, the benzamidine compounds that United States Patent (USP) (US 2002123489) relates to is δ-opioid receptor modulators, and the substituted diaryl amidine compound that the present invention relates to is a serotonin reuptake inhibitor.
Summary of the invention
The objective of the invention is to develop the new medicine of treatment or prevention dysthymia disorders.
The inventor has been found that the new diaryl amidine compound of following general formula I and II by deep research, rat synaptosome serotonin reuptake transporter had the activity of inhibition, antidepressant activity is arranged on whole animal, therefore can be used as the medicine of treatment or prevention dysthymia disorders.
First aspect present invention relates to general formula I and II compound, its steric isomer and pharmaceutical salts thereof.
The present invention relates to the method for preparing general formula I and II compound, its steric isomer and pharmaceutical salts thereof on the other hand.
Further aspect of the present invention relates to the pharmaceutical composition that is used to prevent or treat dysthymia disorders, and it comprises at least one general formula I and II compound, its steric isomer and pharmaceutical salts thereof and pharmaceutical carrier or vehicle.
The invention still further relates to general formula I and II compound, its steric isomer and pharmaceutical salts thereof and be used for preventing or treating the application of the medicine of dysthymia disorders in preparation.
The invention still further relates to the method for prevention or treatment dysthymia disorders, it comprises to the human Mammals that comprises of needs takes general formula I and II compound, its steric isomer and the pharmaceutical salts thereof of prevention or treatment significant quantity.
For realizing purpose of the present invention, specifically use following technical scheme:
The present invention relates to the diaryl amidine compound shown in the general formula (I) or its steric isomer or its pharmaceutical salts,
Wherein:
Ar represents aromatic nucleus; Aromatic nucleus comprises phenyl ring and C
5-14Aromatic heterocycle, wherein heteroatoms is selected from one to three N, O or S;
Preferred aromatic heterocycle comprises phenyl ring, pyridine ring, furan nucleus, pyrrole ring, thiphene ring;
R1 is selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro,
The C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
1-18Alkoxyl group,
The C of replacement or non-replacement
1-18Alkylthio [substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro],
[R7, R8 are selected from hydrogen or C
1-6Alkyl],
-COOR9[R9 is selected from hydrogen or C
1-6Alkyl], replace or the C of non-replacement
3-8[substituting group is selected from C to the fat cyclic group
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the phenyl of non-replacement [substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the C of non-replacement
5-14[substituting group is selected from C to heterocyclic radical
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], R1 represents single substituting group or multi-substituent, can be identical or different when substituting group is a plurality of, substituting group can be connected each different positions of phenyl ring;
R1 also represents and the ring mode replaces, and the ring mode can be 2,3 also can be at 3,4, can be and phenyl ring, also can be and five Yuans or six element heterocycles also can be and 5～7 Yuans carbocyclic rings of fractional saturation, for example, the acene ring forms naphthalene nucleus, and five Yuans or six element heterocycles can be and pyridine ring, pyranoid ring, pyrrole ring, furan nucleus, thiphene ring; And ring can be substituted or non-replacement, optional position that substituting group can be positioned at and encircle, and substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, the C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
1-18The C of alkoxyl group, replacement or non-replacement
1-18Alkylthio [substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro],
-COOR9[R9 is selected from hydrogen or C
1-6Alkyl],
The C of replacement or non-replacement
3-8[substituting group is selected from C to the fat cyclic group
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the phenyl of non-replacement [substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro],
The C of replacement or non-replacement
5-14[substituting group is selected from C to heterocyclic radical
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], preferred R1 is hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group, 2,3 or the 4-pyridyl, the 2-pyrryl, the 2-furyl, the 2-thienyl;
R2 is selected from hydrogen, hydroxyl, sulfydryl, halogen, nitro, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, the amino of non-replacement, C
1-6The alkyl amino, sulfamic, the methylmesylate base that replace, but do not comprise carboxyl, thiocarboxyl group, carboxylicesters, carbothioic acid ester, acid amides and thioamides; The substituting group number that R2 represents can be one, also can two or more, can be identical or different when the substituting group number is two or more, can be connected on the different positions of aromatic ring;
Preferred R2 is hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R3 is selected from hydrogen, C
1-6Alkyl, the number of the substituting group number that R3 represents can be a substituting group, also can two or more, different positions that can be on piperazine ring;
Preferred R3 is a methyl.
R4 is selected from hydrogen or C
1-6Alkyl.
Preferred R4 is hydrogen and methyl.
The aromatic nucleus of two replacements can be in the same side of C=N, is cis-configuration, is E formula configuration by naming rule.
The aromatic nucleus of two replacements can be in the both sides of C=N, is transconfiguration,
The compound of general formula (I) can also and pharmacodynamics on acceptable mineral acid or organic acid salify; Preferred acid is hydrochloric acid, sulfuric acid, toxilic acid, fumaric acid, methylsulfonic acid, oxalic acid.
According to the present invention, preferred compound shown in general formula (I) is including but not limited to the compound shown in general formula (Ia)
R1 is selected from hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R2 is selected from hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R3 is selected from hydrogen atom, methyl;
R4 is selected from hydrogen atom, methyl.
According to the present invention, preferred compound shown in general formula (I) is including but not limited to the compound shown in general formula (Ib)
R1 hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, nitro, cyano group, the tertiary butyl;
R2 is methyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group;
R3, hydrogen atom, methyl;
R4, hydrogen atom, methyl.
The present invention relates to the diaryl amidine compound shown in the general formula (II) or its steric isomer or its pharmaceutical salts,
Wherein:
Ar represents aromatic nucleus; Aromatic nucleus comprises phenyl ring and aromatic heterocycle;
Preferred aromatic heterocycle comprises phenyl ring, pyridine ring, furan nucleus, pyrrole ring, thiphene ring;
R1 is selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro, the C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
1-18The C of alkoxyl group, replacement or non-replacement
1-18Alkylthio [substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro],
-COOR9[R9 is selected from hydrogen or C
1-6Alkyl], replace or the C of non-replacement
3-8[substituting group is selected from C to the fat cyclic group
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the phenyl of non-replacement [substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the C of non-replacement
5-14[substituting group is selected from C to heterocyclic radical
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro],
R1 represents single substituting group or multi-substituent, can be identical or different when substituting group is a plurality of, and substituting group can be connected each different positions of phenyl ring;
R1 also represents and the ring mode replaces, and the ring mode can be 2,3 also can be at 3,4, can be and phenyl ring, also can be and five Yuans or six element heterocycles also can be and 5～7 Yuans carbocyclic rings of fractional saturation, for example, the acene ring forms naphthalene nucleus, and five Yuans or six element heterocycles can be and pyridine ring, pyranoid ring, pyrrole ring, furan nucleus, thiphene ring;
And ring can be substituted or non-replacement, optional position that substituting group can be positioned at and encircle, and substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, the C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
1-18The C of alkoxyl group, replacement or non-replacement
1-18Alkylthio [substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro],
-COOR9[R9 is selected from hydrogen or C
1-6Alkyl], replace or the C of non-replacement
3-8[substituting group is selected from C to the fat cyclic group
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the phenyl of non-replacement [substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro], replace or the C of non-replacement
5-14[substituting group is selected from C to heterocyclic radical
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro],
Preferred R1 is hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group, 2,3 or the 4-pyridyl, and 2-pyrryl, 2-furyl, 2-thienyl;
R2 is selected from hydrogen, hydroxyl, sulfydryl, halogen, nitro, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, the amino of non-replacement, C
1-6The alkyl amino, sulfamic, the methylmesylate base that replace, but do not comprise carboxyl, thiocarboxyl group, carboxylicesters, carbothioic acid ester, acid amides and thioamides; The substituting group number that R2 represents can be one, also can two or more, can be identical or different when the substituting group number is two or more, can be connected on the different positions of aromatic ring;
Preferred R2 is hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
The aromatic nucleus of two replacements can be in the same side of C=N, is cis-configuration, is E formula configuration by naming rule.
The aromatic nucleus of two replacements can be in the both sides of C=N, is transconfiguration,
The compound of general formula (II) can also and pharmacodynamics on acceptable mineral acid or organic acid salify; Preferred acid is hydrochloric acid, sulfuric acid, toxilic acid, fumaric acid, methylsulfonic acid, oxalic acid.
X represents C
2-4The carbochain that is with or without side chain;
Preferred X is-CH
2CH
2-;
Y is hydrogen or C
1-3Alkyl,
Preferred Y is hydrogen atom and methyl;
R5, R6 are selected from hydrogen or C
1-6Alkyl.
Preferred R5, R6 are hydrogen and methyl.
According to the present invention, preferred compound shown in general formula (II) is including but not limited to the compound shown in general formula (IIa)
R1 is selected from hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R2 is selected from hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R3, hydrogen atom, methyl;
R4, hydrogen atom, methyl.
According to the present invention, used term " C
1-6Alkyl " be meant the straight or branched alkyl that contains 1-6 carbon atom, say for example: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the sec-butyl or the tertiary butyl, amyl group, neo-pentyl, hexyl etc.
According to the present invention, used term " C
1-6Alkoxyl group " be meant the straight or branched alkoxyl group that contains 1-6 carbon atom, say for example: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.
According to the present invention, used term " C
1-6Alkylthio " be meant for example and say: methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, secondary butylthio or uncle's butylthio, penta sulfenyl, new penta sulfenyl, own sulfenyl etc.
According to the present invention, used term " halogen " comprises fluorine, chlorine, bromine, iodine.
According to the present invention, used term " aromatic heterocycle " comprises phenyl ring, pyridine ring, furan nucleus, pyrrole ring, thiphene ring.
According to the present invention, formula (I) and formula (II) compound can exist with the form of steric isomer.The asymmetric center that exists in formula (I) and formula (II) compound can have S configuration or R configuration.The present invention includes all possible steric isomer such as enantiomer or diastereomer, and the mixture of two or more steric isomers, for example mixture of any required ratio of enantiomer and/or diastereomer.Therefore, the present invention relates to enantiomer, for example left-handed-and the mixture or the racemic modification of two kinds of enantiomorphs existing of dextrorotation-enantiomorph and different ratios that exists with enantiomeric form.There is suitable/trans isomer in compound of the present invention, the present invention relates to the mixture of cis form and trans forms and these forms.If desired, the preparation of single stereoisomers can split mixture according to conventional methods, or by for example synthetic preparation of three-dimensional selection.If there is the mobile hydrogen atom, the present invention also relates to the tautomeric form of compound.
Above-mentioned formula (Ia) and (Ib) shown in compound or its steric isomer or its pharmaceutical salts be the special case or the subclass of I compound of the present invention, (Ia) and the compound (Ib) all in formula I compound scope of the present invention.Compound shown in the above-mentioned formula (IIa) or its steric isomer or its pharmaceutical salts are the special case or the subclass of II compound of the present invention, and (IIa) compound shown in is all in formula II compound scope of the present invention.
According to the present invention, particular compound or its steric isomer or its pharmaceutical salts below formula I of the present invention and formula II compound are preferred.
The title of the salt of Table I diaryl amidine compound and pharmaceutically acceptable acid thereof, structural formula and essential constant
Preparation method according to the salt that the invention still further relates to such substituted diaryl amidine compound and pharmaceutically acceptable acid thereof.
The synthetic route of compound shown in formula I and the formula II:
R1 in the formula, R2, R3, R4, R5, R6, Ar, X, Y, identical with top definition, HA represents and the salifiable acid of formula (I) compound.
Above-mentioned reaction scheme is the logical method of preparation formula I and formula II compound, comprising comprising the steps:
(a) carboxylic acid halides of the benzoyl halogen of aniline, naphthylamines or the aromatic heterocycle amine of corresponding replacement and corresponding replacement or fragrant heterocyclic carboxylic acid is contracted and, obtain the corresponding amide compound;
(b) amide compound of going up the step gained is handled the back generation together with chloro diaryl group with imine moiety with phosphorus pentachloride,
(c) upward the step is not purified, and directly with selected diamines, piperazine or substituted-piperazinyl reaction make object substituted diaryl amidine compound (free alkali),
The preparation of the salt of the medicinal acid of The compounds of this invention is the known technology that adopts those skilled in the art, with product substituted diaryl amidine class free alkali of last step and selected pharmaceutically useful mineral acid or small molecular organic acid, at the medium equivalent reaction of appropriate solvent, promptly obtain the salt of the pharmaceutically acceptable acid of substituted diaryl amidine compound according to a conventional method.
The used raw material of preparation the present invention, aniline, naphthylamines, the aromatic heterocycle amine of replacement or non-replacement, the diamine derivative of bridged piperazine derivatives, replacement or the non-replacement of carboxylic acid halides, replacement or the non-replacement of the fragrant heterocyclic carboxylic acid of benzoyl halogen, replacement or the non-replacement of replacement or non-replacement all can be commercially available, or be easy to make according to the known technology or the existing literature technology of this area.
In the step (a) carboxylic acid halides of the benzoyl halogen of aniline, naphthylamines or the aromatic heterocycle amine of corresponding replacement and corresponding replacement or fragrant heterocyclic carboxylic acid contract and.In the carboxylic acid halides that drips benzoyl halogen or fragrant heterocyclic carboxylic acid, drip the equivalent aqueous sodium hydroxide solution, keep reaction solution alkalescence in the dropping process all the time.Preferred carboxylic acid halides is an acyl chlorides, for example Benzoyl chloride, substituted benzoyl chloride, heterocyclic carboxylic acid acyl chlorides.Aniline, naphthylamines or aromatic heterocycle amine are dissolved in the methylene dichloride, and the carboxylic acid halides of benzoyl halogen or fragrant heterocyclic carboxylic acid can be the pure carboxylic acid halides liquid or the dichloromethane solution of carboxylic acid halides.The temperature that drips the process control reaction is below 0 ℃.Rise to room temperature after being added dropwise to complete, be stirred to and react completely.
Resulting acid amides mixes the phosphorus pentachloride that the back adds excessive slightly (in mole) with an amount of dry-out benzene.The temperature of reaction is at 60-100 ℃, preferably carries out under the temperature that refluxes.
The residuum in last step is chilled to room temperature, after the appropriate solvent dissolving, stirs adding fresh distillatory bridged piperazine derivatives or diamines after no water treatment down, obtains substituted diaryl amidine crude product (free alkali).Reaction times 1-4 hour, preferably 1.5-2.5 hour.
Above resultant substituted diaryl amidine compound crude product with dissolve with methanol after, stir and to drip saturated HCl absolute methanol solution down to pH=3, concentrating under reduced pressure boils off the first alcohol and water, remaining solid appropriate solvent recrystallization obtains the dihydrochloride of substituted diaryl amidine.In the methanol solution of substituted diaryl amidine, add the sulfuric acid, toxilic acid (or other pharmaceutically useful mineral acid or small molecular organic acids such as methylsulfonic acid, oxalic acid, fumaric acid) of equimolar amount, can obtain corresponding salt.
Substituted diaryl amidine compound (free alkali) adopts silica gel column chromatography or recrystallization to come purifying.The purifying of the salt of the pharmaceutically acceptable acid of substituted diaryl amidine adopts recrystallization purifying.
Contain as the compound of the present invention of active ingredient and the pharmaceutical composition of conventional medicine vehicle or assistant agent according to the invention still further relates to.Usually pharmaceutical composition of the present invention contains acceptable salt on the The compounds of this invention of 0.1-95 weight % and/or its pharmacodynamics.
The pharmaceutical composition of The compounds of this invention can be according to method preparation well known in the art.When being used for this purpose, if desired, The compounds of this invention and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as in oral, muscle, nasal cavity, oral mucosa, skin, transdermal, subcutaneous, intracutaneous, peritonaeum, rectum, intravenously, intramuscular, the sheath, epidural, intraocular, encephalic, vagina administration etc.
The compounds of this invention or the route of administration that contains its pharmaceutical composition can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection therapy, intrathecal injection and peritoneal injection etc.
Form of administration can be liquid dosage form, solid dosage.SOLUTION PROPERTIES as liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.The liquid dosage form form can be syrup, elixir, injection solution, non-aqueous solution, suspension, emulsion, liposome; But solid dosage is tablet, buccal tablet, capsule, dripping pill, pill, granula, pulvis, creme, solution, suppository dispersion powder such as lyophilized injectable powder, aerosol etc. for example.
The compounds of this invention can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier comprises that vehicle is lime carbonate, lactose, calcium phosphate, sodium phosphate for example; Thinner and absorption agent be starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate, dextran, colloidal silica, gum arabic, gelatin, Magnesium Trisilicate, Keratin sulfate etc. for example; Wetting agent and tackiness agent be 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. for example; Disintegrating agent is 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. for example; 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, triethylamine Magnesium Stearate, triethylamine stearic acid, 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 postponing its disintegration and absorption in gi tract, and provide continuous action in a long time thus.
For example, can be extensive use of various carrier well known in the art for pill is made in the administration unit.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, 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 example for capsule is made in the administration unit, the effective constituent The compounds of this invention is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective constituent The compounds of this invention 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 example, comprise emulsion, solution, suspension, syrup etc. for oral liquid is made in the administration unit.Suitable carriers comprises solution, suspension, syrup etc., and optional additive for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and the spices etc. of containing.
For example, The compounds of this invention is made injection preparation,, can use this area all thinners commonly used as solution, suspensoid, emulsion, lyophilized injectable powder.Can be selected from water, ethanol, polyoxyethylene glycol, 1 as thinner, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, vegetables oil be for example ethyl oleate, polyoxyethylene sorbitol, fatty acid ester etc. of sweet oil and Semen Maydis oil, gelatin and injectable organic ester for example.This preparation can be moisture or non-water, also can contain sanitas, tensio-active agent, wetting agent, emulsifying agent or dispersion agent.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 for example for example sucrose, lactose, asccharin etc. or other material of peppermint, Chinese ilex wet goods, sweeting agent of tinting material, sanitas, spices, correctives.
The used sterile media of the present invention can make by the well-known standard technique of those skilled in the art.They can be sterilized, for example by filter via biofilter, by in composition, add disinfectant, by with the composition radiotreatment or by composition being heated Song's sterilization.Can also they be made sterile injectable medium facing with preceding.
For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.Certainly the route of administration that is used to implement compound of the present invention depends on the position that disease and needs are treated.Because the pharmacokinetics of The compounds of this invention and pharmacodynamic profile have to a certain degree different, the most preferred method that therefore obtains treatment concentration in tissue is to increase dosage gradually and monitor clinical effectiveness.For such therapeutic dose of increase gradually, predose will depend on route of administration.
For any particular patient, the concrete treatment effective dose level of The compounds of this invention pharmaceutical composition depends on many factors, for example to prevent or treat the character of disease, disease severity, route of administration, administration number of times, therapeutic purpose, the removing speed of this compound, the treatment time length, this particular compound associating or the concrete medicine that uses simultaneously, the sex of patient or animal, age, body weight, personality, diet, the well-known factors in medical science field such as individual reaction and general health situation, therefore therapeutic dose of the present invention can have large-scale variation.According to treatment patient's illness, may must make some change, and under any circumstance, all determine the suitable dose of individual patient by the doctor to dosage.
Dosage is meant and does not comprise the weight of vehicle weight at the compound of interior (when using carrier).In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.Can be according to the actual drug quantity that is contained in the preparation last in the The compounds of this invention composition, in addition suitable adjustment to reach the requirement of its treatment significant quantity, is finished prevention of the present invention or therapeutic purpose.The suitable dose scope of the every day of The compounds of this invention is preferably the 0.01-10mg/kg body weight, more preferably the 0.1-1mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations; This is subject to administration doctor's clinical experience and comprises the dosage regimen of using other treatment means.Compound of the present invention or composition can be taken separately, or merge use and adjust dosage with other treatment medicine or symptomatic drugs.
Pharmacological action
The rat synaptosome that passes through classics of The compounds of this invention [
3H]-serotonin reuptake transporter experimental evaluation 5-HT reuptake inhibitory activity.Experimental result shows that all compound all shows the 5-HT reuptake inhibitory activity of varying strength.Particularly, compound 002,024 and 076 shows very strong 5-HT reuptake inhibitory activity.
The compounds of this invention comprises mouse tail suspension and free movable experiment and the experiment of mouse 5-hydroxyryptophan enhancement also by its antidepressant activity of evaluation of whole animal.Experimental result shows, wherein two compounds (024 and 052) with positive control drug fluoxetine same dose under (5mg/kg irritates stomach), have quite or strong slightly activity, and on two kinds of animal models unanimity as a result.Its antidepressant activity is equivalent to such (serotonin reuptake inhibitor) thymoleptic of (or being higher than) present clinical use at least.The salt of this type of substituted diaryl amidine compound and pharmaceutically acceptable acid thereof may become new treating depression medicine.
The molecular structure of The compounds of this invention, be different from existing serotonin reuptake inhibitor class thymoleptic fully, also being different from and existingly having serotonin reuptake transporter and suppress active classes of compounds, is the serotonin reuptake inhibitor of a class formation novelty.What special meaning was arranged is, compound of the present invention is compared with existing serotonin reuptake inhibitor, shows as to act on not that target spot and existing serotonin reuptake inhibitor have the incomplete same mechanism of action in the consubstantiality.
Embodiment
The following examples are in order to the important physical chemical index of concrete experimental procedure, reaction conditions, post-treating method, purifying products, intermediate and the object of the preparation of the salt that specifies substituted diaryl amidine compound involved in the present invention and pharmaceutically acceptable acid thereof and purge process and spectroscopic data, biologically active data.The following examples just for a better understanding of the present invention, wherein said method, the purification refine that comprises used raw material and reagent, solvent, reaction conditions, post-treating method and product, can not be interpreted as any limitation of the invention, can not contain whole preparations and purification process involved in the present invention fully, listed compound is preferred compound, does not also comprise the whole compounds that the present invention relates to.
Embodiment 1
The preparation of 1-(N-phenyl benzimidoyl) piperazine (compound 001)
Add N-phenylbenzamaide 1.0 gram (5.1mmol) and benzene 2ml in the reaction flask, 50 ℃ of heating 30 minutes, add phosphorus pentachloride 1.1 grams (5.3mmol) then in batches, 90 ℃ of stirring reactions 2 hours, solid was molten entirely.Remove benzene and phosphorus oxychloride under reduced pressure, residuum is chilled to room temperature, once adds the solution that Piperazine anhydrous 0.9 gram (10.5mmol) is dissolved in benzene 20ml, stirring at room 2 hours.Room temperature is placed and is spent the night.Filter, solid is washed with acetone, and filtrate and washing lotion merge the back concentrating under reduced pressure, get crude product.Crude product silica gel column chromatography column separating purification, petrol ether/ethyl acetate/triethylamine (100: 50: 1) wash-out, silica gel thin-layer detects, and contains product (compound 001) elute soln and merges the back evaporate to dryness, use ether-sherwood oil recrystallization again, get white crystals shape solid 0.41 gram.Yield 30%.
1HNMR(DMSO-d
6+D
2O)δ(ppm)：2.70(m，4H)，3.23(m，4H)，6.43(d，2H，J＝7.5Hz)，6.66(t，1H，J＝7.5Hz)，6.92(t，2H，J＝7.5Hz)，7.08(m，2H)，7.24(m，3H)。
MS(EI)m/z：265(M
+)，264，235，221，210，197，180，173。
Embodiment 2
1-[N-(4 '-trifluoromethyl) benzimidoyl] preparation of piperazine (compound 002)
A) preparation of N-(4-trifluoromethyl) benzamide
(15.4 restrain, and 0.099mol), ice bath cools off, and (12.1 grams 0.086mol) with 10% aqueous sodium hydroxide solution 60ml, are kept reaction solution all the time and are alkaline to drip Benzoyl chloride 10ml under stirring simultaneously to add 4-5-trifluoromethylaniline 12ml in the reaction flask.Finish, room temperature continues to stir 1 hour.The solid that filter collection is separated out use ethyl alcohol recrystallization, white crystals 19 restrain (yield 83%), mp203～204 ℃.
B) 1-[N-(4 '-trifluoromethyl) benzimidoyl] add a) gained N-(4-trifluoromethyl) benzamide 1.0 gram (3.8mmol) and benzene 2ml in the preparation feedback bottle of piperazine (compound 002), 50 ℃ were heated 30 minutes, add phosphorus pentachloride 0.85 gram (4.0mmol) then in batches, 90 ℃ of stirring reactions 2 hours, solid was molten entirely.Remove benzene and phosphorus oxychloride under reduced pressure, residuum is chilled to room temperature, once adds Piperazine anhydrous 0.86 gram (10mmol) and is dissolved in solution among the anhydrous dioxane 10ml.Stirring at room 1 hour, room temperature are placed and are spent the night.Filter, solid is washed with acetone, and filtrate and washing lotion merge back pressure reducing and steaming solvent, products therefrom crude product silica gel column chromatography separating purification, petrol ether/ethyl acetate/triethylamine (100: 50: 1) wash-out, silica gel thin-layer detects, and contains the product elute soln and merges back concentrating under reduced pressure, residue petroleum ether-ethyl acetate recrystallization, get compound 002, white crystals type solid, 0.63 gram, yield 50%.
1HNMR(CDCl
3)δ(ppm)：2.98(m，4H)，3.47(m，4H)，6.59(d，2H，J＝8.4Hz)，7.11(m，2H)，7.28(m，5H)。
MS(EI)m/z：333(M
+)332，314，304，277，265，248。
Embodiment 3
1-[N-(3 '-aminomethyl phenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 003)
A) preparation of N-(3-aminomethyl phenyl) benzamide
Add 3-monomethylaniline 5.0 gram (46.7mmol) and methylene dichloride 12ml in the reaction flask, the ice bath cooling, stir and drip Benzoyl chloride 5.4ml (6.6 grams down simultaneously, 46.7mmol) be dissolved in solution and the 10% aqueous sodium hydroxide solution 30ml of methylene dichloride 20ml, all the time keep reaction solution alkalescence, finish, room temperature continued stirring reaction 1 hour.The solid that the filter collection is separated out with saturated sodium bicarbonate aqueous solution and washing, drying, ethyl alcohol recrystallization, gets white crystals 8.02 grams, 122～124 ℃ of mp, yield 81.3%.
B) 1-[N-(3 '-aminomethyl phenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 003)
Add a) gained N-(3-aminomethyl phenyl) benzamide 2.0 gram (9.47mmol) and benzene 5ml in the reaction flask, 50 ℃ were heated 30 minutes, add phosphorus pentachloride 2.27 grams (10.9mmol) then in batches, 90 ℃ of stirring reactions 2 hours, remove benzene and phosphorus oxychloride under reduced pressure, residuum is chilled to room temperature, and the quick down solution that Piperazine anhydrous 2.45 grams (28.4mmol) are dissolved in methylene dichloride 20ml that adds is stirred in the 10ml that adds methylene chloride dissolving.Stirring at room 2 hours is filtered, and solid is washed with acetone, and filtrate and washing lotion merge back pressure reducing and steaming solvent.Add ether and saturated aqueous sodium carbonate in the residuum, jolting is left standstill, and tells ether layer.After saturated aqueous sodium carbonate and 10% aqueous sodium hydroxide washes, fully extract with 1NHCl, hcl as extraction agent liquid merges, respectively wash once with ether and methylene dichloride, transfer pH to alkalescence with 10% aqueous sodium hydroxide solution then, extracted with diethyl ether three times of gained alkaline mixt, ether extraction liquid Anhydrous potassium carbonate drying.Pressure reducing and steaming solvent behind the filtering siccative, residuum add methyl alcohol 10ml dissolving, stir down and drip saturated HCl absolute methanol solution to pH=3, and concentrating under reduced pressure adds proper amount of acetone, leaves standstill, and separates out solid.The solid that the filter collection is separated out gets compound 003 crude product.Crude product gets white crystals shape solid 1.45 grams, yield 43.5% with methyl alcohol-acetone recrystallization.
1HNMR(CD
3OD)δ(ppm)：2.14(s，3H)，3.40(br，2H)，3.67(br，4H)，4.26(br，2H)，6.82(d，1H，J＝7.2Hz)，6.89(s，1H)，6.95(d，1H，J＝7.2Hz)，7.04(dd，1H，J＝7.8Hz)7.39～7.44(m，2H)，7.48～7.52(m，3H)。
MS(EI)m/z：279(M
+)223，211，194，173。
Embodiment 4
1-[N-(3 '-fluorophenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 004)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with the 3-fluoroaniline is feedstock production, yield 29.4%.
1HNMR(DMSO-d
6)δ(ppm)：3.31(br，2H)，3.47(br)3.64(br)(4H)，4.41(br，2H)，6.83～6.96(m，3H)，7.18～7.28(m，1H)，7.42～7.58(m，5H)。
MS(FAB)m/z：384(M+1)，215，198。
Embodiment 5
1-[N-(4 '-chloro-phenyl-) benzimidoyl] preparation of piperazine maleate (compound 005)
1-[N-(4 '-chloro-phenyl-) benzimidoyl] preparation of piperazine free alkali is identical with embodiment 3 described methods, and difference is that replacing the 3-monomethylaniline with the 4-chloroaniline is raw material.
After reaction is finished the diethyl ether solution of gained free alkali with the Anhydrous potassium carbonate drying after the pressure reducing and steaming ether get the free alkali crude product, the crude product acetone solution, the acetone soln that adds the toxilic acid of equimolar amount, leave standstill, separate out maleate, filter collection back gets white crystals, yield 44.0% with methyl alcohol-acetone recrystallization.
1HNMR(DMSO-d
6)δ(ppm)：3.19(br，4H)，3.53(br，4H)，6.06(s，2H)，6.49(d，2H，J＝8.5Hz)，7.01(d，2H，J＝8.5Hz)，7.18～7.20(m，2H)，7.32～7.33(m，3H)。
MS(FAB)m/z：302，300(M+1)，233，231，108，111。
Embodiment 6
1-[N-(3 '-chloro-phenyl-) benzimidoyl] preparation of piperazine hydrochloride (compound 006)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with the 3-chloroaniline is feedstock production, yield 30.6%.
1HNMR(CD
3OD)δ(ppm)：3.39～3.43(t，2H)，3.69(t)3.75(t)(4H)，4.28(m，2H)，6.98～7.00(m，1H)，7.14～7.17(m，3H)，7.43～7.47(m，2H)，7.51～7.54(m，3H)。
MS(EI)m/z：301，299(M+1)，271，269，245，243，233，231，216，214，173。
Embodiment 7
1-[N-(4 '-bromophenyl) benzimidoyl] preparation of piperazine maleate (compound 007)
Press embodiment 5 described methods, difference is that replacing the 4-chloroaniline with the 4-bromaniline is feedstock production, yield 28.5%.
1HNMR(DMSO-d
6)δ(ppm)：3.30(br，4H)，3.50(br，4H)，6.02(s，2H)，6.42(d，2H)，7.11～7.18(d，4H)，7.30～7.34(m，3H)。
MS(EI)m/z：345，343(M+)，289，287，277，275，260，258，180，173，155，153。
Embodiment 8
1-[N-(betanaphthyl) benzimidoyl] preparation of piperazine hydrochloride (compound 008)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with beta-naphthylamine is feedstock production, yield 39.7%.
1HNMR(DMSO-d
6)δ(ppm)：3.30(br，2H)，3.60(br，4H)，4.49(br，2H)，7.21～7.30(m，5H)，7.54～7.74(m，5H)，7.86(d，1H)，8.37(d，1H)。
MS(EI)m/z：315(M
+)，285，259，247，230，173，143，127。
Embodiment 9
1-[N-(Alpha-Naphthyl) benzimidoyl] preparation of piperazine maleate (compound 009)
Press embodiment 5 described methods, difference is that replacing the 4-chloroaniline with alpha-naphthylamine is feedstock production, yield 44.1%.
1HNMR(DMSO-d
6)δ(ppm)：3.25(br，4H)，3.64(br，4H)，6.11(s，2H)，6.36(d，1H)，7.04～7.23(m，6H)，7.30(d，1H)，7.42～7.48(m，2H)，7.72～7.75(m，1H)，8.07～8.09(m，1H)。
MS(EI)m/z：315(M
+)，259，247，230，156，127，118。
Embodiment 10
1-[N-(3 '-nitrophenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 010)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with the 3-N-methyl-p-nitroaniline is feedstock production, yield 65.2%.
1HNMR(DMSO-d
6)δ(ppm)：3.27(br，2H)，3.63(br，4H)，4.39(br，2H)，7.42～7.57(m，7H)，7.84(m，1H)，7.92～7.93(m，1H)。
MS(FAB)m/z：311(M+1)，295，225。
Embodiment 11
1-[N-(4 '-nitrophenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 011)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with the 4-N-methyl-p-nitroaniline is feedstock production, yield 43.7%.
1HNMR(DMSO-d
6)δ(ppm)：3.16(br，4H)，3.63(br，4H)，6.63～6.69(m，2H)，7.22～7.25(m，2H)，7.32～7.35(m，3H)，7.85～7.91(m，2H)。
MS(EI)m/z：310(M
+)，280，254，242，225，179，173，149，122。
Embodiment 12
1-[N-(3 '-nitro-4 ' aminomethyl phenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 012)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with 3-nitro-4-methyl aniline is feedstock production, yield 70%.
1HNMR(DMSO-d
6)δ(ppm)：2.39(s，1H)，3.43(br，2H)，3.70(br)3.77(br)(4H)，4.31(br，2H)，7.26(d，2H，J＝1.8Hz)，7.43～7.48(m，2H)，7.52～7.56(m，3H)，7.69(m，1H)。
MS(EI)m/z：323(M-1)，280，268，256，239，173，133。
Embodiment 13
1-[N-(4 '-ethoxyl phenenyl) benzimidoyl] preparation of piperazine maleate (compound 013)
Press embodiment 5 described methods, difference is that replacing the 4-chloroaniline with the 4-phenetidine is feedstock production, yield 30.5%.
1HNMR(DMSO-d
6)δ(ppm)：1.23(t，3H，J＝7.0Hz)，3.28(br，4H)，3.64(br，4H)，3.85(q，2H，J＝7.0Hz)，6.11(s，2H)，6.65(m，4H)，7.32～7.39(m，5H)。
MS(FAB)m/z：310(M+1)，224。
Embodiment 14
1-[N-(2 '-chloro-phenyl-) benzimidoyl] preparation of piperazine maleate (compound 014)
Press embodiment 5 described methods, the 2-chloroaniline is a feedstock production, yield 21.7%.
1HNMR(DMSO-d
6)δ(ppm)：3.20(br，4H)，3.55(br，4H)，6.13(s，2H)，6.47～6.50(m，1H)，6.70～6.75(m，1H)，6.88～6.93(m，1H)，7.17～7.34(m，6H)。
MS(FAB)m/z：302，300(M+1)，231，214。
Embodiment 15
1-[N-(4 '-p-methoxy-phenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 015)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with the 4-anisidine is feedstock production, yield 17.8%.
1HNMR(DMSO-d
6)δ(ppm)：3.21(br，2H)，3.51(br，4H)，4.38(br，2H)，6.73(d，2H，J＝9.0Hz)，6.96(d，2H，J＝9.0Hz)，7.40～7.54(m，5H)。
MS(EI)m/z：295(M
+)，251，239，227，210，173，123。
Embodiment 16
1-[N-(4 '-fluorophenyl) benzimidoyl] preparation of piperazine hydrochloride (compound 016)
Press embodiment 3 described methods, difference is that replacing the 3-monomethylaniline with the 4-fluoroaniline is feedstock production, yield 29.2%.
1HNMR(DMSO-d
6)δ(ppm)：3.41(br，2H)，3.71(br，4H)，4.29(br，2H)，6.90～6.96(m，2H)，7.08～7.13(m，2H)，7.40～7.45(m，2H)，7.49～7.53(m，3H)。
MS(EI)m/z：283(M
+)，239，227，198，173，133，111。
Embodiment 17
1-[N-(2 '-bromophenyl) benzimidoyl] preparation of piperazine maleate (compound 017)
Pressing embodiment 5 described methods, is feedstock production with the 2-bromaniline, yield 48.7%.
1HNMR(DMSO-d
6)δ(ppm)：3.18(br，4H)，3.58(br，4H)，6.16(s，2H)，6.46(m，1H)，6.65～6.68(m，1H)，6.91～6.96(m，1H)，7.20～7.21(m，2H)，7.30～7.33(m，3H)，7.37～7.38(m，1H)。
MS(FAB)m/z：346，344(M+1)，258。
Embodiment 18
The preparation of 1-(N-phenyl benzimidoyl)-3-methylpiperazine (compound 018)
Add N-phenylbenzamaide 1.0 gram (5.1mmol) and benzene 2ml in the reaction flask, 50 ℃ of heating 30 minutes add phosphorus pentachloride 1.1 then in batches and restrain (5.3mmol), and 100 ℃ of stirring reactions 2 hours, solid was molten entirely.Benzene and phosphorus oxychloride are divided exactly in decompression, and residuum is chilled to room temperature, add anhydrous diethyl ether and make it dissolving, stir to add Alpha-Methyl piperazine 1.1 grams (11mmol) next time and be dissolved in solution among the anhydrous diethyl ether 20ml, and stirring at room 2 hours, placement is spent the night.The filtering solid is also washed with sherwood oil, and filtrate and washing lotion merge the back concentrating under reduced pressure, crude product.The crude product silica gel column chromatography separating purification, petrol ether/ethyl acetate/triethylamine (100: 50: 1) wash-out gets 1-(N-phenyl benzimidoyl)-3-methylpiperazine, with ether-sherwood oil recrystallization, gets 0.41 gram (yield 29%).
1HNMR(CD
3COCD
3)δ(ppm)：0.96(d，3H，J＝6.0Hz)，2.43(dd，1H，J＝10.5，12.9Hz)，2.85(m，5H)，3.76(br，1H)，6.45(m，2H)，6.62(m，1H)，6.89(m，2H)，7.12(m，2H)，7.22(m，3H)。
MS(EI)m/z：279(M
+)，278，235，209，197，180。
Embodiment 19
1-[N-(4 '-fluorophenyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 019)
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(4-fluorophenyl) benzamide is feedstock production, yield 30%.
1HNMR(CDCl
3)δ(ppm)：1.25(br，3H)，2.61(q，1H)，3.01(m，6H)，6.59(m，2H)，7.09(m，2H)，7.29(m，5H)。
MS(EI)m/z：279(M
+)，296，253，227，215，198，133，118。
Embodiment 20
1-[N-(4 '-trifluoromethyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 020)
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(4-trifluoromethyl) benzamide is feedstock production, yield 30%.
1H-NMR(CDCl
3)δ(ppm)：1.06(br，3H)，2.54(m，1H)，2.90(m，5H)，3.54(m，1H)，6.60(m，2H)，7.09(m，2H)，7.23(m，5H)。
MS(EI)m/z：347(M
+)，346，303，277，265，248，188，187，145。
Embodiment 21
1-[N-(4 '-chloro-phenyl-) benzimidoyl]-preparation of 3-methylpiperazine (compound 021)
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(4-chloro-phenyl-) benzamide is feedstock production, yield 41%.
1HNMR(CDCl
3)δ(ppm)：1.08(br，3H)，2.55(m，1H)，2.95(m，5H)，3.70(m，1H)，6.50(m，2H)，6.95(m，2H)，7.10(m，2H)，7.28(m，3H)。
MS(EI)m/z：315，313(M
+)，271，269，256，245，243，233，231，216，187，130，111。
Embodiment 22
1-[N-(4 '-bromophenyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 022)
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(4-bromophenyl) benzamide is feedstock production, yield 73%.
1HNMR(CDCl
3)δ(ppm)：1.13(br，3H)，2.63(m，1H)，2.97(m，5H)，3.80(m，1H)，6.44(m，2H)，7.11(m，4H)，7.28(m，3H)。
MS(EI)m/z：359，357(M
+)，315，313，302，300，289，287，277，275，260，258，187，157，155，133，130，118。
Embodiment 23
1-[N-(3 '-fluorophenyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 023)
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(3-fluorophenyl) benzamide is feedstock production, yield 33%.
1HNMR(CDCl
3)δ(ppm)：1.07(br，3H)，1.94(br，1H，NH)2.55(m，1H)，2.90(m，5H)，3.80(m，1H)，6.24～6.43(m，4H)，6.89(m，2H)，7.11～7.26(m，3H)。
MS(EI)m/z：297(M
+)，215，198，104。
Embodiment 24
1-[N-(Alpha-Naphthyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 024) and hydrochloride (compound 024a) maleate (compound 024b) thereof
A) preparation of compound 024
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(Alpha-Naphthyl) benzamide is feedstock production, yield 60%.
1HNMR(CDCl
3)δ(ppm)：1.14(d，3H，J＝5.7Hz)，2.72(dd，1H，J＝10.2，12.6Hz)，3.06(m，5H)，4.01(m，1H)，6.29(m，1H)，7.02～7.17(m，6H)，7.29(m，1H)，7.38～7.48(m，2H)，7.70(m，1H)，8.17(m，1H)。
MS(EI)m/z：329(M
+)，328，327，285，272，259，247，230，187，155，143，127，118。
B) preparation of compound 024a
Add N-(Alpha-Naphthyl) benzamide 1.24 gram (5.0mmol) and benzene 3ml in the reaction flask, 50 ℃ of heating 30 minutes add phosphorus pentachloride 1.15 then in batches and restrain (5.5mmol), and 90 ℃ of stirring reactions 2 hours, solid was molten entirely.Benzene and phosphorus oxychloride are divided exactly in decompression, and residuum dissolves with exsiccant methylene dichloride 15ml after being chilled to room temperature, and the dichloromethane solution of agitation and dropping 2-methylpiperazine 1.5 grams (15mmol) under the ice bath cooling added the back room temperature reaction 5 hours.Remove methylene dichloride under reduced pressure, residuum adds diethyl ether and the saturated aqueous sodium carbonate dissolving, standing demix, and water layer discarded, diethyl ether solution is respectively given a baby a bath on the third day after its birth inferior with saturated aqueous sodium carbonate and saturated sodium-chloride water solution, the Anhydrous potassium carbonate drying.Concentrating under reduced pressure behind the filtering siccative, residue separates with silica gel column chromatography, use sherwood oil/triethylamine (100: 1) successively, petroleum ether/ethyl ether/triethylamine (100: 50: 1) and ether/triethylamine (100: 1) wash-out, silica gel thin-layer detects, the part that contains product (compound 024) merge after concentrating white solid 0.65 gram.
Gained white solid (0.65 gram) drips HCl-methyl alcohol saturated solution to pH=3 with methyl alcohol (drying) 5ml dissolving under the stirring, concentrating under reduced pressure adds acetone 4ml, and refrigerator is placed, and separates out white solid, filters, and washes with acetone, gets the 024a crude product.Crude product gets white solid 0.72 gram, yield 35.8% with methyl alcohol-acetone recrystallization.
MS(FAB)m/z：330(M+1)，230。
C) preparation of compound 024b
B as stated above) prepared compound 024 (free alkali) solid 0.65 gram (2.0mmol) with acetone 5ml dissolving, adds toxilic acid 0.23 gram (2.0mmol), is stirred to whole dissolvings, and refrigerator is placed, and separates out solid.Filter, acetone is washed, and drying gets compound 024 maleate (024b) 0.86 gram, white solid, yield 38.6% (in raw material N-(Alpha-Naphthyl) benzamide).
MS(ESI)m/z：330(M+1)，230。
Embodiment 25
1-[N-(4 '-phenelyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 025)
Press embodiment 18 described methods, difference is that replacing the N-phenylbenzamaide with N-(4-ethoxyl phenenyl) benzamide is feedstock production, yield 26%.
1HNMR(CDCl
3)δ(ppm)：1.09(d，3H，J＝6.0Hz)，1.33(t，3H，J＝6.9Hz)，2.55(m，1H)，2.95(m，5H)，3.88(m，3H)，6.46～6.59(m，4H)，7.12(m，2H)，7.24～7.30(m，3H)。
MS(EI)m/z：324(M+1)，323(M
+)，322，294，279，253，241，224，196，187，167，148，135，118。
Embodiment 26
1-[N-(3 '-aminomethyl phenyl) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 026)
N-(3-aminomethyl phenyl) benzamide 1.2 gram (5.68mmol) and benzene 5ml are added in the reaction flask, made moltenly entirely 50 ℃ of heated and stirred in 30 minutes, be chilled to room temperature, add phosphorus pentachloride 1.36 and restrain (6.53mmol), 90 ℃ of reflux 2 hours.Benzene and phosphorus oxychloride are removed in underpressure distillation.Residuum is chilled to room temperature, adds methylene dichloride 10ml dissolving, stirs to add the solution that anhydrous 2-methylpiperazine 1.71 grams (17.04mmol) are dissolved in methylene dichloride 20ml, stirring at room reaction 2 hours down fast.The filtering solid, solid is washed with acetone, and filtrate and washing lotion remove solvent under reduced pressure after merging, and residuum adds ether and saturated aqueous sodium carbonate, and jolting is left standstill, and tells ether layer, with saturated aqueous sodium carbonate and 10% aqueous sodium hydroxide solution thorough washing.The gained diethyl ether solution extracts with 1NHCl, aqueous acid is respectively washed twice with methylene dichloride and ether, be neutralized to alkalescence with 10% aqueous sodium hydroxide solution then, become muddy, with ether extraction 3 times, ether solution merges back Anhydrous potassium carbonate drying, filters back pressure reducing and steaming solvent, residuum methyl alcohol 10ml dissolving, stir and drip HCl-methyl alcohol saturated solution down to pH=3, concentrating under reduced pressure adds proper amount of acetone, leaves standstill, the solid that the filter collection is separated out, through methyl alcohol-acetone recrystallization, get compound 026 again, white crystals 0.63 gram (30.3%).
1HNMR(DMSO-d
6)δ(ppm)：1.17(br)1.43(br)(3H)，2.11(s，3H)，3.23～3.75(m，6H)，4.79(br)4.91(br)(1H)，6.79～7.04(m，4H)，7.45(br，5H)。
MS(EI)m/z：293(M
+)，249，236，223，211，194，187，133，118。
Embodiment 27
1-[N-(4 '-aminomethyl phenyl) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 027)
Press embodiment 26 described methods, difference is that replacing N-(3-aminomethyl phenyl) benzamide with N-(4-aminomethyl phenyl) benzamide is feedstock production, yield 37.4%.
1HNMR(DMSO-d
6)δ(ppm)：1.24(d，3H，J＝5.0Hz)，2.09(s，3H)，2.98～3.34(m，6H)，3.80(br，1H)，6.38(d，2H，J＝8.0Hz)，6.78(d，2H，J＝8.0Hz)，7.16(d，2H)，7.29～7.32(m，3H)。
MS(FAB)m/z：294(M+1)，211，194。
Embodiment 28
1-[N-(2 '-chloro-phenyl-) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 028)
Press embodiment 26 described methods, difference is that replacing N-(3-aminomethyl phenyl) benzamide with N-(2-chloro-phenyl-) benzamide is feedstock production, yield 67.0%.
1HNMR(CD
3OD)δ(ppm)：1.25(d)1.52(d，3H)，3.44～4.08(m，6H)，4.66(m，1H)，7.13～7.23(m，2H)，7.33～7.52(m，6H)，7.66(d，1H)。
MS(EI)m/z：314，312(M-1)，298，271，269，256，245，243，233，231，216，214，187。
Embodiment 29
1-[N-(3 '-chloro-phenyl-) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 029)
Press embodiment 26 described methods, be that with difference it is feedstock production that N-(3-chloro-phenyl-) benzamide replaces N-(3-aminomethyl phenyl) benzamide, yield 27.9%.
1HNMR(DMSO-d
6)δ(ppm)：1.28(br)1.39(br，3H)，3.15(br)3.57(br，6H)，4.93(br，1H)，6.94(d，1H)，7.12～7.23(m，3H)，7.45～7.52(m，5H)。
MS(FAB)m/z：316，314(M+1)，216，214，180。
Embodiment 30
1-[N-(3 '-nitrophenyl) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 030)
Press embodiment 26 described methods, difference is that replacing N-(3-aminomethyl phenyl) benzamide with N-(3-nitrophenyl) benzamide is feedstock production, yield 36.1%.
1HNMR(DMSO-d
6)δ(ppm)：1.17(br)1.28(d)(3H，J＝6.1Hz)，1.43(br，3H)，3.01～4.05(m，6H)，4.80(br)4.98(br，1H)，7.33～7.64(m，7H)，7.90～8.02(d，2H)。
MS(EI)m/z：324(M
+)，307，280，267，254，242，225，187。
Embodiment 31
1-[N-(4 '-p-methoxy-phenyl) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 031)
Press embodiment 26 described methods, difference is that replacing N-(3-aminomethyl phenyl) benzamide with N-(4-p-methoxy-phenyl) benzamide is feedstock production, yield 30.1%.
1HNMR(DMSO-d
6)δ(ppm)：1.16(br)1.43(br，3H)，3.14～3.86(m，6H)，3.62(s，3H)，4.76(br)，4.92(br，1H)，6.73(d，2H，J＝9.0Hz)，6.97(d，2H，J＝9.0Hz)，7.44～7.55(m，5H)。
MS(EI)m/z：309(M
+)，294，252，239，227，210，187。
Embodiment 32
1-[N-(2 '-bromophenyl) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 032)
Press embodiment 26 described methods, difference is that replacing N-(3-aminomethyl phenyl) benzamide with N-(2-bromophenyl) benzamide is feedstock production, yield 37.5%.
1HNMR(DMSO-d
6)δ(ppm)：1.16(br)1.44(br，3H)，3.25～4.98(m，7H)，7.06～7.11(m，1H)，7.14～7.26(m，1H)，7.34～7.59(m，7H)。
MS(EI)m/z：360，358(M+1)，344，342，315，313，289，287，277，275，260，258，209，187。
Embodiment 33
1-[N-(3 '-nitro-4 '-aminomethyl phenyl) benzimidoyl]-preparation of 3-methylpiperazine hydrochloride (compound 033)
Press embodiment 26 described methods, difference is that replacing N-(3-aminomethyl phenyl) benzamide with N-(3-nitro-4-methyl phenyl) benzamide is feedstock production, yield 75.4%.
1HNMR(CD
3OD)δ(ppm)：1.26(br)1.40(d，J＝6.6Hz)(3H)，1.51(d，3H，J＝4.8Hz)，2.38(s，3H)，3.40～3.79(m，6H)，4.00(br，1H)，7.24～7.31(m，2H)，7.42～7.73(m，5H)，7.74(d，1H)。
MS(EI)m/z：338(M+)，294，268，256，239，193。
Embodiment 34
1-[N-(betanaphthyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 034)
Press embodiment 26 described methods, it is 1-[N-(betanaphthyl) benzimidoyl that feedstock production obtains that difference is to replace N-(3-aminomethyl phenyl) benzamide with N-(betanaphthyl) benzamide]-3-methylpiperazine (free alkali).
1-[N-(betanaphthyl) benzimidoyl]-3-methylpiperazine (free alkali) crude product diethyl ether solution is with after the Anhydrous potassium carbonate drying, the pressure reducing and steaming ether, the residuum acetone solution, stir the acetone soln that adds the toxilic acid of equimolar amount down, leave standstill, the solid that the filter collection is separated out, with methyl alcohol-acetone recrystallization, get compound 034, white crystals, yield 38.4%.
1HNMR(DMSO-d
6)δ(ppm)：1.24(br，3H)，3.06～3.48(m，6H)，3.95(br，1H)，6.15(s，2H)，6.81(d，1H)，7.00(s，1H)，7.28～7.34(m，7H)，7.56(m，2H)，7.68(m，1H)。
MS(FAB)m/z：330(M+1)，230，127。
Embodiment 35
1-methyl-4-[(N-phenyl) benzimidoyl] preparation of piperazine (compound 035)
Benzamide 1.0 gram (5.0mmol) and benzene 2ml are added in the reaction flask, and it is molten entirely that 50 ℃ of heating made in 30 minutes, adds phosphorus pentachloride 1.1 then in batches and restrain (5.3mmol), 80 ℃ of stirring reactions 2 hours.Remove benzene and phosphorus oxychloride under reduced pressure, residuum is chilled to room temperature, adds a small amount of benzene and makes dissolving, and dropping N methyl piperazine 1.2 grams (12mmol) are dissolved in the solution among the benzene 2ml under stirring then, and stirring at room 30 minutes is warmed up to 80 ℃ of reactions 1 hour again.Cooling removes solvent under reduced pressure, and residuum adds sherwood oil 15ml, removes by filter insolubles, and filtrate concentrates, and gets crude product.Crude product sherwood oil recrystallization gets compound 035, white crystals 0.8 gram (yield 53%).
1HNMR(CDCl
3)δ(ppm)：2.48(s，3H)，2.67(br，4H)，3.64(br，4H)，6.60(d，2H，J＝7.8Hz)，6.79(t，1H，J＝7.8Hz)，7.01(t，2H，J＝7.8Hz)，7.12(m，2H)，7.35(m，3H)。
MS(EI)m/z：279(M
+)，222，209，197，187。
Embodiment 36
1-methyl-4-[N-(4 '-fluorophenyl) benzimidoyl] preparation of piperazine (compound 036)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-fluorophenyl) benzamide is feedstock production, yield 51%.
1HNMR(CDCl
3)δ(ppm)：2.34(s，3H)，2.46(br，4H)，3.44(br，4H)，6.46(m，2H)，6.67(m，2H)，7.07(m，2H)，7.23(m，3H)。
MS(EI)m/z：297(M
+)，240，227，215，198，187。
Embodiment 37
1-methyl-4-[N-(4 '-trifluoromethyl) benzimidoyl] preparation of piperazine (compound 037)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-trifluoromethyl) benzamide is feedstock production, yield 61.5%.
1HNMR(CDCl
3)δ(ppm)：2.44(s，3H)，2.59(br，4H)，3.57(br，4H)，6.59(d，2H，J＝8.4Hz)，7.08(m，2H)，7.25(m，5H)。
MS(EI)m/z：347(M
+)，328，290，277，265，248，187。
Embodiment 38
1-methyl-4-[N-(4 '-bromophenyl) benzimidoyl] preparation of piperazine (compound 038)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-bromophenyl) benzamide is feedstock production, yield 90%.
1HNMR(CDCl
3)δ(ppm)：2.40(s，3H)，，2.54(br，4H)，3.49(br，4H)，6.40～6.43(m，2H)，7.09(m，4H)，7.25(m，3H)。
MS(EI)m/z：359，357(M
+)，302，300，289，287，277，275，260，258，207，187。
Embodiment 39
1-methyl-4-[N-(4 '-cyano-phenyl) benzimidoyl] preparation of piperazine (compound 039)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-cyano-phenyl) benzamide is feedstock production, yield 61.0%.
1HNMR(CDCl
3)δ(ppm)：2.42(s，3H)，2.57(br，4H)，3.58(br，4H)，6.56(m，2H)，7.08(m，2H)，7.26(m，5H)。
MS(EI)m/z：305(M+1)，304(M+)，247，234，222，205，187。
Embodiment 40
1-methyl-4-[N-(4 '-chloro-phenyl-) benzimidoyl] preparation of piperazine (compound 040)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-chloro-phenyl-) benzamide is feedstock production, yield 79%.
1HNMR(CDCl
3)δ(ppm)：2.40(s，3H)，2.54(br，4H)，3.50(br，4H)，6.48(m，2H)，6.95(m，2H)，7.10(m，2H)，7.24(m，3H)。
MS(EI)m/z：315，313(M
+)，258，256，245，243，233，231，216，214，187。
Embodiment 41
1-methyl-4-[N-(4 '-p-methoxy-phenyl) benzimidoyl] preparation of piperazine (compound 041)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-p-methoxy-phenyl) benzamide is feedstock production, yield 61%.
1HNMR(CDCl
3)δ(ppm)：2.40(s，3H)，2.56(br，4H)，3.56(br，4H)，3.66(s，3H)，6.55(m，4H)，7.12(m，2H)，7.25(m，3H)。
MS(EI)m/z：309(M
+)，252，239，226，210，187。
Embodiment 42
1-methyl-4-[N-(4 '-ethoxyl phenenyl) benzimidoyl] preparation of piperazine (compound 042)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-ethoxyl phenenyl) benzamide is feedstock production, yield 50%.
1HNMR(CDCl
3)δ(ppm)：1.31(t，3H，J＝6.9Hz)，2.40(s，3H)，2.63(br，4H)，3.58(br，4H)，3.86(q，2H，J＝6.9Hz)，6.53(m，4H)，7.12(m，2H)，7.25(m，3H)。
MS(EI)m/z：323(M
+)，266，253，240，224，196，187。
Embodiment 43
1-methyl-4-[N-(3 '-fluorophenyl) benzimidoyl] preparation of piperazine (compound 043)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(3-fluorophenyl) benzamide is feedstock production, yield 85%.
1HNMR(CDCl
3)δ(ppm)：2.40(s，3H)，2.51(br，4H)，3.50(br，4H)，6.30(m，2H)，6.45(m，1H)，6.91(m，1H)，7.11(m，2H)，7.25(m，3H)。
MS(EI)m/z：297(M
+)，240，227，215，198，187。
Embodiment 44
1-methyl-4-[N-(4 '-tert-butyl-phenyl) benzimidoyl] preparation of piperazine (compound 044)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(4-tert-butyl-phenyl) benzamide is feedstock production, yield 75%.
1HNMR(CDCl
3)δ(ppm)：1.18(s，9H)，2.43(s，3H)，2.63(br，4H)，3.57(br，4H)，6.55(m，2H)，7.15(m，2H)，7.19(m，2H)，7.25(m，3H)。
MS(EI)m/z：335(M
+)，334，278，265，253，252，251，236，209，187。
Embodiment 45
1-methyl-4-[N-(2 '-chloro-phenyl-) benzimidoyl] preparation of piperazine (compound 045)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(2-chloro-phenyl-) benzamide is feedstock production, yield 64%.
1HNMR(CDCl
3)δ(ppm)：2.46(s，3H)，2.56(br，4H)，3.57(br，4H)，6.47(m，1H)，6.71(m，1H)，6.88(m，2H)，7.16(m，2H)，7.23(m，3H)。
MS(EI)m/z：316，314(M+1)，315，313(M
+)，258，256，245，243，233，231，216，214，187。
Embodiment 46
1-methyl-4-[N-(2 '-bromophenyl) benzimidoyl] preparation of piperazine (compound 046)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(2-bromophenyl) benzamide is feedstock production, yield 44%.
1HNMR(CDCl
3)δ(ppm)：2.42(s，3H)，2.63(br，4H)，3.55(br，4H)，6.42(m，1H)，6.65(m，1H)，6.90(m，2H)，7.18(m，2H)，7.23(m，2H)，7.40(m，1H)。
MS(EI)m/z：360，358(M+1)，359，357(M
+)，302，300，289，287，277，275，260，258，243，231，221，214，207，187。
Embodiment 47
1-methyl-4-[N-(3 '-aminomethyl phenyl) benzimidoyl] preparation of piperazine (compound 047)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(3-aminomethyl phenyl) benzamide is feedstock production, yield 41%.
1HNMR(CDCl
3)δ(ppm)：2.15(s，3H)，2.43(s，3H)，2.62(br，4H)，3.54(br，4H)，6.34(m，1H)，6.48(m，1H)，6.60(m，1H)，6.89(m，1H)，7.12(m，2H)，7.24(m，3H)。
MS(EI)m/z：293(M
+)，236，223，211，194，187。
Embodiment 48
1-methyl-4-[N-(Alpha-Naphthyl) benzimidoyl] preparation of piperazine (compound 048)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(Alpha-Naphthyl) benzamide is feedstock production, yield 91%.
1HNMR(CDCl
3)δ(ppm)：2.45(s，3H)，2.61(br，4H)，3.64(br，4H)，6.33(m，1H)，7.10(m，7H)，7.42(m，2H)，7.76(m，1H)，8.19(m，1H)。
MS(EI)m/z：329(M
+)，272，259，246，230，187。
Embodiment 49
1-methyl-4-[N-(3 '-chloro-phenyl-) benzimidoyl] preparation of piperazine (compound 049)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(3-chloro-phenyl-) benzamide is feedstock production, yield 79%.
1HNMR(CDCl
3)δ(ppm)：2.42(s，3H)，2.56(br，4H)，3.57(br，4H)，6.40(m，1H)，6.59(m，1H)，6.73(m，1H)，6.90(m，1H)，7.10(m，2H)，7.25(m，3H).
MS(EI)m/z：316，314(M+1)，315，313(M
+)，258，256，245，243，233，231，216，214，187。
Embodiment 50
1-methyl-4-[N-(3 '-cyano-phenyl) benzimidoyl] preparation of piperazine (compound 050)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(3-cyano-phenyl) benzamide is feedstock production, yield 88%.
1HNMR(CDCl
3)δ(ppm)：2.39(s，3H)，2.51(br，4H)，3.60(br，4H)，6.78(m，2H)，7.08(m，5H)，7.25(m，2H)。
MS(EI)m/z：304(M
+)，247，234，222，205，187。
Embodiment 51
1-methyl-4-[N-(2 '-p-methoxy-phenyl) benzimidoyl] preparation of piperazine (compound 051)
Press embodiment 35 described methods, difference is that replacing benzamide with N-(2-p-methoxy-phenyl) benzamide is feedstock production, yield 52%.
1HNMR(CDCl
3)δ(ppm)：2.34(s，3H)，2.47(br，4H)，3.48(br，4H)，3.66(s，3H)，6.51(m，1H)，6.61(m，2H)，6.75(m，1H)，7.15(m，4H)，7.25(m，2H)。
MS(EI)m/z：309(M
+)，252，239，226，210，195，187。
Embodiment 52
1-[N-(Alpha-Naphthyl)-(4 '-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 052)
A) preparation of N-(Alpha-Naphthyl)-(4 '-methoxyl group) benzamide
Add naphthalidine 1.8 grams (10mmol), triethylamine 1.11 gram (11mmol) and methylene dichloride 20ml in the reaction solution.Drip the dichloromethane solution of 4-methoxy benzoyl chloride in the ice bath cooling downhill reaction bottle.Drip and finish, remove ice bath.Stirring at room 3 hours, the adularescent precipitation generates.Filter, filter cake is used 6N HCl and water washing respectively.The solid crude product oven dry back ethyl alcohol recrystallization that obtains gets white crystal 2.10 grams.Productive rate: 75.07%.
B) 1-[N-(Alpha-Naphthyl)-(4 '-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine toxilic acid (compound 052)
Add a) N-(Alpha-Naphthyl) of preparation-(4 '-methoxyl group) benzamide 1.38 gram (5mmol) and benzene 3ml in reaction flask, 50 ℃ of stirrings of outer temperature add phosphorus pentachloride totally 1.15 grams (5.5mmol) in three batches after half hour.Reflux after being warming up to 90 ℃ and stirred 2 hours, solid all dissolves in the reaction flask.Cooling, benzene and phosphorus oxychloride are removed in decompression, and residuum dissolves with methylene dichloride (drying) 10ml after being chilled to room temperature, this solution is splashed in the methylene dichloride 15ml solution of ice bath refrigerative 2-methylpiperazine 1.50 (15mmol).Drip and finish, stirring at room reduces pressure after 8 hours and removes methylene dichloride.Residuum dissolves with ether and saturated aqueous sodium carbonate, and standing demix discards water layer, and ether layer is respectively given a baby a bath on the third day after its birth inferior respectively with saturated aqueous sodium carbonate and saturated sodium-chloride water solution, the Anhydrous potassium carbonate drying.Concentrating under reduced pressure behind the filtering siccative, resistates separates with silica gel column chromatography, use sherwood oil/triethylamine (100: 1) successively, petroleum ether/ethyl ether/triethylamine (100: 50: 1) and ether/triethylamine (100: 1) wash-out, silica gel thin-layer detects, the part that contains product merge after concentrating yellow resin solid 1.30 grams.The gained solid adds toxilic acid 0.42 gram with acetone (drying) 5ml dissolving back, is stirred to solid and all dissolves, and refrigerator is placed.Separate out white solid, filter solids washed with acetone.Get 052 crude product, 1.28 grams.Crude product gets white solid 0.86 gram, productive rate 36.2% with acetone-recrystallizing methanol.
MS(ESI)m/z：360(M+1)，260。
Embodiment 53
1-[N-(Alpha-Naphthyl)-(4 '-fluorine) benzimidoyl]-preparation of 3-methylpiperazine (compound 053)
A) preparation of N-(Alpha-Naphthyl)-(4 '-fluorine) benzamide
Press embodiment 52a) described method, difference is that replacing the 4-methoxy benzoyl chloride with the 4-fluorobenzoyl chloride is feedstock production.Productive rate: 78.6%.
B) 1-[N-(Alpha-Naphthyl)-(4 '-fluorine) benzimidoyl]-preparation of 3-methylpiperazine (compound 053)
Add a) N-(Alpha-Naphthyl) of preparation-(4 '-fluorine) benzamide 1.33 gram (5mmol) and benzene 3ml in reaction flask, 50 ℃ of stirrings of outer temperature add phosphorus pentachloride totally 1.15 grams (5.5mmol) in three batches after half hour.Reflux after being warming up to 90 ℃ and stirred 2 hours, solid all dissolves in the reaction flask.Cooling, benzene and phosphorus oxychloride are removed in decompression, and residuum dissolves with methylene dichloride (drying) 10ml after being chilled to room temperature, this solution is splashed in the methylene dichloride 15ml solution of ice bath refrigerative 2-methylpiperazine 1.50 (15mmol).Drip and finish, stirring at room reduces pressure after 6 hours and removes methylene dichloride.Residuum dissolves with ether and saturated aqueous sodium carbonate, and standing demix discards water layer, and ether layer is respectively given a baby a bath on the third day after its birth inferior respectively with saturated aqueous sodium carbonate and saturated sodium-chloride water solution, the Anhydrous potassium carbonate drying.The filtering siccative, the filtrate refrigerator is placed, and separates out white solid.Filter, solid washs with ether.Get white solid 0.48 gram, productive rate: 27.6%.
MS(FAB)m/z：348(M+1)，248。
Embodiment 54
1-[N-(Alpha-Naphthyl)-(3 '-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 054)
A) preparation of N-(Alpha-Naphthyl)-(3 '-nitro) benzamide
Press embodiment 52a) described method, difference is that replacing the 4-methoxy benzoyl chloride with the 3-nitrobenzoyl chloride is feedstock production.Productive rate: 71.4%.
B) 1-[N-(Alpha-Naphthyl)-(3 '-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 054)
Press embodiment 52b) described method, difference is that replacing N-(Alpha-Naphthyl)-(4 '-methoxyl group) benzamide with N-(Alpha-Naphthyl)-(3 '-nitro) benzamide is feedstock production.Productive rate: 34.6%.
MS(FAB)m/z：375(M+1)，359，275。
Embodiment 55
1-[N-(Alpha-Naphthyl)-(4 '-chlorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 055)
A) preparation of N-(Alpha-Naphthyl)-(4 '-chlorine) benzamide
Press embodiment 52a) described method, difference is that replacing the 4-methoxy benzoyl chloride with the 4-chloro-benzoyl chloride is feedstock production.Productive rate: 74.2%.
B) 1-[N-(Alpha-Naphthyl)-(4 '-chlorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 055)
Press embodiment 52b) described method is a feedstock production with N-(Alpha-Naphthyl)-(4 '-chlorine) benzamide.Productive rate: 20.5%.
MS(FAB)m/z：364，364(M+1)，264，266。
Embodiment 56
1-[N-(Alpha-Naphthyl)-(3 ', 5 '-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 056)
A) preparation of N-(Alpha-Naphthyl)-(3 ', 5 '-dimethyl) benzamide
Press embodiment 52a) described method, difference is that with 3 it is feedstock production that the 5-dimethyl benzoyl chloride replaces the 4-methoxy benzoyl chloride.Productive rate: 58.2%.
B) 1-[N-(Alpha-Naphthyl)-(3 ', 5 '-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 055)
Press embodiment 53b) described method, be feedstock production with N-(Alpha-Naphthyl)-(3 ', 5 '-dimethyl) benzamide, productive rate: 46.4%.
MS(ESI)m/z：358.5(M+1)，258.4。
Embodiment 57
1-[N-(Alpha-Naphthyl)-(4 '-ethyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 057)
A) preparation of N-(Alpha-Naphthyl)-(4 '-ethyl) benzamide
Press embodiment 52a) described method, difference is that be feedstock production with 4-ethylbenzoyl chloro for the 4-methoxy benzoyl chloride.Productive rate: 53.3%.
B) 1-[N-(Alpha-Naphthyl)-(4 '-ethyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 057)
Press embodiment 52b) described method is a feedstock production with N-(Alpha-Naphthyl)-(4 '-ethyl) benzamide.Productive rate: 41.4%
MS(ESI)m/z：358.5(M+1)，258.4。
Embodiment 58
1-[N-(Alpha-Naphthyl)-(4 '-tertiary butyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 058)
A) preparation of N-(Alpha-Naphthyl)-(4 '-tertiary butyl) benzamide
Press embodiment 52a) described method, difference is that replacing the 4-methoxy benzoyl chloride with 4-tert.-butylbenzene formyl chloride is feedstock production.Productive rate: 49.21%
B) 1-[N-(Alpha-Naphthyl)-(4 '-tertiary butyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 058)
Press embodiment 52b) described method, be feedstock production with N-(Alpha-Naphthyl)-(4 '-tertiary butyl) benzamide, productive rate: 22.7%.
MS(ESI)m/z：386.3(M+1)，286.2。
Embodiment 59
1-[N-(Alpha-Naphthyl)-(4 '-cyano group) benzimidoyl]-preparation of 3-methylpiperazine (compound 059)
A) preparation of N-(Alpha-Naphthyl)-(4 '-cyano group) benzamide
Press embodiment 52a) described method, difference is that replacing the 4-methoxy benzoyl chloride with the 4-cyano-benzoyl chloride is feedstock production.Productive rate: 70.8%.
B) 1-[N-(Alpha-Naphthyl)-(4 '-cyano group) benzimidoyl]-preparation of 3-methylpiperazine (compound 059)
Press embodiment 53b) described method is a feedstock production with N-(Alpha-Naphthyl)-(4 '-cyano group) benzamide.Productive rate: 56.34%.
MS(ESI)m/z：355.5(M+1)，255.4。
Embodiment 60
1-[N-(betanaphthyl)-(4 '-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 060)
A) preparation of N-(betanaphthyl)-(4 '-nitro) benzamide
Press embodiment 52a) described method, difference is that with beta-naphthylamine and 4-nitrobenzoyl chloride be feedstock production.Productive rate: 88.0%.
B) 1-[N-(betanaphthyl)-(4 '-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 060)
Press embodiment 52b) described method is a feedstock production with N-(betanaphthyl)-(4 '-nitro) benzamide.Productive rate: 56.4%.
MS(FAB)m/z：375(M+1)，359，275。
Embodiment 61
1-[N-(betanaphthyl)-(4 '-fluorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 061)
A) preparation of N-(betanaphthyl)-(4 '-fluorine) benzamide
Press embodiment 52a) described method, difference is that with beta-naphthylamine and 4-fluorobenzoyl chloride be feedstock production.Productive rate: 68%.
B) 1-[N-(betanaphthyl)-(4 '-fluorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 061)
Press embodiment 52b) described method is a feedstock production with N-(betanaphthyl)-(4 '-fluorine) benzamide.Productive rate: 24.3%.
MS(FAB)m/z：348(M+1)，248。
Embodiment 62
1-[N-(betanaphthyl)-(4 '-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 062)
A) preparation of N-(betanaphthyl)-(4 '-methoxyl group) benzamide
Press embodiment 52a) described method, difference is that with beta-naphthylamine and 4-methoxy benzoyl chloride be feedstock production.Productive rate: 74.2%.
B) 1-[N-(betanaphthyl)-(4 '-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 062)
Press embodiment 52b) described method is a feedstock production with N-(betanaphthyl) (4 '-methoxyl group) benzamide.Productive rate: 39.5%.
MS(FAB)m/z：394(M+1)，294。
Embodiment 63
1-[N-(betanaphthyl)-(3 ', 5 '-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 063)
A) preparation of N-(betanaphthyl)-(3 ', 5 '-dimethyl) benzamide
Press embodiment 52a) described method, difference is that with beta-naphthylamine and 3 the 5-dimethyl benzoyl chloride is a feedstock production.Productive rate: 79.3%.
B) 1-[N-(betanaphthyl)-(3 ', 5 '-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine (compound 063)
Press embodiment 53b) described method is a feedstock production with N-(betanaphthyl)-(3 ', 5 '-dimethyl) benzamide.Productive rate: 24.7%.
MS(ESI)m/z：358.5(M+1)，258.4。
Embodiment 64
1-[N-(4 '-bromophenyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 064)
A) preparation of N-(4 '-bromophenyl)-(4 "-methoxyl group) benzamide
Press embodiment 52a) described method, difference is that with 4-bromaniline and 4-methoxy benzoyl chloride be feedstock production.Productive rate: 87.6%.
B) 1-[N-(4 '-bromophenyl) (4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 064)
Press embodiment 52b) described method is a feedstock production with N-(4 '-bromophenyl)-(4 "-methoxyl group) benzamide.Productive rate: 30.5%.
MS(FAB)m/z：388，390(M+1)，288，290，274。
Embodiment 65
1-[N-(4 '-bromophenyl)-(3 "-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 065)
A) preparation of N-(4 '-bromophenyl)-(3 "-nitro) benzamide
Press embodiment 52a) described method, difference is that with 4-bromaniline and 3-nitrobenzoyl chloride be feedstock production.Productive rate: 66.4%.
B) 1-[N-(4 '-bromophenyl)-(3 "-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 065)
Press embodiment 52b) described method is a feedstock production with N-(4 '-bromophenyl)-(3 "-nitro) benzamide.Productive rate: 44.6%.
MS(FAB)m/z：403，405(M+1)；303，305。
Embodiment 66
1-[N-(4 '-bromophenyl)-(4 "-chlorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 066)
A) preparation of N-(4 '-bromophenyl)-(4 "-chlorine) benzamide.
Press embodiment 52a) described method, be that with difference 4-bromaniline and 4-chloro-benzoyl chloride are feedstock production.Productive rate: 42.4%
B) 1-[N-(4 '-bromophenyl)-(4 "-chlorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 066)
Press embodiment 52b) described method is a feedstock production with N-(4 '-bromophenyl) (4 "-chlorine) benzamide.Productive rate: 53.0%.
MS(FAB)m/z：392，394，396(M+1)，348，350，292，294，296。
Embodiment 67
1-[N-(4 '-bromophenyl)-(4 "-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 067)
A) preparation of N-(4 '-bromophenyl)-(4 "-nitro) benzamide
Press embodiment 52a) described method, difference is that with 4-bromaniline and 4-nitrobenzoyl chloride be feedstock production.Productive rate: 89.5%.
B) 1-[N-(4 '-bromophenyl)-(4 "-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 067)
Press embodiment 52b) described method is a feedstock production with N-(4 '-bromophenyl)-(4 "-nitro) benzamide.Productive rate: 50.6%.
MS(FAB)m/z：403，405(M+1)，303，305。
Embodiment 68
1-[N-(4 '-tolyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine (compound 068)
A) preparation of N-(4 '-tolyl)-(4 "-methoxyl group) benzamide
Press embodiment 52a) described method, difference is that with 4-monomethylaniline and 4-methoxy benzoyl chloride be feedstock production.Productive rate: 72.1%
B) 1-[N-(4 '-tolyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine (compound 068)
Press embodiment 53b) described method is a feedstock production with N-(4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzamide.Productive rate: 19.6%.
MS(EI)m/z：323(M
+)，353，241，224。
Embodiment 69
1-[N-(4 '-nitrophenyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 069)
A) preparation of N-(4 '-nitrophenyl)-(4 "-methoxyl group) benzamide
Press embodiment 52a) described method, difference is that with 4-N-methyl-p-nitroaniline and 4-methoxy benzoyl chloride be feedstock production.Productive rate: 91.2%
B) 1-[N-(4 '-nitrophenyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 069)
Press embodiment 52b) described method is a feedstock production with N-(4 '-nitrophenyl)-(4 "-methoxyl group) benzamide.Productive rate: 76.6%.
MS(FAB)m/z：355(M+1)，339，255。
Embodiment 70
1-[N-(4 '-nitrophenyl)-(3 ", 5 "-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 070)
A) N-(4 '-nitrophenyl)-(3 ", 5 "-dimethyl) preparation of benzamide
Press embodiment 52a) described method, difference is that with 4-N-methyl-p-nitroaniline and 3 the 5-dimethyl benzoyl chloride is a feedstock production.Productive rate: 54.2%.
B) 1-[N-(4 '-nitrophenyl)-(3 ", 5 "-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 070)
Press embodiment 52b) described method, with N-(4 '-nitrophenyl)-(3 ", 5 "-dimethyl) benzamide is feedstock production.Productive rate: 88.6%.
MS(FAB)m/z：353(M+1)，337，253，207。
Embodiment 71
1-[N-(4 '-nitrophenyl)-(3 "-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 071)
A) preparation of N-(4 '-nitrophenyl)-(3 "-nitro) benzamide
Press embodiment 52a) described method, difference is that with 4-N-methyl-p-nitroaniline and 3-nitrobenzoyl chloride be feedstock production.Productive rate: 82.4%.
B) 1-[N-(4 '-nitrophenyl)-(3 "-nitro) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 071)
Press embodiment 52b) described method is a feedstock production with N-(4 '-nitrophenyl)-(3 "-nitro) benzamide.Productive rate: 49.4%.
MS(FAB)m/z：370(M+1)，354，270，224。
Embodiment 72
1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-chlorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 072)
A) preparation of N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-chlorine) benzamide
Press embodiment 52a) described method, difference is the nitro with 3-, 4-monomethylaniline and 4-chloro-benzoyl chloride are feedstock production.Productive rate: 86.2%.
B) 1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-chlorine) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 072)
Press embodiment 52b) described method, be feedstock production with N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-chlorine) benzamide, productive rate: 23.7%.
MS(ESI)m/z：373，375(M+1)，273，275。
Embodiment 73
1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 073)
A) preparation of N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzamide
Press embodiment 52a) described method, difference is that with 3-nitro-4-methyl aniline and 4-methoxy benzoyl chloride be feedstock production.Productive rate: 80.4%.
B) 1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 073)
Press embodiment 52b) described method is a feedstock production with N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzamide.Productive rate: 41.3%.
MS(ESI)m/z：369.6(M+1)，269.1。
Embodiment 74
1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(3 ", 5 "-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 074)
A) N-(3 '-nitro-4 '-aminomethyl phenyl)-(3 ", 5 "-dimethyl) preparation of benzamide
Press embodiment 52a) described method, difference is the nitro with 3-, 4-monomethylaniline and 3,5-dimethyl benzoyl chloride are feedstock production.Productive rate: 69.2%.
B) 1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(3 ", 5 "-dimethyl) benzimidoyl]-preparation of 3-methylpiperazine maleate (compound 074)
Press embodiment 52b) described method, with N-(3 '-nitro-4 '-aminomethyl phenyl)-(3 ", 5 "-dimethyl) benzamide is feedstock production.Productive rate: 20.0%.
MS(ESI)m/z：367.5(M+1，)，267.4。
Embodiment 75
1-[N-(Alpha-Naphthyl)-(2 '-furyl) auxotox radical]-preparation of 3-methylpiperazine fumarate (compound 075)
A) preparation of N-(Alpha-Naphthyl)-2-furoylamide
Press embodiment 52a) described method, be that with difference it is feedstock production that furans 2-formyl chloride replaces the 4-methoxy benzoyl chloride.Productive rate: 69.0%.
B) 1-[N-(Alpha-Naphthyl) (2 '-furyl) auxotox radical]-preparation of 3-methylpiperazine fumarate (compound 075)
Press embodiment 52b) described method, be raw material with N-(Alpha-Naphthyl)-2-furoylamide, add the preparation of fumaric acid salify at last.Productive rate: 22.9%.
MS(ESI)m/z：320.2(M+1)，220.3。
Quadrol
Embodiment 76
N, the preparation of N-dimethyl-N '-[(N-phenyl) benzimidoyl] ethylene diamine oxalate (compound 076)
Add N-phenylbenzamaide 1.0 gram (5.0mmol) and benzene 2ml in the reaction flask, 50 ℃ were heated 30 minutes, add phosphorus pentachloride 1.1 grams (5.3mmol) then in batches, 90 ℃ of stirring reactions 2 hours, solid dissolving, pressure reducing and steaming benzene and phosphorus oxychloride, residuum once adds N after being chilled to room temperature, N-dimethyl-ethylenediamine 0.89 gram (10mmol) is dissolved in the solution among the benzene 10ml, stirring at room reaction 2 hours, and placement is spent the night.Filter, solid is washed with acetone, and filtrate and washing lotion merge the back evaporated under reduced pressure, get oily matter.Silica gel column chromatography separating purification, petrol ether/ethyl acetate/triethylamine (100: 50: 1) wash-out, get N, N-dimethyl-N '-[(N-phenyl) benzimidoyl] quadrol (free alkali), free alkali acetone solution, add oxalic acid 2 then and restrain the solution that is dissolved among the acetone 10ml, place, separate out solid, filter, drying gets white crystalline solid 1.89 grams (yield 83%).
MS(EI)m/z：267(M
+)，253，223，209，197。
Embodiment 77
N, the preparation of N-dimethyl-N '-[N-(4 '-trifluoromethyl) benzimidoyl] quadrol (compound 077)
Pressing embodiment 76 described methods, is feedstock production with N-(4-trifluoromethyl) benzamide, and free alkali with ether-sherwood oil recrystallization (not with sour salify), gets white solid, yield 67% after separating with silica gel column chromatography.
1HNMR(CDCl
3)δ(ppm)：2.30(s，6H)，2.62(m，2H)，3.57(m，2H)，5.55(br，1H，NH)，6.70(d，2H，J＝8.4Hz)，7.24～7.31(m，7H)。
MS(EI)m/z：335(M
+)，304，275，265，248，228，208，187。
Embodiment 78
N, the preparation of N-dimethyl-N '-[N-(4 '-fluorophenyl) benzimidoyl] quadrol (compound 078)
Pressing embodiment 76 described methods, is feedstock production with N-(4-fluorophenyl) benzamide, and free alkali is salify not, after silica gel column chromatography separates, with ether-sherwood oil recrystallization, gets white solid, yield 64%.
1HNMR(CDCl
3)δ(ppm)：2.31(s，6H)，2.64(m，2H)，3.60(m，2H)6.58(m，2H)，6.76(m，2H)，7.26(m，5H)。
MS(EI)m/z：285(M
+)，268，254，215，198。
Embodiment 79
N, the preparation of N-dimethyl-N '-[N-(4 '-p-methoxy-phenyl) benzimidoyl] quadrol (compound 079)
Pressing embodiment 76 described methods, is feedstock production with N-(4-p-methoxy-phenyl) benzamide, and free alkali is salify not, after silica gel column chromatography separates, with ether-sherwood oil recrystallization, gets white solid, yield 60%.
1HNMR(CDCl
3)δ(ppm)：2.29(s，6H)，2.62(m，2H)，3.62(m，2H)，3.70(s，3H)，6.63(m，4H)，7.26(m，5H)。
MS(EI)m/z：297(M
+)，253，239，226，210。
Pharmacological evaluation
The evaluation of the 5-HT reuptake inhibitory activity of experimental example 1 The compounds of this invention
Classical rat synaptosome [3H]-serotonin reuptake transporter experimental technique is adopted in experiment.As the standard control medicine, method is measured the reuptake amount in accordance with regulations with chlorpromazine (Chlorpromazine) in experiment, calculates inhibiting rate and IC50 value.
Concrete experimental implementation is seen (H.Gerhard Vogel, Wolfgang H.Vogel, DrugDiscovery and Evaluation-Pharmacological Assays Springer-VerlagBerlin Heidelberg 1997; Chinese translation) and (Li Xuejun, Zhang Yongxiang etc. translate, Science Press, calendar year 2001 for " pharmacological experiment guide---new drug is found and pharmacological evaluation ", Du Guanhua).
Experimental result sees Table 2.
The 5-HT reuptake inhibitory activity of table 2 The compounds of this invention
| Compound number | IC50(mol/L) | Compound number | IC50(mol/L) |
| 001 002 003 004 005 006 007 008 009 010 011 012 013 014 015 | 7.73×10 -7 1.36×10 -9 8.30×10 -7 1.06×10 -6 2.04×10 -7 6.03×10 -7 1.65×10 -7 1.12×10 -7 8.93×10 -8 1.69×10 -7 8.56×10 -8 8.28×10 -8 1.42×10 -6 4.70×10 -7 4.57×10 -7 | 016 017 024 026 027 028 029 030 031 032 033 034 076 | 1.23×10 -6 6.47×10 -7 1.90×10 -10 3.48×10 -6 3.11×10 -6 1.99×10 -7 7.43×10 -8 1.38×10 -7 4.81×10 -7 5.01×10 -7 4.91×10 -8 7.07×10 -8 1.07×10 -10 |
Experimental result shows that all compound all shows the 5-HT reuptake inhibitory activity of varying strength.From Table II as seen, the 5-HT reuptake inhibitory activity that some compound exhibits are very strong is as compound 002,024 and 076.
The whole animal antidepressant activity of experimental example 2 The compounds of this invention is estimated
The laboratory animal evaluation model that adopts comprises:
1. mouse tail suspension and free movable experiment
2. mouse 5-hydroxyryptophan (5-HTP) enhancement experiment
Experiment is all with the positive contrast medicine of clinical treatment dysthymia disorders one line medicine fluoxetine (Fluxetine).Above-mentioned experimental model is the classical way that the antidepressant drug effect is estimated.
The method of testing is in accordance with regulations carried out, and (H.Gerhard Vogel, WolfgangH.Vogel, Drug Discovery and Evaluation-Pharmacological AssaysSpringer-Verlag Berlin Heidelberg 1997 are seen in concrete operations; Chinese translation) and (Li Xuejun, Zhang Yongxiang etc. translate, Science Press, calendar year 2001 for " pharmacological experiment guide---new drug is found and pharmacological evaluation ", Du Guanhua).
Experimental result shows, wherein two compounds (024 and 052) with positive control drug fluoxetine same dose under (5mg/kg irritates stomach), have quite or strong slightly activity, and on two kinds of animal models unanimity as a result.Point out them may become the medicine of new treatment dysthymia disorders.
Claims (16)
1, the diaryl amidine compound shown in general formula (I) or its pharmaceutical salts
Wherein:
Ar is selected from phenyl ring and the individual aromatic heterocycle of carbonatoms 5-14, and wherein heteroatoms is selected from one to three N, O and/or S;
R1 is selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano group, nitro,
The C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
1-18Alkoxyl group,
The C of replacement or non-replacement
1-18Alkylthio, substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, or R1 is
R7 wherein, R8 is selected from hydrogen or C
1-6Alkyl,
Or-COOR9, wherein R9 is selected from hydrogen or C
1-6Alkyl, replace or the C of non-replacement
3-8The fat cyclic group, substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro replace or the phenyl of non-replacement, substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro replace or the C of non-replacement
5-14Heterocyclic radical, wherein substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro, R1 are also represented and the ring mode replaces, and the ring mode can be 2,3 also can be at 3,4, can be and phenyl ring, also can be and five Yuans or six element heterocycles, also can be and 5～7 Yuans carbocyclic rings of fractional saturation, and ring can be substituted or non-replacement, substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, the C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
1-18The C of alkoxyl group, replacement or non-replacement
1-18Alkylthio, wherein substituting group is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro,
-COOR9, wherein R9 is selected from hydrogen or C
1-6Alkyl,
The fatty cyclic group of replacement or non-replacement, wherein substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro,
The phenyl of replacement or non-replacement, wherein substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro,
The heterocyclic radical of replacement or non-replacement, wherein substituting group is selected from C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halogen, hydroxyl, sulfydryl, cyano group, nitro,
R2 is selected from hydrogen, hydroxyl, sulfydryl, halogen, nitro, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, the amino of non-replacement, C
1-6The alkyl amino, sulfamic, the methylmesylate base that replace, but do not comprise carboxyl, thiocarboxyl group, carboxylicesters, carbothioic acid ester, acid amides and thioamides; The substituting group number that R2 represents can be one, also can two or more, can be identical or different when the substituting group number is two or more, can be connected on the different positions of aromatic ring;
R3 is selected from hydrogen, C
1-6Alkyl, the number of the substituting group number that R3 represents can be a substituting group, also can two or more, different positions that can be on piperazine ring;
R4 is selected from hydrogen or C
1-6Alkyl;
The aromatic nucleus of two replacements can be in the same side or the heteropleural of C=N.
According to the compound or pharmaceutically acceptable salt thereof of claim 1, it is characterized in that 2, Ar is selected from phenyl ring, pyridine ring, furan nucleus, pyrrole ring, thiphene ring.
According to the compound or pharmaceutically acceptable salt thereof of claim 1, it is characterized in that 3, the addition of acid of described pharmaceutical salts is selected from hydrochloric acid, sulfuric acid, toxilic acid, fumaric acid, methylsulfonic acid, oxalic acid.
4, according to the compound of claim 1 or itself and pharmaceutical salts thereof, it is characterized in that R1 is selected from hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group, 2,3 or the 4-pyridyl, the 2-pyrryl, the 2-furyl, the 2-thienyl.
5, according to the compound of claim 1 or itself and pharmaceutical salts thereof, it is characterized in that R2 is selected from hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group.
6, according to the compound of claim 1 or itself and pharmaceutical salts thereof, it is characterized in that, shown in general formula (Ia)
R1 is selected from hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R2 is selected from hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R3 is selected from hydrogen atom, methyl;
R4 is selected from hydrogen atom, methyl.
7, according to the compound or pharmaceutically acceptable salt thereof of claim 1, it is characterized in that, shown in general formula (Ib)
R1 is selected from hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R2 is selected from hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R3, hydrogen atom, methyl;
R4, hydrogen atom, methyl.
8, shown in general formula (II) compound or pharmaceutically acceptable salt thereof,
Wherein,
X represents C
2-4The carbochain that is with or without side chain;
Y represents hydrogen or C
1-6Alkyl;
R1, R2 such as claim 1 definition;
R5, R6 are selected from hydrogen or C
1-6Alkyl,
HA is selected from hydrochloric acid, sulfuric acid, toxilic acid, fumaric acid, methylsulfonic acid or oxalic acid.
9, compound or pharmaceutically acceptable salt thereof according to Claim 8 is characterized in that, X is-CH
2CH
2-.
10, according to the compound or pharmaceutically acceptable salt thereof of claim 9, it is characterized in that, shown in general formula (IIa)
R1 is hydrogen atom, trifluoromethyl, methyl, methoxyl group, oxyethyl group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group;
R2 is hydrogen atom, trifluoromethyl, methyl, ethyl, methoxyl group, methylthio group, oxyethyl group, ethylmercapto group, the tertiary butyl, fluorine, chlorine, bromine, nitro, cyano group.
According to the compound or pharmaceutically acceptable salt thereof of claim 1 or 8, it is characterized in that 11, compound is selected from
1-(N-phenyl benzimidoyl) piperazine
1-[N-(4 '-trifluoromethyl) benzimidoyl] piperazine
1-[N-(3 '-aminomethyl phenyl) benzimidoyl] piperazine
1-[N-(3 '-fluorophenyl) benzimidoyl] piperazine
1-[N-(4 '-chloro-phenyl-) benzimidoyl] piperazine
1-[N-(3 '-chloro-phenyl-) benzimidoyl] piperazine
1-[N-(4 '-bromophenyl) benzimidoyl] piperazine
1-[N-(betanaphthyl) benzimidoyl] piperazine
1-[N-(Alpha-Naphthyl) benzimidoyl] piperazine
1-[N-(3 '-nitrophenyl) benzimidoyl] piperazine
1-[N-(4 '-nitrophenyl) benzimidoyl] piperazine
1-[N-(3 '-nitro-4 ' aminomethyl phenyl) benzimidoyl] piperazine
1-[N-(4 '-ethoxyl phenenyl) benzimidoyl] piperazine
1-[N-(2 '-chloro-phenyl-) benzimidoyl] piperazine
1-[N-(4 '-p-methoxy-phenyl) benzimidoyl] piperazine
1-[N-(4 '-fluorophenyl) benzimidoyl] piperazine
1-[N-(2 '-bromophenyl) benzimidoyl] piperazine
1-(N-phenyl benzimidoyl)-3-methylpiperazine
1-[N-(4 '-fluorophenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-trifluoromethyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-chloro-phenyl-) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-bromophenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-fluorophenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-phenelyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-aminomethyl phenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-aminomethyl phenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(2 '-chloro-phenyl-) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-chloro-phenyl-) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-nitrophenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-p-methoxy-phenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(2 '-bromophenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-nitro-4 '-aminomethyl phenyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(betanaphthyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl) benzimidoyl]-the 3-methylpiperazine
1-methyl-4-[(N-phenyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-fluorophenyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-trifluoromethyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-bromophenyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-cyano-phenyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-chloro-phenyl-) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-p-methoxy-phenyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-ethoxyl phenenyl) benzimidoyl] piperazine
1-methyl-4-[N-(3 '-fluorophenyl) benzimidoyl] piperazine
1-methyl-4-[N-(4 '-tert-butyl-phenyl) benzimidoyl] piperazine
1-methyl-4-[N-(2 '-chloro-phenyl-) benzimidoyl] piperazine
1-methyl-4-[N-(2 '-bromophenyl) benzimidoyl] piperazine
1-methyl-4-[N-(3 '-aminomethyl phenyl) benzimidoyl] piperazine
1-methyl-4-[N-(Alpha-Naphthyl) benzimidoyl] piperazine
1-methyl 4-[N-(3 '-chloro-phenyl-) benzimidoyl] piperazine
1-methyl-4-[N-(3 '-cyano-phenyl) benzimidoyl] piperazine
1-methyl-4-[N-(2 '-p-methoxy-phenyl) benzimidoyl] piperazine
1-[N-(Alpha-Naphthyl)-(4 '-methoxyl group) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(4 '-fluorine) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(3 '-nitro) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(4 '-chlorine) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(3 ', 5 '-dimethyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(4 '-ethyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(4 '-tertiary butyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(4 '-cyano group) benzimidoyl]-the 3-methylpiperazine
1-[N-(betanaphthyl)-(4 '-nitro) benzimidoyl]-the 3-methylpiperazine
1-[N-(betanaphthyl)-(4 '-fluorine) benzimidoyl]-the 3-methylpiperazine
1-[N-(betanaphthyl)-(4 '-methoxyl group) benzimidoyl]-the 3-methylpiperazine
1-[N-(betanaphthyl)-(3 ', 5 '-dimethyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-bromophenyl)-(4 "-methoxyl group) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-bromophenyl)-(3 "-nitro) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-bromophenyl)-(4 "-chlorine) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-bromophenyl)-(4 "-nitro) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-nitrophenyl)-(4 "-methoxyl group) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-nitrophenyl)-(3 ", 5 "-dimethyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(4 '-nitrophenyl)-(3 "-nitro) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-chlorine) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(4 "-methoxyl group) benzimidoyl]-the 3-methylpiperazine
1-[N-(3 '-nitro-4 '-aminomethyl phenyl)-(3 ", 5 "-dimethyl) benzimidoyl]-the 3-methylpiperazine
1-[N-(Alpha-Naphthyl)-(2 '-furyl) imino-]-the 3-methylpiperazine
N, N-dimethyl-N '-[(N-phenyl) benzimidoyl] quadrol
N, N-dimethyl-N '-[N-(4 '-trifluoromethyl) benzimidoyl] quadrol
N, N-dimethyl-N '-[N-(4 '-fluorophenyl) benzimidoyl] quadrol
N, N-dimethyl-N '-[N-(4 '-p-methoxy-phenyl) benzimidoyl] quadrol.
12, prepare the method for claim 1 or 8 described compound or pharmaceutically acceptable salt thereofs, it is characterized in that, comprise the steps:
(a) with aniline, naphthylamines or aromatic heterocycle amine and the benzoyl halogen of corresponding replacement or the carboxylic acid halides condensation of fragrant heterocyclic carboxylic acid of corresponding replacement, obtain the corresponding amide compound;
(b) amide compound of going up the step gained is handled the back generation together with chloro diaryl group with imine moiety with phosphorus pentachloride,
(c) upward the step is not purified, and directly with selected diamines, piperazine or substituted-piperazinyl reaction make object substituted diaryl amidine compound,
The preparation of the salt of the medicinal acid of general formula (I) compound is with substituted diaryl amidine class free alkali and selected pharmaceutically useful mineral acid or small molecular organic acid, at the medium equivalent reaction of appropriate solvent, promptly obtain the salt of the pharmaceutically acceptable acid of substituted diaryl amidine compound according to a conventional method.
13, a kind of pharmaceutical composition is characterized in that, contain effective dose as the described arbitrary compound of claim 1-11, and acceptable carrier on the pharmacodynamics.
According to the pharmaceutical composition of claim 13, it is characterized in that 14, described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
15, as the application of the arbitrary compound of claim 1-11 in the medicine for preparing prevention or the treatment diseases of mental and nervous system relevant with serotonin.
According to the application of claim 15, it is characterized in that 16, the relevant diseases of mental and nervous system of described serotonin is a dysthymia disorders.
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| CN101602750B (en) * | 2008-06-10 | 2016-05-18 | 中国医学科学院药物研究所 | Naphthyl, (replacement) aryl, piperazinyl amidine compounds |
| CN110437106B (en) * | 2019-06-27 | 2021-09-07 | 广东药科大学 | Aryl amidine compound and synthetic method thereof |
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