CN1146991A - Arylalkyl-thiadiazinones - Google Patents

Arylalkyl-thiadiazinones Download PDF

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CN1146991A
CN1146991A CN 96100477 CN96100477A CN1146991A CN 1146991 A CN1146991 A CN 1146991A CN 96100477 CN96100477 CN 96100477 CN 96100477 A CN96100477 A CN 96100477A CN 1146991 A CN1146991 A CN 1146991A
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thiadiazine
dihydro
ketone
ethyl
reaction
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CN1064962C (en
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R·乔纳斯
M·沃尔夫
M·科劳寇
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Merck Patent GmbH
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Merck Patent GmbH
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Abstract

Arylalkyl-thiadiazinone derivs. of the formula 1, and physiologically unobjectionable salts thereof in which R1, R2, R3, R4, R5 and Q have the meanings given in claim 1, exhibit phosphodiesterase 4 inhibition and can be used for the therapy of asthmatic disorders.

Description

Aralkyl-thiadiazinones
The present invention relates to the salt that allows on the aralkyl-Thiadiazinone derivatives of formula I and the physiology thereof:
Figure A9610047700051
Wherein:
R 1And R 2Be H or A separately independently of one another,
R 3And R 4Be independently of one another separately-OH ,-OR 10,-S-R 10,-SO-R 10,-SO 2-R 10, Hal, methylene-dioxy ,-NO 2,-NH 2,-NHR 10Or-NR 10R 11,
R 5For unsubstituted or by R 6And/or R 7One or dibasic phenyl,
Q is for existing or for having the alkylidene group of 1-6 carbon atom,
R 6And R 7Be independently of one another separately-NH 2, NR 8R 9,-NHR 10,-NR 10R 11,-NO 2, Hal ,-CN ,-OA ,-COOH or-COOA,
R 8And R 9The acyl group that is H independently of one another separately, has 1-8 carbon atom and replaced by 1-5 following groups: fluorine and/or chlorine atom ,-COOA ,-S-A ,-SO-A ,-SO 2-A ,-CONH 2,-CONHA ,-CONA 2,-CO-COOH ,-CO-COOA ,-CO-CONH 2,-CO-CONHA or-CO-CONA 2,
A is the alkyl with 1-6 carbon atom, and it can be replaced by 1-5 fluorine and/or chlorine atom,
R 10And R 11Separately independently of one another for A, have 3-7 carbon atom cycloalkyl, have the methylene radical cycloalkyl of 4-8 carbon atom or have the alkenyl of 2-8 carbon atom,
Hal is F, Cl, Br or I.
Thiadiazinones is known, for example can be known by DE3719031A1 and DE4134893.
The objective of the invention is to find to have the new compound of useful quality, particularly can be used for preparing the compound of medicine.
Have now found that formula I compound has useful pharmacological properties and has good consistency.
Particularly, these compounds show the phosphodiesterase IN inhibition, therefore can be used for treating asthma disease.For example, can be by T.Olsson, Acta allergologica 26, the method for 438-447 (1971) is measured the anti-asthma effect.
In addition, these compounds show the restraining effect that TNF (tumour necrosis factor) is formed, and therefore are suitable for treating allergic disease and inflammation, autoimmune disease and graft-rejection.These compounds can be used for treatment memory disease.
Therefore these compounds can be used as the active pharmaceutical ingredient of people and veterinary drug, and they can be used for preparing the intermediate of other active pharmaceutical ingredient in addition.
Therefore the present invention relates to formula I compound and preparation method thereof, it is characterized in that making formula II compound:
Figure A9610047700061
R wherein 1, R 2, R 3And R 4Has above-mentioned implication, with the reaction of formula III compound, wherein: R 5Have the implication of being given with Q, X is the OH group of Cl, Br, OH or active esterification, or it is characterized in that by reduction nitro, acidylate or alkylation uncle or secondary amino group or hydrolysis cyano group, with a R in the formula I compound 5Groups converted is another R 5Group, and/or it is characterized in that if necessary will be corresponding to formula I but contain one or two free OH groups rather than R 3And/or R 4Compound respectively with formula R 3-X or R 4The reaction of-X compound, wherein R 3, R 4Have the implication of being given with X, thereby and/or be converted into its salt with the alkali of acid treatment formula I.
In context, except as otherwise noted, R in formula I, II and III group 1, R 2, R 3, R 4, R 5, Q and X have the implication of giving.
In general formula, alkyl preferably is non-side chain, preferably has 1,2,3 or 4 carbon atom, and preferable methyl, also preferred ethyl or propyl group, and preferred in addition sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl also can be n-pentyl or isopentyl.
Cycloalkyl preferably has 3-7 carbon atom, is preferably cyclopropyl or cyclobutyl, is preferably cyclopentyl or cyclohexyl in addition, can be suberyl in addition.
The methylene radical cycloalkyl preferably has 4-8 carbon atom, is preferably methylene radical cyclopropyl or methylene radical cyclobutyl, and also preferred methylene radical cyclopentyl or methylene radical cyclohexyl are the methylene radical suberyl in addition.
Alkenyl is preferably vinyl, propenyl, pseudoallyl, butenyl, isobutenyl or secondary butenyl, also is preferably pentenyl or isopentene group.
Alkylidene group preferably is non-side chain, preferred methylene radical or ethylidene, preferred in addition propylidene or butylidene.
R 1And R 2In the group, one is preferably hydrogen, and another is preferably propyl group or butyl, but is preferably ethyl or methyl especially.In addition, R 1And R 2Be preferably hydrogen together separately.
R 3And R 4Group can be identical or different, is preferably placed at 3 or 4 of phenyl ring, for example they be independently of one another hydroxyl ,-S-CH 3,-SO-CH 3,-SO 2-CH 3, F, Cl, Br or I, or be methylene-dioxy together.Yet, particularly preferably, their respectively do for oneself methoxyl group, oxyethyl group, propoxy-, or also can be fluoro-, two fluoro-or three fluoro-methoxyl groups, or 1-fluoro-, 2-fluoro-, 1,2-two fluoro-, 2,2-two fluoro-, 1,2,2-three fluoro-or 2,2,2-trifluoro ethoxy.
R 5Group is preferably phenyl.Phenyl is preferably one or two replacements.Preferred substituted is cyano group, nitro, amino, kharophen, trifluoroacetamido, methoxyl group and/or chlorine; also preferable methyl sulfonamido, propionamido, 2-methyl-prop amido, isobutyryl amino and/or valeryl, preferred in addition methoxycarbonyl amino, methoxalyl amino, urea groups and/or carboxyl.
Q-R 5Be preferably benzyl, 2-, 3-or 4-nitrobenzyl, 2-, 3-or 4-cyano group benzyl, 2-, 3-or 4-aminobenzyl, 2-, 3-or 4-kharophen benzyl, 2-, 3-or 4-trifluoroacetamido benzyl, 2-, 3-or 4-methoxy-benzyl, 2-, 3-or 4-benzyl chloride base, preferred in addition 2-, the amino benzyl of 3-or 4-sulfonyloxy methyl, 2-, 3-or 4-propionamido benzyl, 2-, 3-or 4-(2-methyl-prop amido) benzyl, 2-, 3-or 4-isobutyryl aminobenzyl, 2-, 3-or 4-pivalyl aminobenzyl, 2-, 3-or 4-methoxycarbonyl aminobenzyl, 2-, 3-or 4-urea groups benzyl, 2-, 3-or 4-carboxyl benzyl, 2-, 3-or 4-methoxalyl aminobenzyl, and 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dinitrobenzene benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-diamino benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-diacetylamino benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, two (trifluoroacetamido) benzyls of 5-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dimethoxy-benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, the 5-dichloro benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dimethyl methyl amido benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-two propionamido benzyls, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, two (the 2-methyl-prop amido) benzyls of 5-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-two isobutyryl aminobenzyls, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-two pivalyl aminobenzyls, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dimethoxy carbonylamino benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-diformazan oxamido-benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-two urea groups benzyls, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dicarboxyl benzyl.
The present invention be more particularly directed at least one above-mentioned group wherein and have the formula I compound of an above-mentioned preferred definition.A preferred compounds can represent with following inferior formula Ia to Ie, and inferior formula Ia to Ie is corresponding to formula I, do not have indicated group to have the implication of being given among the formula I above wherein, but wherein: in Ia, R 1Be H, R 2Be H or A, R 3Be OA; In Ib, R 1Be H, R 2Be methyl or ethyl, R 3And R 4OA respectively does for oneself; In Ic, R 1Be H, R 2Be methyl or ethyl, R 3Be OA; R 4The alkyl that replaces for one, two or trifluoro with 1-6 carbon atom; In Id, R 1Be H, R 2Be methyl or ethyl, R 3And R 4Be OR 10, R 5For having one or dibasic phenyl; And in Id, R 1And R 2Be H, R 3And R 4Be OA; R 5For having one or dibasic phenyl;
In addition, formula I compound can with itself known and at document (for example at authoritative works such as Houben-Weyl, Methoden der Organischen chemie, [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) method of describing in, and under the condition of known and suitable above-mentioned reaction, prepare.In this respect, also can use itself known and modified method in greater detail not in this article.
In formula II compound, R 1, R 2, R 3And R 4Has the definition of being given, particularly preferred definition of giving.
In the formula III compound, Q is preferably methylene radical or ethylidene, also preferred propylidene or butylidene.
In the formula III compound, R 5Have the definition of being given, particularly preferred definition of giving, and X is the OH group of Cl, Br, OH or active esterification.
If X is the OH group of active esterification, then preferably have the alkylsulfonyloxy of 1-6 carbon atom, mesyloxy or have the aryl-sulfonyl oxygen of 6-10 carbon atom for example, for example benzene-, to toluene-or 1-or 2-naphthalene sulfonyl oxygen base.
If necessary, but also on-site preparation of starting raw material, and it is not separated from reaction mixture, and react immediately, obtain formula I compound.But also proceed step by step reaction in addition.
Some formula II and III starting raw material are known, are not that known starting raw material can prepare with known method itself.
For example, formula II thiadiazinones and preparation thereof have been described in German patent application P4134893.
In addition, the formula III compound can with itself known and at document (for example at authoritative works such as Houben-Weyl, Methoden der Organschen chemie, [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) method of describing in, and under the condition of known and suitable above-mentioned reaction, prepare.In this respect, also can use itself known and modified method in greater detail not in this article.
In more detail, the thiadiazinones of formula II and formula III compound can be with or without in the presence of the inert solvent approximately-20 to approximately+150 carrying out under ℃ preferred 20 to the 100 ℃ temperature.The example of suitable solvent is hydrocarbon such as benzene,toluene,xylene or 2,4, the 6-trimethylbenzene; Halohydrocarbon such as methylene dichloride, trichloroethane or chlorobenzene; Alcohol is as methyl alcohol, ethanol or Virahol; Dibasic alcohol and glycol ether such as ethylene glycol, glycol ether and 2-methyl cellosolve; Nitrile such as acetonitrile; Ether such as tetrahydrofuran (THF) (THF) or dioxan; Acid amides such as dimethyl formamide (DMF) and sulfoxide such as methyl-sulphoxide.The mixture of these solvents also is suitable.
In addition, by reduction nitro, acidylate or alkylation uncle or secondary amino group or hydrolysis cyano group, with a R in the formula I compound 5Groups converted is another R 5Group.
Also can make corresponding to formula I but contain one or two free OH groups rather than R 3And/or R 4Compound respectively with formula R 3-X or R 4The reaction of-X compound, wherein R 3, R 4Has the implication of being given with X.Available itself known and at document (for example at authoritative works such as Houben-Weyl, Methoden der Organischenchemie, [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) method of describing in, and under the condition of known and suitable above-mentioned reaction etherificate OH group.In this respect, also can use itself known and modified method in greater detail not in this article.
The alkali usable acid of the formula I of gained is converted into corresponding acid salt.The acid that is suitable for this reaction is the acid of the salt that can obtain allowing on the physiology.For example, can use mineral acid, as sulfuric acid, haloid acid example hydrochloric acid or Hydrogen bromide, phosphoric acid such as ortho-phosphoric acid, nitric acid, thionamic acid, and organic acid, particularly aliphatic series, alicyclic, araliphatic, aromatics or heterocycle one or polycarboxylic acid, sulfonic acid or sulfuric acid, as formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, phenylformic acid, Whitfield's ointment, the 2-phenylpropionic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, first-or ethyl sulfonic acid, ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene one or disulfonic acid and dodecyl sulphate.
If necessary, can handle, from its salt, disengage the free alkali of formula I by using highly basic such as sodium hydroxide or potassium hydroxide, yellow soda ash or salt of wormwood.
Formula I compound can contain one or more asymmetric centers.In this case, they are generally racemic modification.Resulting racemic modification can mechanically or chemically be separated into its enantiomorph with known method own.Preferably, by reacting, prepare diastereomer by raceme mixture with optically active separating agent.
Certainly, using with aforesaid method has been optically active starting raw material, also can obtain optically active formula I compound.
Formula I compound comprises all steric isomers and composition thereof, for example racemic modification.
The present invention relates to the purposes that the salt that allows on formula I compound and the physiology thereof is used for useful in preparing drug formulations in addition, particularly passes through method non-chemically.In this respect, these compounds can mix with at least a solid, liquid and/or semisolid excipient or auxiliary, perhaps if necessary, are mixed and made into suitable formulation with one or more other activeconstituents.
The present invention relates to composition, particularly pharmaceutical preparation in addition, comprises the salt that allows at least a formula I compound and/or a kind of its physiology.
These preparations can be used as people or animal doctor's medicine.Suitable vehicle is for being suitable for through intestines (for example oral), parenteral or topical application, and not with the organic or inorganic material of new compound reaction, for example water, vegetables oil, benzylalcohol, polyoxyethylene glycol, vanay, gelatin, carbohydrate such as lactose or starch, Magnesium Stearate, talcum and Vaseline.For oral administration, can specifically use common tablet, coated tablet, capsule, syrup, liquor or drops, for rectal administration, can use suppository, for administered parenterally, can use preferred oiliness of solution or aqueous solution agent, also can use suspension liquor, emulsion or implant, for topical application, can use ointment, emulsifiable concentrate or pulvis.But new compound is lyophilize also, and the lyophilized preparation of gained can be used for preparing injection formulations.Above-mentioned preparation can be sterilized and/or can be contained auxiliary such as lubricant, sanitas, stablizer and/or wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer substance, tinting material, seasonings and/or aromatoising substance.If necessary, they can contain one or more other activeconstituentss, for example one or more VITAMIN.
Formula I compound can be used for disease preventing and treating, asthma particularly, and can be used in the treatment of human or animal body.
In this respect, compound of the present invention is usually by the administering mode administration that is similar to known antasthmatic such as Atrovent, and preferred dosage is that per unit dosage is about 1 to 100mg, and particularly 2 to 20mg.Per daily dose is preferably about 0.02 to 2mg/kg body weight.Yet, the patient's that each is concrete concrete dosage depends on various factors, for example the seriousness of the compound formulation of the drug effect of employed particular compound, age, body weight, general state of health, sex, diet, administration time and approach, drainage rate, medicine and the disease specific of being treated.The preferred oral administration.Compare with the digitalis glycoside that is used for the treatment of cardiac insufficiency, formula I compound is characterised in that and has improved therapeutic domain and periphery expansion.
In the following example, " handling according to a conventional method " is meant:
If necessary, add entry or dilute sodium hydroxide aqueous solution, extract, separate each phase, use the dried over sodium sulfate organic phase, filter and evaporation concentration, resistates chromatography and/or crystallization purifying with organic solvent such as ethyl acetate, chloroform or methylene dichloride.
In context, all temperature are centigradetemperature.Embodiment 1
In the presence of 4g salt of wormwood, make 2.8g5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3, the 150ml acetone soln of 4-thiadiazine-2-ketone (" A ") [reaction of 1-(3, the 4-Dimethoxyphenyl)-2-bromine fourth-1-ketone and hydrazine bamic acid methyl esters is made] and the boiling of 3g4-nitrobenzyl chloride 8 hours.Filter out insolubles, concentrated solution.Handle 3-(4-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3 that resistates obtains colorless oil according to a conventional method, 6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, by making compound " A " and corresponding compounds reaction make following compounds: obtain with the reaction of 3-nitrobenzyl chloride:
3-(3-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 2-nitrobenzyl chloride:
3-(2-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 2, the reaction of 3-dinitrobenzene benzyl chloride obtains:
3-(2,3-dinitrobenzene benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 2, the reaction of 4-dinitrobenzene benzyl chloride obtains:
3-(2,4-dinitrobenzene benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 2-methoxy-benzyl chlorine:
3-(2-methoxy-benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 4-methoxy-benzyl chlorine:
3-(4-methoxy-benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; M.p.120 ℃; Obtain with the reaction of 2-chlorobenzyl chloride:
3-(2-benzyl chloride base)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp.77 ℃; With 2, the reaction of 6-dichlorobenzyl chloride obtains:
3-(2, the 6-dichloro benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.187 ℃; Obtain with the reaction of 4-cyano group benzyl chloride:
3-(4-cyano group benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 4-carboxyl benzyl chloride:
3-(4-carboxyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; M.p.106 ℃; Embodiment 2
Be similar to embodiment 1, make 5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone (" B ") obtains 3-(4-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1 with the reaction of 4-nitrobenzyl chloride, 3,4-thiadiazine-2-ketone, mp.155 ℃.
Similarly, by making compound " B " and corresponding compounds reaction make following compounds: obtain with the reaction of 3-nitrobenzyl chloride:
3-(3-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 2, the reaction of 4-dinitrobenzene benzyl chloride obtains:
3-(2,4-dinitrobenzene benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 4-methoxy-benzyl chlorine:
3-(4-methoxy-benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 2-chlorobenzyl chloride:
3-(2-benzyl chloride base)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 2, the reaction of 6-dichlorobenzyl chloride obtains:
3-(2, the 6-dichloro benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of 4-cyano group benzyl chloride:
3-(4-cyano group benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Embodiment 3
Be similar to embodiment 1, make 5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and 4-nitrobenzyl chloride (" C ") reaction obtains 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, by making compound " C " and corresponding compounds reaction make following compounds: with 5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-methoxyl group-4-ethoxyl phenenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-ethoxyl phenenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3-hydroxyl-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3-hydroxyl-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(4-methyl sulphonyl phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(4-methyl sulphonyl phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 5-(3, the inferior p-methoxy-phenyl of 4-)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-nitrobenzyl)-5-(3, the inferior p-methoxy-phenyl of 4-)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Embodiment 4
Hydrogenation 3.9g3-in the presence of Raney nickel (4-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3, the 40ml tetrahydrofuran solution of 4-thiadiazine-2-ketone.Filter out catalyzer, concentrated solution.Recrystallization obtains 3-(4-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p105 ℃.
Similarly, make following compounds by following reaction: with 3-(3-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-and 6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(3-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-and 6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.112 ℃; With 3-(2-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(2-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(2,3-dinitrobenzene benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(2,3-diamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(2,4-dinitrobenzene benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(2,4-diamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-ethoxyl phenenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-methoxyl group-4-ethoxyl phenenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-hydroxyl-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-hydroxyl-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(4-methyl sulphonyl phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(4-methyl sulphonyl phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3, the inferior p-methoxy-phenyl of 4-)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3, the inferior p-methoxy-phenyl of 4-)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(3-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(3-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.176 ℃; With 3-(4-nitrobenzyl)-5-(4-oxyethyl group-3-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(4-oxyethyl group-3-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-oil of mirbane ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; With 3-(4-nitrobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Embodiment 5
Under agitation, with 10g3-(4-cyano group benzyl)-5-(3, the 4-dihydroxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone are added in the 100ml aqueous solution of refrigerative 1.3gNaOH, then mixture are stirred 10 hours.
Careful heated solution, in this process, the bubbling air air-flow.Add refrigerative sulfuric acid and water then, treating mixture obtains 3-(4-carboxyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.106 ℃ according to a conventional method.Embodiment 6
In stirring and ice-cooled following, the 0.8ml trifluoroacetyl chloride is added to 1.4g3-(4-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3, in the 60ml methylene dichloride and 1ml triethylamine solution of 4-thiadiazine-2-ketone (" D "), then mixture was stirred 3 hours.Remove and desolvate, handle resistates according to a conventional method.Obtain 19g3-(4-trifluoroacetamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p124 ℃ with Virahol/sherwood oil recrystallization.
Similarly, by making compound " D " and corresponding compounds reaction make following compounds: obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, be oily matter, MS (EI) M +427; Obtain with the Methanesulfonyl chloride reaction: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +463; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +441; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +455; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.141 ℃; Obtain with the pivalyl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.155 ℃; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp115 ℃; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +457; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +472; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p140 ℃; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp.77 ℃; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.113 ℃.
Similarly, make 3-(4-aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp.155 ℃; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p136 ℃; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.160 ℃; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +481; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.146 ℃; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido styroyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen styroyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.112 ℃; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino styroyl of 4-sulfonyloxy methyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido styroyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups styroyl)-5-(3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino styroyl)-5-(3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of cyclopentadienyl carbonyl chlorine: 3-(4-cyclopentyl formamyl styroyl)-5-(3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(the amino styroyl of 4-valeryl)-5-(3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-kharophen styroyl)-5-(3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl amino-benzene ethyl)-5-(3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Similarly, make 3-(3-aminobenzyl)-5 (3, the 4-dimethoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(3-trifluoroacetamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance, MS (EI) M +481; Obtain with excess acetyl chloride: 3-(3-kharophen benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 3-sulfonyloxy methyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(3-propionamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.159 ℃; Obtain with the cyclopentane-carboxylic acid reaction: 3-(3-cyclopentyl carbamyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(3-isobutyryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(3-methoxycarbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(3-ethoxy carbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance; Obtain with the reaction of methoxalyl chlorine: 3-(3-methoxalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(3-urea groups benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(3-butyrylamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(3-valeryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(3-hexanamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(3-five fluorine propionamido benzyls)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the pivalyl chloride reaction: 3-(3-pivalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone;
Similarly, make 3-(4-aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-fluorine methoxyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-difluoro-methoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-methoxyl group-4-fluorine p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-methoxyl group-4-difluoro-methoxy phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-methoxyl group-4-Trifluoromethoxyphen-l)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.176 ℃; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.186 ℃; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.186 ℃; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp.137 ℃; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.188 ℃; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp184 ℃; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p95 ℃; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-oxyethyl group-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.196 ℃; Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 4-sulfonyloxy methyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.103 ℃; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.72 ℃; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(4-valeryl aminobenzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido benzyls)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl benzyl)-5-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(4-amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido styroyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(4-kharophen styroyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino styroyl of 4-sulfonyloxy methyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(4-propionamido styroyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(4-isobutyryl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(4-methoxycarbonyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(4-ethoxy carbonyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(4-pivalyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(4-methoxalyl amino-benzene ethyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(4-urea groups styroyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(4-butyrylamino styroyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(the amino styroyl of 4-valeryl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(4-hexanamido styroyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(4-five fluorine propionamido styroyls)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(4-cyclopentyl formamyl styroyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
Similarly, make 3-(3-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds: obtain with the trifluoroacetyl chloride reaction: 3-(3-trifluoroacetamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with excess acetyl chloride: 3-(3-kharophen benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methyl sulphonyl chlorine: 3-(the amino benzyl of 3-sulfonyloxy methyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the propionyl chloride reaction: 3-(3-propionamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the isobutyryl chloride reaction: 3-(3-isobutyryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the methyl-chloroformate reaction: 3-(3-methoxycarbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the Vinyl chloroformate reaction: 3-(3-ethoxy carbonyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the pivalyl chloride reaction: 3-(3-pivalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of methoxalyl chlorine: 3-(3-methoxalyl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of chloromethane acid amides: 3-(3-urea groups benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the butyryl chloride reaction: 3-(3-butyrylamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the valeryl chloride reaction: 3-(3-valeryl aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the caproyl chloride reaction: 3-(3-hexanamido benzyl)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone; Obtain with the reaction of five fluorine propionyl chlorides: 3-(3-five fluorine propionamido benzyls)-5-(3, the 4-Dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Obtain with the reaction of pentamethylene carbonyl chlorine: 3-(3-cyclopentyl formamyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Embodiment 7
In stirring and ice-cooled following, the 1.5ml butyl bromide that will be dissolved in the 20ml methylene dichloride is added to 1.4g3-(4-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3, in the 60ml methylene dichloride and 1ml triethylamine solution of 4-thiadiazine-2-ketone, then mixture was stirred 3 hours.Remove and desolvate, handle resistates according to a conventional method and obtain 3-(4-N, N-dibutylamino benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Embodiment 8
The trifluoromethyl iodine of monovalent is added to 1.4g3-(4-propionyl aminobenzyl)-5-(3-hydroxyl-4-p-methoxy-phenyl)-6-ethyl-3; 6-dihydro-1; 3; 4-thiadiazine-2-ketone [makes 3-(4-aminobenzyl)-5-(hydroxyl-4-p-methoxy-phenyl)-6-ethyl-3; 6-dihydro-1; 3, the reaction of 4-thiadiazine-2-ketone and propionyl chlorine makes] THF solution in, then with mixture boiling 2 hours.Then remove and desolvate, handle resistates according to a conventional method, obtain 3-(4-propionyl amino)-5-(3-trifluoromethoxy-4-p-methoxy-phenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.Embodiment 9
Similarly, make following compounds by following reaction: with 3-(2-nitrobenzyl)-5-(3, the 4-dimethoxy)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(2-aminobenzyl)-5-(3, the 4-dimethoxy)-3,6-dihydro-1,3,4-thiadiazine-2-ketone (" E "), m.p.127 ℃; With 3-(4-nitrobenzyl)-5-(3-propoxy--4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(2-aminobenzyl)-5-(3-propoxy--4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.125 ℃; With 3-(4-nitrobenzyl)-5-(3-cyclopentyloxy-4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-reactive ketone obtains: 3-(4-aminobenzyl)-5-(3-cyclopentyloxy-4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-ketone (" E "), m.p.123 ℃.Embodiment 10
By the method that is similar to embodiment 6, obtain following compounds by making compound " E " and corresponding compounds reaction.Obtain with excess acetyl chloride: 3-(2-kharophen benzyl)-5-(3, the 4-dimethoxy)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p210 ℃; Obtain with the trifluoroacetyl chloride reaction: 3-(2-trifluoroacetamido benzyl)-5-(3, the 4-dimethoxy)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, m.p.200 ℃;
Make 3-(4-aminobenzyl)-5-(3-propoxy--4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-ketone and corresponding compounds reaction obtain following compounds.Obtain with excess acetyl chloride: 3-(4-kharophen benzyl)-5-(3-propoxy--4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, amorphous substance; Obtain with the propionyl chloride reaction: 3-(4-propionamido benzyl)-5-(3-propoxy--4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp.150 ℃; Obtain with the trifluoroacetyl chloride reaction: 3-(4-trifluoroacetamido benzyl)-5-(3-propoxy--4-methoxyl group)-3,6-dihydro-1,3,4-thiadiazine-2-ketone, mp167 ℃.
The following example relates to pharmaceutical preparation: embodiment A: the injection bottle agent
With 2N hydrochloric acid the 3L bi-distilled water solution of 100g formula I activeconstituents and 5g Sodium phosphate dibasic being adjusted to pH is 6.5, carries out sterilising filtration, is divided in the injection bottle, and lyophilize under aseptic condition is with sterile manner sealing injection bottle.Each injection bottle contains the 5mg activeconstituents.Embodiment B: suppository
The mixture of active principles of 20g formula I is melted with 100g soybean lecithin and 1400g theobroma oil, in mixture impouring mould, cooling then, each suppository contains the 20mg activeconstituents.Embodiment C: solution
Active compound, the 9.38gNaH of preparation 1g formula I 2PO 42H 2O, 28.48gNa 2HPO 412H 2The 940ml bi-distilled water solution of O and 0.1g Zephiran chloride.It is 68 that solution is adjusted to pH, adds to 11, passes through radiation sterilization.This solution can be used as eye drops.Embodiment D: ointment
Under aseptic condition, the activeconstituents of 500mg formula I is mixed with 99.5g Vaseline.Embodiment E: tablet
According to a conventional method, with the mixture compacting of activeconstituents, 4kg lactose, 1.2kg yam starch, 0.2kg talcum and the 0.1kg Magnesium Stearate of 1kg formula I in flakes, each tablet contains the 10mg activeconstituents.Embodiment F: the tablet of dressing
By the method compressed tablets that is similar to embodiment E, use sucrose, yam starch, talcum, Tragacanth and tinting material dressing according to a conventional method then.Embodiment G: capsule
According to a conventional method the active compound of 2kg formula I is packed in the hard gelatin capsule, each capsule contains the 20mg activeconstituents.Embodiment H: ampulla
601 bi-distilled water solution of the activeconstituents of 1kg formula I are carried out sterilising filtration, be divided in the ampoule, lyophilize under aseptic condition is with sterile manner sealed ampoule bottle.Each ampoule contains the 10mg activeconstituents.

Claims (8)

1, the salt that allows on the aralkyl-Thiadiazinone derivatives of formula I and the physiology thereof:
Figure A9610047700021
Wherein:
R 1And R 2Be H or A separately independently of one another,
R 3And R 4Be independently of one another separately-OH ,-OR 10,-S-R 10,-SO-R 10,-SO 2-R 10, Hal, methylene-dioxy ,-NO 2,-NH 2,-NHR 10Or-NR 10R 11,
R 5For unsubstituted or by R 6And/or R 7One or dibasic phenyl,
Q is for existing or for having the alkylidene group of 1-6 carbon atom,
R 6And R 7Be independently of one another separately-NH 2, NR 8R 9,-NHR 10,-NR 10R 11,-NO 2, Hal ,-CN ,-OA ,-COOH or-COOA,
R 8And R 9The acyl group that is H independently of one another separately, has 1-8 carbon atom and replaced by 1-5 following groups: fluorine and/or chlorine atom ,-COOA ,-S-A ,-SO-A ,-SO 2-A ,-CONH 2,-CONHA ,-CONA 2,-CO-COOH ,-CO-COOA ,-CO-CONH 2,-CO-CONHA or-CO-CONA 2,
A is the alkyl with 1-6 carbon atom, and it can be replaced by 1-5 fluorine and/or chlorine atom,
R 10And R 11Separately independently of one another for A, have 3-7 carbon atom cycloalkyl, have the methylene radical cycloalkyl of 4-8 carbon atom or have the alkenyl of 2-8 carbon atom,
Hal is F, Cl, Br or I.
2, according to the enantiomorph of the formula I compound of claim 1.
3, (a) 3-(4-nitrobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone;
(b) 3-(4-aminobenzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone;
(c) 3-(4-trifluoroacetyl group benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone;
(d) 3-(4-ethanoyl benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone;
(e) 3-(4-methoxy-benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone;
(f) 3-(2, the 6-dichloro benzyl)-5-(3, the 4-Dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2-ketone.
4, the formula I compound of claim 1 and the preparation method of salt thereof is characterized in that making formula II compound: R wherein 1, R 2, R 3And R 4Has above-mentioned implication, with the reaction of formula III compound, wherein: R 5Have the implication of being given with Q, X is the OH group of Cl, Br, OH or active esterification, or it is characterized in that by reduction nitro, acidylate or alkylation uncle or secondary amino group or hydrolysis cyano group, with a R in the formula I compound 5Groups converted is another R 5Group, and/or it is characterized in that if necessary will be corresponding to formula I but contain one or two free OH groups rather than R 3And/or R 4Compound respectively with formula R 3-X or R 4The reaction of-X compound, wherein R 3, R 4Have the implication of being given with X, thereby and/or be converted into its salt with the alkali of acid treatment formula I.
5, the preparation method of pharmaceutical preparation is characterized in that the salt that allows on the formula I compound of claim 1 and/or a kind of its physiology and at least a solid, liquid and/or semisolid excipient or auxiliary are mixed and made into suitable formulation.
6, pharmaceutical preparation is characterized in that containing the salt that allows on the formula I compound of at least a claim 1 and/or a kind of its physiology.
7, the salt that allows on the formula I compound of claim 1 and/or a kind of its physiology is used to prepare the purposes of the medicine for the treatment of disease.
8, the purposes of the salt that allows on formula I compound and/or its physiology in the treatment disease.
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