CN107935953A - COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure - Google Patents
COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure Download PDFInfo
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- CN107935953A CN107935953A CN201711496066.4A CN201711496066A CN107935953A CN 107935953 A CN107935953 A CN 107935953A CN 201711496066 A CN201711496066 A CN 201711496066A CN 107935953 A CN107935953 A CN 107935953A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
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- C07D251/50—Two nitrogen atoms with a halogen atom attached to the third ring carbon atom
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Abstract
The present invention relates to COMT inhibitor field.Specifically, the present invention relates to a kind of COMT inhibitor containing terminal olefinic link and hydrazide structure, its preparation method and the application in treatment schizophrenia etc. is prepared.
Description
Technical field
The present invention relates to the field of COMT inhibitor.In particular it relates to produce treatment to suppressing COMT and make
A kind of COMT inhibitor containing terminal olefinic link and hydrazide structure, its preparation method and the use in treatment schizophrenia
On the way.
Background technology
Schizoid symptom generally falls into three classes：The positive, negative and cognition.Positive symptom includes illusion, illusion and
Chaotic behavior, and negative symptoms has the feature for lacking happy sense and/or the interest to life.Cognitive defect is included to idea
Tissue and priorization to task in terms of difficulty.Patient with bipolar disorders is usually shown from serious depressed to tight
The manic periodic emotional change feature of mental disease (with or without) of weight.Schizophrenia and bipolar disorders belong to
Cause the phrenoblabia of the most serious type of overlapping cognitive defect 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 it is discontented be 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).
Being considered being related in spite of a plurality of path causes negative and cognition symptom schizoid pathogenesis, but more
More concerns has concentrated on the reduction of dopamine neuronal transmission in prefrontal cortex.Dopamine neuronal transmission 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.It has been found that before the relevant prefrontal lobe defect of schizophrenia (unrelated with treatment or psychotic state) and evaluation
Frontal lobe participates in perform function task (such as the n-back or Wisconsin Card of (prefrontal engagement)
Sorting Test) in bad luck performance it is related.Work(is controlled except performing
Outside the defects of energy, the reduction of dopamine neuronal transmission is related with several cerebration in prefrontal cortex, bag
Including the activity note that enjoyment, instinct feedback (natural rewards), and biological action, (such as cell signal passes
Lead).Therefore, the compound of the dopamine neuronal transmission inside Selective long-range DEPT prefrontal cortex may have treatment cognition and the moon
The acology potential of property symptom.
Dopamine level in brain is and its diffusion rate by biosynthesis and release, and reuptake and degraded 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 changed into 3-methoxytyramine and by Dopamine metabolites dihydroxyphenyl acetic acid (DOPAC).In fact,
COMT acts on the catecholamines and catechol estrogen class of various biological sources, meals 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
The adjusting of dopamine transmission 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
Optionally 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) of film combination is involved in human brain
Principal mode (Lachman the et al., Pharmacogenetics, 1996,6 (3) of the degraded of cynapse frontal lobe dopamine:243-
250).Another form is soluble COMT (S-COMT), it is from different from the promoter transcription of MB-COMT and removing this
Outside 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 the single nucleotide polymorphism at Val158Met (MB-COMT) place.Since the heat endurance of enzyme has differences, homozygous Met
Carrier has relatively low COMT activity, and heterozygote shows medium activity and the Val carriers of 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 relation 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 the efficiency and dopamine level of forehead.
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 medicines still without departing from side effect, such as group agranulocytosis,
Calmness, weight gain, hyperlipidemia and hyperglycemia, all these side effects limit their application.Therefore, still deposit
In the demand to such medicine, it effectively treats negative symptoms and cognitive defect, 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 medicine can be used for
Reduce the symptom.
The invention discloses a kind of COMT inhibitor containing terminal olefinic link and hydrazide structure, these compounds can be used for preparing
The medicine of schizophrenia etc..
The content of the invention
It is an object of the present invention to provide a kind of COMT inhibitor with Formulas I.
It is a further object to provide the method for preparing the compound with Formulas I.
It is also another object of the present invention to provide the compound containing Formulas I to treat the application of schizophrenia etc..
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 compound III, obtains compound IV；Compound IV is in the presence of KOH
Reacted with compound V, obtain compound VI；Compound VI obtains compound VII with hydration hydrazine reaction, hydrazinolysis；Compound VII with
Cyanuric Chloride VIII reacts, and obtains compound IX；Compound IX and X reacts, and obtains final product I；Wherein X be selected from Cl, Br and
I。
Compound of formula I of the present invention has COMT inhibitory action, can be used to prepare schizophrenia as active ingredient
Medicine.The activity of compound of formula I of the present invention is verified by suppressing COMT experiments in vitro.
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
Change 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 at room temperature stirring 1 it is small when.MeI (III-1,2.84g, 20mmol) is added, continues to be stirred at room temperature
Night.Then add bromo-acetic acid tert-butyl V (3.90g, 20mmol), continue stirring 12 it is small when, TLC detection find reaction complete.
Reaction mixture is carefully poured into 200mL frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses 100mL
5% salt water washing, anhydrous sodium sulfate drying.Filter and remove drier, filtrate is evaporated on a rotary evaporator, and residue uses silicon
It is gel column chromatography eluting, obtain compound VI-I, 2.99g (merging yield 77%).ESI-MS, m/z=195 ([M+H]+)。
The synthesis of step 2. compound VII-1
Compound VI-1 (1.94g, 10mmol) is dissolved in 20mL absolute ethyl alcohols, is stirred at room temperature, adds 80% hydration
Hydrazine (5mL), when then stirring 3 is small at room temperature, 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-I, 1.23g (yield 81%).ESI-MS, m/z=
153([M+H]+)。
The synthesis of step 3. compound I-1
Compound VII-1 (0.76g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and the lower stirring of ice-water bath cooling, adds three second
Amine (2.02g, 20mmol), is then slowly added portionwise Cyanuric Chloride VIII (0.92g, 5mmol), adds rear reaction mixture again
Continue at room temperature stirring 3 it is small when, at this time TLC display reaction complete.Added into reaction system isopropylamine X (0.30g,
5mmol), then stirring was continued at room temperature overnight for compound of reaction, and the reaction of TLC displays at this time is completed.Reaction mixture is direct
It is evaporated on a rotary evaporator, residue is purified using short silica gel column chromatography, is obtained compound I-I, 1.21g and (is merged yield
75%).ESI-MS, m/z=324 ([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 at room temperature stirring 1 it is small when.III-2 (2.42g, 20mmol) is added, continues to be stirred at room temperature overnight.And
After add V 20mmol, continue stirring 12 it is small when, TLC detection find reaction complete.Reaction mixture carefully pours into 200mL
In frozen water, stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, with 5% salt water washings of 100mL, anhydrous sodium sulfate drying.
Filter and remove drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtains compound VI-
2.ESI-MS, m/z=235 ([M+H]+)。
The synthesis of step 2. compound VII-2
Compound VI-2 (2.34g, 10mmol) is dissolved in 20mL absolute ethyl alcohols, is stirred at room temperature, adds 80% hydration
Hydrazine (5mL), when then stirring 3 is small at room temperature, 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=193 ([M+H]+)。
The synthesis of step 3. compound I-2
Compound VII-2 (0.96g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and the lower stirring of ice-water bath cooling, adds three second
Amine (2.02g, 20mmol), is then slowly added portionwise Cyanuric Chloride VIII (0.92g, 5mmol), adds rear reaction mixture again
Continue at room temperature stirring 3 it is small when, at this time TLC display reaction complete.X (0.23g, 5mmol) is added into reaction system, and
Stirring was continued at room temperature overnight for compound of reaction afterwards, and the reaction of TLC displays at this time is completed.Reaction mixture is directly in rotary evaporation
It is evaporated on instrument, residue is purified using short silica gel column chromatography, obtains compound I-2, white solid.ESI-MS, m/z=364 ([M
+H]+)。
3 Compound ira vitro of embodiment suppresses 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 based on substrate (6,7- dihydroxycoumarins) by COMT to generate the product (7- hydroxyl -6- methoxyl groups of high fluorescent
Cumarin).The reaction needs the presence of magnesium ion and methyl donor [being in this case s-adenosylmethionine (SAM)].Adopt
Prepared 10: 3 times of dilution series with storing solution of the 10mM compounds in DMSO and be positioned over the 1 μ L dilutions being adapted 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 to comprising 1 μ L compounds
Analyze in hole.When the preculture 2 of room temperature progress COMT enzymes and compound is small.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, launches 460nm, no delay, when 100 μ s are integrated to 2 microplate reader of Safire (plate reader)
Between, 5 flickers, top set is read) monitor formation of the product (scopoletin) with the time.With the time to this point
Analysis monitoring, until producing 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, then it is expressed as percentage and is subtracted from 100 to obtain the suppression percentage of COMT activity.
Test result see the table below.
| Compound | IC50(nM) |
| Compound I-1 | 348.1 |
| Compound I-2 | 25.5 |
The compound that can be seen that the present invention from upper table result has very strong inhibitory action to COMT, can be used as system
The medicine of the diseases such as standby treatment schizophrenia.
Claims (3)
1. the compound with logical formula (I) structure,
2. synthesize the method for compound described in claim 1：
Cyclopentadiene II reacts in the presence of KOH with compound III, obtains compound IV；Compound IV in the presence of KOH with change
Compound V reacts, and obtains compound VI；Compound VI obtains compound VII with hydration hydrazine reaction, hydrazinolysis；Compound VII and trimerization
Chlorine cyanogen VIII reacts, and obtains compound IX；Compound IX and X reacts, and obtains final product I；Wherein X is selected from Cl, Br and I.
3. application of the compound described in claim 1 in terms for the treatment of schizophrenia drug is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496066.4A CN107935953A (en) | 2017-12-31 | 2017-12-31 | COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711496066.4A CN107935953A (en) | 2017-12-31 | 2017-12-31 | COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure |
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| Publication Number | Publication Date |
|---|---|
| CN107935953A true CN107935953A (en) | 2018-04-20 |
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|---|---|---|---|
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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 CN201711496066.4A patent/CN107935953A/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 |
Non-Patent Citations (1)
| Title |
|---|
| 孟令芝，等: "《有机波谱分析》", 31 March 1997 * |
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