CN108191783A - COMT inhibitor, the preparation method and its usage of a kind of benzene methanamine triazine structure - Google Patents
COMT inhibitor, the preparation method and its usage of a kind of benzene methanamine triazine structure Download PDFInfo
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- CN108191783A CN108191783A CN201711496047.1A CN201711496047A CN108191783A CN 108191783 A CN108191783 A CN 108191783A CN 201711496047 A CN201711496047 A CN 201711496047A CN 108191783 A CN108191783 A CN 108191783A
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- 0 CC(C)(C)*C(CC1(C)C=CC=C1)=O Chemical compound CC(C)(C)*C(CC1(C)C=CC=C1)=O 0.000 description 1
- AFMMIOCEEHYHMR-OUPQRBNQSA-N CC/C=C\C=C/CCC(NN)=O Chemical compound CC/C=C\C=C/CCC(NN)=O AFMMIOCEEHYHMR-OUPQRBNQSA-N 0.000 description 1
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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
- C07D251/48—Two nitrogen atoms
- 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 fields.Specifically, the present invention relates to the COMT inhibitor of one kind base containing benzene methanamine triazine structure, preparation method and the applications in treatment schizophrenia etc. is prepared.Wherein, R is selected from H, C1‑C5Alkyl, halogenic substituent.
Description
Technical field
The present invention relates to the fields of COMT inhibitor.In particular it relates to it generates treatment to inhibiting COMT and makees
COMT inhibitor, preparation method and the use in treatment schizophrenia of a kind of triazine structure of base containing benzene methanamine
On the way.
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.Work(is controlled except performing
Except the defects of energy, the reduction that dopamine neuronal transmits in prefrontal cortex is related with several cerebration, packet
The activity note that enjoyment is included, (such as cell signal passes for instinct feedback (natural rewards) and biological action
It leads).Therefore, the compound that the dopamine neuronal inside Selective long-range DEPT prefrontal cortex transmits may have treatment cognition and the moon
The acology potential of property symptom.
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 the COMT inhibitor of one kind base containing benzene methanamine triazine structure, these compounds can be used for preparing essence
The medicine of refreshing Split disease etc..
Invention content
It is an object of the present invention to provide a kind of COMT inhibitor with general formula I.Another object of the present invention is
It provides and prepares the method with compounds of formula I.It is also another object of the present invention to provide controlled containing compounds of formula I
Treat the application of schizophrenia etc..The content of present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the present invention with logical formula (I) is with following structural formula：
Wherein, R is selected from H, C1-C5Alkyl, halogenic substituent.
The more preferred compound with logical formula (I) is as follows,
Logical formula (I) compound of the present invention can be synthesized by following route：
Cyclopentadiene II reacts in the presence of KOH with halogenated hydrocarbons III, obtains compound IV；Compound IV is in the presence of KOH
It is reacted with compound V, obtains 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 is reacted with X, obtains final product I；Wherein X be selected from Cl, Br and
I, R are defined as described above.
Compound of Formula I of the present invention has COMT inhibiting effect, can be used as an active ingredient in the preparation of schizophrenia
The medicine of disease.The activity of compound of Formula I of the present invention is verified by inhibiting COMT experiments 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.Bromo-acetic acid tert-butyl V-1 (3.90g, 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, 2.99g (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 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, 1.23g (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 ice-water bath cooling is lower to stir, and adds in three second
Amine (2.02g, 20mmol) is then slowly added portionwise Cyanuric Chloride VIII (0.92g, 5mmol), adds rear reaction mixture again
Continue stirring 3 hours at room temperature, the reaction of TLC displays at this time is completed.Added into reaction system isopropylamine X-1 (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 directly evaporated on a rotary evaporator, and residue is purified using short silica gel column chromatography, obtains chemical combination
Object I-I, 1.21g (merge 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 stirring 1 hour at room temperature.MeI (III-1,2.84g, 20mmol) is added, continues to be stirred at room temperature
Night.20mmol V-2 are then added, continue stirring 12 hours, TLC detections find that reaction is completed.Reaction mixture is carefully toppled over
Enter in 200mL ice water, stir, with 50mL × 3CH2Cl2Extraction merges extraction phase, with 5% salt water washings of 100mL, anhydrous slufuric acid
Sodium is dried.It filters and removes drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, is changed
Close object VI-2.ESI-MS, m/z=209 ([M+H]+)。
The synthesis of step 2. compound VII-2
Compound VI-2 (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 on a rotary evaporator
It is evaporated, residue is purified using short silica gel column chromatography, obtains compound VII-2.ESI-MS, m/z=167 ([M+H]+)。
The synthesis of step 3. compound I-2
Compound VII-2 (0.83g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and ice-water bath cooling is lower to stir, and adds in three second
Amine (2.02g, 20mmol) is then slowly added portionwise Cyanuric Chloride VIII (0.92g, 5mmol), adds rear reaction mixture again
Continue stirring 3 hours at room temperature, the reaction of TLC displays at this time is completed.X-1 (0.54g, 5mmol) is added into reaction system,
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 directly steamed in rotation
It is evaporated on hair instrument, residue is purified using short silica gel column chromatography, obtains compound I-2, white solid.ESI-MS, m/z=386
([M+H]+)。
Embodiment 3-5
With reference to the method for embodiment 1,2, following compounds have been synthesized：
6 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 | 348.1 |
| Compound I-2 | 125.3 |
| Compound I-3 | 41.9 |
| Compound I-4 | 16.7 |
| Compound I-5 | 64.5 |
Upper table result can be seen that the compound of the present invention has very strong inhibiting effect to COMT, can be used as and prepare
Treat the drug of the diseases such as schizophrenia.
Claims (4)
1. the compound with logical formula (I) structure,
Wherein, R is selected from H, C1-C5Alkyl, halogenic substituent.
2. compound of Formula I defined in claim 1, is selected from,
Belong to the method for the compound of logical formula (I) defined in 3. synthesis claim 1-2 is any：
Cyclopentadiene II reacts in the presence of KOH with halogenated hydrocarbons III, obtains compound IV；Compound IV in the presence of KOH with change
Object V reactions are closed, obtain 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 is reacted with X, obtains final product I；Wherein X is selected from Cl, Br and I；R's
Definition is as described in claim 1-2 is any.
4. claim 1-2 logical formula (I) compounds as defined in any one answering in terms for the treatment of schizophrenia drug is prepared
With.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050137162A1 (en) * | 2003-12-19 | 2005-06-23 | Francois Diederich | New COMT inhibitors for the treatment of depression and impaired cognition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050137162A1 (en) * | 2003-12-19 | 2005-06-23 | Francois Diederich | New COMT inhibitors for the treatment of depression and impaired cognition |
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|---|
| 孟令芝等: "分子离子与分子式", 《有机波谱分析》 * |
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Application publication date: 20180622 |