CN108191775A - A kind of terminal allylic propionyl hydrazine structural compounds and application thereof - Google Patents
A kind of terminal allylic propionyl hydrazine structural compounds and application thereof Download PDFInfo
- Publication number
- CN108191775A CN108191775A CN201711496315.XA CN201711496315A CN108191775A CN 108191775 A CN108191775 A CN 108191775A CN 201711496315 A CN201711496315 A CN 201711496315A CN 108191775 A CN108191775 A CN 108191775A
- Authority
- CN
- China
- Prior art keywords
- compound
- comt
- application
- dopamine
- structural compounds
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Abstract
The invention belongs to pharmaceutical technology fields.Specifically, the present invention relates to a kind of hydrazine of propionyl containing terminal allylic structural compounds, Its Preparation Method And Uses.
Description
Technical field
The invention belongs to pharmaceutical technology fields.In particular it relates to a kind of the third hydrazide structure containing terminal allylic
Compound, preparation method and its prepare treat mental disease drug in terms of application.
Background technology
Schizoid symptom generally falls into three classes：The positive, negative and cognition.Positive symptom include illusion, illusion and
Chaotic behavior, and negative symptoms have the feature for lacking happy sense and/or the interest to life.Cognitive defect is included to idea
Tissue and to the difficulty in terms of the priorization of task.Patient with bipolar disorders is usually shown from serious depressed to tight
The periodic emotional change feature of mental disease (with or without) of the mania of weight.Schizophrenia and bipolar disorders belong to
Cause the phrenoblabia of the most serious type of the cognitive defect of overlapping and the disease is intended to be chronic/progressive.
Compared with positive symptom, schizoid negative and cognition symptom is considered to long-term disability, treats consequence and function is extensive
There is the influence of bigger again.To treatment be not full of due to lack efficiency or can not endure and unacceptable side effect caused by
's.It has been found that the adverse events in terms of the side effect and important metabolism, extrapyramidal system, prolactin and heart are related
(referring to Lieberman et al., N.Engl.J.Med.2005,353:1209-1223).
It is considered being related to leading to negative and cognition symptom schizoid pathogenesis, but more in spite of a plurality of access
More concerns has concentrated on the reduction that dopamine neuronal transmits in prefrontal cortex.Dopamine neuronal transmits in prefrontal cortex
The regional cerebral blood flow amount in schizophreniac that the evidence of reduction obtained reduces or the activity of tergolateral prefrontal cortex
The support of decline.Before having been found that the relevant prefrontal lobe defect of schizophrenia (unrelated with treatment or psychotic state) and evaluating
Frontal lobe participates in execution functional task (such as the n-back or Wisconsin Card of (prefrontal engagement)
Sorting Test) in bad luck performance it is related.In addition to the defects of control function is performed, dopamine god in prefrontal cortex
Reduction through transmission is related with several cerebration, including note that the activity of enjoyment, instinct feedback (natural
) and biological action (such as cellular signal transduction) rewards.Therefore, the DOPA inside Selective long-range DEPT prefrontal cortex
The compound of amine neurotransmission may have the acology potential for the treatment of cognition and negative symptoms.
Dopamine level in brain is by biosynthesis and release and its diffusion rate, and reuptake and degradation are determined
's.Catechol O-methyltransferase (COMT) is to involve the important enzyme that dopamine decomposes in cortex.COMT is by Dopamine Turnover
Homovanillic acid (HVA) is converted into 3-methoxytyramine and by Dopamine metabolites dihydroxyphenyl acetic acid (DOPAC).In fact,
COMT acts on the catecholamines of various biological sources and catechol estrogen class, diet phytochemicals and ascorbic acid.
In infracortical structure (such as corpus straitum), dopaminergic signal mainly (is passed through by dopamine from the elimination in synaptic cleft
The quick intake of Dopamine Transporter (DAT) and/or norepinephrine transporter (NET)) adjusting.In prefrontal cortex
Dopamine transmit adjusting be dramatically different.DAT is expressed in prefrontal cortex with relatively low density and (passes through in this dopamine
The intake of NET, diffusion or the metabolism of COMT and monoamine oxidase and eliminate) in cynapse in.Therefore, COMT inhibitor will
Selectively increase cortex dopaminergic signal can be expected and improve cognitive function whereby.
COMT genes are located in Chromosome 22q11 .21 regions, it has been found that the region and schizophrenia, bipolar disorders,
ADHD is related with substance depilatory.There are the COMT of two kinds of predominant isoforms, the COMT (MB-COMT) that film combines is involved in human brain
Principal mode (Lachman the et al., Pharmacogenetics, 1996,6 (3) of the degradation of cynapse frontal lobe dopamine:243-
250).Another form is soluble COMT (S-COMT), is from different from the promoter transcription of MB-COMT and except this
Except it is identical with subtracting the people MB-COMT of 50 amino acid in the N- ends of albumen.In people, COMT activity by
The adjusting of single nucleotide polymorphism at Val158Met (MB-COMT).Since the thermal stability of enzyme has differences, homozygous Met
Carrier has relatively low COMT activity, and heterozygote shows that the Val carriers of medium activity and homozygosis have stronger enzymatic activity.To the greatest extent
The difference that pipe is observed in the activity based on genotype, pass only appropriate between Val158Met genotype and cognitive performance
System is shown by the meta-analysis (meta-analysis) in normal individual, and is not seen in schizophrenia
Observe effect.Based on the U-shaped relationship for being considered as the existing reversing between dopamine receptor activation and the function of prefrontal cortex
(inverted-U relationship), these have found that it is likely that consistent with following facts：Morbid state and a variety of environment and
The factor of heredity together contributes to the efficiency of forehead and dopamine level.
Although Clozapine, Zyprexa, Risperidal and other antipsychotic drugs have been used to treatment schizophrenia and two-phase
The positive and negative (remaining dispute) symptom of obstacle, these drugs still without departing from side effect, such as group agranulocytosis,
Calmness, weight gain, hyperlipidemia and hyperglycemia, all these side effects limit their application.Therefore, it still deposits
In the demand to such drug, negative symptoms and cognitive defect are effectively treated, without serious side effect, and in essence
In the treatment of refreshing Split disease, bipolar disorders, depression, substance depilatory and ADD/ADHD etc. effectively.When it is as another essence
The part that refreshing disease learns syndrome exists or when it occurs with nerve problems, and such drug can be used for
Reduce the symptom.
The invention discloses a kind of COMT inhibitor of the third hydrazide structure containing terminal allylic, these compounds can be used for making
The medicine of standby schizophrenia etc..
Invention content
It is an object of the present invention to provide a kind of COMT inhibitor with Formulas I；Another object of the present invention is to carry
Method for preparing the compound with Formulas I；It is also another object of the present invention to provide the compound containing Formulas I in treatment spirit
The application of Split disease etc..The content of present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the invention with formula (I) is with following structural formula：
Formula (I) compound of the present invention can be synthesized by following route：
Cyclopentadiene II reacts in the presence of KOH with halogenated hydrocarbon compound III, obtains compound IV；Compound IV is in KOH
In the presence of reacted with compound V, obtain compound VI；Compound VI obtains compound VII with hydration hydrazine reaction, hydrazinolysis；Chemical combination
Object VII is reacted with pyrimidine compound VIII, obtains compound I；Wherein described X is selected from Cl, Br and I.
Compound of formula I of the present invention has COMT inhibiting effect, can be used as an active ingredient in the preparation of schizophrenia
Medicine.The activity of compound of formula I of the present invention is by the way that COMT experiments is inhibited to be verified in vitro.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.General technical staff's training centre according to the present invention in the art is made various
Variation should all be within the protection domain required by the application claim.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step 1. compound VI-1
Compound II (1.32g, 20mmol) is dissolved in 20mL DMSO, is stirred at room temperature, addition KOH solids (2.24g,
40mmol), continue stirring 1 hour at room temperature.MeI (III-1,2.84g, 20mmol) is added, continues to be stirred at room temperature
Night.Tert-butyl acrylate V-1 (2.56g, 20mmol) is then added, continues stirring 12 hours, TLC detections find to have reacted
Into.
Reaction mixture is carefully poured into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, uses
5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated on a rotary evaporator, residue
It is purified using silica gel column chromatography, obtains compound VI-I, 2.96g (merging yield 71%).ESI-MS, m/z=209 ([M+H
]+)。
The synthesis of step 2. compound VII-1
Compound VI-1 (2.08g, 10mmol) is dissolved in 20mL absolute ethyl alcohols, is stirred at room temperature, adds in 80% hydration
Hydrazine (5mL) then stirs 3 hours at room temperature, and TLC detections find that reaction is completed.
Reaction mixture is directly evaporated on a rotary evaporator, and residue is purified using short silica gel column chromatography, obtains chemical combination
Object VII-I, 1.40g (yield 84%).ESI-MS, m/z=167 ([M+H]+)。
The synthesis of step 3. compound I-1
Compound VII-1 (0.83g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and ice-water bath cooling is lower to stir, and adds in three second
Pyrimidine compound VIII-1 (0.93g, 5mmol) is then slowly added portionwise in amine (2.02g, 20mmol) again, reacts mixed after adding
Closing object, stirring was continued at room temperature overnight, and the reaction of TLC displays at this time is completed.
Reaction mixture is directly evaporated on a rotary evaporator, and residue is purified using short silica gel column chromatography, obtains chemical combination
Object I-I, 1.06g (yield 78%).ESI-MS, m/z=273 ([M+H]+)。
The synthesis of 2 compound I-2 of embodiment
The synthesis of step 1. compound VI-2
Compound II (1.32g, 20mmol) is dissolved in 20mL DMSO, is stirred at room temperature, addition KOH solids (2.24g,
40mmol), continue stirring 1 hour at room temperature.Again plus compound III-2 (2.42g, 20mmol), continue to be stirred at room temperature
Night.20mmol compound V-2 are then added, continue stirring 12 hours, TLC detections find that reaction is completed.Reaction mixture is small
The heart is poured into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, with 5% salt water washings of 100mL, nothing
Aqueous sodium persulfate is dried.It filtering and removes drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography,
Obtain compound VI-2.ESI-MS, m/z=249 ([M+H]+)。
The synthesis of step 2. compound VII-2
Compound VI-2 (2.48g, 10mmol) is dissolved in 20mL absolute ethyl alcohols, is stirred at room temperature, adds in 80% hydration
Hydrazine (5mL) then stirs 3 hours at room temperature, and TLC detections find that reaction is completed.Reaction mixture is directly on a rotary evaporator
It is evaporated, residue is purified using short silica gel column chromatography, obtains compound VII-2.ESI-MS, m/z=207 ([M+H]+)。
The synthesis of step 3. compound I-2
Compound VII-2 (1.03g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and ice-water bath cooling is lower to stir, and adds in three second
Pyrimidine compound VIII-2 (1.09g, 5mmol) is then slowly added portionwise in amine (2.02g, 20mmol) again, reacts mixed after adding
Closing object, stirring was continued at room temperature overnight, and the reaction of TLC displays at this time is completed.Reaction mixture directly steams on a rotary evaporator
Dry, residue is purified using short silica gel column chromatography, obtains compound I-2, ESI-MS, m/z=345 ([M+H]+) white solid.
3 Compound ira vitro of embodiment inhibits COMT analyses
The COMT inhibitory activity of the compound of the present invention is determined using experimental method described below.The fluorescence analysis
It is to be methylated by COMT with the product (7- hydroxyl -6- methoxyl groups for generating high fluorescent based on substrate (6,7- dihydroxycoumarins)
Cumarin).The reaction needs the presence of magnesium ion and methyl donor [being in this case s-adenosylmethionine (SAM)].It adopts
It is prepared 10: 3 times of dilution series with storing solution of the 10mM compounds in DMSO and is positioned over the 1 μ L dilutions being suitble to minute
Analyse hole (the 96 hole round bottom polystyrene board of black from Costar；Catalog number (Cat.No.) 3792) in.Recombinase is diluted in analysis buffering
Liquid (100mM Na2HPO4PH 7.4,1mM DTT, 0.005%Tween-20) in and 35 μ L are added in comprising 1 μ L compounds
It analyzes in hole.The preculture 2 hours of COMT enzymes and compound is carried out in room temperature.40 μM of SAM (USB catalog number (Cat.No.)s are included with 5 μ L
US10601), 4 μM of Esculetins (substrate) and 40mM MgCl2Mixture start enzyme analysis.Use Tecan
By fluorescence, (excitation 340nm emits 460nm to 2 microplate reader of Safire (plate reader), non-delay, when 100 μ s are integrated
Between, 5 flickers, top set is read) formation of monitoring product (scopoletin) at any time.At any time to this point
Analysis monitoring, until generating 4:1 signal:Background ratio.Titration curve and IC are calculated using standard method50Value.In short, data are pressed
According to " (average of instrument connection)-(average of no enzyme control)/(average of total enzyme control)-(average of no enzyme control) "
To calculate, be then expressed as percentage and the suppression percentage to obtain COMT activity subtracted from 100.
Test result see the table below.
| Compound | IC50(nM) |
| Compound I-1 | 271.6 |
| Compound I-2 | 5.8 |
Can be seen that the compound of the present invention from upper table result has very strong inhibiting effect to COMT, can be used as system
Medicines are waited for schizoid.
Claims (3)
1. the compound with logical formula (I) structure,
2. synthesize the method for claim 1 compound：
Cyclopentadiene II reacts in the presence of KOH with halogenated hydrocarbon compound III, obtains compound IV；Compound IV exists in KOH
It is lower to be reacted with compound V, obtain compound VI；Compound VI obtains compound VII with hydration hydrazine reaction, hydrazinolysis；Compound VII
It is reacted with pyrimidine compound VIII, obtains compound I；Wherein described X is selected from Cl, Br and I.
3. application of claim 1 compound in terms for the treatment of schizophrenia drug is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496315.XA CN108191775A (en) | 2017-12-31 | 2017-12-31 | A kind of terminal allylic propionyl hydrazine structural compounds and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496315.XA CN108191775A (en) | 2017-12-31 | 2017-12-31 | A kind of terminal allylic propionyl hydrazine structural compounds and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108191775A true CN108191775A (en) | 2018-06-22 |
Family
ID=62587578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711496315.XA Pending CN108191775A (en) | 2017-12-31 | 2017-12-31 | A kind of terminal allylic propionyl hydrazine structural compounds and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108191775A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050080087A1 (en) * | 2003-10-10 | 2005-04-14 | Annapurna Pendri | Pyrazole derivatives as cannabinoid receptor modulators |
| US20050137162A1 (en) * | 2003-12-19 | 2005-06-23 | Francois Diederich | New COMT inhibitors for the treatment of depression and impaired cognition |
| WO2005103055A1 (en) * | 2004-04-21 | 2005-11-03 | Schering Corporation | PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO-[1,5-c]-PYRIMIDINE ADENOSINE A2A RECEPTOR ANTAGONISTS |
| CN101248064A (en) * | 2005-07-26 | 2008-08-20 | 坡特拉有限公司 | Nitrocatechol derivatives as COMT inhibitors |
-
2017
- 2017-12-31 CN CN201711496315.XA patent/CN108191775A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050080087A1 (en) * | 2003-10-10 | 2005-04-14 | Annapurna Pendri | Pyrazole derivatives as cannabinoid receptor modulators |
| US20050137162A1 (en) * | 2003-12-19 | 2005-06-23 | Francois Diederich | New COMT inhibitors for the treatment of depression and impaired cognition |
| WO2005103055A1 (en) * | 2004-04-21 | 2005-11-03 | Schering Corporation | PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO-[1,5-c]-PYRIMIDINE ADENOSINE A2A RECEPTOR ANTAGONISTS |
| CN101248064A (en) * | 2005-07-26 | 2008-08-20 | 坡特拉有限公司 | Nitrocatechol derivatives as COMT inhibitors |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mahmudov et al. | Synthesis and inhibition profiles of N-benzyl-and N-allyl aniline derivatives against carbonic anhydrase and acetylcholinesterase–A molecular docking study | |
| Herr et al. | HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury | |
| Rodrigues et al. | Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities | |
| Legoabe et al. | Monoamine oxidase inhibition by selected anilide derivatives | |
| US9295672B2 (en) | Optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof | |
| Mostert et al. | Inhibition of monoamine oxidase by 8-[(phenylethyl) sulfanyl] caffeine analogues | |
| Patagar et al. | Synthesis, antioxidant and anti-diabetic potential of novel benzimidazole substituted coumarin-3-carboxamides | |
| Chi et al. | Design, synthesis and antitumor activity study of PARP-1/HDAC dual targeting inhibitors | |
| Bolognino et al. | Synthesis and Biological Evaluation of Dantrolene‐Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases | |
| Ibrahim et al. | Design, Synthesis, In‐Vivo Anti‐Diabetic Activity, In‐Vitro α‐Glucosidase Inhibitory Activity and Molecular Docking Studies of Some Quinazolinone Derivatives | |
| Alam et al. | Discovery of (S)-flurbiprofen-based novel azine derivatives as prostaglandin endoperoxide synthase-II inhibitors: Synthesis, in-vivo analgesic, anti-inflammatory activities, and their molecular docking | |
| Güzel et al. | Carbonic anhydrase inhibitors. Phenacetyl-, pyridylacetyl-and thienylacetyl-substituted aromatic sulfonamides act as potent and selective isoform VII inhibitors | |
| CN108191775A (en) | A kind of terminal allylic propionyl hydrazine structural compounds and application thereof | |
| CN108148004A (en) | The compound of a kind of hydrazine containing propionyl and pyrimidine structure, preparation method and its usage | |
| CN107903216A (en) | A kind of compound of hydrazine containing propionyl and pyrimidine structure and application thereof | |
| CN107987026A (en) | The compound of the propionyl hydrazine pyrimidine structure of terminal allylic, preparation method and its usage | |
| CN108148010A (en) | COMT inhibitor, preparation method and its usage containing hydrazide structure | |
| CN108218796A (en) | Compound, preparation method and its usage containing hydrazide structure | |
| CN107987025A (en) | Compound of the one kind containing the third hydrazide structure, preparation method and its usage | |
| CN108129406A (en) | A kind of COMT inhibitor containing terminal olefinic link and hydrazide structure and application thereof | |
| CN108191783A (en) | COMT inhibitor, the preparation method and its usage of a kind of benzene methanamine triazine structure | |
| CN107935953A (en) | COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure | |
| Li et al. | Identification of metoprolol tartrate-derived reactive metabolites possibly correlated with its cytotoxicity | |
| CN107973758A (en) | COMT inhibitor, the preparation method and its usage of a kind of triazine and hydrazide structure | |
| EP2931266B1 (en) | Composition and kit comprising piperazine derivatives and metformin, and use thereof in the treatment of diabetes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180622 |