CN105085479A - Novel nitrogen containing heterocyclic compound - Google Patents

Abstract

The invention provides a novel compound (as shown in a formula I) and salts thereof, and the compound and the salts thereof are used for treating and preventing cerebral ischemic disease and improving sleep according experiment results. The compound can be prepared into salts with inorganic acids, such as phosphoric acid, nitric acid, sulfuric acid or the like, and organic acid, such as formic acid, acetic acid, propionic acid, oxalic acid, propane diacid, glycine valine, maleate, fumaric acid, succinic acid or the like, and the salts have the same effects for treating and preventing cerebral ischemic disease and improving sleep.

Description

A kind of new nitrogen-containing heterocycle compound

Technical field:

The invention belongs to the field of medicaments of compound, relate to a kind of new compound and salt thereof of pyrido thiophene, and disclose its Preparation Method And The Use.

Background technology: the cerebral infarction being broad sense, refers to that the cerebral tissue local feeding artery blood perfusion occurred suddenly reduces or blood flow interrupts completely, stops blood supply, oxygen supply, for sugar etc., this local brain tissue disintegration is destroyed.The major cause of cerebral infarction is 1. thromboembolism caused by atherosclerosis; 2. heart source embolus caused by cerebral embolism; 3. vasculitis, blood vessel injury and the wound etc. that cause of a variety of causes.Cerebral infarction is generally fallen ill in nighttime sleep, and Chang Weici WA in morning finds limb adynamia or hemiplegia, and how unconscious obstacle, blood pressure can be normal or higher, can have arteriosclerosis history.Cerebral infarction accounts for 60% ~ 70% of cerebral apoplexy patient sum, mainly comprises cerebral thrombosis and cerebral embolism.The former make the narrow or obturation of arterial lumen cause cerebral tissue local intra-arterial blood perfusion to reduce due to the atherosis and thrombosis in cerebral arteries system or local brain tissue caused by stopping downright bad.The medicine of cerebral infarction: the first kind is vasodilator (as dipyridamole etc.).As long as think that medicine can make cerebral vasodilators in the past, blood multithread from the blood vessel of blocking just can be made to go over.But find that not only Pimobendane does not accomplish this point, the blood reflux of diseased region also can be made to flow in healthy cerebral tissue and go (this is called steal syndrome in brain), so do not advocated to use this type of medicine.Equations of The Second Kind is the medicine (as low molecular dextran etc.) improving microcirculation, expanding blood volume.This type of is morely medicinal at present, but has cardiopathic patient to be cautious use of, otherwise may cause heart failure.3rd class is thrombolytic medicine (as urokinase etc.).If apply this type of medicine can reach that to dissolve the object of embolus be ideal, but often need heavy dose during systemic vein medication, cause hemorrhage danger sometimes.Present multidirectional patient's recommendation interventional therapy, by conduit, embolus is dissolved at the position that medicine directly injects infarct exactly, but take the front and back of this methods for the treatment of all will do a cerebral angiograpathy, this inherently has again certain danger, in addition interventional therapy requires that patient carries out in obtaining 6 hours after being ill, sometimes often misses opportunity.4th class is anticoagulant therapy (as heparin etc.).This kind of medicine can prevent blood coagulation, but will look into prothrombin time and mobility every day when using, and the poor hospital of condition cannot carry out.In addition anticoagulant therapy also has hemorrhage danger.5th class uses calcium ion antagonist (as nimodipine etc.).This kind of medicine can prevent calcium ion from flowing in cell from extracellular, plays the mild dilation cerebrovascular, protection brain cell, increases brain cell and utilizes the effect such as oxygen and glucose.6th class is the medicine (as acetylsalicylic acid etc.) preventing platelet aggregation.At the beginning of hematoblastic cohesion cerebral thrombosis often, if can the cohesion of blocking platelet effectively, perhaps can be formed further in anti-hemostasis osmanthus.Current this kind of medicine is applied very extensive in the world, not equal to but be more appropriate as prophylactic agent as medicine, because the acute phase of cerebral apoplexy, uses this kind of effect of drugs unsatisfactory.

Summary of the invention:

The object of this invention is to provide a kind of new compound of the pyrido thiophene for cerebral infarction, and its production and use.

To achieve these goals, present invention employs following technical scheme:

Proved by animal experiment, placebo does not reduce the effect of rat cerebral ischemia infarct volume, can not improve the symptom of cerebral ischemia, does not possess the effect of improving water flood yet, in the present invention, compound then has the effect well improving symptoms of cerebral ischemia, and can improve the sleep state of animal.

Because formula I is insoluble in water, therefore we make it and sour salify, described acid refers to pharmaceutically acceptable mineral acid or organic acid, mineral acid refers to nitric acid, sulfuric acid or phosphoric acid, described organic acid except acid group at least also containing a kind of group in amino, hydroxyl or carboxyl, at least containing one.The salt become can be water-soluble, can prepare the formulation of injection liquid or freeze-dried powder.

Organic acid can be amino acids, specifically can refer to glycine, L-Ala, Methionin, arginine, Serine, phenylalanine, proline(Pro), tyrosine, aspartic acid, L-glutamic acid, Histidine, leucine, methionine(Met), Threonine, Pyrrolidonecarboxylic acid, tryptophane or α-amino-isovaleric acid.

Thanomin.

The ester that compound shown in formula I generates with phosphoric acid preferably becomes disodium salt.

Present invention also offers the pharmaceutical composition being used for the treatment of cerebral infarction, it is characterized in that general formula (1) compound or its salt containing treatment significant quantity and pharmaceutically acceptable carrier.Can be oral preparations or injection formulations.

Specific embodiment:

Embodiment 1: the preparation of each compound:

Because compound described herein has very strong continuity, in order to describe each compounds process for production thereof in detail, accurately, easily, it is expressed with 1 embodiment, the sequence number of compound is shown below each compound of following synthetic route, for simpler and clearer elaboration, replace with sequence number in preparation method below:

1, the synthesis of (1), compound 3:

The compound 2 of 47.1 grams and the morpholine ethanol of 15.7 grams are dissolved in the THF of 100mL, under ice bath, drip 23.8 grams of thionyl chlorides (being dissolved in the THF of 50mL), dropwise in 30min.Continue to stir 30min in ice bath, then reaction system is moved to room temperature and continue reaction one hour, stopped reaction, pours into reaction solution in the trash ice of 200mL, regulates about pH=7.0or8.0, at this moment have a large amount of Precipitations with ammoniacal liquor.Suction filtration, filter cake washes twice with water, obtains the crude product of 52.5 g of compound 3 after vacuum-drying, and purity is 92% (HPLC), obtains 45 grams of sterlings after ethyl alcohol recrystallization, and productive rate is 75%.HNMR(400Hz，DMSO)：9.59(s，1H)，8.39(s，1H)，8.23(d，J＝4.8Hz，1H)，7.95(d，J＝5.2Hz，1H)，7.88(d，J＝5.2Hz，1H)，7.40(m，1H)，7.26(d，J＝4.8Hz，1H)，7.0(d，J＝5.6Hz，2H)，6.40(d，J＝5.6Hz，2H)，4.32(s，2H)，4.18(t，J＝3.6Hz，2H)，3.67(t，J＝3.2Hz，4H)，3.63(s，3H)，3.59(t，J＝4.0Hz，2H)，2.64(t，J＝3.6Hz，2H)，2.55(t，J＝4.0Hz，2H)，2.37(t，d＝3.2Hz，4H)；MS(m/z)：585.9。

2, the synthesis of (2), compound 1:

The compound 3 of 40.0 grams is dissolved in the THF of 200mL, add the triethylamine of 14.0 grams, slowly 16.0 grams of morpholine ethanol ester formyl chlorides (being dissolved in the THF of 50mL) are dripped under ice bath, dropwise in 30min, then reaction solution is moved to room temperature and continue reaction three hours, stopped reaction, suction filtration, filter cake THF washs three times, merging filtrate, underpressure distillation obtains the crude product of 49 g of compound 1 after removing desolventizing, with obtaining 41.2 grams of sterlings after ethyl alcohol recrystallization, productive rate is 80%, and purity is 99% (HPLC).HNMR(400Hz，DMSO)：9.59(s，1H)，8.39(s，1H)，8.23(d，J＝4.8Hz，1H)，7.95(d，J＝5.2Hz，1H)，7.88(d，J＝5.2Hz，1H)，7.40(m，1H)，7.26(d，J＝4.8Hz，1H)，7.0(d，J＝5.6Hz，2H)，6.40(d，J＝5.6Hz，2H)，4.32(s，2H)，4.26(t，J＝3.6Hz，2H)，4.18(t，J＝3.6Hz，2H)，3.67(t，J＝3.2Hz，8H)，3.63(s，3H)，3.59(t，J＝4.0Hz，2H)，2.64(t，J＝3.6Hz，4H)，2.55(t，J＝4.0Hz，2H)，2.37(t，d＝3.2Hz，8H)；MS(m/z)：742.2。

Embodiment 2: on the impact of local rats with cerebral ischemia cerebral infarct volume

(1) experiment material and method

Wistar rat, body weight 250-280g.Perioperatively is raised separately, and room temperature keeps 23-25 DEG C, own feed and water inlet.TMCAO model is prepared according to the method for longa etc.Rat 10% chloral hydrate anesthesia (350mg/kg, i.p.), body temperature maintains 37 ± 0.5 DEG C, and dorsal position is fixed on operating table.Cut skin along neck median line, be carefully separated right carotid (CCA), external carotid artery (ECA), internal carotid artery (ICA).ECA ligation is cut off, stretching with ICA in line.ECA cuts an osculum, by a long 4.0cm, the round end silication nylon rope (with 0.1% poly-lysine bag quilt) of diameter 0.26mm thus opening inserts ICA and is about 1.85-2.00cm, refers to rat brain prerolandic artery Rolando section start, blocks the supply of blood flow of arteria cerebri media.Ischemic carefully extracted nylon wire out after 2 hours, ligation ECA opening suture operation otch, and animal is put back in cage and fills with 24 hours again.

(2) experiment grouping and administration

Rat divides 12 groups at random: model control group, water for injection (100ml/kg), compound 1 administration group in embodiment 1 (25,50,100mg/kg), and MCA blocks oral administration when causing after ischemic 10 minutes.

(3) mensuration of cerebral infarct volume

Rat reperfusion injury is after 24 hours, and broken end gets brain at once, removes tractus olfactorius, cerebellum and low brain stem, it to be crownly cut into 6 (first to the 5th 2mm/ sheet, the 6th 4mm), to be placed in rapidly 5ml and to contain 1.5ml4%TTC and 0.1ml1MK ₂hPO ₄solution in dyeing (37 DEG C, lucifuge) 20-30 minute, stirred once every 5 minutes therebetween.After TTC dyeing, healthy tissues engrain takes on a red color, and infarction tissue is in white.Often will organize brain sheet marshalling, preservation of taking pictures.Ask the infarct size calculating every sheet, and final superposition is converted into infarct volume.Infarct volume represents with shared Interhemispheric percentage, to eliminate the impact of cerebral edema.

The volume * 100% of cerebral infarct volume (%)=(volume of operation contralateral hemisphere volume-non-infarcted portion of operation side hemisphere)/operation contralateral hemisphere

(4) experimental result

Ischemic 2 hours of reperfusion is after 24 hours, and the cerebral infarct volume (%) of solvent control group is 33.8%.Sham operated rats occurs without any cerebral infarction.Other group cerebral infarct volume results are as shown in table 1:

Table 1: gastric infusion is on the impact of ischemic rat cerebral infarct volume (%)

With solvent control group ratio, compound 1 oral administration all significantly can reduce cerebral infarct volume.

Embodiment 13: compound 1 is on the impact of Sleep in Rats effect:

(1) improving water flood Experiment on Function

Animal-origin: Kun Ming mice, 18-22 gram, male, the cleaning grade animal provided by Guangdong Experimental Animal Center.Laboratory animal breeding room's temperature 22 ± 2 DEG C, relative humidity 50-70%, animal rearing material, is provided by Guangdong Experimental Animal Center.

This experiment sets compound 1 dosage as 25mg/kg, separately establishes distilled water control group.

Sample preparation: each sample thief 25mg respectively adding distil water, to 20ml, makes uniformly suspension, for examination.

To sample approach: gavage

Experimental technique:

(2) vetanarcol above threshold dosage hypnosis test:

Select body weight 18-22g male mice 40, be divided into four groups at random, often organize 10, give sample 30 days continuously, in the 30th day sample gavage after 15 minutes, to the vetanarcol abdominal injection of each treated animal 50mg/kg.b.w, injection volume is 0.2ml/20g.b.w, reach more than 1 minute as sleep judging criterion using mouse righting reflex loss, observe to the time for falling asleep of each treated animal in vetanarcol 60 minutes and the length of one's sleep.

Result:

Sample is on the impact of the weight of animals

As seen from the above table, sample each dosage treated animal body weight compared with control group, difference that there are no significant.

The above threshold impact of vetanarcol inducing mouse length of one's sleep of dosage

* P < 0.05 (Analysis of variance) compared with control group

As seen from the above table, the time for falling asleep of compound 1 group of sample animal under above threshold dose of sodium pentobarbitone induction compared with control group, has significant difference with the length of one's sleep.

(3) vetanarcol sub-threshold dose hypnosis test:

Select body weight 18-22g male mice 40, be divided into four groups at random, often organize 10, give sample 28 days continuously, in the 28th day sample gavage after 15 minutes, to the vetanarcol abdominal injection of each treated animal 30mg/kg.b.w, injection volume is 0.2ml/20g.b.w, reaches observe the number of animals that sleep occurs to treated animal each in vetanarcol 25 minutes as sleep judging criterion in more than 1 minute using mouse righting reflex loss.

Result:

The impact of the vetanarcol inducing mouse sleep incidence of sub-threshold dose

* P < 0.05 (through chi square test) compared with control group

As seen from the above table, compound 8 groups and the DL group sleep animal under the induction of sub-threshold dose vetanarcol compared with control group, all has significance poor with sleep incidence.

Sum up: per os gave mouse samples after 30 days, and compound 1 has improving water flood effect.

Claims (4)

1. there is a compound for prevention and therapy cerebrovascular ischemic disease, as shown below:

2. the salt that generates of compound as claimed in claim 1 and acid-respons, acid is selected from pharmaceutically acceptable mineral acid or organic acid, and wherein mineral acid is selected from nitric acid, sulfuric acid or phosphoric acid, organic acid is selected from glycine, acetic acid, α-amino-isovaleric acid, formic acid, propionic acid, butyric acid, succinic acid, fumaric acid, Phenylsulfonic acid, methylsulfonic acid, phenylformic acid, toluylic acid, L-Ala, Methionin, arginine, Serine, phenylalanine, proline(Pro), tyrosine, aspartic acid, L-glutamic acid, Histidine, leucine, methionine(Met), Threonine, Pyrrolidonecarboxylic acid, tryptophane or α-amino-isovaleric acid, dextrocamphoric acid, oxysuccinic acid, citric acid, toxilic acid, succsinic acid, oxalic acid, pentanedioic acid, oxalic acid, lactic acid or propanedioic acid, pamoic acid, hydroxynaphthoic acid, gentisinic acid, Whitfield's ointment, oxyacetic acid, amygdalic acid, lactic acid, 4-acetaminobenzoic acid or nicotinic acid.

3. the application of compound described in claim 1-2 in preparation treatment cerebral ischemia diseases medicine.

4. compound described in claim 1-2 is preparing the application in improving water flood medicine.