CN102633731B - 6-quinoxaline formic acid amide compounds, preparation method and application thereof - Google Patents

Abstract

The invention relates to 6-quinoxaline formic acid amide compounds, which have a structure shown in formula (I) in the specification, wherein R1 and R2 are respectively and independently selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or H, but R1 and R2 are not simultaneously H or methyl, or one of R1 and R2 is H and the other one is methyl. Experiments show that the compounds can generate central excitation effect on human or animals and resist sleeping, so that the mobility of the human or animals is kept for a long time. The formula (I) is shown in the description.

Description

6-quinoxaline benzoic acid amides compound, preparation method and application

Technical field

The present invention relates to a kind of compound with central excitation effect, 6-quinoxaline formic acid compounds particularly, and the preparation method of this compound and pharmaceutical application.

Background technology

Central stimulant refers to and temporarily steps up vigilance and the medicine of realizing, because the side effect that usually band is served synergy class (is the excessive increase of excited effect, even not only be confined to maincenter and can cause producing as too much in palpitating speed, blood pressure excessively rises and waits also excited side effect of peripheral nerve) and quilt is regarded prescription drug or forbidden drug.Stimulant may increase activity or the central nervous system (CNS) of sympathetic nervous system, or both all increase.Some stimulants produce excited sensation by acting on central nervous system.Stimulant in the situation that can not sleeping (as automobile operation) to increase or on your toes, offset tired, antagonism error state (ERST) (as Narcolepsy), or be used for fat-reducing (phentermine), or the attention that increases attention deficit companion hyperkinetic syndrome (ADHD) crowd is concentrated, is also used to once in a while Cure of depression.Stimulant is also used for improving endurance and throughput sometimes, because can depress appetite, if abuse potential causes apositia.The excitement that some stimulants produce causes its recreational use, and such use great majority are illegal.Recently, the improvement aspect stimulant pharmacology, produces ampakine compounds (ampakines or eugeroics).These stimulants can increase alertness, and smaller for the anti-depressant periphery of tradition or maincenter side effect.They are very micro-on Sleep architecture impact, and the effect that can not draw backlash, and they increase Dopamine HCL and the norepinephrine of maincenter, have the effect that suppresses GABA simultaneously, illustrate at present its mechanism of action not yet completely.

AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid) receptor stimulant is a study hotspot in the research of novel ampakine class medicine in recent years.Ampa receptor is a class hypotype important in ionic glutamate receptor, mainly mediates excitatory synapse transmission fast in central nervous system.Newer ampakine is as An Palaisi (CX516, CAS:154235-83-3) and CX717(CAS:867276-98-0, US6110935 report) be synthesized, they have obvious and gentle central excitation effect, can make animal or human resist for a long time sleep.

Summary of the invention

On above-mentioned Research foundation, first the present invention provides a kind of 6-quinoxaline carboxylic acid derivatives having the long-time gentle excitation of nervus centralis, and the preparation method of this compound is further provided, and the pharmaceutical application of this compound.

6-quinoxaline benzoic acid amides compound of the present invention, structure is as shown in formula I:

R in formula I ₁and R ₂respectively independently selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or H, but R ₁and R ₂when different, be H or simultaneously for one of in methyl or the two for H and another are methyl.

A kind of preferred structure in above-claimed cpd of the present invention is the R in said formula I structure ₁and R ₂be respectively cyclopentyl and hydrogen.Another kind of preferred structure is the R in said formula I structure ₁and R ₂be respectively cyclopentyl and methyl.

A kind of basic preparation method of above-claimed cpd of the present invention, be by the conventional activated carboxylic reagent such as corresponding 6-quinoxaline formic acid and pivaloyl chloride (U.S. chemical abstract numbering (CAS) 3282-30-2) in non-proton alkalescence (as triethylamine etc.) environment with replace amine and react, obtain formula I product.For example, the reaction process of several typical compounds is as follows:

。

Experimentation on animals shows, the above-mentioned formula I compound of the present invention has gentle central excitation pharmacological action, with acceptable ancillary component in medicine, according to the preparation method of current routine and technique, can prepare and become the relative medicine with central excitation, preferably as approach outside vein or vein, human or animal is produced to the pharmaceutical preparation of the excitation of long period, for human or animal is produced to central excitation effect, opposing sleep, is maintained human or animal's mobility for a long time.

Below in conjunction with the embodiment of embodiment form, foregoing of the present invention is described in further detail again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.Without departing from the idea case in the present invention described above, various replacements or the change according to ordinary skill knowledge and customary means, made, all should comprise within the scope of the invention.

Embodiment

embodiment 1

6-quinoxaline formic acid (CAS:6925-00-4) 0.96g is suspended in 30ml dry methylene chloride, adds triethylamine 0.55g, add afterwards 0.66ml pivaloyl chloride.Stir after 15min.Add 0.46g cyclopentamine, stirred overnight at room temperature.Next day, filtering reacting liquid, in filtrate, add the dilution of 60ml methylene dichloride, with 10% sodium bicarbonate aqueous solution washing organic layer, separate anhydrous sodium sulphate and Anhydrous potassium carbonate dried overnight for organic layer, filter to get filtrate, the hexanaphthene recrystallization of the resistates after solvent evaporated, obtains formula I faint yellow solid product 0.93g(R ₁for cyclopentyl, R ₂for H), productive rate 70%.

The structure detection result of product:

1) nuclear magnetic resonance analyser: BRUKER 400M, with CDCl ₃for solvent, TMS is interior mark, and δ unit is ppm.

¹ （δ）：1.5513~1.7643(m,8H)，2.1084~2.1389(t,2H)，4.4272~4.5128(m,1H)，6.5503(s,1H)，8.1091~8.2083(m,2H)，8.4006(s,1H)，8.8869(s,2H)。

2) nuclear magnetic resonance analyser: BRUKER 400M, with CDCl ₃for solvent, TMS is interior mark, and δ unit is ppm.

¹³ （δ）：23.8243，33.1906，33.3520，52.0852，127.8162，128.6180，129.9614，136.3686，142.2472，144.0405，145.7930，146.0961，166.0240。

3) high resolution mass spectrum detects: mass spectrograph: the API3000 LC-Ms/Ms of American AB I company, ionization mode: ESI.

⁺ ：242.1295（M+H）。

embodiment 2

6-quinoxaline formic acid 0.96g is suspended in 30ml dry methylene chloride, adds pyridine 0.43g, add afterwards 0.66ml pivaloyl chloride.Stir after 15min.Add 0.46g cyclopentamine, stirred overnight at room temperature.Next day, filtering reacting liquid, in filtrate, add the dilution of 60ml methylene dichloride, with 10% sodium bicarbonate aqueous solution washing organic layer, separate anhydrous sodium sulphate and Anhydrous potassium carbonate dried overnight for organic layer, filter to get filtrate, the hexanaphthene recrystallization of the resistates after solvent evaporated, obtains formula I faint yellow solid product 0.93g(R ₁for cyclopentyl, R ₂for H) 0.73g, productive rate 55%.

embodiment 3

6-quinoxaline formic acid (CAS:6925-00-4) 0.96g is suspended in 30ml dry methylene chloride, adds triethylamine 0.55g, add afterwards 0.66ml pivaloyl chloride.Stir after 15min.Add 0.54g cyclopentamine methylamine, stirred overnight at room temperature.Next day, filtering reacting liquid, in filtrate, add the dilution of 60ml methylene dichloride, with 10% sodium bicarbonate aqueous solution washing organic layer, separate anhydrous sodium sulphate and Anhydrous potassium carbonate dried overnight for organic layer, filter to get filtrate, the hexanaphthene recrystallization of the resistates after solvent evaporated, obtains compound (I) faint yellow solid product 0.78g(R ₁for cyclopentyl, R ₂for methyl ), productive rate 55.5%.

embodiment 4

6-quinoxaline formic acid (CAS:6925-00-4) 0.96g is suspended in 30ml dry methylene chloride, adds pyridine 0.43g, add afterwards 0.66ml pivaloyl chloride.Stir after 15min.Add 0.54g cyclopentamine methylamine, stirred overnight at room temperature.Next day, filtering reacting liquid, in filtrate, add the dilution of 60ml methylene dichloride, with 10% sodium bicarbonate aqueous solution washing organic layer, separate anhydrous sodium sulphate and Anhydrous potassium carbonate dried overnight for organic layer, filter to get filtrate, the hexanaphthene recrystallization of the resistates after solvent evaporated, obtain faint yellow solid product 0.68g, productive rate 48.4%.

The structure detection result of product:

¹ HNMR（δ）：1.2412~2.0491(m,8H)，2.9015~3.0496(d,3H)，4.1137~5.1102(d,1H)，7.8065~7.8271(d,1H)，8.1296~8.1868(t,2H)，8.9067(s,2H)。

¹³ （δ）：24.4896，26.8779，27.6694，28.2134，29.2631，29.6786，32.1701，55.0283，60.1977，127.1970，128.5711，130.1305，138.7702，142.4936，142.9811，145.7083， 145.7602，170.2032。

⁺ ：256.143(M+H)。

embodiment 5

pharmacologically active experiment:

the excitation determination experiment of the compounds of this invention:

The compounds of this invention being dissolved and to be configured to solution with 50% DMSO solution, and blank group, positive drug CX516(CAS numbering: 173047-75-1, a kind of central stimulant) control group tests together.24 body weight are divided into 4 groups, 6 every group at random at the kunming mice of 20 ~ 30 grams.Mouse is placed on before administration and in movable appearance, adapts to 10 min, through subcutaneous administration, give respectively afterwards solution, blank reagent (50% DMSO solution) and the positive drug of compound described in this patent.Start afterwards select time point record, total activity number of times in selected time point continuous recording 5 min.Record administration front and back independent activity of animals number of times result, as shown in table 1.

Independent activity of animals number of times before and after table 1 administration

Medicine	Dosage (mg/kg)	Before administration (inferior)	2h after administration (inferior)	24h after administration (inferior)	48h after administration (inferior)
						50% DMSO	—	225±67.8	212±80.1	230±45.6	209±61.9
CX516	70	209±33.9	390±70.1	350±102.5	269±91.3
							70	198±110.6	401±67.9	389±89.5	394±45.7
	70	204±72.9	412±90.4	409±77.7	389±101.6

The result demonstration of table 1, compound of the present invention can cause that mouse autonomic activities suitably increases and is maintained for a long time, has lasting central excitation effect.

Claims (3)

1. the 6-quinoxaline benzoic acid amides compound of formula I structure has the application in central excitation medicine in preparation, the R in formula ₁and R ₂respectively independently selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or H, but R ₁and R ₂when different, being H, is methyl when also different, and R ₁and R ₂one of another is not methyl while being H,

。

2. application as claimed in claim 1, is characterized in that the R in said formula I structure ₁and R ₂be respectively cyclopentyl and hydrogen.

3. application as claimed in claim 1, is characterized in that the R in said formula I structure ₁and R ₂be respectively cyclopentyl and methyl.