CN1012365B - 2- (N-substituted guanidino) -4-heteroaryl thiazole antiulcer agent and its preparation method - Google Patents

Abstract

A process for the preparation of the compound 2,4-disubstituted thiazole of formula (I) or its pharmaceutically usable acid addition salt. These compounds or their salts are used in the method for treating gastric ulcer in mammals and the preparation method of the pharmaceutical composition containing the above compounds.

Wherein: X, Y, R ¹ , R ² and R ⁴ are as defined in the specification and claims.

Description

Prepn. of 2-(N-subst-guanidyl)-4-heteroaryl thiazole antiulcer agent

The present invention is the guanidine radicals that relevant new compound 2-(N-replaces)-method for making of 4-heteroaryl thiazole.Wherein: above-mentioned guanidine radicals is monobasic, dibasic or trisubstituted.Above-mentioned heteroaryl substituting group is imidazol-4 yl, thiazole-4-base, or 1,2,4-triazole-5-base, these compounds have as the secretion inhibitor agent, the activity of histamine-hydrogen receptor antagonistic.And/or the activity of the stomach ulcer inhibitor that causes as alcohol arranged, and in suppressing the stomach ulcer that (promptly prevent and treat) Mammals comprises the people, be effective.

Chronic gastric ulcer and duodenal ulcer, common name stomach ulcer is common disease.To these diseases, various methods of treatment comprise that dietary measure, pharmacotherapy and surgical treatment all can adopt with the state of an illness.Can be used for treating the valuable especially therapeutical agent of hyperchlorhydria and stomach ulcer is histamine-hydrogen receptor antagonistic, and it plays and stops the effect of physiologically active compound histamine on the hydrogen receptor position in the animal body, thereby has suppressed gastric acid secretion.The mensuration of the ulcer by chemical compound lot of the present invention being suppressed the mouse that alcohol causes further reflects the clinical value of compound of the present invention in suppressing stomach ulcer.

Lamattina and Lipinski disclose a kind of compound 2-guanidine radicals-4-heteroaryl thiazole that is used for the treatment of hyperchlorhydria and stomach ulcer in the United States Patent (USP) of announcing February 22 nineteen eighty-three 4,374,843.The structural formula of this compound is as follows:

Wherein: X is S or NH; Y is CH, CCH ₃Or N; R is H, CH ₂OH, (C ₁-C ₆) alkyl, Ph(CH ₂) _XOr NH ₂, it can be arbitrarily by alkylation or acidylate; Ph is phenyl or mono-substituted phenyl, and X is 2 to 4 integer.

In the foregoing invention people's who announces on March 6th, 1984 the United States Patent (USP) 4,435,396, amino-4-imidazolyl that 2-guanidine radicals-4-(2-replaces is disclosed) thiazole, its structural formula is (XII), and wherein X is N, and Y is CH, and R is NH ₃, it is arbitrarily replaced by some alkyl or phenyl alkyl list or two replacements, and this compound is used for the treatment of stomach ulcer.

The invention relates to the guanidine radicals that the new compound 2-(N-of structure formula I replaces)-4-heteroaryl thiazole or its be at available acid salt pharmaceutically.

Wherein:

Perhaps X is NH, and Y is CH or N, and perhaps X is S, and Y is CH;

R ¹But (the C of straight or branched ₄-C ₁₀) alkyl, or R ¹Be (R ³) ₂C ₆H ₃Or (R ³) ₂Ar(CH ₂) _n, wherein n is 1 to 4 integer.R ³Base can be identical or different, is H, F, Cl, Br, I, CH ₃, CH ₃O, NO ₂, NH ₂, OH, CN, COOR ⁵Or OCOR ⁶, and R ⁵Be (C ₁-C ₃) alkyl; Ar is the residue of phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidyl, thiazolyl or imidazolyl;

R ²Be H or (C ₁-C ₄) alkyl; Or work as R ¹And R ²Together the time, form pyrrolidyl, piperidino-(1-position only), morpholino with the nitrogen-atoms that is connected them, or 4-methylpiperazine base R ⁴Be H, (C ₁-C ₅) alkyl, NH ₂Or CH ₃OH.

Above-mentioned various situation, the carbonatoms in the bracket refers to the sum of carbon atom in the group.But carbochain straight or branched.

Pharmaceutically the available acid salt is those additive salt of the additive salt that one to three normal acid is arranged, particularly one or two angelic acid.The acid that is suitable for comprises, for example HCl, HBr, H ₂SO ₄, H ₃PO ₄, CH ₃SO ₃H, tosic acid, maleic acid, FUMARIC ACID TECH GRADE, succsinic acid and citric acid, but be not limited to these acid.The table of enumerating about above-mentioned general salt, referring to Berge etc. at J.Pharm, Sci.The article of delivering (66.1-19(1977)).

Because these compounds or their salt prepare easily; with secretion inhibitor activity, histamine-hydrogen antagonistic activity and/or protection cytoactive, so the compound of the preferential selection of structure formula I is as height represented in the ulcer test that causes at inhibition alcohol:

(1) compound of formula (IX)

Wherein: R ¹, R ²And R ⁴Define as the front.The preferential especially compound of selecting is these compounds, wherein: R ¹Be abovementioned alkyl, (R ³) ₂C ₅H ₃Or (R ³) ₂Ar(CH ₂) _nR in the formula ³Be H, another is H, CH ₃O or Cl, Ar are phenyl, furyl, thienyl, pyridyl or naphthyl.The preferential especially compound of selecting of formula (IX) is these compounds, wherein R ¹Be n-pentyl, n-hexyl, n-heptyl, n-octyl, 2-octyl group, phenylbenzyl, styroyl, hydrocinnamyl, benzene butyl, 4-benzyl chloride base, 4-chlorobenzene ethyl, 4-chlorobenzene propyl group, 4-methoxy-benzyl, 4-anisole ethyl, furfuryl, thienyl methyl, 3-pyridylmethyl, 1-naphthyl methyl or 2-naphthyl methyl; R ²Be H, R ⁴Be abovementioned alkyl, CH particularly ₃;

(2) compound of formula (VII)

Wherein: R ¹Be abovementioned alkyl, (R ³) ₂C ₆H ₃Or (R ³) ₂Ar(CH ₂) _n, Ar is the residue of phenyl in the formula; Particularly preferred R ¹Be n-hexyl, 2-octyl group or benzyl, R ²Be H, R ⁴Be H, CH ₃Or NH ₂;

(3) compound of formula (VIII)

Wherein: R ¹, R ²And R ⁴Definition as above-mentioned formula (VII) compound.

The present invention is also relevant to suppress Mammals, comprises the medical composition of people's stomach ulcer, and it comprises the pharmaceutically stomach ulcer amount of suppression of available diluent or carrier and formula I compound.In addition, the also relevant method of the mammal stomach ulcer of treatment like this that suppresses of the present invention, it comprises takes the stomach ulcer amount of suppression of formula I compound to treatment target.

The compound of the most preferentially selecting for use of the present invention is:

N-[4-(2-Methylimidazole-4-yl) thiazol-2-yl]-N '-n-hexyl guanidine;

N-[4-(2-Methylimidazole-4-yl) thiazol-2-yl]-N '-2-octyl group guanidine;

N-[4-(2-Methylimidazole-4-yl) thiazol-2-yl]-N '-benzyl guanidine;

N-[4-(2-Methylimidazole-4-yl) thiazol-2-yl]-N '-(2-furyl methyl) guanidine;

N-[4-(2-Methylimidazole-4-yl) thiazol-2-yl]-N '-(2-thienyl methyl) guanidine;

Or the acid salt of arbitrary above-claimed cpd.

The guanidine radicals that the compound 2-(N-of the present invention of formula VI replaces)-the 4-(imidazol-4 yl)-guanidine radicals that thiazole and 2-(N-replace)-4-(thiazole-4-yl) thiazole, for example, can be by following reaction scheme preparation:

Route 1

The guanidine radicals that the compound 2-(N-of the present invention of formula (VII) replaces)-and 4-(1,2,4-triazole-5-yl) thiazole, for example, can prepare by the method shown in following:

Route 2

In the first step of route 1, N-itrile group guanidine compound.(V) is at J.Chem.Soc.(1630(1948 according to former Curd etc.)) in and Redmon and Nagg at United States Patent (USP) 2,455, the method described in 807.Suitable amine and dintrile amine prepared in reaction by about equimolar amount.Typical reaction is at polar organic solvent (C for example ₁-C ₄) alkanol, water or their mixture, preferably propyl carbinol exists down in temperature from 40 ℃ to 120 ℃.Be preferably under the solvent refluxing temperature and heat.Then, by cooling segregation N-itrile group guanidine product, remove by filter sedimentary salt, evaporated filtrate.

Amidinothiourea intermediate product (IV) obtains by suitable N-itrile group guanidine and hydrogen sulfide reaction.This reaction is usually at polar organic solvent.(C for example ₁-C ₄) alkanol, acetone, ethyl acetate and dimethyl sulfoxide (DMSO) carry out under existing.Preferred solvents is a methyl alcohol.Typically be reflected at secondary amine, particularly the diethylamine catalytic amount carries out under existing.Be reflected at normal atmosphere or elevated pressures, for example under 3 to 10 normal atmosphere, about 10 to 100 ℃ in temperature, best 25 to 80 ℃ are carried out.Certainly, when carrying out under the comparatively high temps in being reflected at preferred range, the reaction times can be shorter.On the contrary, at a lower temperature, the required reaction times can be longer.Usually, product is emanated simply with evaporating solvent.In many cases, the crude product that obtains like this is enough pure for being used in next reactions steps.On the other hand, crude product can separate purification with column chromatography.

In the 3rd step of route 1, the 2-(R of the amidinothiourea compound (IV) that N-replaces and the molar equivalent of formula (X) ⁴-replace)-4-halo acetyl imidazole or 2-(R ⁴-replace)-reaction of 4-halo acetylthiazole intermediate product.When halogen atom is chlorine or bromine in the above-claimed cpd, usually with the latter for well.Carry out under the organic solvent that is reflected at reactionlessness exists, used solvent has tetrahydrofuran (THF), low-grade alkane alcohol, as methyl alcohol, ethanol or Virahol; Lower alkyl ketone is as acetone or methylethylketone, dimethyl sulfoxide (DMSO) or dimethyl formamide.Preferred solvent is acetone or dimethyl formamide.Preferred temperature by above-mentioned prepared in reaction compound of the present invention is from 20 ℃ to 120 ℃, particularly about 50 ℃ to 60 ℃.Compound (VI) is used method known in the art, as the cooling segregation, generates precipitation, evaporating solvent, or with adding non-solvent such as ether generation precipitation, obtain as the such product of hydrobromate, hydrobromate changes into free alkali very soon with the neutralization/extracting process of standard.In order to obtain other pharmaceutically available acid salt, free alkali is added in the organic solvent, add an equivalent or at least two normal and require salt acid accordingly again.Then, with filtering and concentrating or add non-solvent and reclaim salt, or reclaim salt with these comprehensive steps.

Shown in above-mentioned route 2, three steps that the compound triazolyl thiazole of formula (VII) uses intermediate product (amidino groups that the N-replaces) thiocarbamide from formula IV to begin obtain.Suitable compound (IV) and equimolar halogenated alkyl pyruvate, the ethyl bromide acetone that preferably obtains easily, condensation in the presence of the inert organic solvents of reaction generates the guanidine radicals of the 2-(replacement of corresponding formula III) thiazole-4-carboxylic acid's ester.This is reflected at about 40 to 120 ℃ of temperature.Best 60 to 80 ℃ are carried out.The inert solvent of reaction is (C ₁-C ₄) alkanol, acetone, ethyl acetate, acetonitrile, benzene or toluene.Preferred solvent is above-mentioned alkanol, particularly ethanol, is reflected in the solvent and carries out easily under reflux temperature.The product of formula III is with the method for standard, and as evaporation/extraction segregation, if desired, also the available standards method as recrystallization, or is carried out column chromatography and separated on silica gel.

In next one of route 2, the compound of formula III and hydrazine or its salt or its hydrate reaction.The reagent in back is used with molar excess usually.For example excessive 10 to 40 moles.The product that generates is the hydrazides of the respective acids of formula II.This step also can be at inert reaction solvent.As carrying out under those used solvents existence of front reactions steps.For the preferred solvent of the reason of economy and efficient is an ethanol.Carry out the preferred temperature of this step reaction and be about 40 to 120 ℃, particularly 60 to 80 ℃.When using preferred solvent ethanol, be reflected under the mixture reflux temperature and successfully carry out.As preceding step carry out, the acylhydrazine intermediate product is emanated with the evaporation/extracting technological method of standard.

In the final step of route 2, acylhydrazine and formula R ⁴CSHN ₂The thioamides contact in R ⁴Define as the front.This step is reflected at the inert organic solvents of reaction.In disclosed those solvents of the first step of top this route.Carry out for about 50 to 150 ℃ in temperature.In preferred aforesaid method.This step is reflected at the thioamides molar excess.In the time of more than 10 times, under the propyl carbinol reflux temperature, carry out.Under these conditions, reaction was finished in 1 to 4 day usually.After reaction was finished, the compound 2-(N-of formula (VII) replaced-guanidine radicals)-4-(1,2,4-triazole-5-yl) thiazole is emanated with the processing method such as the evaporating solvent of standard, and the thick product of purifying, in case of necessity, purify with recrystallization and column chromatography separation method.

The intermediate product 2-(R of formula (X) ⁴-replace)-4-bromo acetyl imidazole and corresponding 4-bromo acetylthiazole be by corresponding 4-acetyl compounds

With elemental bromine currently known methods prepared in reaction with the halogenation methyl ketone in the presence of hydrogen bromide.Typical method is that the ketone (XI) that is dissolved in the about equimolar amount in 48% aqueous solution of hydrogen bromide is contacting near under the room temperature with bromine, finishes reaction in 2 to 6 hours 60-80 ℃ of heating then.Then, use standard method, for example evaporation reaction mixture segregation bromo acetyl compounds (X) is with the extraction of standard and the recrystallizing technology method thick product of purifying.

The corresponding intermediate product of formula (X) (Hal is a chlorine in the formula) and 4-chloracetyl imidazoles and 4-chloracetyl thiazole also can be from the compounds of suitable formula (XI), typically with the sulfuryl chloride prepared in reaction.Compound (XI) is dissolved in the methylene dichloride, adds exsiccant hydrogenchloride, and that continues selectively uses the sedimentary hydrogen chlorate of dissolve with methanol.Then, the sulfuryl chloride of equimolar amount at room temperature adds, and chloro ketone is emanated with standard method.

The initial compound acetylthiazole of formula (XI) (X is S in the formula) for example passes through 1-bromo-2, the thiocarbamide of 3-dimethyl diketone and equimolar amount and formula R ⁴CSNH ₂Sulphamide reaction obtain.Typically be reflected at the inert solvent of reaction.In ethanol or Virahol,, preferably at room temperature carry out 20 to 80 ℃ of temperature.The product of formula (XI) is emanated with standard method known in the art.

The initial acetyl imidazole of formula (XI) (X is NH in the formula).For example, by Lamattina and Lipinski at United States Patent (USP) 4,374, disclosed method preparation in disclosed method and the U.S. Patent application 445,787 that proposes December 1 nineteen eighty-two and the U.S. Patent application 483,787 that proposes April 11 nineteen eighty-three in 843.Above-mentioned two parts of U.S. Patent applications are assigned as direct application and are allowed the people to same awarding.

Formula R ¹R ²Can be available on the initial alkylamine market of NH.Necessary initial aniline compound, (R ³) ₂C ₈H ₃NH ₂And aralkylamine, (R ³) ₂Ar(CH ₂) _nNH ₂, perhaps can buy on the market, perhaps the method preparation of knowing with present technique field those skilled in the art.Aralkylamine (n is 1 in the formula) is by reducing the preparation of corresponding nitrile with hydrogen and precious metal, or by use alkalimetal hydride, and for example lithium aluminium hydride press currently known methods and reduced and prepare.Corresponding aralkylamine, (R ³) ₂ArCH ₂CH ₂NH ₂More available known methods are for example used corresponding halogenated methyl compound, (R ³) ₂ArCH ₂Cl(Br) with the sodium cyanide prepared in reaction.Obtain the aryl acetonitrile intermediate product.Then, with aforesaid method it is hydrogenated to the 2-aryl amine of requirement.

Suitable aldehyde, (R ³) ₂ArCHO or its acetal and the reaction of 2-cyano group ethyl ester have obtained an aryl propane nitrile intermediate product succeeded by hydrolysis and decarboxylation, and this intermediate product can progressively reduce and obtain corresponding amine, (R ³) ₂Ar(CH ₂) ₃NH ₂

The preparation of 4-aryl butylamine, for example, from suitable aldehyde, (R ³) ₂ArCHO by obtaining corresponding 4-aryl-3-butenoic acid with the Wittig reagent reaction for preparing from the 3-bromo acid, restores into corresponding 4-aryl butyric acid.Then, the 4-aryl butyric acid changes into corresponding amide again, and the metal hydride hydrogenation of this acid amides generates the 4-aryl butylamine that requires.

Formula (R ³) ₂Ar(CH ₂) _nNHR ²(R in the formula ²Be (C ₁-C ₄) alkyl) and secondary amine by corresponding primary amines with the method alkylation known preparation, for example use and (C ₁-C ₄) alkyl halide or alkyl sodium sulfate acid-respons, or with suitable Schiff's base, as (R ³) ₂Ar(CH ₂) _nNH=CH(CH) ₂CH ₃The catalytic hydrogenation preparation.

The present invention also comprises the pharmaceutically available acid salt of formula I new compound.These salt are used free alkali and suitable inorganic or organic acid easily.Perhaps contact preparation in the aqueous solution or in appropriate organic solvent.Then, obtain solid salt with precipitation or evaporating solvent.Particularly preferred salt is hydrochloride and dihydrochloride.

The formula I compound comprises people's antiulcer agent effectiveness to Mammals.As what describe in detail in the following example,, reflect in the mouse ulcer that histamine hydrogen antagonism and/or inhibition alcohol cause by the secretion inhibitor of these compounds.In order to suppress the stomach ulcer of (prevention or treatment) mammal, product of the present invention comprises oral and parenteral method administration according to various medications easily.The most handy oral administration of these compounds.Usually, these compounds are arrived 20mg with every day by treatment target per kilogram of body weight about 0.1, and preferably about 0.2 to 2.5mg oral dose administration is once taken or separately taken.Parenteral if desired administration, so, these compounds are that treatment target per kilogram of body weight about 0.1 is to 1.0mg with whole day dosage.But, according to the situation of treatment target and the specific compound of application, with the nursing doctor by oneself, the institute dosage of giving must the difference.

This compound can be individually dosed, or with pharmaceutically available carrier or thinner co-administered or once take or repeatedly take.The medical carrier that is suitable for comprises inert diluent or weighting agent, aseptic aqueous solution and various organic solvent.By the new compound of formula I or their salt and pharmaceutically the available carrier mix the medical composition that forms easily with various formulation administrations.For example: tablet, pulvis, capsule, lozenge, syrup, or the like.If desired, these medical compositions can comprise the Synergist S-421 95 of interpolation, for example flavouring agent, tackiness agent, vehicle, or the like.Like this,, use and to comprise various vehicle, the tablet of Trisodium Citrate for example, various dispersion agents of logotype also, for example starch, alginic acid and some comprehensive silicon acid esters, tackiness agent, for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic for oral administration.In addition, lubricant.For example Magnesium Stearate, sodium lauryl sulphate and talcum are also through being usually used in making tablet.The solids composition of similar type also can be used as the weighting agent in the gelatine capsule of soft and hard filling.Therefore, preferable material comprises lactose and high-molecular weight polyoxyethylene glycol.When needing aqueous suspension or elixir for oral administration, basic active Synergist S-421 95 can with various sweetening agents, coloring material or dyestuff, when needed, with emulsifying agent or suspension agent and thinner, for example water, ethanol, polyoxyethylene glycol, glycerine, or the mixture of these thinners is mixed together.

Compound of the present invention is preferably oral with unit dosage form, promptly contains the in fact once single dose unit oral administration of the active compound of appropriate amount and available carrier pharmaceutically or thinner.The example of this unit dosage form is that tablet or glue are whole.It contains 5 to the 1000mg activity of having an appointment and joins and contain agent, and contains the compound that accounts for about 10% to 90% the formula I of dose unit total amount.

About parenteral administration, the formula I compound is made into aseptic aqueous solution, and for example ethylene glycol, sodium-chlor, dextrose or sodium bicarbonate aqueous solution or suspension all can be used.Above-mentioned if desired dosage form is fit to buffering.Those of skill in the art to the present technique field know about the preparation of the suitable sterile liquid medium of enteron aisle external administration.

The present invention is by following example explanation.But, be understood that to the invention is not restricted to specifying of these examples.All temperature are centigradetemperatures.Nuclear magnetic resonance spectrum (NMR) is for deuterated chlorine part (CDCl ₃), deuterated methyl alcohol (CD ₃OD) or deuterated dimethyl sulfoxide (DMSO) (DMSO-d ₆) measured in solution, peak is used following peak shape abbreviation by the mark record of per 1,000,000 downfields from tetramethylsilane: bs wide range line; S. singlet; D. doublet; T. triplet; Q. quadruple spectral line; M. multiplet.

Embodiment 1

2-(1-just-hexyl-3-guanidine radicals)-thiazole-4-carboxylic acid ethyl ester, 1-(just-the hexyl amidino groups) thiocarbamide (4.05g, 20mmol) ethyl bromide acetone (409g, 20mmol) and 200ml alcoholic acid mixture.Heating is four hours in backflow, then cooling.This mixture is condensed to yellow solid in a vacuum, and chloroform extraction is handled and used to this solid with sodium hydrogen carbonate solution.Dried extract is condensed to orange oily matter in a vacuum, makes its curing with the hexane development.From hexane/ethyl acetate, obtained 3.72g(62% behind the recrystallization) yellow crystal.The treated 1.20g(that gets back of mother liquor/20%) product.118～119 ℃ of the product sample fusing points that analysis obtains from the hexane/ethyl acetate crystallization, mass spectrum (m/e): 29.8(M ⁺); The H-NMR(nuclear magnetic resonance spectrum) (CDCl ₃) ppm(δ); 0.6～1.8(m, 14H), 3.2(m, 2H), 4.3(qJ=7H ₂, 2H), 7.03(s, br, 3H), 7.41(S, 1H).

Ultimate analysis: C ₁₈H ₂₂N ₄O ₂S

Calculated value: C, 52.32, H, 7.43, N, 18.78%

Experimental value: C, 52.41, H, 7.55, N, 18.36%

Embodiment 2

2-(1-just-hexyl-3-guanidine radicals) thiazole-4-acylhydrazine

3.36g(11.3mmol) 2-(1-just-hexyl-3-guanidine radicals) thiazole-4-carboxylic acid ethyl ester and 6.5ml(110mmol) heating 24 hours under refluxing of the mixture of 85% hydrazine hydrate in 110ml ethanol.Add the 6.5ml hydrazine hydrate again, and continue heating 24 hours again.The cooling of the mixture that obtains, solvent wherein evaporates in a vacuum and remaining colorless solid is developed with Virahol.Filter then and obtain 2.52g(8%) colourless powder.The analytic sample that recrystallization obtains from Virahol.Fusing point: 136～137 ℃, mass spectrum (m/e) 284(M ⁺); H-nuclear magnetic resonance spectrum dimethyl sulfoxide (DMSO) ppm(δ), 0.7～1.7(m, 11H), 3.2(m, 2H), 7.31(S, 1H)

Ultimate analysis: C ₁₁H ₂₀N ₆OS

Calculated value: C, 46.45, H, 7.09, N, 29.55%

Experimental value: C, 46.16, H, 7.18, N, 29.93%

Embodiment 3

2-(1-just-hexyl-3-guanidine radicals)-4-(3-methyl isophthalic acid H-1,2,4-triazole-5-yl) thiazole

(VII, R ¹=just-C ₆H ₁₃R ²=H, R ⁴=CH ₃)

568mg(20mmol) 2-(1-just-hexyl-3-guanidine radicals) thiazole-4-acylhydrazine and 751mg(100mmol) thioacetamide 20ml just-mixture in the butanols refluxing under heating 48 hours; concentrate in a vacuum through the refrigerative reaction mixture, residuum carries out chromatographic separation with silica gel glue post and obtains 241mg(39%) pure thiazole yellow foams.207～209 ℃ of fusing points, mass spectrum (m/e), 307(M ⁺), ¹H-nuclear magnetic resonance spectrum (CD ₃OD) ppm(δ): 0.7～1.8(m, 11H), 2.43(S, 3H), 3.3(m, 2H), 7.22(S, 1H)

Ultimate analysis: C ₁₃H ₂₁N ₇S0.5H ₂O

Calculated value: C, 49.34, H, 7.01, N, 30.99%

Experimental value: C, 49.42, H, 6.73, W, 30.82%

Embodiment 4

2-(1-just-hexyl-3-guanidine radicals)-4-(3-amino)-1H-1,2,4-triazole-5-yl) thiazole

(VII: R ¹=just-C ₆H ₃, R ²=H, R ⁴=NH ₂)

852mg(30mmol) 2-(1-just-hexyl-3-guanidine radicals) thiazole-4-acylhydrazine; and 835mg(3mmol) 5-methyl-isothiourea sulfuric ester and 492mg(6mmol) mixture of sodium acetate in the 30ml propyl carbinol be heated 4 hours under refluxing; cooling then; the mixture that obtains after filtration; gained filtrate concentrates in a vacuum; residuum twice of chromatographic separation in silicagel column; wash with 85: 15 chloroform/methanol earlier; and then acetone wash-out; obtain 491mg(53%) title compound of yellow solid; 210～211 ℃ of fusing points, mass spectrum (m/e): 308(M ⁺), ¹H nuclear magnetic resonance spectrum (CD ₃OD) ppm(δ): 0.7～1.9(m, 11H), 3.2(m, 2H), 7.13(S, 1H)

Ultimate analysis: C ₁₂H ₂₀N ₈S

Calculated value: C, 46.73, H, 6.54, N, 36.34%

Experimental value: C, 46.63, H, 6.42, N, 36.03%

Embodiment 5

2-(N-hexyl-N '-guanidine radicals)-and 4-(2-Methylimidazole-4-yl) the thiazolyl-dihydro muriate

A. 10.25g(50.66mmol) 1-(just-the hexyl amidino groups) solution of thiocarbamide in 50ml acetone is added to 13.08g(46.05mmol) 2-bromo-1-(2-Methylimidazole-4-yl) the ethyl ketone hydrobromide is in the solution of 150ml acetone, this mixture refluxed 6 hours, and at room temperature placed 16 hours.This mixture reheat 1 hour under refluxing.Product is collected in cooling then, obtain 19.44g(90%) yellow solid (two hydrobromates), this solid is dissolved in the 300ml water, and be added to 20.59g(166mmol) place after 15 minutes in the 200ml aqueous solution of yellow soda ash-hydrate, solid filters, wash with water, the wet solid that obtains is dissolved in the 400ml acetone, remove by filter insoluble substance, filtrate is used 8ml(37%W/V) concentrated hydrochloric acid handles, the acidifying mixture stirred 1 and a half hours, filtered and the dry solid of collecting, and obtained the 16.31g faint yellow solid.It is dissolved in the 50ml methyl alcohol, carries out the carbon processing and pass through diatomite filtration, the dilution of filtrate first isopropyl ether.Solid collected by filtration throw out drying and obtain 11.50g(66%) required pale yellow powder product.303～305 ℃ of fusing points, mass spectrum (m/e) 306(M ⁺), ¹H-nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)) ppm(δ) 0.7～1.8(m, 1H), 2.70(S, 3H), 3.25(M, 2H), 7.83(S, 1H), 8.03(S, 1H), 8.6(m, 3H)

Ultimate analysis: C ₁₄H ₂₂N ₆S2HCl

Calculated value: C, 44.32, H, 6.48, N, 22.15%

Experimental value: C, 43.83, H, 6.29, N, 21.89%

B. when repeating above-mentioned steps; use 114mg(0.71mmol) 4-chloracetyl-glyoxal ethyline; 144mg(0.71mmol) 1-(just-the hexyl amidino groups) thiocarbamide and the 8mmol hydrogenchloride in 7ml acetone; reflux 65 hours; then obtain the product of required chocolate brown powder material, productive rate 36%.

Embodiment 6

With the operation steps of embodiment 5, use suitable N-replace amidinothiourea replace 1-(just-the hexyl amidino groups) thiocarbamide, then obtain the compound of following structural, a kind of salt of sour addition.

Embodiment 7

2-(N-just-hexyl-N '-guanidine radicals)-4-(amidine azoles-4-yl) thiazole dihydrogen bromide

(VI, R ¹=just-C ₆H ₁₃, R ², R ⁴=H)

511mg(4.64mmol) the solution 1ml(9mmol of 4-acetyl amidine azoles in 6ml acetate) 48% Hydrogen bromide handles, and then use 741mg(4.64mmol) solution of bromine in 4ml acetyl handles, mixture stirred 4 hours down at 50 ℃, add 938mg(4.64mmol) 1-(just-the hexyl amidino groups) thiocarbamide, and 50 ℃ of following continuously stirring 20 hours, the refrigerative reaction mixture filters and obtains 735mg(35% through using acetone diluted) title compound of white powder.Fusing point: 254～255 ℃, mass spectrum (m/e) 292(M ⁺), ¹H nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)) ppm(δ) 0.7～1.9(m, 11H), 3.5(m, 2H) 7.87(S, 1H), 8.25(S, 1H), and 8.6(S, Br, 3H), 9.28(S, 1H)

Ultimate analysis: C ₁₃H ₂₀N ₆S2HBr

Calculated value: C, 34.37, H, 4.88, N, 18.50%

Experimental value: C, 34.24, H, 5.01, N, 18.48%

Embodiment 8

2-(N-just-hexyl-N '-guanidine radicals)-4-(2-ethyl imidazol(e)-4-yl) thiazole dihydrogen bromide.

(VI, R ¹-just-C ₆H ₁₃, R ²=H, R ⁴=C ₂H ₅)

Repeating the operation steps of front embodiment, with 1.45g(10.5mmole) 4-ethanoyl-2-ethyl-imidazoles is as initial reactant.Add equimolar 1-(just-the hexyl amidino groups) stirred 6 hours down at 50 ℃ before the thiocarbamide, stirred 20 hours down at 50 ℃ after adding, reaction mixture is condensed into soup compound in a vacuum, be added to then in the acetone, through the cooling after obtain 1.58g(31%) pink solid.This solid is used ethyl acetate extraction after handling with saturated sodium carbonate solution again, this extraction liquid drying, and with the silica gel column chromatography resistates of purifying, the product cut merges and is condensed into oily matter, and it is dissolved in the 100ml ethanol, uses the salt acid treatment of 2ml37% again.It is evaporated in a vacuum obtain yellow solid, this solid is developed with acetone, obtains 776mg(19% after the filtration) chocolate brown powder, 285～287 ℃ of fusing points; Mass spectrum (m/e): 320(M ⁺) ¹H-nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 0.7～2.0(m, 14H) 3.05(q, J=7HZ, 2H), 3.5(m, 2H), 7.88(S, 1H), 8.02(S, 1H), 8.7(m, 3H).

Ultimate analysis: C ₁₅H ₂₄N ₆S2HCl

Calculated value: C, 45.80, H, 6.66, N, 21.37%

Experimental value: C, 45.42, H, 6.66, N, 21.10%

Embodiment 9

4-(2-aminothiazole-4-yl)-2-(1-just-hexyl-3-guanidine radicals) thiazole

(VIII, R ¹=just-C ₆H ₁₃, R ²=H, R ⁴=NH ₂)

A.2-amino-4-bromo acetyl thiazole hydrobromide; to method (Japanese Chemical Society circular 39.2745 with people such as Masak; 1966); from 1-bromo-2; the 1.11g(50mmole that 3-dimethyl diketone and thiocarbamide prepare) 2-amino-4-acetylthiazole hydrobromide; the Hydrogen bromide and the 799mg(5.0mmole that add 5 48% in the slurries in 50ml acetyl) bromine, mixture heated 1 hour down at 60 ℃.By filtering the collecting precipitation thing, this throw out obtains 1.32g(88% with acetate and washing with acetone) light brown brown powder, 198 ℃ of fusing points (do not melt and will not decompose); Mass spectrum (m/e): 220(M ⁺), 222(M ^{++ 2}) ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 4.83(S, 2H) 8.27(S, 1H)

Ultimate analysis: C ₅H ₅N ₂OSBrHBr

Calculated value: C, 19.88, H, 2.00, N, 9.28%

Experimental value: C, 20.33, H, 2.04, N, 9.28%

B. 1-positive group amidino groups 2-amino-4-bromo-acetylthiazole hydrobromide and 880mg(4.35mmole 1.316g(4.35mmole in the 44ml dimethyl formamide))) the thiocarbamide mixture is 60 ℃ of heating 4 hours down; after the reaction mixture cooling; be condensed into oily matter in a vacuum and add 10% sodium carbonate solution and make its alkalize; use ethyl acetate extraction then; after the extract drying that obtains after filtration; concentrating the back residuum in the vacuum separates twice with the hi-sil column chromatography; reclaim by evaporating solvent with the product behind 9: 1 the chloroform/methanol elution; it is put into ethyl acetate; and handle with excessive hydrogen chloride gas; collect the solid that generates; and, obtain 640mg(37% with ethyl acetate washing) product of required colourless powder.205～207 ℃ of (decomposition) mass spectrums of fusing point (m/e): 324(M+); ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 0.89(m, 3H), 1.32(m, 6H), 1.60(m, 2H), 3.44(m, 2H), 7.36(S, 1H), 7.80(S, 1H), 8.63(S, br, 2H), and 8.92(S, br, 1H).

Ultimate analysis: C ₁₃H ₂₀N ₆S ₂2HCl

Calculated value: C, 39.29, H, 5.58, N, 21.15%

Experimental value: C, 38.89, H, 5.56, N, 21.09%

Embodiment 10

2-(1-just-hexyl-3-guanidine radicals)-4-(2-methyl-thiazole-4-yl) thiazole

(VIII, R ¹=just-C ₆H ₁₃, R ²=H, R ⁴=GH ₃)

A.2-2 acyl group-2-methylthiazol hydrobromide

1. 13g(15.0mmole) thioacetamide and 2.47g(15.0mmole) 1-bromo-2, the aqueous isopropanol of 3-dimethyl diketone at room temperature stirred 10 days, throw out is collected with washed with isopropyl alcohol after filtration and is obtained 0.619g(18%) colourless powder.Evaporated filtrate, remaining solid is developed with acetone, obtains 2.329g(70%) pale yellow powder.200 ℃ of fusing points (distillation); Mass spectrum (m/e): 141(M+); ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 2.60(S, 3H), 2.78(S, 3H), 8.42(S, 1H)

Ultimate analysis: C ₆H ₇NOSHBr

Calculated value: C, 32.44, H, 3.63, N, 6.31%

Experimental value: C, 32.41, H, 3.71, N, 6.29%

B.4-bromo ethanoyl-2-methylthiazol hydrobromide

8.28mg(3.73mmole) 4-ethanoyl-2-methyl-thiazole hydrobromide; The Hydrogen bromide and the 596mg(3.73mmole that add 4 48% in the slurries in 37ml acetate) bromine handles, this mixture heating up to 60 ℃.Under this temperature after three hours, the mixture cool to room temperature.The adding crystal seed is also placed a night.The product of collecting precipitation and with acetate washing, drying obtains 1.01g(90% then) brown crystal.Fusing point, 187-189 ℃; Mass spectrum (m/e): 219(M ⁺), 221(M ⁺+ 2); ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 2.77(S, 3H); 4.82(S, 2H); 8.30(S, 1H)

Ultimate analysis: C ₆H ₆NOSBrHBr

Calculated value: C, 23.94, H, 2.34, N, 4.65%

Experimental value: C, 23.71, H, 2.30, N, 4.51%

C.960mg(3.19mmole) 4-bromo-ethanoyl-2-methylthiazol hydrobromide; 645mg(3.19mmole) 1-(just-the ethyl amidino groups) thiocarbamide and 32ml dimethyl formamide mixture be 60 ℃ of heating 4 hours down, obtains 801mg(52% through cooled mixture with ether dilution and collecting precipitation thing then) pale powder, recrystallization obtain 332mg(21%) product.Fusing point 160-162 ℃; Mass spectrum (m/e): 323(m+); ¹H-nucleus magnetic resonance-d ₆) ppm(δ): 0.7-2.0(m, 11H), 2.75(S, 3H), 3.43(m, 2H), 7.60(S, 1H), 8.55(S, br, 2H), 8.90(S, br, 1H)

Ultimate analysis: C ₁₄H ₂₁N ₅S ₂2HBr

Calculated value: C, 34.64, H, 4.78, N, 14.43%

Experimental value: C, 34.26, H, 4.68, N, 14.28%

Embodiment 11

Anti-gastric acid secretion activity

The anti-gastric acid secretion activity overnight fasted of compound of the present invention, the dog of sentient HeidenhainShi capsule is measured.Continuously inject epidermis veins of lower extremity from the gastral cavity moderate stimulation near the dosage of maximal acid work output with what measure previously with pentagastrin (Pentavolon-Ayerst), with the stimulating acid work output.After beginning to inject pentagastrin, every 30 minutes, collect gastric juice and measure near 0.1ml, at experimental session, each dog is collected 10 times.By the gastric juice of development 1.0ml, use the titration of 0.1N sodium hydroxide to pH7.4 with automatic burette and glass electrode pH instrument (radiometer), measure the concentration of acid.

After beginning to inject pentagastrin 90 minutes, supply with medicine or vehicle with 2mg/kg or dosage vein still less or oral cavity, by minimum sour work output after the administration and the comparison of the average acid work output before the administration, can calculate anti-gastric acid secretion effect.

Product f, g, n and the o of embodiment 6 with the oral dosage of 2mg/kg, can suppress at least 24% gastric acid secretion.5 ° of embodiment and embodiment 6a ° preferable product b °, c, j, l and m with identical or littler dosage, can suppress at least 64% stomachial secretion.With the 0.1mg/kg(intravenous injection) dosage, the compound that embodiment is 5 ° can obtain 58% restraining effect.

* test with two hydrobromates.

Embodiment 12

Histamine-H ₂Antagonistic activity

Histamine-the H of compound of the present invention ₂Antagonistic activity is measured through the following step:

Hit the cavy head with rapid execution it, take out heart, the anatomical isolation right atrium.Ground such as atrium are suspended in temperature controlled (32 ± 2 ℃) the tissue baths (10ml), and this bath contains the (95%O of oxygenation ₂, 5%CO ₂) Krebs-Henseleit damping fluid (pH7.4).Stablized about one hour, during this period, flushing organizes solvent for several times.Accept the shrinking percentage in each atrium with connecting power deviation sensor that many kinds of heart operameter and Grass trace register.After obtaining the dosage～sensitivity curve of a histamine, the bath that each atrium is housed for several times, and then make the atrium balance to basic flat ratio with fresh buffered soln flushing.After being returned to basic rate, add test compound with the ultimate density of selecting.In the presence of antagonist, measure the dosage-sensitivity curve of histamine once more.The result is expressed as dosage-ratio produces the required histamine concentration of half maximum hormesis under antagonist existence and non-existent situation ratio, H ₂The apparent dissociation constant PA of-receptor antagonist ₂Determined.

Embodiment 5 ^*With embodiment 6a ^*, b ^*, c, f, g, j and l-o compound can both obtain at least 6.9 PA ₂Value, embodiment 5 and embodiment 6a ^*, b ^*, f, j, l, m and n preferred compounds obtain at least 7.2 PA ₂Value.

* test with two hydrobromates.

Embodiment 13

Ulcer to the mouse of alcohol-induced suppresses

The antiulcer activity of product of the present invention also can be by alcohol-induced the ulcer calibrating of mouse measure.In this test, the male mouse of overnight fasted is by administration (30 or 3mg/kg) or oral preceding 15 minutes oral water, oral then dehydrated alcohol (1.0ml).Ethanol was attacked back 1 hour, put to death animal (8/group) to check the damage that exists in the stomach.After death cut belly open animal, clamp deep and remote mouthful, use the stomach supply-pipe, in stomach, inject the formaldehyde solution of 6ml4%, then with second locking mosquito forceps sealing oesophagus with the locking mosquito forceps.Take out stomach, cut, check ulcer along greater gastric curvature.

Provide the hierarchical system of quantifying the damage that alcohol causes below.

The ulcer table of grading

The grade explanation

The stomach of 1 conventional appearance

2 atomic little damages

3 damages, 2 or littler, have an atomic little damage

4 damages,＞2; There is atomic little damage

5 hemorrhage damages

Be calculated as follows for every treated animal, ulcer index:

Ulcer index=(sum of this group grade) * (sum of this group ulcer number) * (mark that has the animal of ulcer morbidity in this group).

The inhibition percentage of ulcer is calculated as follows:

Suppress %=100 * I [(control group ulcer index)-(administration group ulcer index)]+(control group ulcer index).

At the oral dosage of 30mg/kg, the compound exhibits of embodiment 5 and embodiment 6a to c, f, j, l, m and o goes out the ulcer that at least 77% inhibition alcohol causes.With identical dosage.The compound c of embodiment 6, f and o prove 90% or better cytoprotective, and with the oral dosage of 3mg/kg, embodiment 5 ^*With embodiment 6a ^*, b ^*, f, j and l compound exhibits go out at least 40% inhibiting rate, the compound of embodiment 5 and embodiment 6f obtains at least 48% inhibiting rate.

* test with two Hydrogen bromides.

Preparation A

Preparation N-replaces-general method of 3-dicyanodiamide (V).

(I) 1-n-hexyl-3-dicyanodiamide (V.R ¹=just-C ₆H ₁₃R ²=H)

With 13.8g(0.10mole) n-hexyl amine hydrochloride, 8.9g(0.125mole) dicyano imines and 75ml propyl carbinol mixture stirred in reflux 3 hours.Cooling mixture; Filtration flashes to soup compound to remove sedimentary salt with filtrate, and crystallization Cong diox.

Mass spectrum (m/e): 169 molecular ion peaks

The N-of (II) following structural (V) replaces-and the 3-dicyanodiamide are from suitable amine.R ¹R ²NH uses method for preparing.

(III) uses suitable amine, R ¹R ²NH and dinitrile imines, HN(CN) ₂With aforesaid method, generation corresponding compounds

R ¹R ²

CH ₃（CH ₂） ₉H

（CH ₃） ₂CH（CH ₂） ₇H

（CH ₃） ₂CH（CH ₂） ₅CH ₃

CH ₃（CH ₂） ₅C（CH ₃） ₂C ₂H ₅

(CH ₃) ₂CH(CH ₂) ₂Different-C ₃H ₇

CH ₂CH(CH ₃) (CH ₂) ₃Just-C ₄H ₉

2-BrC ₆H ₄H

3-BrC ₆H ₄CH ₂CH ₃

4-IC ₆H ₄（CH ₂） ₂CH ₃

2-CH ₃C ₆H ₄（CH ₂） ₃C ₂H ₅

3-NO ₂C ₆H ₄(CH ₂) ₄Just-C ₃H ₇

4-NH ₂C ₆H ₅H

3-HOC ₆H ₄CH ₂CH ₃

4-FC ₆H ₄The second month in a season-C ₄H ₉

4-CNC ₆H ₄CH ₃

4-（COOCH ₃）C ₆H ₄H

Preparation B

The general method of the amidinothiourea (IV) that preparation N-replaces.

(I) 1-(just-the hexyl amidino groups) thiocarbamide (IV .R ¹=just-C ₆H ₁₃, R ²=H)

Present method is about parent compound (R ¹=R ²=H) the improvement of Kurzer method (Org.Syn.Coll.Vol. IV .P.502).

Hydrogen sulfide is introduced 4.5g(0.0027mole) 1-n-hexyl-3-dicyanodiamide, in the mixture of 75ml methyl alcohol and 0.5ml diethylamide, by this mixture bubbling 8 hours.At room temperature, stir one night of this mixture, then, logical again H ₂S6 hour, one night of restir.At this moment, the thin-layer chromatographic analysis of reaction mixture is represented the existence of raw material.At logical H ₂In the time of the S bubbling,, continue the night of refluxing again reaction mixture reheat 6 hours under refluxing.Solvent vacuum-evaporation, resistates is purified with the fast silica gel chromatogram method, and the chloroform/methanol wash-out with 9: 1 obtains the 4.49g product.Mass spectrum (m/e): 202(M+).

(II) on the other hand, (example 17) described in the United States Patent (USP) 4,009,163 of available Cutler of compound (IV) and Shalit as following about 1-(benzyl amidino groups)-the method preparation of thiocarbamide explanation.

The 2ml diethylamide being added contains 6.73g(38.6mmole) in the solution of the 100ml methyl alcohol of 1-benzyl-3-dicyanodiamide, this mixture is cooled to 0 ℃, and is saturated with hydrogen sulfide.Cold soln is transferred in the stainless steel pressure storage tank, and the sealing basin was 80 ℃ of heating 48 hours.Then, mixture is added in the flask, wash to get rid of excessive hydrogen sulfide, solution vacuum-evaporation with nitrogen.The remaining oily matter that produces with 20: 1 chloroform/methanol wash-out, obtains the light yellow oily product of 3.06g with purifying with flash chromatography (silica gel).Mass spectrum (m/e): 209(M+).

(III) is in preparation A(II) the remaining 1-that obtains of part replaces-and the 3-dicyanodiamide change into that the N-of structure formula IV replaces-amidinothiourea with aforesaid method.

Preparation C

2-hydroxymethyl-4-bromo acetyl imidazole hydrobromide

(I) 3-bromo-4-oxyethyl group-3-butene-2-ketone

The mixture heating up of 400ml dehydrated alcohol and 60ml toluene is extremely refluxed, remove the 20ml azeotrope through Dean-Stark trap, with 33.0g(0.2mole) 3-bromo-4-hydroxyl-3-butene-2-ketone adds in ethanol-toluene solution, refluxed 2 hours through continuous, during this period, trisection 20ml ethanol-toluene is removed the solution vacuum concentration through water trap, obtains 38.6g(100%) 3-bromo-4-oxyethyl group-3-butene-2-ketone mobile oil. ¹H-nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 8.21(S, 1H), 4.23(q, 2H), 2.33(S, 3H), 1.31(S, 3H).

(II) 2-hydroxymethyl-4-acetyl imidazole

With 9.7g(0.05mole) 3-bromo-4-oxyethyl group-3-butene-2-ketone and 5.53g(0.05mole) the hydroxyl acetamidine hydrochloride is blended in the 100ml acetone, generates slurries.With 11.5g(0.1mole) 1,1,3, the 3-tetramethyl guanidine added in 5 minutes in these slurries at 25 ℃; stir after 48 hours; filter slurries; the mother liquor vacuum concentration; obtain oily matter; at silica gel 60(E.Merck) go up and carry out chromatographic separation with the chloroform give elutriant, obtain 1.48g(21%) 2-hydroxymethyl-4-acetyl imidazole, fusing point: 147-148 ℃. ¹H-nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 7.73(S, 1H), the very wide S of 5.46(, 1H), 4.5(bs, 2H), 2.4(S, 3H).

(III) 1.826g(0.013mole) 2-hydroxymethyl-4-acetyl imidazole is dissolved in the Hydrogen bromide of 40ml48%, adds 2.1g(0.013mole again) bromine.Reactant then, is used vacuum concentration 80 ℃ of heating 2 hours, obtains solid.This material is developed with isopropyl ether, and the solid of generation is collected with filtering, and is dry then with the ether washing, obtains 2.2g(56%) 2-hydroxymethyl-4-bromo acetyl imidazole hydrobromide, 183 ℃ of fusing points.Decomposition is arranged, ¹H-nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)-d ₆) ppm(δ): 8.8(S, 1H), 4.8(S, 2 * 2H)

Preparation D

4-ethanoyl-glyoxal ethyline

(I) 1,2-two chloro-1-butylene-3-ketone

With 392g(5.0mole) ethanoyl chlorine and 1817g(18.75mole) suitable, the mixture of anti--1,2-dichloroethene is cooled to 0 ℃ (acetone-the dry ice bath) under anhydrous condition.When keeping mixture temperature to be lower than 25 ℃, 734g(5.5mole) aluminum trichloride (anhydrous) adds in this mixture the other 606g(6.25mole of aluminum chloride in batches) the 1,2-dichloroethene rinsing.After adding, remove cooling bath, mixture reflux (50-60 ℃) night.The refrigerative reaction mixture is poured on ice, separates organic layer, and water layer is with 3 * 500ml dichloromethane extraction.The blended organic layer firmly stirs, and adds 450g sodium-chlor, removes isolating less water.Organic layer filters to remove inorganic salt by diatomite (Celite), then, adds and contains 748g(6mole) in the aqueous solution of yellow soda ash-hydrate, add enough water and just become 2.5 liters of solution.The mixture that obtains stirred 1.5 hours, and precipitated solid filters out with crossing, and uses washed with dichloromethane.Separate organic layer, water layer is with using 200ml dichloromethane extraction secondary respectively, dry mixed organic layer (Na ₂SO ₄).Except that desolvating, distill remaining oily matter with vacuum-evaporation, obtain 517.5g(74.5%) the light yellow liquid product.Boiling point 40-52 ℃ (at 8mm). ¹H-nuclear magnetic resonance spectrum (CDCl ₃) ppm(δ): 2.50(S, 3H), 7.55(S, 1H).

(II) 2-chloro-1,1-dimethoxy-3-butanone

With 695g(5.0mole) 1,2-two chloro-1-butylene-3-ketone slowly adds 297g(5.5mole at 0 ℃) in 5 liters of methanol solutions of sodium methylate.After adding, mixture stirred 1 hour at 0 ℃, added 54g(1.0ole again) sodium methylate continues to stir 1 hour at 0 ℃.This mixture at room temperature stirs a night, adds 1 gram moles of sodium methoxide again, continues to stir 1 hour.Mixture filters (flocculating aids) and desalts to remove, and washs with fresh methanol.Filtrate is dissolved in the isopropyl ether through vacuum concentration pulp thing, and water, saturated sodium bicarbonate solution and salt water washing successively is then, dry on anhydrous magnesium sulfate.Extracting solution obtains remaining oily matter with vacuum concentration, uses vacuum distilling again, obtains main fraction 628g(75%) product, boiling point 66-75 ℃ (at 8mm). ¹H-nuclear magnetic resonance spectrum (CDCl ₃) ppm(δ): 2.33(S, 3H), 3.43(S, 3H), 3.47(S, 3H), 4.23(d, 1H), 4.63(d, 1H).

(III) is with 83.5g(0.50mole) 2-chloro-1,1-dimethoxy-3-butanone, 94.5g(1.0mole) ethanamidine hydrochloride and 123g(1.5mole) sodium acetate adds in the 500ml diox, mixture reflux refrigerative reaction mixture at one night filters by silica filler on the sintered glass filter funnel, with the washing of 3500ml diox.Filtrate and washings mix, and obtain remaining oily matter with vacuum-evaporation, and (600g) uses chromatographic purification on silicagel column, uses eluent ethyl acetate.With every 200ml fraction collection.Collect overhead product behind 16 cuts and be 95: 5 ethyl acetate/methanol.The 18-35 cut is merged, use vacuum evaporating solvent, obtain requiring product 28.82g(46.4%).Recrystallization produces 19.27g(31% from ethyl acetate/isopropyl ether of 1: 1) crystal, fusing point 132-133 ℃.Handle the mother liquor 4.24g(6.8% that gets back again) product. ¹H-nuclear magnetic resonance spectrum (CD ₃OD) ppm(δ): 2.40(S, 3H), 2.43(S, 3H), 7.68(S, 1H).

(IV) is with 1.66g(10mmole) 2-chloro-1,1-dimethoxy-3-butanone, 143g(15mmole) ethanamidine hydrochloride and 2.05g(25mmole) the mixture reflux of sodium acetate in the 50ml diox 24 hours.(40: 60 ethyl acetate/hexane 40mm) are carried out flash chromatography and are separated, and obtain three fractions on silicagel column for diox vacuum-evaporation, remaining oily matter.The 3rd cut white solid (1.121g) is used chromatographic separation (40mm, acetone) once more, obtains 933mg(75.1%) white solid product, by nuclear magnetic resonance spectrum (CDCl ₃) and silicagel column on thin-layer chromatographic analysis judge.This product is pure (spot, 1: 9 methyl alcohol/chloroform).

Preparation E

4-ethanoyl-glyoxal ethyline

(I) 1 benzyl 2 methyl imidazole

Under nitrogen atmosphere, stirring to containing 2.4g(0.1mole) add 8.2g(0.1mole in the 50ml dimethyl formamide pulpous state liquid of sodium hydride) glyoxal ethyline slow thermopositive reaction takes place, temperature reaches 43 ℃.When heat release is gone down, with vapor bath 70 °～75 ℃ internal heating reactant half an hour, then 95 ℃ of heating 15 minutes, no longer produce proved response to finish by gas, it is cooled to 68 ℃, add 12.7g(0.1mole dropwise) benzyl chloride, thermopositive reaction takes place, temperature reaches 95 ℃ and adds back the stirring half an hour, reactant is poured in the 600ml water, (2 * 200ml) extraction products, extract is lumped together successively water, and ((1 * 100ml), 6NHCl(1 * 50ml washing HCl washings is with ether (1 * 25ml) extraction for 1 * 400ml) saturated sodium-chloride water solution with ethyl acetate.Adding sodium hydroxide then makes it become alkalescence.Isolating yellow oil is extracted in the ether, extract MgSO ₄Drying, decompression evaporation down obtain-faint yellow oily thing output: 11.5g(60.5%), nuclear magnetic resonance spectrum shows that the compound that obtains is a monohydrate, and it is used for hydroxymethylation.

(II) 1-benzyl-4-methylol-glyoxal ethyline

8.5g(0.05mole) 1 benzyl 2 methyl imidazole-hydrate, the formaldehyde of 50ml36%, 6ml acetate and 8.0g(0.098mole) the mixture of sodium acetate stirring reflux 26 hours, 1 week of restir (about 65 hours) at room temperature then, and neutralize with solid sodium carbonate.With this neutral solution extract of ethyl acetate extraction MgSO ₄Dry.Decompression down evaporation obtains an oily matter, adds entry (10ml) and Virahol (50ml) in oily matter, one night of solution stirring, vapourisation under reduced pressure is added to the yellow oil that obtains in the water then, adds solid sodium hydroxide and makes solution become strong basicity, with its cooling, use the ether layering.By filtering, separate the white solid that forms, at air drying, output=1.8g(18%), fusing point: 140-146 ℃.It is dissolved in (50 ℃) ethyl acetate of 30ml heat, and filters and purify.Filtrate is concentrated to about 2/3 volume, and cooling obtains the 1.3g white solid, 147～151 ℃ of fusing points.In ethyl acetate: methyl alcohol: the thin-layer chromatographic analysis in the system of diethylamine (80: 10: 10) obtains single spot.

(III) 1 benzyl 2 methyl imidazole-4-formaldehyde

9.0g(0.446mole) 1-benzyl-4-methylol-glyoxal ethyline, 750ml methylene dichloride and 50.0g(0.575mole) mixture of Manganse Dioxide, at room temperature stirred 2 hours, then, it is filtered, use the washed with dichloromethane filter cake, filtrate and washings are lumped together, reduction vaporization obtains oily matter, and oily matter is added in the 100ml ether.And the hexane and a spot of title crystal that add 100ml do solution crystal seed, under nitrogen purging, and cycle displacement hexane, concentrated solution, by filtering, segregation obtains crystalline product: 7.2g, productive rate: 81%; Fusing point: 57～60 ℃.

By concentrated filtrate, obtain second batch of product (0.75g), 57～59.5 ℃ of fusing points, overall yield=89.4%.

(IV) 1-benzyl-4-(1-hydroxyethyl)-glyoxal ethyline

To containing 7.2g(0.306mole) the 100ml tetrahydrofuran solution of 1 benzyl 2 methyl imidazole-4-formaldehyde in add methylmagnesium-chloride (0.044mole) tetrahydrofuran solution of 15ml2.9M, generate white precipitate at once.Mixture at room temperature stirred 30 minutes, and the aqueous ammonium chloride solution with 50ml25% heats together then.Sedimentation and filtration is come out.With the tetrahydrofuran (THF) washing, then at air drying.Filtrate and washings lump together uses Na ₂SO ₄Drying concentrates under vacuum and obtains solid residue, and this residuum is dissolved in the 300ml ebullient ethyl acetate, uses Na ₂SO ₄Drying, decompression are concentrated into the volume of half down, have just separated once cooling solid, filter, and at air drying, ultimate production=7.1g(90%); Fusing point: 162.5～167.5 ℃.

(V) 4-(1-hydroxyethyl)-glyoxal ethyline

With 10.0g(46.23mole) 1-benzyl-4-(1-hydroxyethyl)-glyoxal ethyline, the palladium carbon catalyst of 60ml methyl alcohol and 2.0g5% (50% water), pack in the Pa Er vibrator, import hydrogen to 30 pound/square inch (204 normal atmosphere), with mixture heating up to 50 ℃, and vibrate 16 hours, be cooled to 30 ℃ then, by diatomite filtration, with 10ml methanol wash filter cake.Filtrate and washings are lumped together vapourisation under reduced pressure obtain 6.44g(productive rate 97%) the buttery title product.

Dissolve oily matter by the tetrahydrofuran (THF) that adds capacity, and at room temperature stirred 2 hours, can make the product crystallization.By filtering the crystalline solid of collecting white, at air drying, 107～111 ℃ of fusing points.

(VI) is to containing 1240g(9.989mole) 4(5)-mixture that 101 tetrahydrofuran (THF)s of (1-hydroxyethyl)-glyoxal ethyline reflux in, in 10 minutes, add 2200g(25.293mole) Manganse Dioxide.Mixture refluxes a night (18 hours), then by the diatomite heat filtering, with 41 tetrahydrofuran (THF) washing leaching cakes.

The filtrate and the washings of above-mentioned two batch reactions are lumped together, under normal pressure, stir and be concentrated into about 61.At this moment, mixture becomes solid, adds ethyl acetate (21).Mixture heating up is formed solution, and further remove tetrahydrofuran (THF).When becoming solid, mixture adds 21 ethyl acetate again, and reheat, when mixture becomes solid again, stop heating and stirring, mixture is cooled off a night, add ethyl acetate (3.81) then, with spatula solid matter is smashed to pieces.When it can stir, with this soup compound 50 ℃ of heating be chilled to then in 3 hours 5 ℃ 1 hour, filter then.In the time of 5 ℃, the ethyl acetate washing xanchromatic filter cake 1.51 is then at air drying.The fusing point of output=1887g(76.08%): 128～130 ℃.

Preparation F

4-chloracetyl-glyoxal ethyline and its hydrochloride

To containing 248mg(2.0mmole) logical 5 minutes exsiccant hydrogen chloride gas in the 20ml dichloromethane solution of 4-ethanoyl-glyoxal ethyline, add 192mg(6mmole then) anhydrous methanol.In the solution that obtains, add 297mg(2.2mmole) SULPHURYL CHLORIDE, and mixture at room temperature stirred 1 hour, add SULPHURYL CHLORIDE more at twice.Add 155ml, it reacted completely guaranteeing at interval in 10 minutes, added a few ml methyl alcohol, under vacuum, mixture was concentrated into dried at every turn.The colorless oil that obtains alkalizes with solid sodium bicarbonate, and the solid of collecting precipitation washes with water, and is dry under high vacuum, obtains 167mg(53%) thin white solid.

¹H-nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)-deuterium 6) ppm(δ): 2.25(S, 3H), 4.75(S, 2H), 7.8(S, 1H); Mass spectrum (m/e): 158(M+), 109(M-CH ₂Cl).

Repeat above-mentioned steps with same scale, but, at room temperature stirred 2 hours, obtain 395mg(100% without methyl alcohol and the SULPHURYL CHLORIDE that adds subsequently) hydrochloride, fusing point: 159～166 ℃, decomposition.

Preparation G

2-amino methyl naphthalene

With 10.0g(65.3mmole) 2-cyano group naphthalene, the 2.0g Raney nickel, the mixture of the ammonium hydroxide that 100ml ethanol and 9ml are dense is at 36 pounds of/square inch (2.53kg/cm ²) hydrogenation 4.5 days under the pressure, mixture is filtered, filtrate is condensed into oily matter under vacuum, this oily matter distills under vacuum and obtains colourless aqueous purpose amine, place and solidify, output 2.02g makes thin-layer chromatographic analysis on silica-gel plate, launching with 19: 1 chloroform/methanol, is that 0.1 place shows a spot at Rf value.

Preparation H

The 2-(3-trifluoromethyl) ethamine

(I) 2-(3-trifluoromethyl) acetonitrile

With 12.0g(61.5mmole) the m-trifluoromethyl phenyl-chloride, 9.56g(195mmole) mixture of sodium cyanide and 60ml dimethyl sulfoxide (DMSO) heated 4 hours down at 50 ℃ to 80 ℃, poured in the water then.Use the dichloromethane extraction aqueous mixture, extraction liquid is dry on sodium sulfate, and solvent obtains the 12.2g yellow oil in vacuum-evaporation, uses it for down the step. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 3.80(S, 2H), 7.60(S, 4H).

(II) 7.20g(38.9mmole) the mixture purging with nitrogen gas of acetonitrile, 0.75g Raney nickel, 30ml ethanol and the dense ammonium hydroxide of 4.0ml 2-(3-trifluoromethyl) is then at 3.5kg/cm ²Hydrogenation is 18 hours under the pressure, and by removing by filter catalyzer, filtrate vacuum-evaporation obtains 6.86g(93% in the presence of nitrogen) red oily title amine. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 0.65-1.40(bs, 2H), 2.65-3.40(m, 4H), 7.30-7.60(m, 4H).

The preparation I

The preparation structural formula is (R ³) ₂Ar(CH ₂) ₃NH ₂The general method of 3-arylpropyl amine be described as follows:

3-(4-just-the propyl group phenyl) propyl group amine

(I) 2-cyano group-3-(4-just-the propyl group phenyl) ethyl propenoate

With 20.0g(90mmole) 4-just-propylbenzene formaldehyde diethyl acetal, 20.4g(180mmole) ethyl cyanacetate, 7.2g(93.4mmole) ammonium acetate and 60ml toluene mixture reflux 6 hours, cooling and pour in the water.The mixture that produces extracted with diethyl ether, drying (MgSO ₄), volatiles vacuum-evaporation obtains the thick yellow oil of 23.0g, and it obtains by chromatographic purification on silicagel column, with 2: 1 ethylene dichloride/hexane wash-out, obtains 20.58g(94%) required product. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 0.85-1.95(m, 8H), 2.45-2.70(t, 2H), 4.15-4.60(q, 2H), 7.15-8.05(q, 4H), 8.25(S, 1H).

(II) 3-(4-just-the propyl group phenyl) propionitrile

With 20.50g(84.3mmole) (J) portion of product, 8.75g magnesium chips and 200ml methanol mixture stirred 6 hours under the nitrogen atmosphere, cooled off that to keep temperature be about 30 ℃ the employing cycle.This mixture with hcl acidifying, use extracted with diethyl ether, extraction liquid usefulness sodium hydrogen carbonate solution, water, salt water washing, and at MgSO ₄Last dry, evaporating solvent obtains the 23.8g crude product, purifies by separating at the silica gel upper prop, obtains 11.55g(59% with the ethylene dichloride wash-out) pure 2-cyano group-3-(4-just-the propyl group phenyl) methyl propionate.It mixes with 4.17g sodium-chlor, 175ml dimethyl sulfoxide (DMSO) and 5ml water in the presence of nitrogen, and this mixture heated five hours down at 150 ℃.Reaction mixture is poured in the 700ml water.Extract with 2 * 500ml ethyl acetate.Hybrid extraction liquid is with salt solution (300ml) washing, dry on anhydrous sodium sulphate, and vacuum concentration obtains the required nitrile of 12.5g through the distillation purification: boiling point: 124-128 ℃ (1.0mm) ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 0.75-1.15(t, 3H), 1.30-2.00(m, 2H), 2.40-3.10(m, 6H), 7.15(S, 4H).

(III) 14.13g(81.6mmole) Shang Mian nitrile (distillatory), the mixture of 1.5g Raney nickel, 60ml ethanol and the dense ammonium hydroxide of 8ml is at 3.5kg/cm ²Pressure under hydrogenation 18 hours.This mixture with purging with nitrogen gas, remove by filter catalyzer, the filtrate vacuum concentration is obtained 12.3g(84.8%) clean oily matter, its distillation is obtained 8.60g(59%) the pure amine of colorless oil. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 0.75-1.05(t, 3H), 1.05(S, 3H), 1.15-1.75(m, 4H), 2.30-2.85(m, 6H), 6.95-7.10(m, 4H).

Preparation J

The 4-(4-chloro-phenyl-) butylamine

The preparation structural formula is (R ³) ₂Ar(CH ₂) ₄NH ₂The general method of 4-aryl butylamine be described as follows:

(I) 4-(4-chloro-phenyl-)-the 3-butenoic acid

With 4-chlorobenzaldehyde (10.0g, 68.2mmole), 34.0g(81.9mmole) the 3-(triphenyl phosphonium) propionic acid bromide (prepared in reaction in dimethylbenzene) by triphenyl phosphonium and 3-bromo-propionic acid, 12.5g the mixture of sodium hydride (50% mineral oil solution) and 200ml dimethyl sulfoxide (DMSO) heated 5 hours down at 120 ℃, cooling, and pour in the frozen water.Make the mixture alkalize with yellow soda ash, use extracted with diethyl ether, get rid of extraction liquid, the acidifying water, with ether extract again, dry (MgSO ₄), evaporation ether obtains 6.9g(51% under the vacuum) required acid. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 3.10-3.30(d, 2H), 6.10-6.35(m, 2H), 7.20(S, 4H), 11.55-11.75(bs, 1H)

(II) 4-(4-chloro-phenyl-) butyric acid

With 19.5g(98.2mmole) above the mixture of part unsaturated acid, 1.95g palladium carbon catalyst and 200ml ethyl acetate of (I) at 3.5kg/cm ²Hydrogenation under the pressure is handled with general method, obtains required saturated acid, and productive rate is 91%. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 1.75-2.80(m, 6H), 6.95-7.40(q, 4H), 9.15-10.25(bs, 1H)

(III) 4-(4-chloro-phenyl-) butyramide

Will be from the 8.8g(44.3mmole of part (III)) saturated acid and 45ml thionyl chloride mixture reflux 3 hours.Cool off this mixture, excessive thionyl chloride is removed in vacuum-evaporation.Thick chloride of acid is dissolved in the 20ml ether.In 0 ℃, 20 minutes, the dense ammonium hydroxide of 67ml is dropwise added in this solution, form brown solid immediately.0 ℃ down this mixture stir 1 hour, add water 80ml, mixture with the extraction of 3 * 100ml ethyl ester, mixed ether layer with salt water washing, drying (MgSO ₄), vacuum concentration obtains 8.70g(97%) acid amides. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 1.60-2.40(m, 4H), 2.45-2.85(t, 2H), 5.25-6.10(bs, 2H), 6.90-7.30(q, 4H).

The 8.70g(44mmole that (IV) will obtain from top (III) part) mixture of acid amides and 71ml1.0M borine/tetrahydrofuran (THF) (the 60ml tetrahydrofuran (THF) is wherein arranged) stirred 4 hours, reactant hydrochloric acid (36ml) chilling of 6N, with this mixture of extracted with diethyl ether, dry extraction liquid (Na ₂SO ₄), concentrate in a vacuum.Remaining oil stirs with isopropyl ether, filters, and vacuum-evaporation filtrate obtains the 2.08g product.With the ethyl acetate extraction solution 2.4g that gets back. ¹H-NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃) ppm(δ): 1.15(S, 2H), 1.30-1.90(m, 4H), 2.40-2.90(q, 4H), 6.90-7.35(q, 4H)

* hydrobromic salt replaces acid to make with 48% Hydrogen bromide.

Claims (9)

1, the preparation compound of following structural or its method of available acid salt pharmaceutically,

Wherein:

Y is CH, and X is S or NH, or

Y is N, and X is NH,

R ¹Be (the C of straight or branched ₄-C ₁₀) alkyl, (R ³) ₂C ₆H ₃Or (R ⁵) ₂Ar (CH ₂) _n, n is 1 to 4 integer in the formula, R ³Base can be identical or different, is H, F, Cl, Br, I, CH ₃, CH ₃O; Ar is phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidyl, thiazolyl, or the residue of imidazolyl;

R ²Be H or (C ₁-C ₄) alkyl;

R ⁴Be H, (C ₁-C ₅) alkyl, NH ₂Or CH ₂OH; It is characterized in that:

(a) when Y be CH and X when being S or NH, the compound of structure formula IV

Compound with the structural formula (X) of equimolar amount

In the formula: R ¹, R ², R ⁴As above-mentioned definition, X is S or NH, and Hal is preferably Br of Cl or Br;

In the presence of the organic solvent of reactionlessness, reaction when 20 to 120 ℃ of temperature; Or

(b) when Y be N and X when being NH, the acylhydrazine compound of structure formula II

Formula R with at least one molar equivalent ⁴CSNH ₂Thiamides, R in the formula ⁴By above-mentioned definition.

In the presence of the organic solvent of reactionlessness, reaction when 50 to 150 ℃ of temperature.

2, according to claim 1(a) part method, wherein, above-mentioned solvent is acetone or dimethyl formamide.

3, according to claim 1(a) method of part, wherein, above-mentionedly carry out when being reflected at 50 to 60 ℃ of temperature.

4, according to claim 1(a) part method, wherein, R ²Be H, R ⁴Be CH ₃, R ¹Be n-pentyl, n-hexyl, n-heptyl, n-octyl, 2-octyl group, phenyl, benzyl, phenylethyl, phenyl propyl, phenyl butyl, 4-chloro benzyl, 4-chlorophenyl ethyl, 4-chlorophenyl propyl group, 4-methoxy-benzyl, 4-p-methoxy-phenyl ethyl, furyl methyl, thienyl methyl, pyridylmethyl, 1-naphthyl methyl or 2-naphthyl methyl.

5, according to the method for claim 4, wherein, the R in raw material ⁴Be methyl, R ²During for H, R ¹Be respectively n-hexyl, 2-octyl group, benzyl, furfuryl or 2-thenyl.

6, according to claim 1(b) part method, wherein above-mentioned solvent is a butanols.

7, according to claim 1(b) part or the method for claim 6, wherein, carry out under the above-mentioned temperature that is reflected at solvent refluxing.

8, according to claim 1(b) part method, wherein, R ¹Be n-heptyl, 2-octyl group or benzyl; R ²Be H, R ⁴Be H, CH ₃Or NH ₂

9, according to the process of claim 1 wherein the above-claimed cpd produced form segregation with hydrobromate.