CN102887910A - 7-alkoxy-[1,2,4]triazolo[3,4-b]benzothiazol-3(2H)-one derivatives used as antiepileptic medicines and preparation method thereof - Google Patents

Abstract

The invention provides 7-alkoxy-[1,2,4]triazolo[3,4-b]benzothiazol-3(2H)-ones of formula (I), and a preparation method thereof. The invention also relates to the use of the compounds in the preparation of antiepileptic medicines.

Description

As the 7-alkoxyl group of antiepileptic drug-[1,2,4] triazolos [3,4-b] benzothiazoles-3 (2H)-ketone derivatives and preparation method thereof

Technical field

The present invention relates to 7-alkoxyl group-[1,2,4] triazolos [3,4-b] benzothiazoles-3 (2H)-ketone derivatives the preparation method, with and in the purposes of preparation in the antiepileptic drug.

Background technology

Epilepsy is for the collective term of describing one group of chronic convulsions illness, and the common trait of these symptoms is temporary epileptic seizures to occur and be attended by the loss of consciousness or obstacle.Epilepsy is only second to the second largest disease of cerebrovascular disease as Neurology Department, and patient's body and mind is come to harm, and have a strong impact on study, work and daily life, even cause unexpected death, be the common disease of serious threat people life and health.

According to the WHO statistics, present global epileptic has 5,000 ten thousand people approximately, and wherein 80% in developing country, every year also occurs 2,000,000 new epileptics.Country variant epilepsy invasion rate is different, average about 5-10 ‰, and the epilepsy morbidity of China is 7 ‰, and is approaching with the sickness rate of the developing country 7.2 ‰ of WHO report.China epileptic number has reached 1,000 ten thousand more than at present, and 400,000 new patient is nearly arranged every year.The Main Means of at present control epileptic seizures is pharmacological agent, and the purpose of its treatment is to reduce or prevent epileptic seizures.Existing multiple antiepileptic drug is available in the clinical application; such as phenylethyl barbituric acid, Phenytoin Sodium Salt, Carbamzepine, valproic acid, lamotrigine, non-ammonia ester, topiramate etc.; although these medicines can both protect the patient that various epileptic convulsions do not occur in varying degrees; but it exists side effect and feeling bad property, uses them thereby stoped in long-term treatment.In order to improve result for the treatment of and elimination or to reduce side reaction, need to have the novel cpd of new constitutional features and the new mechanism of action.

Summary of the invention

For solving as above problem, the invention provides the novel 7-alkoxyl group of a class-[1,2,4] triazolos [3,4-b] benzothiazoles-3 (2H)-ketone compound, with and preparation method thereof.This compounds has the strong and little feature of toxicity of anti-convulsant activity, can be used for preparing antiepileptic drug.

The invention provides the compound that is represented by general formula I

Wherein, R is n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, dodecyl, benzyl, 2-luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, the 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, the 3-bromobenzyl, 4-methyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, the 4-methoxy-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl.

It is activeconstituents that the present invention also provides more than one to state the invention compound, contains simultaneously one or more pharmaceutically pharmaceutical compositions of acceptable carrier or assistant agent.

Indication of the present invention is acceptable carrier or assistant agent pharmaceutically, can be selected from vehicle, auxiliary material or solvent commonly used in the pharmaceutical preparation.Such as lactose, sucrose, dextrin, talcum powder, gelatin, agar, pectin, Sudan Gum-arabic, Magnesium Stearate, stearic acid, cellulosic lower alkyl ether W-Gum, yam starch, natural gum, syrup, peanut oil, sweet oil, phosphatide, single stearic resin acid glyceryl ester, distearyl resin acid glyceryl ester, lipid acid, fatty acid amine, tinting material, sanitas, correctives, water, ethanol, propyl alcohol, physiological saline, glucose solution etc.

Prepare among the present invention by the method for thing shown in the general formula I, the method is take general formula I I as initial substance:

Compound (II) carries out ring-closure reaction with urea, obtains the compound shown in the general formula I.

Such compou nd synthesis method is simple, and rationally, production cost is low.

The compound that is represented by general formula I with and pharmaceutical composition can be used for the preparation of antiepileptic drug.

The compounds of this invention has anti-convulsant activity, thereby so that they can be used as antiepileptic drug.Preferred compound 7-butoxy among the present invention-[1,2,4] triazolos [3,4-b] benzothiazoles-3 (2H)-ketone (Compound I d) the pharmacological results see Table 1.The median effective dose of Compound I d is 34.1mg/kg during oral administration, and the half toxic dose is 1710.4mg/kg, and protective index PI is that the ratio of neurotoxicity and effective dose is up to 50.2.And the half toxic dose of contrast medicine Carbamzepine when oral administration is 204.4mg/kg, and protective index is 11.1.Compound I d is than Carbamzepine neurotoxicity low 9 times (1710.4/204.4), and protective index is more than 4 times of Carbamzepine.The maximum untoward reaction of the antiepileptic drug of existing clinical application is exactly to neural toxic reaction.So when now developing new antiepileptic drug, neurotoxicity has been extremely important evaluation index.The advantage of the maximum of compound of the present invention is that neurotoxicity is very low, and protective index is apparently higher than the clinical medicine Carbamzepine.

Embodiment

Below embodiment by the synthetic example of preferred compound Id and pharmacological evaluation example foregoing of the present invention is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.

Preparation example 1:

Introduce the synthetic logical method of Compound I for example with 7-butoxy-[1,2,4] triazolos [3,4-b] benzothiazoles-3 (2H)-ketone (Compound I d)

Compound I I (10mmol) and urea (80mmol) are heated to melting.TLC follows the tracks of reaction, after reacting completely reactant is poured into to stir 0.5 hour suction filtration in the hot water and obtain crude product, and column chromatography for separation (methylene dichloride: methyl alcohol, 50: 1) obtains Compound I d.Fusing point 162-164 ℃, yield 63.5%; ¹H NMR (300MHz, CDCl ₃): δ 10.15 (s, 1H ,-NH), 7.89 (d, J=8.8Hz, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 6.95 (d, J=8.8Hz, 1H, Ar-H), 3.99 (t, J=6.3Hz, 2H ,-OCH ₂-), 1.90-1.67 (m, 2H ,-CH ₂-), 1.62-1.39 (m, 2H ,-CH ₂-), 0.99 (t, J=7.2Hz, 3H ,-CH ₃) .IR (KBr, cm ^-1): 3152 (N-H), 1697 (C=O) .MS m/z 264 (M+1) .Anal.Calcd.for C ₁₂H ₁₃N ₃O ₂S:C, 54.74; H, 4.98; N, 15.96.Found:C, 54.83; H, 4.79; N, 16.01.

Embodiment A: anticonvulsion pharmacology experiment and neurotoxicity experiment

Introduce the pharmacological experimental method of Compound I for example with 7-butoxy-[1,2,4] triazolos [3,4-b] benzothiazoles-3 (2H)-ketone (Compound I d)

Adopt the anti-convulsant activity of maximal electrical seizure (MES) assessing compound.Get 9 kunming mices (male and female regardless of) and be divided into 3 groups; every group 3; difference oral administration 30mg/kg; 100mg/kg; the Compound I d of 300mg/kg dosage carries out 60 hertz to tested mouse after 0.5 hour, 110 volts; 0.3 compound is induced convulsions to electricity irritation protection situation is observed in the single electricity irritation of second.Be not decided to be effectively so that hind leg is tetanic.For a hundred per cent compounds effective under the 100mg/kg dosage, further estimate its median effective dose by the improvement karber's method.The median effective dose that records Compound I d is 34.08mg/kg.The test of mouse rotating rod ataxia is in order to the neurotoxicity of assessing compound, the mouse of oral administration after 0.5 hour is placed on the coarse rotating rod of 1 inch of diameter, the speed that turns with per minute 6 is rotated, mouse can be kept balance 1 minute and not fall down and be thought there is not neurotoxicity, otherwise then neurotoxicity was arranged.Further estimate its half neurotoxicity by the improvement karber's method equally, and then calculate protective index PI value (seeing Table 1).Anticonvulsion pharmacology experiment and neurotoxicity experiment see document Krall, R.J. for details; Penry, J.K.; White, B.G.; Kupferberg, H.J.; Swinyard, E.A.Epilepsia.1978,19,409.

The anticonvulsion pharmacology experiment of table 1: Compound I d and neurotoxicity experimental result (mg/kg, oral)

Above-described only is several embodiment of the present invention; can not therefore be interpreted as the restriction to claim of the present invention; should be understood that; for the member of ordinary skill in the art; without departing from the inventive concept of the premise; can also make some other distortion and improvement, these all belong to protection scope of the present invention.

Claims (4)

1. the compound shown in the formula (I):

Wherein, R is n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, dodecyl, benzyl, 2-luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, the 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, the 3-bromobenzyl, 4-methyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, the 4-methoxy-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl.

2. a pharmaceutical composition is characterized in that it take compound claimed in claim 1 as activeconstituents, contains simultaneously one or more pharmaceutically acceptable carrier substance and/or assistant agents.

3. the according to claim 1 application on the preparation antiepileptic drug with 2 described compounds or pharmaceutical composition.

4. the preparation method of compound according to claim 1 is characterized in that using general formula I I to be initial substance:

Wherein, R is n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, dodecyl, benzyl, 2-luorobenzyl, 3-luorobenzyl, 4-luorobenzyl, the 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, the 3-bromobenzyl, 4-methyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, the 4-methoxy-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl.