CN105399700A - Thiazolidine derivative, as well as preparation method and application thereof - Google Patents

Thiazolidine derivative, as well as preparation method and application thereof Download PDF

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CN105399700A
CN105399700A CN201510747924.2A CN201510747924A CN105399700A CN 105399700 A CN105399700 A CN 105399700A CN 201510747924 A CN201510747924 A CN 201510747924A CN 105399700 A CN105399700 A CN 105399700A
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compound
oxo
thiazolidine
amino
ethyl
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严洁
李轩
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Tianjin Hankang Pharmaceutical Biotechnology Co Ltd
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to the field of anti-diabetic medicines, and provides a thiazolidine derivative having a structure in a formula (I) shown in the specification or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and R6 are defined in the specification. The invention further provides a preparation method of the derivative and pharmaceutically acceptable salt thereof, a medicine composition and application of the thiazolidine serving as effective ingredients in preparation of diabetes mellitus treatment medicines.

Description

Tetrahydrothiazole derivates, Preparation Method And The Use
The application is the divisional application being entitled as the Chinese Patent Application No. 201310002359.8 of " tetrahydrothiazole derivates, Preparation Method And The Use " submitted on January 6th, 2013.
Technical field
The invention belongs to medical art, or rather, relate to a class through the tetrahydrothiazole derivates of chemosynthesis or its pharmacy acceptable salt, the preparation method of these derivatives or its pharmacy acceptable salt, pharmaceutical composition and as the purposes of effective constituent in preparation treatment diabetes medicament.
Background technology
Along with the problem of an aging population is day by day serious, diabetes have become the formidable enemy having a strong impact on health of people and life.
Diabetes are a kind of common chronic diseases, and according to International Diabetes Federation's prediction, within 2010, whole world diabetes prevalence is about 6.4% (about 2.85 hundred million patient), and expect the year two thousand thirty, diabetes number of patients will rise to 4.38 hundred million.China existing diabetic subject about 3,980 ten thousand, expect 2025 and will reach 5,930 ten thousand, wherein 90% is diabetes B patient, and current Type 2 Diabetes In China patient occupies first of the whole world, and Type 2 Diabetes In China pharmaceutical market will reach 2,500,000,000 dollars in 2014.Along with improving constantly of standard of living, the sickness rate in children also has the trend of rising.Diabetes have cures difficult, costly feature, have the title of " rich man disease ".
The medicine being used for the treatment of diabetes at present mainly contains Regular Insulin and insulin analog, biguanides, sulfonylurea, non-sulfonylurea Insulin secretagogues (repaglinide and nateglinide), thiazolidinediones, alpha-glucosidase inhibitor and amylin analogs (tripro-amylin) etc.Above medicine is only effective within the specific limits, effectively can not control the development of diabetes, and tolerance is limited and/or have untoward reaction in various degree, as: single therapy be difficult to make that patient blood glucose is up to standard, glucose intolerance, hypoglycemia, body weight increase, lactic acidosis and oedema etc.
In the research to diabetes pathophysiological mechanism with in being familiar with, find glucagon-like peptide (glucagon-likepeptide1, GLP-1) play an important role in adjustment blood sugar, the action character of dipeptidyl peptidase-IV (DPP-IV) inhibitor developed on this basis is different from traditional antidiabetic drug, provides new selection for diabetic subject controls blood sugar.The appearance of DPP-IV inhibitor, overcoming the shortcoming that traditional insulin preparation can not simulate Regular Insulin physiologic secretion and compliance difference very well, providing more choices for effectively controlling blood sugar.Prolonged application DPP-IV inhibitor can also increase the quantity of B cell, the Progressive symmetric erythrokeratodermia of diabetes B can be prevented well to develop, cure diabetes even completely.Therefore, DPP-IV inhibitor will have more extensive research in treatment diabetes, and become the focus and emphasis of the world of medicine's research and development in recent years with the mechanism of action of its uniqueness and good tolerance.
Such medicine has good security and tolerance, but there is certain untoward reaction, as Xi Gelieting have upper respiratory tract infection, rhinopharyngitis, headache, feel sick, diarrhoea, stomachache etc., also there are the anaphylaxis such as angioedema, fash, urticaria, cutaneous vasculitis, denuded skin infringement, the rising of liver enzyme, urinary tract infections, rhinorrhea, cough, expiratory dyspnea, weak and pancreatitis etc. after listing.Vildagliptin has headache, dizzy, nauseating, cough, rhinopharyngitis, hypertension deterioration etc.BMS-477118 also has upper respiratory tract infection, headache, rhinopharyngitis, urinary tract infections etc.So the DPP-IV inhibitor finding new chemical structure is the focus of research both at home and abroad.
Present invention finds novel DPP-IV inhibitor, these compounds are find that the medicine being used for the treatment of diabetes, particularly non insulin dependent diabetes brings hope further.
Summary of the invention
One object of the present invention is, discloses tetrahydrothiazole derivates or its pharmacy acceptable salt.
Another object of the present invention is, discloses the synthetic method of tetrahydrothiazole derivates or its pharmaceutically-acceptable salts.
Another object of the present invention is, the pharmaceutical composition that to disclose with tetrahydrothiazole derivates or its pharmacy acceptable salt be activeconstituents.
A further object of the invention is, discloses the application as ofhypoglycemic medicine aspect of tetrahydrothiazole derivates or its pharmacy acceptable salt, for the preparation of the purposes for the treatment of diabetes medicament aspect.
The present invention relates to compound or its pharmacy acceptable salt of logical formula I structure:
（Ⅰ）
Wherein, R 1for: the cycloalkyl of C3-C8; By the alkyl of C1-C4, halogen, cyano group, carboxyl, the alkoxyl group of C1-C4, replaces the alkoxyl group of C1-C4, the cycloalkyl of the C3-C8 that hydroxyl replaces;
R 2for: hydrogen, the alkyl of C1-C4;
R 3, R 4: be at the same time or separately, hydrogen, the alkyl of C1-C4, the carbalkoxy of C1-C6, carboxyl, by hydrogen, the alkyl of C1-C4, the phenyl of halogen substiuted;
R 3, R 4representative:
R 5, R 6: hydrogen, carboxyl is carbonyl time on same carbon atom.
Representative compound is:
N-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-Nitromethylene thiazolidine (compound 1),
N-(1-oxo-2-(1-itrile group cyclopropylamino)) ethyl-2-Nitromethylene thiazolidine (compound 2),
N-(1-oxo-2-ring penta is amino) ethyl-2-Nitromethylene thiazolidine (compound 3),
N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta amino)) ethyl-2-Nitromethylene thiazolidine (compound 4),
N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy basic ring penta amino)) ethyl-2-Nitromethylene thiazolidine (compound 5),
The trans-4-hydroxy cyclohexylphenyl of N-(1-oxo-2-(is amino)) ethyl-2-Nitromethylene thiazolidine (compound 6),
N-(1-oxo-2-(4-t-butylcyclohexyl is amino)) ethyl-2-Nitromethylene thiazolidine (compound 7),
N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) ethyl-2-Nitromethylene thiazolidine (compound 8),
N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy Cyclohexylamino)) ethyl-2-Nitromethylene thiazolidine (compound 9),
N-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 10),
N-(1-oxo-2-ring penta is amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 11),
N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 12),
N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy basic ring penta amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 13),
N-(1-oxo-3-(1-itrile group cyclopropylamino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 14),
N-(1-oxo-3-((1s, 2s)-(+)-2-benzyloxy basic ring penta amino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 15),
N-(1-oxo-3-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 16),
N-(1-oxo-3-(1-carboxy cyclohex is amino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 17),
N-(1-oxo-2-(2-difluoro cyclopropylamino)) propyl group-2-Nitromethylene thiazolidine (compound 18),
N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta amino)) propyl group-2-Nitromethylene thiazolidine (compound 19),
N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy Cyclohexylamino))) propyl group-2-Nitromethylene thiazolidine (compound 20),
N-(1-oxo-2-(Cyclohexylamino)) propyl group-2-Nitromethylene thiazolidine (compound 21),
N-(1-oxo-2-(4-t-butylcyclohexyl is amino)) propyl group-2-Nitromethylene thiazolidine (compound 22),
N-(1-oxo-2-((1R, 2R)-(+)-2-benzyloxy basic ring penta amino)) propyl group-2-methylthiazol alkane (compound 23),
N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) propyl group-2-methylthiazol alkane (compound 24),
N-(1-oxo-2-Cyclohexylamino) propyl group-2-methoxycarbonyl thiazolidine (compound 25),
N-(1-oxo-2-(4-t-butylcyclohexyl is amino)) propyl group-4-L-methoxycarbonyl thiazolidine (compound 26).
The compound of logical formula I structure contains basic group, pharmacy acceptable salt, refers to and the salt that organic acid, inorganic acid reaction generate.Mineral acid has hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid etc., and organic acid has Citric Acid, methylsulfonic acid, fumaric acid, propanedioic acid etc.
The compound of logical formula I structure contains acidic-group, pharmacy acceptable salt, refers to and basic metal; Alkalimetal hydride, as sodium hydride, potassium hydride KH; Alkali metal hydroxide, as sodium hydroxide, potassium hydroxide; Alkali-metal carbonate, supercarbonate, as sodium carbonate, salt of wormwood, sodium bicarbonate, the salt that the reaction such as saleratus generates.Equally, also can with alkaline-earth metal; Alkaline earth metal hydride; Alkaline earth metal hydroxides; The carbonate of alkaline-earth metal, the salt that the reaction such as supercarbonate generates.
The preparation method of type I compound of the present invention, is undertaken by following reaction scheme:
A. thiazolidine compounds (1) in the basic conditions, reacts with halogen acyl halide (2), generates intermediate 3;
B. intermediate 3 in the basic conditions, reacts with substituted cycloalkyl ammonia (R1NH2), generates the compound of structure shown in formula I;
Wherein, R 1, R 2, R 3, R 4, R 5, R 6definition with described in claim 1, X, Y are chlorine or bromine.
The compound that compound thiazolidine (1) represents has:
2-Nitromethylene thiazolidine (CAS registration number: 66357-40-2), 2-methylthiazol alkane (CAS registration number: 24050-16-6), thiazolidine-2-methyl-formiate hydrochloride (CAS registration number: 24050-16-6),
Thiazolidine (CAS registration number: 504-78-9), thiazolidine-2-formic acid (CAS registration number: 504-78-9),
L-thiazolidine-4-formic acid (CAS registration number: 34592-47-4) and 2-(4-bromophenyl)-2-methylthiazol base-4-ketone etc., can buy and obtain.
The compound that halogen acyl halide (2) represents has:
Chloroacetyl chloride (CAS registration number: 79-04-9), bromoacetyl bromide, bromoacetyl chloride, 3-chlorpromazine chloride (CAS registration number: 625-36-5), 4-chlorobutanoylchloride (CAS registration number: 4635-59-0) etc., can buy and obtain.
The compound that substituted cycloalkyl ammonia (R1NH2) represents has:
1-amino-1-cyclopropane nitrile hydrochloride (CAS registration number: 127946-77-4), 1-amino-1-cyclopropane carboxylic acid acid hydrochloride (CAS registration number: 68781-13-5), cyclopropylamine (CAS registration number: 765-30-0),
2,2-difluoro cyclopropylamine (CAS registration number: 105614-25-5), ring butylamine (CAS registration number: 2516-34-9),
Cyclopentamine (CAS registration number: 1003-03-8), (1s, 2s)-(+)-2-benzyloxy cyclopentamine (CAS registration number: 181657-57-8), (1R, 2R)-(-)-2-benzyloxy cyclopentamine (CAS registration number: 181657-56-7), aminocyclohexyl formic acid (CAS registration number: 2756-85-6), trans-4-Trans-4-Amino Cyclohexanol (CAS registration number: 27489-62-9), trans-2-aminocyclohexyl alcohol hydrochloride, (1s, 2s)-(+)-2-benzyloxy hexahydroaniline, (1R, 2R)
-(-)-2-benzyloxy hexahydroaniline, 4-isobutyl-hexahydroaniline, hexahydroaniline (4998-76-9), cycloheptylamine and cyclooctylamine etc., can buy and obtain.
Reactions steps a, thiazolidine compounds (1) in the basic conditions, reacts with halogen acyl halide (2), and generate intermediate 3, described alkaline condition refers to and adds organic bases and mineral alkali at the same time or separately, and organic bases has triethylamine, pyridine, morpholine, piperidines etc.; Mineral alkali has sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate etc.An alkali metal salt of alcohol, as sodium methylate, sodium ethylate, potassium tert.-butoxide etc.
Reactions steps b, intermediate 3 in the basic conditions, reacts with substituted cycloalkyl ammonia (R1NH2), and generate the compound of structure shown in formula I, described alkaline condition is identical with reactions steps a.
Action solvent range of choice is comparatively large, preferred polar aprotic solvent, as acetonitrile, and methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane, acetone, DMSO, DMF etc.
Reaction can be carried out in larger scope, and reactions steps a carries out at-20 DEG C-50 DEG C, and reactions steps b carries out at 20 DEG C-120 DEG C, the long reaction time needed under low temperature, and the reaction times needed under high temperature is short, all can reach satisfied effect.
This compounds is effective for treatment human diabetes.Although compound of the present invention can without the direct administration of any preparation, described various compounds are preferably to use with the acceptable pharmaceutical excipient pharmaceutical compositions of pharmaceutics.The acceptable pharmaceutical excipient of pharmaceutics comprises thinner, lubricant, tackiness agent, disintegrating agent, stablizer, solvent etc.
Thinner of the present invention includes but not limited to starch, Microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose, low molecular dextran etc.; Described lubricant includes but not limited to Magnesium Stearate, stearic acid, sodium-chlor, sodium oleate, DL-LEUCINE, sodium laurylsulfate, Macrogol 4000-6000, the husky mother in pool Lip river etc.; Described tackiness agent includes but not limited to water, ethanol, starch slurry, syrup, gelatin, methylcellulose gum, Vltra tears, Xylo-Mucine, sodium alginate, polyvinylpyrrolidone etc.; Described disintegrating agent includes but not limited to starch, sodium starch glycolate, effervescent mixture and sodium bicarbonate and Citric Acid, tartrate, low-substituted hydroxypropyl cellulose etc.; Described stablizer includes but not limited to that polysaccharide is as kordofan gum, agar, alginic acid, acrylate resins, ether of cellulose and carboxymethyl crusta ester etc.; Described solvent includes but not limited to the salts solution etc. of water, phosphate buffered saline buffer, balance;
The difference that described composition needs according to treatment, can make various different preparation, comprise various solid orally ingestible, liquid oral medicine, injection etc.The acceptable oral preparation solid preparation of pharmaceutics has: conventional tablet, dispersible tablet, enteric coated tablet, particle, capsule, dripping pill, powder etc., and oral liquid has oral liquid, emulsion; Injection has: little liquid drugs injection, transfusion, freeze-dried powder etc.Each preparation can be prepared from according to the technique of routine.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 1% ~ 90%(weight of composition).
The hypoglycemic activity of the compounds of this invention is further illustrated below by experiment.
the restraining effect of DPP IV
Sample, reagent and instrument:
DPP IV (DipeptidylPeptidaseIV, DPP-4, Sigma Co., USA), glycyl proline(Pro) p-Nitroaniline (Gly-Pro-pNA, 25MG, Sigma Co., USA), Tris-HCL damping fluid (pH:8.2), press down dipeptides element A (IIe-Pro-IIe, Sigma Co., USA).The full-automatic microplate reader of Coda (French Bio-Rad company).
Experiment is divided into 27 groups: 26 compound groups and a positive drug group.Often group establishes 2 multiple holes, is respectively blank group (damping fluid+substrate), negative control group (enzyme+damping fluid+substrate) and experimental group (test-compound+enzyme+damping fluid+substrate).First by test-compound, DPP-4, substrate and damping fluid water-bath 30min at 37 DEG C of temperature, then add in 96 orifice plates successively according to the order of test-compound, enzyme, damping fluid, substrate, add-on: blank group adds damping fluid 95 microlitre, substrate 5 microlitre; Negative control group adds enzyme 10 microlitre, damping fluid 85 microlitre, substrate 5 microlitre; Experimental group adds test-compound 10 microlitre, enzyme 10 microlitre, damping fluid 75 microlitre, and substrate 5 microlitre hatches 60min for 37 DEG C, surveys absorbancy (A) under 400nm wavelength.The IIe-Pro-IIe of configuration different concns gradient (concentration is respectively 0.10,0.05,0.03,0.02,0.01g/L), observe the IIe-Pro-IIe inhibiting rate changing conditions of different concns.Test-compound is mixed with the solution of different concns gradient, observes the change of the inhibiting rate to DPP-4.
Statistical procedures adopts SPSS17.0 statistical software to carry out data processing, and data represent with mean ± standard deviation (± s), and inspection level a is 0.05.
To the restraining effect of DPP-4, test-compound all has the effect of certain suppression DPP-4 activity, and along with the restraining effect of rising to DPP-4 activity of concentration stronger.
Concentration (the IC of DPP-4 activity inhibited one half test-compound 50value), be by the solution of test-compound different concns gradient to the data of the inhibiting rate of DPP-4, undertaken by SPSS17.0 statistical software that data processing obtains.Result is as follows:
Test-compound IC 50Value (μM) mean value ± SD Test-compound IC 50Value (μM) mean value ± SD
Compound 1: 0.025±0.002 Compound 14: 0.065±0.007
Compound 2: 0.029±0.003 Compound 15: 0.062±0.006
Compound 3: 0.015±0.002 Compound 16: 0.055±0.005
Compound 4: 0.025±0.003 Compound 17: 0.052±0.004
Compound 5: 0.019±0.003 Compound 18: 0.020±0.003
Compound 6: 0.017±0.002 Compound 19: 0.024±0.002
Compound 7: 0.015±0.002 Compound 20: 0.022±0.003
Compound 8: 0.016±0.003 Compound 21: 0.020±0.004
Compound 9: 0.022±0.003 Compound 22: 0.026±0.005
Compound 10: 0.024±0.002 Compound 23: 0.033±0.004
Compound 11: 0.026±0.004 Compound 24: 0.038±0.005
Compound 12: 0.020±0.003 Compound 25: 0.030±0.004
Compound 13: 0.022±0.004 Compound 26: 0.031±0.004
IIe-Pro-IIe 0.01±0.001mg/ml
IC 50value (μM) mean value: the mean value being 3 experiments.
tetraoxypyrimidine is caused to the hypoglycemic activity research of diabetic mice
Test-compound is made into the suspension of 5mg/ml with 2% Xylo-Mucine, by 50mg/kg dosed administration; Gliclazide is made into the suspension of 5mg/ml with 2% Xylo-Mucine, by 80mg/kg dosed administration;
Tetraoxypyrimidine is made into 15mg/ml with fresh physiological salt solution, by 75mg/kg dosed administration.
Healthy mice, male and female half and half, body weight 18-22 gram, primary standard, animal fasting is tail vein injection tetraoxypyrimidine after 16 hours.Fasting 6 hours after 48 hours, blood is got from mouse ball rear vein beard with kapillary, centrifugation serum, use determination of glucose oxidase serum glucose level, select blood glucose value higher than the mouse random packet of 400mg/dl: model group, positive drug group and test-compound, administration 3 days, 24 h fast, get blood in 1 hour after last administration, measure blood-sugar content.Result is as follows:
Grouping Blood-sugar content (mg/dl) Grouping Blood-sugar content (mg/dl)
Model 587.9±52.1 Gliclazide 220.2±31.8
Compound 1 211.2±29.1 Compound 4 204.1±30.3
Compound 8 206.9±26.7 Compound 13 205.2±24.4
Compound 16 212.5±21.4 Compound 22 209.3±20.6
Compound 23 200.4±23.2 Compound 26 210.6±27.4
embodiment:
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that it limits the scope of the invention by any way.
reference example 1: n-(2-chloracetyl)-2-Nitromethylene thiazolidine (3-1)
14.6g(0.1mol is added in round-bottomed flask) 2-Nitromethylene thiazolidine, the methylene dichloride of 75ml drying and 12.1g triethylamine, stir lower ice bath and be cooled to-20 DEG C ~ 5 DEG C, drip the mixed solution that chloroacetyl chloride (12.3g) is dissolved in methylene dichloride (20ml), after dropwising, stirring at room temperature 1h.After adding 20ml dchloromethane in reaction system, then wash with water, organic over anhydrous dried over sodium sulfate, revolve and steam organic solvent to the greatest extent, residue over silica gel column chromatography for separation, i.e. give light yellow oil, productive rate 90.3%(HPLC:96.8%), MS:222.99 (M+H).Without the need to purifying.
reference example 2: n-(2-chloracetyl)-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (3-2)
With reference to the method for reference example 1, replace 2-Nitromethylene thiazolidine with 2-(4-the bromophenyl)-2-methylthiazol base-4-ketone of 0.1mol, can yellow oil be obtained, productive rate 93.6%(HPLC:97.4%),
MS:347.94(M+H)。Without the need to purifying.
reference example 3: n-(2-chloracetyl)-2-methoxycarbonyl thiazolidine (3-3)
18.3g thiazolidine-2-methyl-formiate hydrochloride (0.1mol) is added in round-bottomed flask, the tetrahydrofuran (THF) of 90ml drying and 29.6g pyridine, drip at 15 DEG C ~ 25 DEG C the mixed solution that chloroacetyl chloride (12.9g) is dissolved in tetrahydrofuran (THF) (36ml) under stirring, after dropwising, insulated and stirred 3h.Revolve and steam organic solvent to the greatest extent, add 65ml methylene dichloride and 45ml water in reaction system, separate organic layer, organic over anhydrous dried over sodium sulfate, revolves and steams organic solvent, i.e. give light yellow oil to the greatest extent, productive rate 91.1%(HPLC:98.2%), MS:224.0 (M+H).Without the need to purifying.
reference example 4: n-(2-chloracetyl)-4-L-methoxycarbonyl thiazolidine (3-4)
With reference to the method for reference example 1, replace 2-Nitromethylene thiazolidine with the 4-L-methoxycarbonyl thiazolidine of 0.1mol, can following compounds be obtained:
N-(2-chloracetyl)-4-L-methoxycarbonyl thiazolidine (3-4), light yellow oil, productive rate 92.4%(HPLC:97.6%), MS:224.0 (M+H).Without the need to purifying.
reference example 5: n-(3-bromine propionyl)-2-methoxycarbonyl thiazolidine (3-5)
With reference to the method for reference example 3, replace chloroacetyl chloride with 3-bromo propionyl chloro, can yellow oil be obtained, productive rate 87.7%(HPLC:97.0%), MS:281.97 (M+H).Without the need to purifying.
reference example 6: n-(3-bromine propionyl)-4-L-methoxycarbonyl thiazolidine (3-6)
With reference to the method for reference example 3, chloroacetyl chloride is replaced with 3-bromo propionyl chloro, thiazolidine-2-methyl-formiate hydrochloride (0.1mol) is replaced with 0.1molL-thiazolidine-4-methyl-formiate, yellow oil can be obtained, productive rate 89.5%(HPLC:97.8%), MS:281.97 (M+H).Without the need to purifying.
reference example 7: n-(2-bromine propionyl)-2-Nitromethylene thiazolidine (3-7)
14.6g(0.1mol is added in round-bottomed flask) 2-Nitromethylene thiazolidine, the trichloromethane of 110ml drying and 15.0g piperidines, drip at 20 DEG C-30 DEG C the mixed solution that 2-bromo propionyl chloro (17.5g) is dissolved in trichloromethane (56ml) under stirring, after dropwising, 1.5h is stirred in insulation DEG C.Reaction system adds 50ml water washing, organic over anhydrous dried over sodium sulfate, revolves and steams organic solvent to the greatest extent, residue over silica gel column chromatography for separation, i.e. give light yellow oil, productive rate 88.9%(HPLC:96.3%), MS:280.95 (M+H).Without the need to purifying.
reference example 8-12:
With reference to the method for reference example 7, replace 2-Nitromethylene thiazolidine with the different thiazolidine compounds of 0.1mol, can following compounds be obtained:
N-(2-bromine propionyl)-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (3-8), light yellow oil, productive rate 86.8%(HPLC:98.3%), MS:407.9 (M+H).
N-(2-bromine propionyl)-2-methylthiazol alkane (3-9), light yellow oil, productive rate 88.7%(HPLC:97.7%), MS:237.98 (M+H).
N-(2-bromine propionyl) thiazolidine (3-10), light oil, productive rate 90.1%(HPLC:97.1%), MS:223.97 (M+H).
N-(2-bromine propionyl)-2-methoxycarbonyl thiazolidine (3-11), light yellow oil, productive rate 87.4%(HPLC:96.6%), MS:281.97 (M+H).
N-(2-bromine propionyl)-4-methoxycarbonyl thiazolidine (3-12), light yellow oil, productive rate 89.5%(HPLC:98.2%), MS:281.97 (M+H).
Above compound, all without the need to purifying, is directly used in next step reaction.
embodiment 1: n-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-Nitromethylene thiazolidine (compound 1)
11.1g intermediate N (2-chloracetyl)-2-Nitromethylene thiazolidine (3-1) is added in reaction flask; dissolved with the tetrahydrofuran (THF) of 170ml drying and 15.1g triethylamine; add 6.1g2 again; 2-difluoro cyclopropylamine; stirring at room temperature 36h; react complete; revolve the most organic solvent of steaming and obtain crude product; this crude product purification by silica gel column chromatography (n-hexane/ethyl acetate; 3:1); obtain faint yellow solid, i.e. N-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-Nitromethylene thiazolidine (compound 1), MS:280.05 (M+H).Productive rate 87.6%(HPLC:98.3%).
embodiment 2-9:
With reference to the method for embodiment 1, target compound 2 ~ compound 9 can be obtained.
With reference to the method for embodiment 1, replace 2,2-difluoro cyclopropylamine with equimolar 1-itrile group cyclopropylamine, compound 2:N-(1-oxo-2-(1-itrile group cyclopropylamino can be obtained)) ethyl-2-Nitromethylene thiazolidine.MS:269.06。Productive rate 81.2%(HPLC:97.6%).
With reference to the method for embodiment 1, replace 2,2-difluoro cyclopropylamine by equimolar cyclopentamine, compound 3:N-(1-oxo-2-ring penta can be obtained amino) ethyl-2-Nitromethylene thiazolidine.MS:272.1(M+H)。Productive rate 78.5%(HPLC:97.9%).
With reference to the method for embodiment 1, with equimolar (1s, 2s)-(+)-2-benzyloxy cyclopentamine replaces 2,2-difluoro cyclopropylamine, compound 4:N-(1-oxo-2-((1s can be obtained, 2s)-(+)-2-benzyloxy basic ring penta amino)) ethyl-2-Nitromethylene thiazolidine.MS:378.1(M+H)。Productive rate 83.2%(HPLC:98.8%).
With reference to the method for embodiment 1, with equimolar (1R, 2R)-(+)-2-benzyloxy cyclopentamine replaces 2,2-difluoro cyclopropylamine, compound 5:N-(1-oxo-2-((1R can be obtained, 2R)-(-)-2-benzyloxy basic ring penta amino)) ethyl-2-Nitromethylene thiazolidine.MS:378.1(M+H)。Productive rate 84.1%(HPLC:98.6%).
With reference to the method for embodiment 1, replace 2,2-difluoro cyclopropylamine with equimolar trans-4-hydroxy cyclohexylphenyl amine, the trans-4-hydroxy cyclohexylphenyl of compound 6:N-(1-oxo-2-(can be obtained amino)) ethyl-2-Nitromethylene thiazolidine.MS:302.11(M+H)。Productive rate 88.9%(HPLC:98.8%).
With reference to the method for embodiment 1, replace 2,2-difluoro cyclopropylamine with equimolar 4-t-butylcyclohexyl amine, compound 7:N-(1-oxo-2-(4-t-butylcyclohexyl can be obtained amino)) ethyl-2-Nitromethylene thiazolidine.MS:342.18(M+H)。Productive rate 90.3%(HPLC:99.1%).
With reference to the method for embodiment 1, with equimolar (1s, 2s)-(+)-2-benzyloxy hexahydroaniline replaces 2,2-difluoro cyclopropylamine, compound 8:N-(1-oxo-2-((1s can be obtained, 2s)-(+)-2-benzyloxy Cyclohexylamino)) ethyl-2-Nitromethylene thiazolidine.MS:392.2(M+H)。Productive rate 84.2%(HPLC:97.7%).
With reference to the method for embodiment 1, use equimolar 1R, 2R)-(-)-2-benzyloxy hexahydroaniline replaces 2,2-difluoro cyclopropylamine, compound 9:N-(1-oxo-2-((1R can be obtained, 2R)-(-)-2-benzyloxy Cyclohexylamino)) ethyl-2-Nitromethylene thiazolidine.MS:392.2(M+H)。Productive rate 82.8%(HPLC:98.4%).
embodiment 10: n-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 10)
17.4g intermediate N (2-chloracetyl)-2-(4-bromophenyl)-2-methylthiazol base-4-ketone is added in reaction flask; dissolved with the acetonitrile of 250ml drying and 14.4g piperidines, then added 4.7g2,2-difluoro cyclopropylamine; 38 DEG C are stirred 21h; react complete, revolve the most organic solvent of steaming and obtain crude product, this crude product purification by silica gel column chromatography (n-hexane/ethyl acetate; 4:1); obtain faint yellow solid, i.e. compound 10, MS:407.0 (M+H).Productive rate 84.5%(HPLC:97.8%).
embodiment 11-13:
With reference to the method for embodiment 10, target compound 11 ~ compound 13 can be obtained.
With reference to the method for embodiment 10, replace 2,2-difluoro cyclopropylamine by equimolar cyclopentamine, compound 11:N-(1-oxo-2-ring penta can be obtained amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone.MS:399.1(M+H)。Productive rate 82.6%(HPLC:97.5%).
With reference to the method for embodiment 28, with equimolar (1s, 2s)-(+)-2-benzyloxy cyclopentamine replaces 2,2-difluoro cyclopropylamine, compound 12:N-(1-oxo-2-((1s can be obtained, 2s)-(+)-2-benzyloxy basic ring penta amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone.MS:503.1(M+H)。Productive rate 80.8%(HPLC:98.3%).
With reference to the method for embodiment 28, with equimolar (1R, 2R)-(-)-2-benzyloxy cyclopentamine replaces 2,2-difluoro cyclopropylamine, compound 13:N-(1-oxo-2-((1R can be obtained, 2R)-(-)-2-benzyloxy basic ring penta amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone.MS:503.1(M+H)。Productive rate 86.4%(HPLC:98.7%).
embodiment 14: n-(1-oxo-3-(1-itrile group cyclopropylamino)) propyl group-2-methoxycarbonyl thiazolidine (compound 14)
14.1g intermediate N (3-bromine propionyl)-2-methoxycarbonyl thiazolidine (3-5) is added in reaction flask; dissolved with the tetrahydrofuran (THF) of 250ml drying and 14.4g triethylamine; add 4.1g1-itrile group cyclopropylamine again, stirring at room temperature 17h, react complete; revolve the most organic solvent of steaming and obtain crude product; this crude product, with purification by silica gel column chromatography (n-hexane/ethyl acetate, 4:1), obtains faint yellow solid; i.e. compound 14, MS:284.1 (M+H).Productive rate 81.7%(HPLC:98.0%).
Salify: be dissolved in dehydrated alcohol by compound 14, adds appropriate hydrochloric acid ethanol, obtains hydrochloride.
embodiment 15-17:
With reference to the method for embodiment 14, target compound 15 ~ compound 17 can be obtained.
With reference to the method for embodiment 14, with equimolar (1s, 2s)-(+)-2-benzyloxy cyclopentamine replaces 2,2-difluoro cyclopropylamine, compound 15:N-(1-oxo-3-((1s can be obtained, 2s)-(+)-2-benzyloxy basic ring penta amino)) propyl group-2-methoxycarbonyl thiazolidine.MS:393.2(M+H)。
Salify: be dissolved in methyl alcohol by compound 15, adds equimolar methylsulfonic acid, obtains mesylate.
With reference to the method for embodiment 14, replace 2,2-difluoro cyclopropylamine with equimolar (1s, 2s)-(+)-2-benzyloxy hexahydroaniline; N-(3-bromine propionyl)-2-methoxycarbonyl thiazolidine is replaced with equimolar N-(3-bromine propionyl)-4-L-methoxycarbonyl thiazolidine (3-6); compound 16:N-(1-oxo-3-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino) can be obtained) propyl group-2-methoxycarbonyl thiazolidine.MS:407.2(M+H)。
With reference to the method for embodiment 14, replace 2,2-difluoro cyclopropylamine with equimolar 1-carboxy cyclohex amine; Replace N-(3-bromine propionyl)-2-methoxycarbonyl thiazolidine with equimolar N-(3-bromine propionyl)-4-L-methoxycarbonyl thiazolidine (3-6), compound 17:N-(1-oxo-3-(1-carboxy cyclohex can be obtained amino)) propyl group-2-methoxycarbonyl thiazolidine.MS:345.1(M+H)。
Salify: be dissolved in methyl alcohol by compound 17, adds equimolar salt of wormwood, obtains its sylvite.
embodiment 18: n-(1-oxo-2-(2-difluoro cyclopropylamino)) propyl group-2-Nitromethylene thiazolidine (compound 18)
14.1g intermediate N (2-bromine propionyl)-2-Nitromethylene thiazolidine (3-7) is added in reaction flask; dissolved with the tetrahydrofuran (THF) of 210ml drying and 17g triethylamine; add 6.5g2 again; 2-difluoro cyclopropylamine; stirring at room temperature 24h; react complete; revolve the most organic solvent of steaming and obtain crude product; this crude product purification by silica gel column chromatography (n-hexane/ethyl acetate; 3:1); obtain faint yellow solid, i.e. N-(1-oxo-2-(2-difluoro cyclopropylamino)) propyl group-2-Nitromethylene thiazolidine (compound 18), productive rate 73.4%(HPLC:97.2%).MS:294.1(M+H)。
embodiment 19-22:
With reference to the method for embodiment 18, target compound 19 ~ compound 22 can be obtained.
With reference to the method for embodiment 18, with equimolar (1s, 2s)-(+)-2-benzyloxy cyclopentamine replaces 2,2-difluoro cyclopropylamine, can obtain compound 19:N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta amino)) propyl group-2-Nitromethylene thiazolidine, faint yellow solid, productive rate 75.2%, HPLC:98.5%, MS:392.2 (M+H).
With reference to the method for embodiment 18, with equimolar (1R, 2R)-(-)-2-benzyloxy hexahydroaniline replaces 2,2-difluoro cyclopropylamine, compound 20:N-(1-oxo-2-((1R can be obtained, 2R)-(-)-2-benzyloxy Cyclohexylamino))) propyl group-2-Nitromethylene thiazolidine, faint yellow solid, productive rate 77.0%, HPLC:98.9%.MS:406.2(M+H)。
With reference to the method for embodiment 18, replace 2,2-difluoro cyclopropylamine with equimolar hexahydroaniline, compound 21:N-(1-oxo-2-(Cyclohexylamino can be obtained)) propyl group-2-Nitromethylene thiazolidine, faint yellow solid, productive rate 71.6%, HPLC:98.3%.MS:286.1(M+H)。
With reference to the method for embodiment 18, replace 2,2-difluoro cyclopropylamine with equimolar 4-t-butylcyclohexyl amine, compound 22:N-(1-oxo-2-(4-t-butylcyclohexyl can be obtained amino)) propyl group-2-Nitromethylene thiazolidine, faint yellow solid, productive rate 78.8%, HPLC:98.4%.MS:356.2(M+H)。
embodiment 23: n-(1-oxo-2-((1R, 2R)-(+)-2-benzyloxy basic ring penta amino)) propyl group-2-methylthiazol alkane (compound 23)
11.9g intermediate N (2-bromine propionyl)-2-methylthiazol alkane (3-9) is added in reaction flask; dissolved with the tetrahydrofuran (THF) of 150ml drying and 12.3g triethylamine; add (1s again; 2s)-(+)-2-benzyloxy cyclopentamine) 9.6g, 40 DEG C are stirred 20h, react complete; revolve the most organic solvent of steaming and obtain crude product; this crude product purification by silica gel column chromatography, obtains faint yellow solid, productive rate 88.0%(HPLC:97.2%).MS:349.5(M+H)。
embodiment 24: n-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) propyl group-2-methylthiazol alkane (compound 24)
With reference to the method for embodiment 23, replace (1R, 2R)-(+)-2-benzyloxy cyclopentamine can obtain compound 24 with waiting mole (1s, 2s)-(+)-2-benzyloxy hexahydroaniline.Faint yellow solid, productive rate 86.5%, HPLC:97.8%.MS:363.5(M+H)。
embodiment 25: n-(1-oxo-2-Cyclohexylamino) propyl group-2-methoxycarbonyl thiazolidine (compound 25)
14.1g intermediate N (2-bromine propionyl)-2-methoxycarbonyl thiazolidine (3-10) is added in reaction flask; dissolved with the tetrahydrofuran (THF) of 150ml drying and 11.5g triethylamine; add hexahydroaniline 6.5g again; 35 DEG C are stirred 24h; react complete, steam organic solvent to the greatest extent and obtain crude product, this crude product purification by silica gel column chromatography; obtain faint yellow solid, productive rate 70.7%(HPLC:97.%).MS:301.4(M+H)。
embodiment 26: n-(1-oxo-2-(4-t-butylcyclohexyl is amino)) propyl group-4-L-methoxycarbonyl thiazolidine (compound 26)
14.1g intermediate N (2-bromine propionyl)-4-L-methoxycarbonyl thiazolidine (3-11) is added in reaction flask; dissolved with the tetrahydrofuran (THF) of 180ml drying and 12.8g triethylamine; add 4-t-butylcyclohexyl amine 8.1g again; 50 DEG C are stirred 14h; react complete, steam organic solvent to the greatest extent and obtain crude product, this crude product purification by silica gel column chromatography; obtain faint yellow solid, productive rate 73.5%(HPLC:97.6%).MS:357.5(M+H)。
In order to the pharmaceutical composition of tetrahydrothiazole derivates of the present invention is described more fully, provide following example of formulations, described embodiment only for illustration of, instead of for limiting the scope of the invention.Described preparation can use any compound in the compounds of this invention.
embodiment 27:
Compound 115g, adds dextrin 12g, lactose 75g, with 60% alcohol granulation, drying, encapsulated, and obtained 1000 seed lac wafers.
embodiment 28:
Compound 445g, adds 66g(lactose-microcrystalline cellulose 5:1), stearic acid 2%, namely obtain 1000 tablets of tablets with 70% alcohol granulation, compressing tablet.
embodiment 29:
The hydrochloride 70g of compound 14, adds 1000ml water for injection and dissolves, supply water for injection to 4000ml, and add proper amount of active carbon except thermal source, 0.2um millipore filtration filters, filling, obtained 2000 little liquid drugs injections.
embodiment 30:
The sylvite 60g of compound 17, N.F,USP MANNITOL 45g, add 1000ml water for injection and dissolve, supply water for injection to 2000ml, and add proper amount of active carbon except thermal source, 0.2um millipore filtration filters, filling, lyophilize,
Obtained 2000 freeze-dried powders.Injection for intravenous is used.

Claims (7)

1. there is compound or its pharmacy acceptable salt of structure shown in formula I,
（Ⅰ）
Wherein, R 1for: the cycloalkyl of C3-C8; The alkyl of C1-C4, halogen, cyano group, carboxyl, the alkoxyl group of C1-C4, replaces the alkoxyl group of C1-C4, the cycloalkyl of the C3-C8 that hydroxyl replaces;
R 2for: hydrogen, the alkyl of C1-C4;
R 3, R 4: be at the same time or separately, hydrogen, the alkyl of C1-C4, the carbalkoxy of C1-C6, carboxyl, by hydrogen, the alkyl of C1-C4, the phenyl of halogen substiuted;
R 3, R 4representative:
R 5, R 6: hydrogen, carboxyl is carbonyl time on same carbon atom.
2. the compound of structure shown in formula I as described in claim 1, representative compound is:
N-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-Nitromethylene thiazolidine (compound 1),
N-(1-oxo-2-(1-itrile group cyclopropylamino)) ethyl-2-Nitromethylene thiazolidine (compound 2), N-(1-oxo-2-ring penta is amino) ethyl-2-Nitromethylene thiazolidine (compound 3), N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta is amino)) ethyl-2-Nitromethylene thiazolidine (compound 4)
N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy basic ring penta is amino)) ethyl-2-Nitromethylene thiazolidine (compound 5), the trans-4-hydroxy cyclohexylphenyl of N-(1-oxo-2-(is amino)) ethyl-2-Nitromethylene thiazolidine (compound 6), N-(1-oxo-2-(4-t-butylcyclohexyl is amino)) ethyl-2-Nitromethylene thiazolidine (compound 7), N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) ethyl-2-Nitromethylene thiazolidine (compound 8), N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy Cyclohexylamino)) ethyl-2-Nitromethylene thiazolidine (compound 9), N-(1-oxo-2-(2-difluoro cyclopropylamino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 10), N-(1-oxo-2-ring penta is amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 11), N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta is amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 12), N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy basic ring penta is amino)) ethyl-2-(4-bromophenyl)-2-methylthiazol base-4-ketone (compound 13), N-(1-oxo-3-(1-itrile group cyclopropylamino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 14), N-(1-oxo-3-((1s, 2s)-(+)-2-benzyloxy basic ring penta is amino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 15), N-(1-oxo-3-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 16), N-(1-oxo-3-(1-carboxy cyclohex is amino)) propyl group-2-methoxycarbonyl thiazolidine (chemical combination 17), N-(1-oxo-2-(2-difluoro cyclopropylamino)) propyl group-2-Nitromethylene thiazolidine (compound 18), N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy basic ring penta is amino)) propyl group-2-Nitromethylene thiazolidine (compound 19), N-(1-oxo-2-((1R, 2R)-(-)-2-benzyloxy Cyclohexylamino))) propyl group-2-Nitromethylene thiazolidine (compound 20), N-(1-oxo-2-(Cyclohexylamino)) propyl group-2-Nitromethylene thiazolidine (compound 21), N-(1-oxo-2-(4-t-butylcyclohexyl is amino)) propyl group-2-Nitromethylene thiazolidine (compound 22), N-(1-oxo-2-((1R, 2R)-(+)-2-benzyloxy basic ring penta is amino)) propyl group-2-methylthiazol alkane (compound 23), N-(1-oxo-2-((1s, 2s)-(+)-2-benzyloxy Cyclohexylamino)) propyl group-2-methylthiazol alkane (compound 24), N-(1-oxo-2-Cyclohexylamino) propyl group-2-methoxycarbonyl thiazolidine (compound 25), N-(1-oxo-2-(4-t-butylcyclohexyl is amino)) propyl group-4-L-methoxycarbonyl thiazolidine (compound 26).
3., as claim 1, the compound pharmacy acceptable salt of structure shown in formula I described in 2, refers to and the salt that organic acid, inorganic acid reaction generate; An alkali metal salt generated, alkaline earth salt.
4. as claim 1, the preparation method of the compound of structure shown in formula I described in 2, is undertaken by following reaction scheme:
A. thiazolidine in the basic conditions, reacts with halogen acyl halide, generates intermediate 3;
B. generate intermediate 3 in the basic conditions, with substituted cycloalkyl ammonia react, generate the compound of structure shown in formula I;
Wherein, R 1, R 2, R 3, R 4, R 5, R 6definition with described in claim 1, X, Y are chlorine or bromine.
5. have a composition for blood sugar reducing function, it comprises the type I compound of claim 1-3 for the treatment of significant quantity or its pharmacy acceptable salt and one or more pharmaceutical excipients.
6. pharmaceutical composition according to claim 5, comprises various solid orally ingestible, liquid oral medicine, injection.
7. in claim 1-3 type I compound or its pharmacy acceptable salt for the preparation of the application in ofhypoglycemic medicine.
CN201510747924.2A 2013-01-06 2013-01-06 Thiazolidine derivative, as well as preparation method and application thereof Pending CN105399700A (en)

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