CN103012314B - Sulfonamide compound and preparation method as well as application thereof - Google Patents
Sulfonamide compound and preparation method as well as application thereof Download PDFInfo
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- CN103012314B CN103012314B CN201210575394.4A CN201210575394A CN103012314B CN 103012314 B CN103012314 B CN 103012314B CN 201210575394 A CN201210575394 A CN 201210575394A CN 103012314 B CN103012314 B CN 103012314B
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Abstract
The invention discloses a sulfonamide compound and a preparation method as well as application thereof, and provides the sulfonamide compound with hypoglycemic activity and the preparation method thereof. The sulfonamide compound has a structure of a general formula I, wherein X is S or O atoms, n is 1, 2, 3 or 4, R1 and R2 are simultaneously or respectively hydrogen or C1-C4 alkyl groups, and R3, R4 and R5 are simultaneously or respectively one out of hydrogen, C1-C6 alkyl groups, C1-C4 alkoxyl groups, halogens, single or multi-halogen replaced C1-C4 alkyl groups, cyan, phenyl groups, single halogenated phenyl groups, C1-C4 alkoxyl phenyl group, C1-C4 alkyl sulfonyl groups and bromomethyl carbonyl groups. The sulfonamide compound with the structure of the formula I and pharmaceutically acceptable salts thereof have obvious effect in terms of resisting hyperglycemia.
Description
Technical field
The invention belongs to medical art, in particular, relate to class compound with hypoglycemic activity and its preparation method and application.
Background technology
The data of the diabetes announced according to IDF (IDF) and impaired glucose tolerance (IGT) and reckoning, within 2003, diabetic subject's number is 1.94 hundred million, within 2025, then will reach 3.33 hundred million; Within 2003, IGT number is 3.14 hundred million, 2025 then will up to 4.72 hundred million.In recent years, along with improving constantly and the change of dietary structure of living standards of the people, also there is extensive growth in the quantity of China diabetic subject.
Insulin type, sulfonylurea, N1,N1-Dimethylbiguanide class and the alpha-glucosidase inhibitor recently gone on the market and Studies of The Insulin Sensitizer Thiazolidinediones medicine etc. is mainly contained at present at the antidiabetic medicine of Clinical practice.These medicines have good curative effect, but still the shortcoming that can not maintain long-term efficacy that there is medicine life-time service and cause, and easily cause hypoglycemia, body weight to increase and produce many untoward reactions such as liver toxicity.
Therefore, finding new ofhypoglycemic medicine is one of focus of domestic and international the world of medicine research.
Summary of the invention
The sulfonamides compound that one object of the present invention is to provide a class to have hypoglycemic activity and pharmacy acceptable salt thereof.
Another object of the present invention is the preparation method providing a class sulfonamides compound and pharmacy acceptable salt thereof.
The pharmaceutical composition that it is main active ingredient that another object of the present invention is to provide with a class sulfonamides compound and pharmaceutical salts thereof.
A further object of the invention is to provide a class sulfonamides compound and pharmaceutical salts thereof as the application of ofhypoglycemic medicine aspect.
Now in conjunction with the object of the invention, content of the present invention is described in detail.
One class sulfonamides compound, has the structure of following formula I:
Wherein:
X is S or O atom;
N=1,2,3 or 4;
R
1with R
2be hydrogen or C1-C4 alkyl at the same time or separately, preferred hydrogen, methyl, ethyl or sec.-propyl.
R
3, R
4with R
5be any one in hydrogen, C1-C6 alkyl, C1-C4 alkoxyl group, halogen, list or many halogen substiuted C1-C4 alkyl, cyano group, phenyl, single halogenophenyl, C1-C4 alkoxyl phenyl, C1-C4 alkyl sulphonyl, brooethyl carbonyl at the same time or separately.Preferred hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, methoxyl group, oxyethyl group, propoxy-, fluorine, chlorine, bromine, trifluoromethyl, cyano group, phenyl, tolyl, bromophenyl, methoxyphenyl, methylsulfonyl or brooethyl carbonyl.
The preferred following compound of sulfonamides compound of the present invention:
I-1, N-(2-(4-(benzothiazole-2-base) piperazine-1-base) ethyl)-3,5-dimethyl benzene sulfonamides, structural formula is
I-2, N-(3-(4-(benzothiazole-2 base) piperazine-1-base) propyl group)-3-cyano group-4-fluorobenzenesulfonamide, structural formula is
I-3, N-(4-(4-(benzothiazole-2-base) piperazine-1-base) butyl)-4 '-methoxyl group biphenylyl-3-sulphonamide, structural formula is
I-4, N-(5-(4-(benzothiazole-2-base) piperazine-1-base) amyl group)-2,6-bis-chloro-4-(trifluoromethyl) benzsulfamides, structural formula is
I-5, N-(2-(4-(benzoxazoles-2-base) piperazine-1-base) ethyl) the fluoro-3-methyl benzenesulfonamide of-4-, structural formula is
I-6, N-(3-(4-(benzoxazoles-2-base) piperazine-1-base) propyl group)-4-(methylsulfonyl) benzsulfamide, structural formula is
I-7, N-(4-(4-(benzoxazoles-2-base) piperazine-1-base) butyl)-3-(2-acetyl bromide) benzsulfamide, structural formula is
I-8, N-(5-(4-(benzoxazoles-2-base) piperazine-1-base) the amyl group)-3-t tertiary butyl-5-propoxy-benzsulfamide, structural formula is
I-9, N-(3-(4-(benzothiazole-2-base)-2,6-dimethyl-piperizine-1-base) propyl group)-5-ethyl-2-methoxybenzenesulphoismide, structural formula is
I-10, N-(3-(4-(benzoxazoles-2-base)-2,6-dimethyl-piperizine-1-base) propyl group)-4 '-bromine biphenylyl-4-sulphonamide, structural formula is
A preparation method for sulfonamides compound, comprises the steps:
(1) have general formula II containing the benzo five-membered heterogeneous ring compound of piperazine and alkyl chloride aminated compounds under acid binding agent exists, in a solvent, 0 ~ 110 DEG C of reaction response obtains the compound with general formula III;
(2) the above-mentioned compound with general formula III with there is the benzene sulfonyl chloride of replacement of general formulae IV under acid binding agent exists, in a solvent, 0 ~ 110 DEG C is obtained by reacting the sulfonamides compound with formula I;
Syntheti c route is expressed as follows:
Wherein, n, X, R
1, R
2, R
3, R
4, R
5as aforementioned definitions.
Described alkyl chloride aminated compounds is haloalkyl amine, described acid binding agent is triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, and described solvent is methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), DMF or toluene.
Sulfonamides compound pharmacy acceptable salt described in one class, the compound that this pharmacy acceptable salt is general formula I and mineral acid or organic acid institute salify.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate, maleate; benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, amino acid salts, gluconate, etc.
The preparation method of the sulfonamides compound pharmacy acceptable salt described in one class, comprise the steps: the one be dissolved in by described sulfonamides compound in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip mineral acid or organic acid, make pharmacy acceptable salt.
Specifically the various compound containing general formula I is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips ethereal HCI to pH=2, make hydrochloride; Or the one various compound containing general formula I is dissolved in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, add gluconic acid equimolar with the compound containing general formula I, heated and stirred obtains its gluconate; Or the compound containing general formula I is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips the vitriol oil to pH=3, make vitriol.
Have a pharmaceutical composition for hypoglycemic activity, it comprises the pharmacy acceptable salt of the described compound containing formula I for the treatment of significant quantity or the compound containing described formula I.
Compound containing formula I is for the preparation of the application in hypoglycemic drug.
The pharmacy acceptable salt of the compound containing formula I is for the preparation of the application in hypoglycemic drug.
The disease that compound containing formula I of the present invention causes because of hyperglycemia for the treatment mankind is effective.Although compound of the present invention can without the direct administration of any configuration, described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition preparation method of the compounds of this invention is as follows: use standard and conventional technology; compound acceptable solid or liquid vehicle on technology of pharmaceutics containing formula I of the present invention is combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension such as injection, pulvis etc.
The amount of the active ingredient (the present invention contains the compound of formula I) 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, and 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, and another preferred scope is 10% ~ 70%.
Compound and the pharmacy acceptable salt thereof with structure shown in formula I of the present invention, has obvious effect in hyperglycemia.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1: the preparation of intermediate III
For intermediate III-1
2-(piperazine-1-base is added in the reaction flask that stirring, condenser, thermometer are housed) benzothiazole (2.19g, 0.01mol), 3-chlorine propylamine (1.2g, 0.015mol) with sodium hydroxide (7.2g, 0.18mol), DMF(30ml) dissolve, 50 DEG C of reaction 4h.Naturally cool to room temperature, filter, in filtrate, add potassium acetate (0.24g), vacuum distilling goes out about 25mL DMF, and adding the dilution of 50mL water in residue, is 4.6 with acetic acid adjust pH, dichloromethane extraction, water layer is after 9.5 with 12% ammonia solution adjust pH, then uses dichloromethane extraction secondary, each 50mL, anhydrous sodium sulfate drying, steams solvent, and obtaining yellow oil is intermediate III-1, HPLC:92%, HRMS (m/z): 263.1325.
Method with reference to embodiment 1 conveniently can prepare compound: preparation process and the result of intermediate III-2-III-10 are as shown in table 1, and the benzo five-membered heterogeneous ring compound wherein containing piperazine is 0.01mol, and alkyl chloride aminated compounds is 0.015mol.
Table 1
Embodiment 2:
The preparation of N-(2-(4-(benzothiazole-2-base) piperazine-1-base) ethyl)-3,5-dimethyl benzene sulfonamides (chemical compounds I-1):
Stirring is being housed, condenser, 2.46g(0.01mol is added in the reaction flask of thermometer) the obtained intermediate III-1 of embodiment 1, dissolved with 10mL methylene dichloride, stir, add Anhydrous potassium carbonate 2.2g, 3 are dripped under condition of ice bath, 5-3,5-dimethylphenyl-1-SULPHURYL CHLORIDE 2.1g(0.01mol), drip and finish, 3h is about in stirred at ambient temperature, TLC detection reaction is complete, filtering solids, filtrate water washs three times, each water 15mL, organic over anhydrous sodium sulfate is fully dry, filter, organic solvent is to the greatest extent steamed in decompression, give light yellow oil, it is chemical compounds I-1(HPLC:99.5% that silica gel column chromatography obtains white solid product).Fusing point 161 DEG C-162.1 DEG C, HRMS(m/z): 431.1570.
Method with reference to embodiment 2 conveniently can prepare chemical compounds I-2-I-10.Preparation process and the result of chemical compounds I-2-I-10 are as shown in table 2.Wherein intermediate III is grade mole with the benzene sulfonyl chloride replaced, and is 0.01mol.
Table 2
Chemical compounds I-2, fusing point 178 DEG C-179.2 DEG C,
Chemical compounds I-5, fusing point 164.4 DEG C-165.7 DEG C,
Chemical compounds I-8, fusing point 180.6 DEG C-182.4 DEG C,
Chemical compounds I-10, fusing point 193.2 DEG C-194.1 DEG C.
Embodiment 3
Chemical compounds I-10 becomes hydrochloride: get chemical compounds I-10 white solid product 2.0g, be dissolved in 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 DEG C, and dripping 25% ethereal HCI solution is 2 to pH value, continues at stir about 1h under ice-water bath.Filter, obtain white solid, be the hydrochloride of chemical compounds I-10.
Embodiment 4:
Chemical compounds I-5 becomes taurate: get chemical compounds I-5 white solid product 2.0g, be dissolved in 15mL dehydrated alcohol.Add taurine equimolar with chemical compounds I-5 after being heated to backflow, continue at stirred at reflux and react about 2h.React complete, in left at room temperature 24h.Filter, obtain the taurate that light yellow solid is chemical compounds I-5.
Embodiment 5:
Chemical compounds I-9 becomes vitriol: get chemical compounds I-9 white solid product 2.0g, be dissolved in 20mL anhydrous methanol.Ice-water bath is cooled to 5 DEG C, and dripping concentrated sulfuric acid solution is 3 to pH value, continues at stir about 0.5h under ice-water bath.Filter, obtain the vitriol that light yellow solid is chemical compounds I-9.
In order to the pharmaceutical composition of sulfonamides compound of the present invention is described more fully, provide following example of formulations below, described embodiment only for illustration of, instead of for limiting the scope of the invention.Described preparation can use any active compound in the compounds of this invention, preferably uses the compound described in embodiment 1-5.
Embodiment 6
Hard gelatin capsule is prepared by following compositions:
Consumption/capsule
Chemical compounds I-2 20mg
Dry starch 200mg
Magnesium Stearate 10mg
After mentioned component is mixed, be packed in hard gelatin capsule.
Embodiment 7
Tablet is prepared by following compositions:
Supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.First the supplementary product starch of recipe quantity, Sodium carboxymethyl starch, Magnesium Stearate, talcum powder are fully mixed.Be added in auxiliary material by bulk drug chemical compounds I-8 to increase progressively dilution method, each added-time fully mixes 2-3 time, ensures that bulk drug and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle crosses the whole grain of 16 mesh sieve, measure intermediates content, mix, compressing tablet on tabletting machine.
Embodiment 8
The preparation of injection liquid:
The hydrochloride 200mg of chemical compounds I-10
Propylene glycol 100mg
Sorbyl alcohol 20mg
Distilled water 300ml
Sorbyl alcohol and propylene glycol are dissolved in distilled water and make water for injection.The hydrochloride getting activeconstituents and chemical compounds I-10 joins in the water for injection dissolving sorbyl alcohol and propylene glycol, adds medicinal basic adjust ph to 6.5 and makes it dissolve.Add gac 10mg, whip attachment 30 minutes, carbon removal, essence filter, embedding, sterilizing.
Embodiment 9
The preparation of injection lyophilized powder:
The taurate 100mg of chemical compounds I-5
Aqueous sodium hydroxide solution 5%
N.F,USP MANNITOL 30mg
The taurate getting activeconstituents and chemical compounds I-5 does not add water for injection 50ml, makes it dissolve by medicinal basic adjust ph to 7.5.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac; adopt filtering with microporous membrane, filtrate carries out packing, adopts freeze-drying; obtained loose block, sealing, obtains the injection lyophilized powder of the taurate containing chemical compounds I-5.
The hypoglycemic activity of the compounds of this invention is further illustrated below by pharmacodynamic experiment.
The oral sugar tolerance model of mouse (oral glucose tolerance test, OGTT) measures.
1, laboratory sample:
Laboratory sample is chemical compounds I-1-chemical compounds I-10 or Walaphage.Sample is mixed with 5mgmL with 1% Xylo-Mucine
-1the suspension of concentration, dosage is every 20g body weight 0.4mL, is equivalent to 100mgkg
-1dosage.
2, experimentation:
Healthy ICR mouse, male and female half and half, body weight 20g ~ 24g, meets primary standard.Animal fasting 16h, gives chemical compounds I-1-chemical compounds I-10, Walaphage respectively, after administration after 15min, 1.5h abdominal injection 2gkg
-1dextrose in saline solution, respectively at 0.50h after modeling, 1.00h, 1.50h, 2.00h, 2.50h, 3.00h, 3.50h and 4.00h timing kapillary gets blood from mouse ball rear vein beard, for the first time 2h injectable dextrose monohydrate salt brine solution again after injectable dextrose monohydrate, centrifugation serum, with each time point serum glucose level of determination of glucose oxidase.If blank group, give 1% Xylo-Mucine of equivalent.
The hypoglycemic activity of compound is weighed by inhibiting rate (inhibitory rate, IR%), the results are shown in Table 3.
IR%={1-[AUC (7a-7u)/AUC (model)] } × 100%, wherein, AUC is the area under curve (area under carve) of " blood sugar concentration-time " curve.
Table 3: to mouse blood sugar restraining effect
From above pharmacological evaluation, compound of the present invention has obvious inhibition compared with blank group, the at present clinical Walaphage the most often used to hyperglycemia.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a class sulfonamides compound, is characterized in that, has the structure of following formula I:
Wherein:
X is S or O atom;
N=1,2,3 or 4;
R
1with R
2be hydrogen or C1-C4 alkyl at the same time or separately;
R
3, R
4with R
5be any one in hydrogen, C1-C6 alkyl, C1-C4 alkoxyl group, halogen, list or many halogen substiuted C1-C4 alkyl, cyano group, C1-C4 alkyl sulphonyl, brooethyl carbonyl at the same time or separately; Or: R
3for phenyl, single halogenophenyl or C1-C4 alkoxyl phenyl, R
4with R
5be hydrogen.
2. according to the sulfonamides compound described in claim 1, it is characterized in that, comprise following compound:
3. a preparation method for sulfonamides compound according to claim 1, is characterized in that, comprises the steps:
(1) have general formula II containing the benzo five-membered heterogeneous ring compound of piperazine and alkyl chloride aminated compounds under acid binding agent exists, in a solvent, 30 ~ 70 DEG C are obtained by reacting the compound with general formula III;
(2) the above-mentioned compound with general formula III with there is the benzene sulfonyl chloride of replacement of general formulae IV under acid binding agent exists, in a solvent, 10 ~ 40 DEG C are obtained by reacting the sulfonamides compound with formula I;
Wherein:
X is S or O atom;
N=1,2,3 or 4;
R
1with R
2be hydrogen or C1-C4 alkyl at the same time or separately;
R
3, R
4with R
5be any one in hydrogen, C1-C6 alkyl, C1-C4 alkoxyl group, halogen, list or many halogen substiuted C1-C4 alkyl, cyano group, C1-C4 alkyl sulphonyl, brooethyl carbonyl at the same time or separately; Or: R
3for phenyl, single halogenophenyl or C1-C4 alkoxyl phenyl, R
4with R
5be hydrogen;
Syntheti c route is expressed as follows:
4. the preparation method of sulfonamides compound according to claim 3, it is characterized in that, described alkyl chloride aminated compounds is haloalkyl amine, described acid binding agent is triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, and described solvent is methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), DMF or toluene.
5. class sulfonamides compound pharmacy acceptable salt according to claim 1, is characterized in that, the compound that this pharmacy acceptable salt is general formula I and mineral acid or organic acid institute salify.
6. the preparation method of class sulfonamides compound pharmacy acceptable salt according to claim 5, it is characterized in that, comprise the steps: the one be dissolved in by the sulfonamides compound described in claim 1 or 2 in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip mineral acid or organic acid, make pharmacy acceptable salt.
7. the preparation method of sulfonamides compound pharmacy acceptable salt according to claim 6, it is characterized in that, sulfonamides compound described in claim 1 or 2 is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip ethereal HCI to pH=2, make hydrochloride; Or the sulfonamides compound described in claim 1 or 2 is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, add and the equimolar gluconic acid of sulfonamides compound described in described claim 1 or 2, heated and stirred obtains gluconate; Or the sulfonamides compound described in claim 1 or 2 is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips the vitriol oil to pH=3, make vitriol.
8. have a pharmaceutical composition for hypoglycemic activity, it comprises the compound of the formula I described in claim 1 or 2 for the treatment of significant quantity or pharmacy acceptable salt according to claim 5.
9. the compound of the formula I described in claim 1 or 2 is for the preparation of the application in hypoglycemic drug.
10. the pharmacy acceptable salt of the compound of formula I according to claim 5 is for the preparation of the application in hypoglycemic drug.
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| CN109651349B (en) * | 2019-01-07 | 2022-01-07 | 天津商业大学 | Novel crystal form of sulfonamide compound, preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4761287A (en) * | 1984-05-03 | 1988-08-02 | Technology Unlimited, Inc. | Diabetes control by serotonin |
| WO2000056712A1 (en) * | 1999-03-23 | 2000-09-28 | Smithkline Beecham Plc | Sulfonamide derivatives as 5-ht7 receptor antagonists |
| CN1756551A (en) * | 2003-01-31 | 2006-04-05 | 普雷迪克医药品控股公司 | New arylpiperazinyl compounds |
-
2012
- 2012-12-25 CN CN201210575394.4A patent/CN103012314B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4761287A (en) * | 1984-05-03 | 1988-08-02 | Technology Unlimited, Inc. | Diabetes control by serotonin |
| WO2000056712A1 (en) * | 1999-03-23 | 2000-09-28 | Smithkline Beecham Plc | Sulfonamide derivatives as 5-ht7 receptor antagonists |
| CN1756551A (en) * | 2003-01-31 | 2006-04-05 | 普雷迪克医药品控股公司 | New arylpiperazinyl compounds |
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