CN102633731A - 6-quinoxaline formic acid amide compounds, preparation method and application thereof - Google Patents
6-quinoxaline formic acid amide compounds, preparation method and application thereof Download PDFInfo
- Publication number
- CN102633731A CN102633731A CN2012100650640A CN201210065064A CN102633731A CN 102633731 A CN102633731 A CN 102633731A CN 2012100650640 A CN2012100650640 A CN 2012100650640A CN 201210065064 A CN201210065064 A CN 201210065064A CN 102633731 A CN102633731 A CN 102633731A
- Authority
- CN
- China
- Prior art keywords
- formula
- methyl
- compound
- preparation
- formic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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.
Description
Technical field
The present invention relates to a kind of compound, 6-quinoxaline formic acid compounds particularly, and the preparation method of this compound and pharmaceutical application with the effect of central excitation property.
Background technology
The central excitation medicine is meant the medicine that temporarily steps up vigilance and realize; Because usually bringing the spinoff of some synergy classes (is the excessive increase of excited effect; Even be not only to be confined to maincenter and can to cause producing as heartbeat is accelerated too much, blood pressure excessively rises and waits the also excited spinoff of peripheral nerve) and quilt is regarded prescription drug or forbidden drug.Stimulant possibly increase the activity or the cns (CNS) of sympathetic nervous system, and perhaps both all increase.Some stimulants produce excited sensation through acting on cns.Stimulant is used under situation about can not sleep (like the automobile operation) to increase or on your toes; Offset tired; Antagonism ERST (like Narcolepsy); Or be used for losing weight (phentermine), or increase attention deficit companion hyperkinetic syndrome (ADHD) crowd's attention is concentrated, also is used to treat dysthymia disorders once in a while.Stimulant also is 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, ampakine compounds (ampakines or eugeroics) is produced in the improvement aspect stimulant pharmacology.These stimulants can increase alertness, and smaller for anti-depressant periphery of tradition or maincenter spinoff.They are very little to the Sleep architecture influence, and the effect that can not draw backlash, and they increase the Dopamine HCL and the sympathin of maincenter, have the effect that suppresses GABA simultaneously, do not illustrate its mechanism of action at present as yet fully.
(receptor stimulant of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid) is the focus of the research of in the research of novel ampakine class medicine in recent years to AMPA.Ampa receptor is one type of important in ionic glutamate receptor hypotype, in cns, mainly mediates excitatory synapse transmission fast.Newer ampakine such as An Palaisi (CX516; CAS:154235-83-3) and CX717 (CAS:867276-98-0; The US6110935 report) be synthesized, they have obvious and gentle central excitation effect, can make the animal or human resist sleep for a long time.
Summary of the invention
On above-mentioned research basis, the present invention at first provides a kind of 6-quinoxaline carboxylic acid derivatives that has the long-time gentle excitation of nervus centralis, and the preparation method of this compound further is provided, and the pharmaceutical application of this compound.
6-quinoxaline benzoic acid amides compound of the present invention, structure is shown in formula I:
R in the formula I
1And R
2Be independently selected from methyl respectively, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or H, but R
1And R
2Be not H or simultaneously simultaneously for being methyl one of in methyl or the two for H and another.
A kind of preferred structure in the above-claimed cpd of the present invention is the R in the said formula I structure
1And R
2Be respectively cyclopentyl and hydrogen.Another kind of preferred structure is the R in the 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 with corresponding 6-quinoxaline formic acid and pivaloyl chloride activated carboxylic reagent commonly used such as (U.S. chemical abstract numbering (CAS) 3282-30-2) in non-proton alkalescence (like triethylamine etc.) environment with replace the amine reaction, obtain the formula I product.For example, the reaction process of several kinds of typical compounds is following:
Experimentation on animals shows; The above-mentioned formula I compound of the present invention has gentle central excitation property pharmacological action; With acceptable ancillary component in the medicine, according to the preparation method and the technology of present routine, can prepare becomes the relative medicine with central excitation property; Preferably the human or animal is produced the pharmaceutical prepn of the excitation of long period as approach outside vein or vein; Be used for the human or animal is produced the central excitation effect, the 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 remake further detailed description.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
Embodiment 1
0.96g is suspended in the 30ml dry methylene chloride with 6-quinoxaline formic acid (CAS:6925-00-4), adds triethylamine 0.55g, adds the 0.66ml pivaloyl chloride afterwards.After stirring 15min.Add the 0.46g NSC 32389, stirred overnight at room temperature.Next day; Filtering reacting liquid adds the dilution of 60ml methylene dichloride in filtrating, with 10% sodium bicarbonate aqueous solution washing organic layer; Tell organic layer with SODIUM SULPHATE ANHYDROUS 99PCT and Anhydrous potassium carbonate dried overnight; Cross and filter filtrating, the resistates after the solvent evaporated is used the hexanaphthene recrystallization, gets formula I faint yellow solid product 0.93g (R
1Be cyclopentyl, R
2Be H), productive rate 70%.
The structure detection result of product:
1) NMR: BRUKER 400M, with CDCl
3Be 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) NMR: BRUKER 400M, with CDCl
3Be 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
0.96g is suspended in the 30ml dry methylene chloride with 6-quinoxaline formic acid, adds pyridine 0.43g, adds the 0.66ml pivaloyl chloride afterwards.After stirring 15min.Add the 0.46g NSC 32389, stirred overnight at room temperature.Next day; Filtering reacting liquid adds the dilution of 60ml methylene dichloride in filtrating, with 10% sodium bicarbonate aqueous solution washing organic layer; Tell organic layer with SODIUM SULPHATE ANHYDROUS 99PCT and Anhydrous potassium carbonate dried overnight; Cross and filter filtrating, the resistates after the solvent evaporated is used the hexanaphthene recrystallization, gets formula I faint yellow solid product 0.93g (R
1Be cyclopentyl, R
2Be H) 0.73g, productive rate 55%.
Embodiment 3
0.96g is suspended in the 30ml dry methylene chloride with 6-quinoxaline formic acid (CAS:6925-00-4), adds triethylamine 0.55g, adds the 0.66ml pivaloyl chloride afterwards.After stirring 15min.Add 0.54g NSC 32389 methylamine, stirred overnight at room temperature.Next day; Filtering reacting liquid adds the dilution of 60ml methylene dichloride in filtrating, with 10% sodium bicarbonate aqueous solution washing organic layer; Tell organic layer with SODIUM SULPHATE ANHYDROUS 99PCT and Anhydrous potassium carbonate dried overnight; Cross and filter filtrating, the resistates after the solvent evaporated is used the hexanaphthene recrystallization, gets compound (I) faint yellow solid product 0.78g (R
1Be cyclopentyl, R
2Be methyl
), productive rate 55.5%.
Embodiment 4
0.96g is suspended in the 30ml dry methylene chloride with 6-quinoxaline formic acid (CAS:6925-00-4), adds pyridine 0.43g, adds the 0.66ml pivaloyl chloride afterwards.After stirring 15min.Add 0.54g NSC 32389 methylamine, stirred overnight at room temperature.Next day, filtering reacting liquid adds the dilution of 60ml methylene dichloride in filtrating; With 10% sodium bicarbonate aqueous solution washing organic layer; Tell organic layer with SODIUM SULPHATE ANHYDROUS 99PCT and Anhydrous potassium carbonate dried overnight, cross and filter filtrating, the resistates after the solvent evaporated is used the hexanaphthene recrystallization; Get 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
The pharmacologically active experiment:
The excitation determination experiment of The compounds of this invention:
The compounds of this invention is configured to solution with the dissolving of 50% DMSO solution, makes an experiment together with blank group, positive drug CX516 (CAS numbering: 173047-75-1, a kind of central excitation medicine) control group.24 body weight are divided into 4 groups, 6 every group at random at the kunming mice of 20 ~ 30 grams.Before the administration mouse is placed on adaptation 10 min in the movable appearance, gives solution, blank reagent (50% DMSO solution) and the positive drug of the said compound of this patent afterwards respectively through subcutaneous administration.Begin select time point record afterwards, total activity number of times in selected time point continuous recording 5 min.Independent activity of animals number of times result is as shown in table 1 before and after the record administration.
Independent activity of animals number of times before and after table 1 administration
| Medicine | Dosage (mg/kg) | Before the administration (inferior) | 2h after the administration (inferior) | 24h after the administration (inferior) | 48h after the 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 of table 1 shows, compound of the present invention can cause that the mouse autonomic activities suitably increases and is maintained for a long time, has persistent central excitation effect.
Claims (5)
1.6-quinoxaline benzoic acid amides compound, structure shown in formula I, the R in the formula
1And R
2Be independently selected from methyl respectively, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or H, but R
1And R
2Be not H or simultaneously simultaneously for being methyl one of in methyl or the two for H and another,
2. compound as claimed in claim 1 is characterized in that the R in the said formula I structure
1And R
2Be respectively cyclopentyl and hydrogen.
3. compound as claimed in claim 1 is characterized in that the R in the said formula I structure
1And R
2Be respectively cyclopentyl and methyl.
4. the preparation method of the said compound of claim 1 is characterized in that corresponding 6-quinoxaline formic acid and pivaloyl chloride are reacted with replacement amine in non-proton alkaline environment, obtains the formula I product, and reaction process is following, R in the formula
1, R
2Scope with claim 1:
5. the said compound of one of claim 1 to 3 has the application in the central excitation property medicine in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210065064.0A CN102633731B (en) | 2012-03-13 | 2012-03-13 | 6-quinoxaline formic acid amide compounds, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210065064.0A CN102633731B (en) | 2012-03-13 | 2012-03-13 | 6-quinoxaline formic acid amide compounds, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102633731A true CN102633731A (en) | 2012-08-15 |
| CN102633731B CN102633731B (en) | 2014-04-30 |
Family
ID=46618326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210065064.0A Active CN102633731B (en) | 2012-03-13 | 2012-03-13 | 6-quinoxaline formic acid amide compounds, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102633731B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997007799A1 (en) * | 1995-08-30 | 1997-03-06 | The Regents Of The University Of California | Facilitation of ampa receptor-mediated synaptic transmission in brain as a treatment for schizophrenia |
| CN1247534A (en) * | 1997-02-13 | 2000-03-15 | 加利福尼亚大学董事会 | Benzofurazan compounds which enhance AMPA receptor activity |
-
2012
- 2012-03-13 CN CN201210065064.0A patent/CN102633731B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997007799A1 (en) * | 1995-08-30 | 1997-03-06 | The Regents Of The University Of California | Facilitation of ampa receptor-mediated synaptic transmission in brain as a treatment for schizophrenia |
| CN1247534A (en) * | 1997-02-13 | 2000-03-15 | 加利福尼亚大学董事会 | Benzofurazan compounds which enhance AMPA receptor activity |
Non-Patent Citations (5)
| Title |
|---|
| COLUMBUS,OHIO,US: "1343299-66-0", 《REGISTRY》, 9 November 2011 (2011-11-09) * |
| COLUMBUS,OHIO,US: "571910-74-2", 《REGISTRY》, 24 August 2003 (2003-08-24) * |
| COLUMBUS,OHIO,US: "571910-75-3", 《REGISTRY》, 24 August 2003 (2003-08-24) * |
| COLUMBUS,OHIO,US: "710945-21-4", 《REGISTRY》, 16 July 2004 (2004-07-16) * |
| COLUMBUS,OHIO,US: "936083-31-7", 《REGISTRY》, 30 May 2007 (2007-05-30) * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102633731B (en) | 2014-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10793538B2 (en) | Cycloalkenyl hydroxamic acid derivatives and their use as histone deacetylase inhibitors | |
| CN1871240B (en) | Pyrrolopyrimidine thion derivatives | |
| EP3143009B1 (en) | Substituted benzoxazolone derivatives as acid ceramidase inhibitors, and their use as medicaments | |
| MX2007003836A (en) | Substituted 2h-1,3-benzoxazin-4(3h)-ones. | |
| CA2650326A1 (en) | N-(2-thiazolyl)-amide derivatives as gsk-3 inhibitors | |
| WO2013066835A2 (en) | Compounds and methods | |
| US5472983A (en) | Benzamide-containing pharmaceutical compositions | |
| CN102295635B (en) | Antitumor medicament tetralin amide compounds and pharmaceutically acceptable salts thereof as well as preparation method and application of antitumor medicament tetralin amide compounds | |
| KR101839716B1 (en) | Crystalline salt form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist | |
| WO2015173168A1 (en) | Benzoxazolone derivatives as acid ceramidase inhibitors, and their use as medicaments | |
| WO2016090230A1 (en) | Pyrimidine hydroxy amide compounds for treating peripheral neuropathy | |
| CA2972835C (en) | Trifluoroacetyl hydrazide compounds and methods of preparation and uses thereof | |
| EP3022179B1 (en) | Phenyl carbamates and their use as inhibitors of the fatty acid amide hydrolase (faah) enzyme and modulators of the d3 dopamine receptor (d3dr) | |
| CN104080335B (en) | Some chemical entities, composition and method | |
| Marwaha et al. | PASS-predicted design, synthesis and biological evaluation of cyclic nitrones as nootropics | |
| US20050049312A1 (en) | Novel adamantane derivatives with neuroprotective, antidepressant and anti-ischaemic activities,and process for preparing them | |
| Theivendren et al. | Graph theoretical analysis, insilico modeling, design, and synthesis of compounds containing benzimidazole skeleton as antidepressant agents | |
| Naseem et al. | Therapeutic potential of 1, 3, 4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease | |
| CN102633731B (en) | 6-quinoxaline formic acid amide compounds, preparation method and application thereof | |
| EP3968990A1 (en) | Pyrrolopyrimidine inhibitors of wild-type and mutant forms of lrrk2 | |
| WO2013178545A1 (en) | Acid ceramidase inhibitors and their use as medicaments | |
| CN101209994B (en) | Selectivity M4 acceptor antagonist and medical use thereof | |
| AU2014234095A1 (en) | Novel breathing control modulating compounds, and methods of using same | |
| CN102617478A (en) | Synthesis of benzimidazole, oxazole and thiazole derivatives and application thereof | |
| Wu et al. | Synthesis and biological evaluation of prodrugs for nitroreductase based HSP90 inhibitor BIIB021as potential anticancer agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |