CN106749033A - Hydantoin compounds and its purposes as beta-secretase inhibitor - Google Patents
Hydantoin compounds and its purposes as beta-secretase inhibitor Download PDFInfo
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- CN106749033A CN106749033A CN201510827740.7A CN201510827740A CN106749033A CN 106749033 A CN106749033 A CN 106749033A CN 201510827740 A CN201510827740 A CN 201510827740A CN 106749033 A CN106749033 A CN 106749033A
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- Prior art keywords
- methyl
- bases
- imino group
- diphenyl
- ketone
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- 0 CN(CC#C)C1c2cccc(C(C3CC3)(C(N3C)=O)NC3=*)c2CC1 Chemical compound CN(CC#C)C1c2cccc(C(C3CC3)(C(N3C)=O)NC3=*)c2CC1 0.000 description 4
- QDPALZNTWFDYDC-UHFFFAOYSA-N CC#CCN(C)C(CC1)c2c1c(C(C(C1CC1)=O)=O)ccc2 Chemical compound CC#CCN(C)C(CC1)c2c1c(C(C(C1CC1)=O)=O)ccc2 QDPALZNTWFDYDC-UHFFFAOYSA-N 0.000 description 1
- FHOGUDCXGMBPQD-UHFFFAOYSA-N CC1=CC(Br)=CC=CC1 Chemical compound CC1=CC(Br)=CC=CC1 FHOGUDCXGMBPQD-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- XZVYDRLPXWFRIS-UHFFFAOYSA-N CCN(C)C(Cl)=O Chemical compound CCN(C)C(Cl)=O XZVYDRLPXWFRIS-UHFFFAOYSA-N 0.000 description 1
- GIMCZSADWKLIBI-UHFFFAOYSA-N CCN(C)C(Oc1cccc(C(C2CC2)(C(N2C)=O)NC2=N)c1)=O Chemical compound CCN(C)C(Oc1cccc(C(C2CC2)(C(N2C)=O)NC2=N)c1)=O GIMCZSADWKLIBI-UHFFFAOYSA-N 0.000 description 1
- ZENQYWUKIBRFFU-UHFFFAOYSA-N CN(C(C(C1CC1)(C1=CC=CC2C1=CC=C2)N1)=O)C1=N Chemical compound CN(C(C(C1CC1)(C1=CC=CC2C1=CC=C2)N1)=O)C1=N ZENQYWUKIBRFFU-UHFFFAOYSA-N 0.000 description 1
- BKPDAABPWUDVEB-UHFFFAOYSA-N CN(C(C(C1CC1)(c1cc(O)ccc1)N1)=O)C1=N Chemical compound CN(C(C(C1CC1)(c1cc(O)ccc1)N1)=O)C1=N BKPDAABPWUDVEB-UHFFFAOYSA-N 0.000 description 1
- VWTJGDUOSKVOKA-BYDSUWOYSA-N C[C@@H](C1)C1C(C(c1cccc(O)c1)=O)=O Chemical compound C[C@@H](C1)C1C(C(c1cccc(O)c1)=O)=O VWTJGDUOSKVOKA-BYDSUWOYSA-N 0.000 description 1
- HNLYJOAFNHPTQV-UHFFFAOYSA-N Cc1c(CCC2N(C)CC#C)c2ccc1 Chemical compound Cc1c(CCC2N(C)CC#C)c2ccc1 HNLYJOAFNHPTQV-UHFFFAOYSA-N 0.000 description 1
- ARCZFTAYFVDCIU-UHFFFAOYSA-N O=C(C1CC1)C(C1=CCCC2=C1CC=C2)=O Chemical compound O=C(C1CC1)C(C1=CCCC2=C1CC=C2)=O ARCZFTAYFVDCIU-UHFFFAOYSA-N 0.000 description 1
- DXNNHQCEUVFPLO-UHFFFAOYSA-N Oc1cccc(C#CC2CC2)c1 Chemical compound Oc1cccc(C#CC2CC2)c1 DXNNHQCEUVFPLO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
Abstract
The invention belongs to field of medicine and chemical technology, it is related to hydantoin compounds and its purposes as beta-secretase inhibitor.In particular it relates to compound of formula I or its officinal salt, solvate or hydrate.Formula I can be used as beta-secretase inhibitor, can be used in preparing the medicine for treating and/or preventing to assemble with beta-amyloid polypeptide or precipitate relevant disease or illness.Wherein G1、G2As defined herein.
Description
Invention field
The invention belongs to field of medicine and chemical technology, it is related to hydantoin compounds, its preparation method, the medicine comprising them
Composition and its as beta-secretase inhibitor be used for prepare prevention and/or treatment Alzheimer disease and other by beta amyloid
The purposes of the medicine of the disease that polypeptide aggregation or precipitation cause.
Background technology
Alzheimer disease (Alzheimer's disease) is a kind of common chronic neurodegenerative disease, clinical
The hypomnesia and cognitive disorder of progressive are shown as, self care ability is finally lost, its pathological characters shows as neural thin
There is neurofibrillary tangles (neurofibrillary tangle) and extracellular there is senile plaque expelling (senile in intracellular
plaque).The main component of senile plaque expelling is a series of beta-amyloid polypeptide (β-amyloid peptide, A β) of varying lengths.
A β are a kind of containing the 39-43 polypeptide of amino acid, from amyloid beta-protein precursor (β-amyloid
precursor protein,β-APP).β-APP have cracked two kinds of approach in vivo：Non-starch sample approach and amyloid approach.
Non-starch sample approach refers to after β-APP are cracked through alpha-secretase enzyme, gamma-secretase, A β not to be produced；Amyloid approach refers to beta-secretase
Enzyme (β-secretase) is cracked in the N-terminal of β-APP, produces the β-CTF (C-terminal comprising complete A β sequences
Fragments), subsequent β-CTF are cracked to form A β by gamma-secretase.
Beta-secretase belongs to aspartic protease, also referred to as BACE1, Asp2 or Memapsin-2 (Sinha S,
Anderson JP,Barbour R,et al:Nature,1999,402(6761):537-540).Generation and generation due to A β
Thank, dissociate unbalanced with what is built up, abnormal many A β gradually build up to form senile plaque expelling, so as to result in other as nerve fibres are twined
The pathological changes such as knot, microglial inflammatory, neuronal cell decline and neurotransmitter shortage, ultimately form senile dementia
Disease.Beta-secretase is the rate-limiting enzyme for producing A β, therefore, by the generation for suppressing the activity of beta-secretase to reduce or block A β,
So as to reduce the content of A β, prevent A β from being built up in intracerebral and continuously form senile plaque expelling to prevent or treat Alzheimer disease (Hardy
J,Dennis DJ.Science,2002,297:353-356).Can be used for preventing or treating other by beta amyloid simultaneously
The amyloidosis angiosis that polypeptide aggregation or precipitation cause, the disease such as Kuru (Kuru) disease and Tang Shi (Down) syndrome.
There is no the generation of A β in the mouse brain of BACE1 gene knockouts, live normal, further demonstrating that can be by resistance
Disconnected A β's produces to prevent or treat the disease caused by A beta peptide aggregations or precipitation, the particularly nervus retrogression such as Alzheimer disease
Disease, and deduction will not produce very big side effect (Roberds SL, Anderson J, Basi G, et al:Hum Mol
Genet,2001,10(12):1317-1324)。
Therefore, the medicine that can effectively suppress beta-secretase activity for needing exploitation new at present.
The content of the invention
The present inventor has obtained the compound shown in Formulas I by in-depth study and performing creative labour.The present inventor shies
Very find, the compound or pharmaceutically acceptable salt thereof of Formulas I can effectively suppress the activity of beta-secretase, it is possible to reduce before amyloid
Body protein, so as to reduce beta-amyloid polypeptide content in vivo, prevents it by beta-secretase metabolism generation beta-amyloid polypeptide
Continue to build up in vivo to form precipitation.Therefore, compound of formula I of the invention or its can be used for treating or preventing Alzheimer
The nerve degenerative diseases such as disease and other diseases related to beta-amyloid polypeptide aggregation or precipitation or illness are for example by β-shallow lake
Amyloidosis angiosis, kuru and Down's syndrome that powder sample polypeptide aggregation or precipitation cause etc..Thus provide following
Invention：
One aspect of the present invention is related to the compound or pharmaceutically acceptable salt thereof shown in Formulas I,
Wherein：
G1For
Wherein R1Selected from hydrogen, halogen, methyl, trifluoromethyl, trifluoromethoxy and nitro；
G2It is selected from
Wherein R2Selected from hydrogen,
R3Selected from hydrogen,
Dotted line in above-mentioned each substitution base represents connection site.
Term " halogen " is selected from fluorine, chlorine, bromine, iodine etc..
In one embodiment of the invention, described compound or pharmaceutically acceptable salt thereof, it is selected from following table 1
Compound, or its officinal salt：
Table 1：Part of compounds of the present invention
Another aspect of the present invention is related to the preparation method of the compound or pharmaceutically acceptable salt thereof described in any one of the present invention, bag
Include following step：
Wherein,
Condition a represents TBAF, PdCl2(PPh3)2, backflow, CuI,
Condition b represents KMnO4, MgSO4, Na2CO3,
Condition c represents 1- methyl guanidine hydrochlorides, Na2CO3,EtOH/H2O；
Above-mentioned G1And G2Implication respectively as described in any one above.
In one embodiment of the invention, the basic synthesis step of compound of Formula I skeleton is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, backflow, CuI,
Condition b represents KMnO4, MgSO4, Na2CO3,
Condition c represents 1- methyl guanidine hydrochlorides, Na2CO3,EtOH/H2O；
For different G1、G2Substituted radical, specific synthetic route can be different.Differ primarily in thatThe structure and G of structure1、G2The derivatization of group, the synthetic method of skeleton is similar to.Above-mentioned G1And G2Implication
Respectively as described in any one above.
In one embodiment of the invention, described preparation method, it is selected from following method (1) to (4)
Any one method：
Method (1)：
Work as G2ForG1ForR2ForWhen, synthetic route is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, backflow, CuI,
Condition b represents KMnO4, MgSO4, Na2CO3,
Condition c represents 1- methyl guanidine hydrochlorides, Na2CO3, EtOH/H2O；
Condition d represents acetone, K2CO3；
Method (2)：
Work as G2ForG1ForR2ForWhen, synthetic route is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, CuI, backflow,
Condition b represents PdCl2(PPh3)2, TBAF,
Condition c represents KMnO4, MgSO4,Na2CO3,
Condition d represents 1- methyl guanidine hydrochlorides, Na2CO3；
Method (3)：
Work as G2ForG1ForWhen, synthetic route is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, CuI, backflow,
Condition b represents KMnO4,MgSO4,Na2CO3,
Condition c represents HCl/THF,
Condition d represents THF, DIPEA,
Condition e represents 1- methyl guanidine hydrochlorides, Na2CO3；
And
Method (4)：
Work as G2ForG1ForWhen, synthetic route is as follows：
Condition a represents PdCl2(PPh3)2,K2CO3,
Condition b represents 1- methyl guanidine hydrochlorides, Na2CO3,
Condition c represents acetone, K2CO3,
Condition d represents PdCl2(PPh3)2,TBAF。
It is each derivative of different substituents for G, its synthetic route is as follows respectively：
1st, G is worked as2For(and R2It is not) when, with G1For/R2ForAs a example by,
Synthetic route is as follows：
a.)TBAF,PdCl2(PPh3)2, backflow, CuI, b.) and KMnO4,MgSO4,Na2CO3,C.) 1- methyl guanidine hydrochloride,
Na2CO3,EtOH/H2O；d.)acetone,K2CO3
G1ForWhen, reaction scheme is ibid.
R2During for other groups, it is only necessary to willChange other corresponding reagents into；Or change m -bromoacetophenone into Boc
The m-bromoaniline of protection, removes Boc protections again after generation hydantoins skeleton, perform the derivatization again afterwards.This area
Technical staff is readily understood that the acylation or substitution reaction of these phenolic hydroxyl groups or aromatic amine.
2nd, G is worked as2For(and R2For) when, with G1ForAs a example by, synthetic route is as follows：
a.)TBAF,PdCl2(PPh3)2, CuI, backflow, b.) and PdCl2(PPh3)2,TBAF,c.)KMnO4,MgSO4,Na2CO3,
D.) 1- methyl guanidine hydrochloride, Na2CO3
G1ForWhen, reaction scheme is ibid.
3rd, G is worked as2ForWhen, with G1ForAs a example by, synthetic route is as follows：
a.)TBAF,PdCl2(PPh3)2, CuI, backflow, b.) and KMnO4,MgSO4,Na2CO3,c.)HCl/THF d.)THF,
DIPEA e.) 1- methyl guanidine hydrochlorides, Na2CO3
Obtain two intermediates when MOM protection groups are removed, it is separated after can obtain a kind of end-product respectively.G1ForWhen, reaction scheme is ibid.
4th, G is worked as2ForWhen, with G1ForAs a example by, it is only necessary to choose key intermediateUsing a corresponding Resocinol-phenol formaldehyde resin/hydroxyl phenyl boric acid/bromobenzeneboronic acid/phenyl boric acid as structure
Unit, can just carry out further derivatization.Synthetic route is as follows, and different routes choose different R3Group is used as representative, ability
Field technique personnel can be freely to substitute between being readily understood that various groups.
a.)PdCl2(PPh3)2,K2CO3,B.) 1- methyl guanidine hydrochloride, Na2CO3 c.)acetone,K2CO3 d.)PdCl2
(PPh3)2,TBAF
G1ForWhen, reaction scheme is ibid.
Detailed teachings of the invention and existing synthesis general knowledge, those skilled in the art can be easily synthesized this
The compound of formula I of invention.
Another aspect of the invention is related to a kind of pharmaceutical composition, its present invention for including treatment and/or prevention effective dose
Compound or pharmaceutically acceptable salt thereof described in any one, and optional pharmaceutically acceptable auxiliary material or carrier.
Usual pharmaceutical composition of the present invention contains the type I compound and/or its officinal salt of 0.1-90 weight %.Medicine
Composition can be prepared according to methods known in the art.When for this purpose, if it is desired, can by type I compound or its can medicine
Combined with one or more solid or liquid medicine auxiliary material with salt, being made can be used as the appropriate administration form of people or dosage shape
Formula.
Type I compound of the invention or the pharmaceutical composition containing it can be administered in a unit, and method of administration can
It is enteron aisle or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.Form of administration is for example
Tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent, emulsion, granule, liposome, transdermal agent, mouth containing
Piece, suppository, freeze drying powder injection etc..Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery systems.In order to
Unit dosage forms for administration is made tablet, various auxiliary materials well known in the art can be widely used.Example on carrier is, for example
Diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate,
White bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, polyethylene glycol, ethanol, propyl alcohol, starch
Slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, lac, Methyl cellulose
Element, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, for example, dry starch, alginate, agar powder, laminaran, carbonic acid
Hydrogen sodium and citric acid, calcium carbonate, polyoxyethylene, sorbitan fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl
Cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；Sorbefacient, such as season
Ammonium salt, lauryl sodium sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, stearate, boric acid, liquid
Paraffin, polyethylene glycol etc..Tablet can also be further made coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coating
Piece, or double-layer tablets and multilayer tablet.In order to administration unit is made into pill, various carriers well known in the art can be widely used.
Example on carrier is, such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, poly- second
Alkene pyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive such as Arabic gum, bassora gum, gelatin, ethanol, honey, liquid
Sugar, rice paste or batter etc.；Disintegrant, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose,
Ethyl cellulose etc..In order to administration unit is made into suppository, various carriers well known in the art can be widely used.On carrier
Example be, such as polyethylene glycol, lecithin, cocoa butter, higher alcohol, the ester of higher alcohol, gelatin, semi-synthetic glyceride etc..For
Administration unit is made capsule, active ingredient type I compound or its officinal salt mixed with above-mentioned various carriers, and will
Thus obtained mixture is placed in hard obviously capsule or soft capsule.Also can be by active ingredient type I compound or its is pharmaceutically acceptable
Salt is made microcapsules, is suspended in aqueous medium and forms supensoid agent, can also be fitted into hard shell capsules or be made injection application.In order to
Administration unit is made injection preparation, such as solution, emulsion, freeze drying powder injection and supensoid agent, it is possible to use commonly used in the art
All diluents, for example, water, ethanol, polyethylene glycol, 1,3-PD, the isooctadecanol of ethoxylation, polyoxygenated different hard
Lipidol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic parenteral solution, can be added in injection preparation
Appropriate sodium chloride, glucose or glycerine, further, it is also possible to add conventional cosolvent, buffer, pH adjusting agent etc..
Additionally, if desired, can also in pharmaceutical preparation add colouring agent, preservative, spices, flavouring, sweetener or
Other materials.
Type I compound of the present invention, or the dosage of its officinal salt depends on many factors, for example, to be prevented or controlled
Treat the property and the order of severity of disease, the sex of patient or animal, age, body weight and individual reaction, particular compound used,
Method of administration and administration number of times etc..Above-mentioned dosage with ingle dose form or can be divided into several, such as two, three or four dosage shapes
Formula is administered.
Term " composition " used herein means to include the product of each specified composition comprising specified amount, and directly or
Any product for being produced from the combination of each specified composition of specified amount indirectly.
The actual dose level of each active component in pharmaceutical composition of the present invention can be changed, so as to the reactive compound of gained
Amount effectively can obtain required therapeutic response for specific patient, composition and administering mode.Dosage level must be according to materialization
The patient's condition and medical history of the activity of compound, method of administration, the order of severity for treating the patient's condition and patient to be treated is selected.
But, the way of this area is, the dosage of compound since less than the level for obtaining required therapeutic effect and requiring, gradually
Incremental dose, until obtaining required effect.
Another aspect of the invention is related to the compound or pharmaceutically acceptable salt thereof described in any one of the present invention preparing for controlling
Treat and/or use that prevention and/or auxiliary treatment and beta-amyloid polypeptide are assembled or precipitate in the medicine of relevant disease or illness
On the way；Preferably, it is described assemble with beta-amyloid polypeptide precipitate relevant disease or illness be by beta-amyloid polypeptide aggregation or
Disease or illness that precipitation causes；Preferably, described disease or illness are selected from Alzheimer disease, amyloidosis blood vessel
In disease, kuru and Down's syndrome any one or it is various.
Another aspect of the invention be related to compound or pharmaceutically acceptable salt thereof described in any one of the present invention prepare suppress β-
Purposes in the medicine or reagent of secretase.
Another aspect of the invention be related to compound or pharmaceutically acceptable salt thereof described in any one of the present invention reduce preparing or
Purposes in the medicine of the generation of blocking A β.
Another aspect of the invention is related to a kind for the treatment of and/or prevention and/or auxiliary treatment and beta-amyloid polypeptide aggregation
Or precipitate the method for relevant disease or illness, including give compound described in any one of the present invention of subject's effective dose or
The step of its officinal salt.
When above-mentioned treatment and/or prevention and/or auxiliary treatment, a kind of this hair for the treatment of and/or prevention effective dose
Bright compound can be applied in a pure form, or the application in the form of pharmaceutically acceptable salt.Or, the compound can be with
Pharmaceutical composition administration containing the purpose compound and one or more acceptable auxiliary material of medicine.It is to be understood that of the invention
Total consumption per day of compound and composition must be maked decision by attending physician in reliable medical judgment scope.For any tool
The patient of body, depending on specific treatment effective dose level must be according to many factors, the factor include treated obstacle and
The order of severity of the obstacle；The activity of the particular compound for being used；The concrete composition for being used；Age of patient, body weight,
General health, sex and diet；The administration time of the particular compound for being used, method of administration and excretion rate；Treatment is held
The continuous time；It is applied in combination with the particular compound for being used or medicine used at the same time；And similar factor known to medical field.
For example, the way of this area is, the dosage of compound since less than the level for obtaining required therapeutic effect and requiring, gradually
Incremental dose, until obtaining required effect.It is, in general, that type I compound of the present invention is used for the agent of mammal particularly people
Amount can be between 0.001-1000mg/kg body weight/days, such as between 0.01-100mg/kg body weight/days, such as between 0.01-
10mg/kg body weight/days.
Compound of the invention can effectively prevent and/or treat various diseases of the present invention or illness.
Term " effective dose " refers to that can realize treating, prevent, mitigate and/or alleviating disease of the present invention in subject
Or the dosage of illness.
Term " disease and/or illness " refers to a kind of condition of the subject, the condition and institute of the present invention
State disease and/or illness is relevant.
Term " subject " can refer to patient or other receive pharmaceutical compositions of the present invention with treat, prevent, mitigate and/
Or the animal of alleviation disease of the present invention or illness, particularly mammal, such as people, dog, monkey, ox, horse etc..
Another aspect of the invention is related to a kind of method of the beta-secretase of suppression in vivo or in vitro, including uses effective dose
Any one of the present invention described in compound or pharmaceutically acceptable salt thereof the step of.In one embodiment of the invention, the side
Method is non-treatment purpose.
Another aspect of the invention is related to a kind of method of the generation for reducing in vivo or in vitro or blocking A β, including uses
The step of compound or pharmaceutically acceptable salt thereof described in any one of the present invention of effective dose.In one embodiment of the invention,
Methods described is non-treatment purpose.
In the context of the present invention, following abbreviation is used：
Boc：Tertbutyloxycarbonyl
TBAF：Tetrabutyl ammonium fluoride
DMSO：Dimethyl sulfoxide (DMSO)
dppf：The double Diphenyl phosphino ferrocenes of 1,1-
PdCl2(PPh3)：1,1- bis-triphenylphosphipalladium palladium dichloride compounds
PdCl2(dppf)：The double Diphenyl phosphino ferrocene palladium chloride compounds of 1,1-.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following examples are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Unreceipted tool in embodiment
Concrete conditions in the establishment of a specific crime person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument,
For can by city available from conventional products.
The fusing point of compound is determined by RY-1 melting point apparatus, the non-calibration of thermometer.Mass spectrum is by Micromass ZabSpec high scores
Resolution mass spectrograph (resolution ratio 1000) is determined.1H-NMR is determined by JNM-ECA-400 SUPERCONDUCTING NMRs instrument, working frequency1H-
NMR400MHz。
Embodiment 1：3- (4- cyclopropyl -2- imino group -1- methyl -5- oxo -4- imidazolidines) phenyl-ethyl group (methyl) ammonia
The preparation (compound 1) of carbamate
Reaction scheme：
It is prepared by intermediate：
3- (acetenyl of ring third) phenol
The acetylene of ring third (1.2g) and m -bromoacetophenone (3.4g) are dissolved in 30ml THF, add TBAF15.6g, PdCl2
(PPh3)20.42g, 80 DEG C of reaction 8h of oil bath.System is cooled to room temperature, the 50ml that adds water, ethyl acetate 40ml, fully vibration, point
Liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation obtains yellow oily liquid 2.9g, yield 92%.
1- cyclopropyl -2- (3- hydroxy phenyls) ethane -1,2- diketone
Upper step intermediate is dissolved in the mixed solvent of 96ml acetone and 60ml water, sequentially adds magnesium sulfate 4.4g, sodium carbonate
2.9g, potassium permanganate 11.6g, room temperature reaction 2h, the 100ml that adds water, ethyl acetate 150ml, fully vibration, point liquid, organic phase with
After anhydrous sodium sulfate drying, concentration obtains yellow oily liquid 2.2g, yield 63%.
5- cyclopropyl -5- (3- hydroxy phenyls) -2- imino group -3- methylimidazole quinoline -4- ketone
Upper step intermediate mixes with 1- methylguanidine hydrochlorides 1.5g, sodium carbonate 3.2g, adds the dissolving of 30ml50% ethanol, oil
90 DEG C of reaction 2h of bath.After the completion of reaction, system is cooled to room temperature, and concentration removes ethanol, and the 25ml that adds water, ethyl acetate 25ml fill
Divide vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, methylene chloride/methanol volume ratio 10:1 wash-out,
Obtain white solid 1.2g, yield 42%.
It is prepared by target product：
Upper step intermediate (0.5g) is dissolved in the anhydrous THF of 15ml, addition N- methyl-N ethyls-carbamyl chloride 0.62g,
DIPEA 2ml, back flow reaction 24h.System is cooled to room temperature, direct silica gel post separation, methylene chloride/methanol volume ratio 30:1 washes
It is de-, obtain colourless oil liquid 0.24g.Oily liquids is dissolved in 5ml ether, is stirred vigorously lower dropwise addition 2.2N HCl/Et2O 0.5ml,
There is white solid to separate out, filter, drying obtains target compound 0.07g, yield 21%.
1H-NMR(400MHz,DMSO-d6),δ:0.4246-0.5458(4H,m),1.0397-1.1048(4H,m),
1.6457-1.6863(1H,m),2.8542(2H,s),2.9572(3H,s),3.0489-3.0840(2H,m),3.3194-
3.3376(1H,m),3.5295-3.5463(1H,m),6.7158-6.7410(1H,m),6.9379-6.9491(2H,m),
7.1803 (1H, t, J=8.12Hz), 9.1468 (1H, d, J=18.48Hz).
Embodiment 2：5- cyclopropyl -5- (3- (acetenyl of ring third) phenyl) -2- imino group -3- methyl-imidazoles quinoline -4- ketone
Prepare (compound 2)
Reaction scheme：
It is prepared by intermediate：
Intermediate syntheti c route is substantially the same manner as Example 1, and simply one of raw material changes m-dibromobenzene into,1- cyclopropyl- 2- (the bromo- phenyl of 3-) ethane -1,2- diketoneA step is had more after preparing, is obtained with the acetylene reaction of ring third1- cyclopropyl -2- (3- (acetenyl of ring third) phenyl) ethane -1,2- diketone.Step operation is as follows：
Ring the third acetylene 0.33g with1- cyclopropyl -2- (the bromo- phenyl of 3-) ethane -1,2- diketone0.6g mixing be dissolved in 30ml without
In water THF, TBAF 3.9g, PdCl are added2(PPh3)20.11g, 80 DEG C of reaction 8h of oil bath.After the completion of reaction, system is cooled to room
Temperature, the 40ml that adds water, ethyl acetate 40ml, fully vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, stone
Oily ether/ethyl acetate volume ratio 25:1 wash-out, obtains yellow oily liquid 0.45g.
It is prepared by target product：
Upper step intermediate 0.21g is mixed with 1- methylguanidine hydrochlorides 0.18g, sodium carbonate 0.36g, 15ml 50% is added
Ethanol dissolves, 90 DEG C of reaction 2h of oil bath.After the completion of reaction, system is cooled to room temperature, and concentration removes ethanol, the 20ml that adds water, acetic acid
Ethyl ester 20ml, fully vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, methylene chloride/methanol volume
Than 20:1 wash-out, obtains white solid 59mg, yield 24%.
1H-NMR(400MHz,DMSO-d6),δ:0.12-0.14(1H,m),0.30-0.35(3H,m),0.72-0.74(2H,
m),0.86-0.88(2H,m),1.46-1.56(2H,m),2.91(3H,s),6.89(1H,s,br),7.22-7.33(2H,m),
7.53-7.56(2H,m)。
Embodiment 3：Preparation (the chemical combination of 5- cyclopropyl -2- imino groups -5- (1H- indenes -7- bases) -3- methylimidazole quinoline -4- ketone
Thing 3)
The embodiment is as follows with the synthetic route of next embodiment：
It is prepared by intermediate：
4- (acetenyl of ring third) -1- (methoxyl group-Asia-methoxyl group) -2,3- dihydro -1H- indenes
The acetylene of ring third (1.2g) is dissolved in 30ml THF with intermediate 47 (5.1g), adds TBAF 15.6g, PdCl2
(PPh3)20.42g, 80 DEG C of reaction 8h of oil bath.After the completion of reaction, system is cooled to room temperature, the 40ml that adds water, ethyl acetate 40ml, fills
Divide vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, petrol ether/ethyl acetate volume ratio 20:1 washes
It is de-, obtain yellow oily liquid 4.5g (mixture).
1- cyclopropyl -2- (1- (methoxyl group-Asia-methoxyl group) -2,3- dihydro -1H- indenes -4- bases) ethane -1,2- diketone
Upper step intermediate is dissolved in the mixed solvent of 96ml acetone and 60ml water, sequentially adds magnesium sulfate 3.6g, sodium carbonate
2.1g, potassium permanganate 9.4g, room temperature reaction 2h, the 100ml that then adds water, ethyl acetate 100ml, fully vibration, point liquid, organic phase
After anhydrous sodium sulfate drying, silica gel post separation, petrol ether/ethyl acetate volume ratio 20:1 wash-out, obtains yellow oily liquid
4.2g (mixture).
1- (the chloro- 2,3- dihydros -1H- indenes -4- bases of 1-) -2- cyclopropyl ethane -1,2- diketone
Upper step intermediate is dissolved in the THF of 30ml, is stirred vigorously lower addition concentrated hydrochloric acid 30ml, and 30min is stirred at room temperature, and is added
Water 20ml, ethyl acetate 25ml, fully vibration, point liquid, organic phase is washed with saturated sodium-chloride, after anhydrous sodium sulfate drying, silicon
Glue post separation, petrol ether/ethyl acetate volume ratio 10:1-5:1 wash-out, obtains title intermediate 0.10g, while getting intermediate4- The chloro- 2,3- dihydros -1H- indenes of (acetenyl of ring third) -1-1.60g。
It is prepared by target product：
Upper step title intermediate is mixed with 1- methylguanidine hydrochlorides 0.1g, sodium carbonate 0.3g, the ethanol of 10ml 50% is added
Dissolving, is heated to 90 DEG C of reaction 2h.After the completion of reaction, system is cooled to room temperature, and concentration removes ethanol, the 15ml that adds water, acetic acid second
Ester 15ml, fully vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, methylene chloride/methanol volume ratio
20:1 wash-out, obtains white solid 38mg, yield 34%.
1H-NMR(400MHz,DMSO-d6),δ:0.1243-0.6119(3H,m),1.2333(1H,s),1.5745-
1.5948(1H,m),2.9694-3.0541(5H,m),6.5374-6.5515(2H,m),6.8933-6.9067(1H,m),
7.1315-7.4062(2H,m),7.6198-7.6934(1H,m)。
Embodiment 4：5- cyclopropyl -2- imino group -3- methyl -5- (1- (methyl (2-propynyl) amino)) -2,3- dihydros -
1H- indenes -4- bases) imidazoline -4- ketone preparation (compound 4)
It is prepared by intermediate：
1- cyclopropyl -2- (1 (methyl (2-propynyl) amino)) -2,3- dihydro -1H- indenes -4- bases) ethane -1,2- diketone
Intermediate4- (acetenyl of ring third) chloro- 2,3- dihydros -1H- indenes of -1-1.60g is dissolved in the anhydrous THF of 10ml, adds first
Base propargylamine 0.5g, DIPEA 2ml, back flow reaction 24h.System is cooled to room temperature, direct silica gel post separation, petroleum ether/acetic acid
Ethyl ester volume ratio 2:1 wash-out, obtains colourless oil liquid 0.62g, yield 34%.
It is prepared by target product：
Intermediate 64 mixes with 1- methylguanidine hydrochlorides 0.3g, sodium carbonate 0.6g, adds the dissolving of 20ml50% ethanol, heating
To 90 DEG C of reaction 2h.After the completion of reaction, system is cooled to room temperature, and concentration removes ethanol, and the 15ml that adds water, ethyl acetate 15ml fill
Divide vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, methylene chloride/methanol volume ratio 20:1 wash-out,
Obtain white solid 53mg.
1H-NMR(400MHz,DMSO-d6),δ:0.1016-0.1247(1H,m),0.3636-0.4715(2H,m),
0.6439-0.6880 (1H, m), 1.0351 (1H, d, J=5.88Hz), 1.5098-1.5630 (1H, m), 1.9035-1.9519
(2H,m),2.1018-2.1123(3H,m),2.5235-2.5810(1H,m),3.0160(3H,s),3.1365-3.1471(1H,
m),3.2199-3.3677(4H,m),4.2603-4.3233(1H,m),7.2329-7.2665(2H,m),7.6952-7.7177
(1H,m)。
Embodiment 5：3'- (4- cyclopropyl -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- diphenyl] -
The preparation (compound 5) of 3- bases-ethyl (methyl) carbamate
Reaction scheme：
It is prepared by intermediate：
The synthesis of the compound intermediate be also with1- (3- bromophenyls) -2- rings the third ethane -1,2- diketoneIn the middle of key
Body, then there is Suzuki reactions with 3- hydroxyls phenyl boric acid.Since the step, concrete operations are as follows：
1- cyclopropyl -2- (3'- hydroxyls-[1,1'- diphenyl] -3- bases) ethane -1,2- diketone
By intermediate1- (3- bromophenyls) -2- rings the third ethane -1,2- diketone(1.2g) is dissolved in 3- hydroxyl phenyl boric acids 1.2g
30ml Isosorbide-5-Nitraes-dioxane, are subsequently adding potassium carbonate 2.4g, PdCl2(PPh3)20.15g, slowly adds water to system clarification, heating
To 90 DEG C of reaction 12h.After the completion of reaction, system is cooled to room temperature, the 30ml that adds water, ethyl acetate 40ml, fully vibration, point liquid,
Organic phase is washed with saturated sodium-chloride, and after anhydrous sodium sulfate drying, silica gel post separation obtains white solid 1.2g, yield 95%.
5- cyclopropyl -5- (3'- hydroxyls-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazole quinoline -4- ketone
Upper step intermediate mixes with 1- methylguanidine hydrochlorides 0.6g, sodium carbonate 1.2g, adds the dissolving of 15ml50% ethanol, oil
90 DEG C of reaction 2h of bath.After the completion of reaction, system is cooled to room temperature, and concentration removes ethanol, and the 25ml that adds water, ethyl acetate 30ml fill
Divide vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, methylene chloride/methanol volume ratio 10:1 wash-out,
Obtain white solid 0.82g, yield 62%.
It is prepared by target product：
Upper step intermediate (0.3g) is dissolved in 10ml THF, adds N- methyl-N ethyls-carbamyl chloride 0.3g, DIPEA
0.5ml, back flow reaction 36h, system are cooled to room temperature, and direct silica gel post separation obtains white solid 0.07g, yield 19%.
1H-NMR(400MHz,DMSO-d6),δ:0.4810-0.5685(4H,m),1.0421-1.1082(3H,m),
1.7348-1.8015 (1H, m), 2.8636 (2H, s), 2.9800 (3H, d, J=4.04Hz), 3.0670 (1H, s), 3.5143-
3.5664 (1H, m), 6.7723-6.7964 (1H, m), 7.0206-7.0615 (2H, m), 7.2722 (1H, t, J=7.64Hz),
7.4482-7.5681 (3H, m), 7.7665 (1H, s), 9.2919 (1H, d, J=20.4Hz), 9.5853 (1H, s).
Embodiment 6：3'- (4- cyclopropyl -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- diphenyl] -
The preparation (compound 6) of 3- bases-dimethylcarbamate
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.4750-0.5664(4H,m),1.7540-1.7904(1H,m),
2.8850(3H,s),2.9854(3H,s),3.0952(3H,s),6.7730-6.7971(1H,m),7.0196-7.0594(2H,
M), 7.2724 (1H, t, J=7.84Hz), 7.4489-7.5683 (3H, m), 7.7555 (1H, s), 9.2945 (1H, s),
9.5919(1H,s)。
Embodiment 7：5- cyclopropyl -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- hexichol
Base] -3- bases) imidazoline -4- ketone preparation (compound 7)
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.1764-0.1966(1H,m),0.3104–0.4389(3H,m),
1.5423-1.5866 (1H, m), 2.9384 (3H, s), 3.6110 (1H, t, J=2.24Hz), 4.8804 (2H, d, J=
2.24Hz),6.9900-7.0152(1H,m),7.1845-7.2114(2H,m),7.3941-7.4417(2H,m),7.5342-
7.5538(1H,m),7.5970-7.6166(1H,m),7.8419(1H,s)。
Embodiment 8：5- cyclopropyl -5- (3'- (2- fluorine ethyoxyl)-[1,1'- diphenyl] -3- bases) -2- imino group -3- first
The preparation (compound 8) of base imidazoline -4- ketone
The synthetic method of reference implementation example 5.This serial final step substitution reaction post processing is slightly different：By intermediate5- rings Propyl group -5- (3'- hydroxyls-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazole quinoline -4- ketone(0.15g) is dissolved in 5ml
In acetone, potassium carbonate 0.92g, 1- bromo- 2- fluorobenzene 0.12g, room temperature reaction 36h are then sequentially added.After the completion of reaction, system is straight
Filter is taken over, filter residue is washed with 5ml acetone, merging filtrate, silica gel post separation, methylene chloride/methanol volume ratio 20:1 wash-out, obtains white
Color solid 58mg, yield 34%.
1H-NMR(400MHz,DMSO-d6),δ:0.18-0.20(1H,m),0.34-0.44(3H,m),1.55-1.62(1H,
m),2.95(3H,s),4.27-4.36(2H,m),4.71-4.85(2H,m),6.98-7.00(1H,m),7.16-7.20(2H,
m),7.39-7.44(2H,m),7.55-7.62(2H,m),7.85(1H,s)。
Embodiment 9：5- cyclopropyl -5- (3'- ethyoxyls-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazoles
The preparation (compound 9) of quinoline -4- ketone
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.40-0.60 (4H, m), 1.36 (3H, t, J=7.00Hz), 1.73-
1.76 (1H, m), 3.09 (3H, s), 4.10 (2H, q, J=7.00Hz), 6.96-6.98 (1H, m), 7.16-7.21 (2H, m),
7.38-7.42(1H,m),7.50-7.53(1H,m),7.60-7.68(2H,m),7.81(1H,s),9.22(2H,s,br)。
Embodiment 10：5- (3'- (3- chlorine propoxyl group)-[1,1'- diphenyl] -3- bases) -5- cyclopropyl -2- imino groups -3-
The preparation (compound 10) of methylimidazole quinoline -4- ketone
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.21-0.22(1H,m),0.36-0.45(3H,m),1.56-1.63(1H,
M), 2.17-2.23 (2H, m), 2.96 (3H, s), 3.83 (2H, t, J=6.44Hz), 4.17 (2H, t, J=6.20Hz), 6.97-
6.99(1H,m),7.14-7.19(2H,m),7.38-7.45(2H,m),7.55-7.62(2H,m),7.84(1H,s)。
Embodiment 11：5- cyclopropyl -2- imino group -3- methyl -5- (3'- propoxyl group-[1,1'- diphenyl] -3- bases) miaow
The preparation (compound 11) of oxazoline -4- ketone
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.15-0.18 (1H, m), 0.28-0.44 (3H, m), 1.00 (3H, t, J=
7.28Hz), 1.53-1.60 (1H, m), 1.71-1.80 (2H, m), 2.93 (3H, s), 3.99 (2H, t, J=6.48Hz), 6.83
(1H,s,br),6.93-6.96(1H,m),7.10-7.15(2H,m),7.36-7.43(2H,m),7.53-7.55(1H,m),
7.60-7.62(1H,m),7.84(1H,s)。
Embodiment 12：5- (3'- butoxy-[1,1'- diphenyl] -3- bases) -5- cyclopropyl -2- imino group -3- methyl miaows
The preparation (compound 12) of oxazoline -4- ketone
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.18-0.19 (1H, m), 0.33-0.44 (3H, m), 0.95 (3H, t, J=
7.28Hz),1.43-1.49(2H,m),1.56-1.59(1H,m),1.69-1.76(2H,m),2.94(3H,s),4.03(2H,t,
), J=6.20Hz 6.93-6.96 (1H, m), 7.10-7.15 (2H, m), 7.36-7.43 (2H, m), 7.53-7.62 (2H, m),
7.83(1H,s)。
Embodiment 13：5- cyclopropyl -5- (3'- (3- fluorine propoxyl group)-[1,1'- diphenyl] -3- bases) -2- imino groups -3-
The preparation (compound 13) of methylimidazole quinoline -4- ketone
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.18-0.21(1H,m),0.35-0.45(3H,m),1.57-1.60(1H,
M), 2.09-2.18 (2H, m), 2.95 (3H, s), 4.15 (2H, t, J=6.16Hz), 4.58 (1H, t, J=5.88Hz), 4.70
(1H, t, J=5.88Hz), and 6.96-6.99 (1H, m), 7.13-7.18 (2H, m), 7.38-7.44 (2H, m), 7.55-7.62
(2H,m),7.84(1H,s)。
Embodiment 14：5- cyclopropyl -2- imino group -3- methyl -5- (3'- (2-propynyl) amino)-[1,1'- hexichol
Base] -3- bases) imidazoline -4- ketone preparation (compound 14)
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.17-0.18(1H,m),0.33-0.44(3H,m),1.51-1.56(1H,
M), 2.93 (3H, m), 3.08 (1H, t, J=2.24Hz), 3.90-3.93 (2H, m), 6.15 (1H, t, J=6.16Hz), 6.63-
6.66(1H,m),6.80-6.85(2H,m),7.19-7.23(1H,m),7.32-7.46(2H,m),7.56-7.58(1H,m),
7.80(1H,s)。
Embodiment 15：5- cyclopropyl -5- (3'- (acetenyl of ring third)-[1,1'- diphenyl] -3- bases) -2- imino groups -3-
The preparation (compound 15) of methylimidazole quinoline -4- ketone
The synthetic method of reference implementation example 5.Intermediate5- cyclopropyl -5- (bromo- [1,1'- the diphenyl] -3- bases of 3'-) -2- is sub- Amino -3- methylimidazole quinoline -4- ketone(0.32g) is dissolved in 20ml THF with the acetylene of ring third (0.2g), adds TBAF 0.78g,
PdCl2(PPh3)221mg, 80 DEG C of reaction 24h of oil bath.After the completion of reaction, system is cooled to room temperature, the 20ml that adds water, ethyl acetate
20ml, fully vibration, point liquid, after organic phase is with anhydrous sodium sulfate drying, silica gel post separation, methylene chloride/methanol volume ratio 20:
1 wash-out, obtains white solid 75mg, yield 24%.
1H-NMR(400MHz,DMSO-d6),δ:0.15-0.16(1H,m),0.30-0.36(3H,m),0.88-0.92(2H,
m),1.23-1.31(2H,m),1.45-1.59(2H,m),2.92(3H,m),6.84(2H,s),7.25-7.33(1H,m),
7.43-7.47(2H,m),7.54-7.67(3H,m),7.72-7.85(2H,m)。
Embodiment 16：5- ([1,1'- diphenyl] -3- bases) -5- cyclopropyl -2- imino group -3- methylimidazole quinoline -4- ketone
Prepare (compound 16)
The synthetic method of reference implementation example 5.
1H-NMR(400MHz,DMSO-d6),δ:0.16-0.18(1H,m),0.30-0.44(3H,m),1.53-1.59(1H,
m),2.93(3H,s),6.76(2H,s,br),7.35-7.54(5H,m),7.59-7.70(3H,m),7.86(1H,s)。
Embodiment 17：3'- (4- (3- chlorphenyls) -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- hexichol
Base] -3- bases-ethyl (methyl) carbamate preparation (compound 17)
It is similar to the basic synthetic route of embodiment 5, the acetylene of ring third is simply replaced with into corresponding phenylacetylene structure (such knot
Structure is commercially available, can also be generated with the acetylene reaction that TMS is protected by 3- substitution iodobenzenes), other steps are consistent.
Intermediate5- (3- chlorphenyls) -5- (3'- hydroxyls-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazoles Quinoline -4- ketone(0.12g) is dissolved in 10ml acetone, adds potassium carbonate 0.48g, N- methyl N-ethyl-amino formyl chloride 0.3g, room temperature
Reaction 36h.After the completion of reaction, system is directly filtered, and filter residue is washed with 5ml acetone, merging filtrate, silica gel post separation, dichloromethane
Alkane/methyl alcohol volume ratio 20:1 wash-out, obtains white solid 0.02g, yield 14%.
1H-NMR(400MHz,DMSO-d6),δ:1.06-1.35(4H,m),2.89-2.91(3H,m),3.03-3.05(3H,
m),3.44-3.46(1H,m),7.11-7.13(1H,m),7.28-7.72(12H,m)。
Embodiment 18：3'- (4- (3- chlorphenyls) -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- hexichol
Base] -3- bases-dimethylcarbamate preparation (compound 18)
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:2.87-2.92(5H,m),3.01(1H,s),3.07(3H,s),7.11-
7.14(1H,m),7.31-7.73(12H,m)。
Embodiment 19：5- (3- chlorphenyls) -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- bis-
Phenyl] -3- bases) imidazoline -4- ketone preparation (compound 19)
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.01 (3H, s), 3.59 (1H, t, J=2.12Hz), 4.87 (2H, d, J=
2.56Hz),6.83(1H,s,br),6.99-7.01(1H,m),7.13-7.15(2H,m),7.33-7.53(8H,m),7.72
(1H,s)。
Embodiment 20：3'- (2- imino group -1- methyl -5- oxos -4- (3- (trifluoromethoxy) phenyl) -4- imidazolidines) -
The preparation (compound 20) of [1,1'- diphenyl] -3- bases-ethyl (methyl) carbamate
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:1.09-1.28(3H,m),2.91(2H,s),3.01-3.05(4H,m),
3.30-3.34(2H,m),3.42-3.47(1H,m),6.91(1H,s,br),7.11-7.13(1H,m),7.24-7.27(2H,
m),7.38-7.58(7H,m),7.72(1H,s)。
Embodiment 21：3'- (2- imino group -1- methyl -5- oxos -4- (3- (trifluoromethoxy) phenyl) -4- imidazolidines) -
The preparation (compound 21) of [1,1'- diphenyl] -3- bases-dimethylcarbamate
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:2.93(3H,s),3.01(3H,s),3.07(3H,s),6.89(1H,s,
br),7.11-7.13(1H,m),7.25-7.27(2H,m),7.39-7.58(9H,m),7.73(1H,s)。
Embodiment 22：2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) -
The preparation (compound 22) of 5- (3- (trifluoromethoxy) phenyl) imidazoline -4- ketone
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.01 (3H, s), 3.58 (1H, t, J=2.24Hz), 4.86 (2H, d, J=
2.52Hz),6.84-7.01(3H,m),7.12-7.14(2H,m),7.25-7.27(1H,m),7.38-7.65(7H,m),7.71
(1H,s)。
Embodiment 23：5- (3- fluorophenyls) -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- bis-
Phenyl] -3- bases) imidazoline -4- ketone preparation (compound 23)
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.00 (3H, s), 3.57 (1H, s), 4.86 (2H, d, J=2.04Hz),
6.78(2H,s,br),6.99-7.01(1H,m),7.08-7.15(3H,m),7.24-7.27(1H,m),7.37-7.42(4H,
m),7.46-7.48(1H,m),7.52-7.54(1H,m),7.72(1H,s)。
Embodiment 24：2- imino group -3- methyl -5- phenyl -5- (3'(2- propinyls)-oxo) [1,1'- diphenyl] -3-
Base) imidazoline -4- ketone preparation (compound 24)
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.00 (3H, s), 3.59 (1H, t, J=2.24Hz), 4.86 (2H, d, J=
2.24Hz),6.72(1H,s,br),6.98-7.00(1H,m),7.12-7.14(2H,m),7.23-7.53(9H,m),7.73
(1H,s)。
Embodiment 25：5- (3- bromophenyls) -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- bis-
Phenyl] -3- bases) imidazoline -4- ketone preparation (compound 25)
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.00 (3H, s), 3.59 (1H, t, J=2.24Hz), 4.86 (2H, d, J=
2.24Hz), 6.82 (2H, s, br), 6.99-7.01 (1H, m), 7.13-7.15 (2H, m), 7.30 (1H, t, J=7.84Hz),
7.38-7.47(4H,m),7.53-7.55(2H,m),7.66-7.71(2H,m)。
Embodiment 26：2- imino group -3- methyl -5- (3- nitrobenzophenones) -5- (3'- (2-propynyl)-oxo)-[1,1'-
Diphenyl] -3- bases) imidazoline -4- ketone preparation (compound 26)
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.02 (3H, s), 3.58 (1H, t, J=2.24Hz), 4.86 (2H, d, J=
1.96Hz),6.91-7.01(3H,m),7.14-7.16(2H,m),7.38-7.49(3H,m),7.55-7.56(1H,m),7.63-
7.67(1H,m),7.73(1H,s),8.00-8.02(1H,m),8.13-8.15(1H,m),8.41(1H,s)。
Embodiment 27：2- imino group -3- methyl -5- (3'(2- propinyls)-oxo)-[1,1'- diphenyl] -3- bases) -5-
The preparation (compound 27) of (3 (trifluoromethyl) phenyl) imidazoline -4- ketone
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:3.01 (3H, s), 3.59 (1H, t, J=2.24Hz), 4.86 (2H, d, J=
2.52Hz),6.88(2H,s,br),6.99-7.01(1H,m),7.13-7.15(2H,m),7.38-7.46(3H,m),7.54-
7.65(3H,m),7.72(1H,s),7.86-7.88(2H,m)。
Embodiment 28：2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) -
The preparation (compound 28) of 5- (3- aminomethyl phenyls) imidazoline -4- ketone
The synthetic method of reference implementation example 17.
1H-NMR(400MHz,DMSO-d6),δ:2.25 (3H, s), 2.99 (3H, s), 3.59 (1H, t, J=2.24Hz),
4.86 (2H, d, J=2.52Hz), 6.71 (2H, s, br), 6.98-7.05 (2H, m), 7.12-7.21 (3H, m), 7.27-7.29
(2H,m),7.37-7.53(4H,m),7.72(1H,s)。
Embodiment 29：Compound suppresses the activity of BACE1
1. experiment reagent
TruPointTM Beta-Secretase Assay Kit384(PerkinElmer, AD0258), comprising BACE1 bottoms
Thing and reaction buffer.
Recombinant Human BACE1 (newly purchase beta-Secretase, Invitrogen, P2947 enzyme, activity
138Units/ml).The BACE14.9 μ L for taking 138mU/ μ L mix with the μ L of reaction buffer 995, prepare dense as 0.67mU/ μ L
Degree is standby.
Deionized water (mili-Q-Biocel preparations)；(DimethyIsulfoxid DMSO, ACROS are public for dimethyl sulfoxide (DMSO)
Department's product, 12779).
2. experimental technique
Experiment is divided into 3 groups, including：Blank control group, negative control group and test medicine group.Experimental procedure is as follows：
[1] test sample (S)：1. BACE1 reaction systems are set up, in 384 orifice plates, dimethyl sulfoxide (DMSO) is separately added into per hole
(DMSO) μ L (the 5 concentration ranks, from 10 of various concentrations the compounds of this invention 2 prepared-5To 10-9)；2. 15 and then per hole are added
Reaction buffers of the μ L 0.67mU/ μ L containing BACE1 enzymes；3. it is incubated at room temperature 30min.4. 15 μ L400nmol/L are added
TruPointTMBACE1 substrates.
[2] negative control (C)：1. to adding 2 μ L DMSO in hole；2. 15 μ L0.67mU/ μ L enzymes containing BACE1 are subsequently adding
Reaction buffer；3. it is incubated at room temperature 30min；4. 15 μ L 400nmol/L TruPoint are addedTMBACE1 substrates.
[3] blank (B)：1. to adding 2 μ L DMSO in hole；2. it is subsequently adding analysis buffers of the 15 μ L without enzyme
(foregoing TruPointTMCarried in kit)；3. it is incubated at room temperature 30min；4. 15 μ L 400nmol/L TruPoint are addedTM
BACE1 substrates.
[4] it is incubated：Incubation at room temperature 6 hours, plank is covered with vaporization prevention during incubation with lid.
[5] terminating reaction：To adding 10 μ L BACE1 terminate liquids in test specimens sample wells, background hole and blank well to terminate
Reaction.
[6] surveyed in excitation wavelength 340nm and wavelength of transmitted light 615nm using VICTOR- Ш (PE) multi-function microplate readers
Amount fluorescence intensity.
Result is calculated：Inhibiting rate (%)=[1- (S-B)/(C-B)] × 100
B：Refer to that blank (DMSO, substrate and analysis buffer) incubates the fluorescence intensity for determining for 6 hours in temperature.C：Refer to
Negative control (substrate and the reaction buffer containing BACE1 enzymes) incubates the fluorescence intensity for determining for 6 hours in temperature.S:It refer to sample (bottom
Thing, is dissolved in the compound of the invention and the reaction buffer containing BACE1 enzymes of DMSO) temperature incubate 6 hours determine fluorescence it is strong
Degree.
5 suppression rate scores of concentration are determined, compound IC is calculated50Value.
3. experimental result
The table 2 that the BACE1 inhibitory activity measurement results of part of compounds of the present invention see below.
Table 2：BACE1 inhibitory activity measurement results
| Embodiment sequence number | Inhibiting rate (%, c=0.1 μM) | IC50(nM) |
| 1 | 39.5 | 1660 |
| 2 | 65.3 | 407 |
| 7 | 90.7 | 134 |
| 8 | 94.5 | 84.7 |
| 9 | 88.8 | 303 |
| 10 | 69.1 | 603 |
| 11 | 69.4 | 541 |
| 13 | 76.9 | 331 |
| 15 | 90.8 | 145 |
| 19 | 62.2 | 182 |
| 22 | 87.9 | 282 |
| 24 | 91.9 | 127 |
| 25 | 94.9 | 129 |
| 26 | 87.9 | 232 |
| 27 | 77.1 | 264 |
| 28 | 78.7 | 270 |
Result shows that compound of the invention can effectively suppress the activity of BACE1.
Although specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that：Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change in guarantor of the invention
Within the scope of shield.Four corner of the invention is given by appended claims and its any equivalent.
Claims (10)
1. the compound or pharmaceutically acceptable salt thereof shown in Formulas I,
Wherein：
G1For
Wherein R1Selected from hydrogen, halogen, methyl, trifluoromethyl, trifluoromethoxy and nitro；
G2It is selected from
Wherein R2Selected from hydrogen,
R3Selected from hydrogen,
Dotted line in above-mentioned each substitution base represents connection site.
2. compound or pharmaceutically acceptable salt thereof according to claim 1, it is selected from following compound, or its officinal salt：
3- (4- cyclopropyl -2- imino group -1- methyl -5- oxo -4- imidazolidines) phenyl-ethyl group (methyl) carbamate,
5- cyclopropyl -5- (3- (acetenyl of ring third) phenyl) -2- imino group -3- methyl-imidazoles quinoline -4- ketone,
5- cyclopropyl -2- imino groups -5- (1H- indenes -7- bases) -3- methylimidazole quinoline -4- ketone,
5- cyclopropyl -2- imino group -3- methyl -5- (1- (methyl (2-propynyl) amino)) -2,3- dihydro -1H- indenes -4- bases)
Imidazoline -4- ketone,
3'- (4- cyclopropyl -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- diphenyl] -3- bases-ethyl (first
Base) carbamate,
3'- (4- cyclopropyl -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- diphenyl] -3- bases-dimethylamino
Carbamate,
5- cyclopropyl -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) imidazoles
Quinoline -4- ketone,
5- cyclopropyl -5- (3'- (2- fluorine ethyoxyl)-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazole quinolines -4-
Ketone,
5- cyclopropyl -5- (3'- ethyoxyls-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazole quinoline -4- ketone,
5- (3'- (3- chlorine propoxyl group)-[1,1'- diphenyl] -3- bases) -5- cyclopropyl -2- imino group -3- methylimidazole quinolines -4-
Ketone,
5- cyclopropyl -2- imino group -3- methyl -5- (3'- propoxyl group-[1,1'- diphenyl] -3- bases) imidazoline -4- ketone,
5- (3'- butoxy-[1,1'- diphenyl] -3- bases) -5- cyclopropyl -2- imino group -3- methylimidazole quinoline -4- ketone,
5- cyclopropyl -5- (3'- (3- fluorine propoxyl group)-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazole quinolines -4-
Ketone,
5- cyclopropyl -2- imino group -3- methyl -5- (3'- (2-propynyl) amino)-[1,1'- diphenyl] -3- bases) imidazoline -
4- ketone,
5- cyclopropyl -5- (3'- (acetenyl of ring third)-[1,1'- diphenyl] -3- bases) -2- imino group -3- methylimidazole quinolines -4-
Ketone,
5- ([1,1'- diphenyl] -3- bases) -5- cyclopropyl -2- imino group -3- methylimidazole quinoline -4- ketone,
3'- (4- (3- chlorphenyls) -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- diphenyl] -3- bases-ethyl
(methyl) carbamate,
3'- (4- (3- chlorphenyls) -2- imino group -1- methyl -5- oxo -4- imidazolidines)-[1,1'- diphenyl] -3- bases-diformazan
Aminocarbamic acid ester,
5- (3- chlorphenyls) -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) miaow
Oxazoline -4- ketone,
3'- (2- imino group -1- methyl -5- oxos -4- (3- (trifluoromethoxy) phenyl) -4- imidazolidines)-[1,1'- hexichol
Base] -3- bases-ethyl (methyl) carbamate,
3'- (2- imino group -1- methyl -5- oxos -4- (3- (trifluoromethoxy) phenyl) -4- imidazolidines)-[1,1'- hexichol
Base] -3- bases-dimethylcarbamate,
2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) -5- (3- (trifluoro methoxies
Base) phenyl) imidazoline -4- ketone,
5- (3- fluorophenyls) -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) miaow
Oxazoline -4- ketone,
2- imino group -3- methyl -5- phenyl -5- (3'(2- propinyls)-oxo) [1,1'- diphenyl] -3- bases) imidazoline -4-
Ketone,
5- (3- bromophenyls) -2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) miaow
Oxazoline -4- ketone,
2- imino group -3- methyl -5- (3- nitrobenzophenones) -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases)
Imidazoline -4- ketone,
2- imino group -3- methyl -5- (3'(2- propinyls)-oxo)-[1,1'- diphenyl] -3- bases) -5- (3 (trifluoromethyls)
Phenyl) imidazoline -4- ketone, and
2- imino group -3- methyl -5- (3'- (2-propynyl)-oxo)-[1,1'- diphenyl] -3- bases) -5- (3- aminomethyl phenyls)
Imidazoline -4- ketone.
3. the preparation method of the compound or pharmaceutically acceptable salt thereof described in claim 1 or 2, comprises the steps：
Wherein,
Condition a represents TBAF, PdCl2(PPh3)2, backflow, CuI,
Condition b represents KMnO4, MgSO4, Na2CO3,
Condition c represents 1- methyl guanidine hydrochlorides, Na2CO3,EtOH/H2O；
Above-mentioned G1And G2Implication respectively as described in claim 1 or 2.
4. preparation method according to claim 3, it is selected from any one method in following method (1) to (4)：
Method (1)：
Work as G2ForG1ForR2ForWhen, synthetic route is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, backflow, CuI,
Condition b represents KMnO4, MgSO4, Na2CO3,
Condition c represents 1- methyl guanidine hydrochlorides, Na2CO3, EtOH/H2O；
Condition d represents acetone, K2CO3；
Method (2)：
Work as G2ForG1ForR2ForWhen, synthetic route is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, CuI, backflow,
Condition b represents PdCl2(PPh3)2, TBAF,
Condition c represents KMnO4, MgSO4,Na2CO3,
Condition d represents 1- methyl guanidine hydrochlorides, Na2CO3；
Method (3)：
Work as G2ForG1ForWhen, synthetic route is as follows：
Condition a represents TBAF, PdCl2(PPh3)2, CuI, backflow,
Condition b represents KMnO4,MgSO4,Na2CO3,
Condition c represents HCl/THF,
Condition d represents THF, DIPEA,
Condition e represents 1- methyl guanidine hydrochlorides, Na2CO3；
And
Method (4)：
Work as G2ForG1ForWhen, synthetic route is as follows：
Condition a represents PdCl2(PPh3)2,K2CO3,
Condition b represents 1- methyl guanidine hydrochlorides, Na2CO3,
Condition c represents acetone, K2CO3,
Condition d represents PdCl2(PPh3)2,TBAF。
5. a kind of pharmaceutical composition, compound described in its claim 1 or 2 for including treatment and/or prevention effective dose or its
Officinal salt, and optional pharmaceutically acceptable auxiliary material.
6. the compound or pharmaceutically acceptable salt thereof described in claim 1 or 2 is being prepared for treating and/or preventing and/or aid in controlling
Treat the purposes assembled or precipitate with beta-amyloid polypeptide in the medicine of relevant disease or illness；Preferably, described and β-starch
Sample polypeptide aggregation or the relevant disease of precipitation or illness are to assemble or precipitate the disease or illness for causing by beta-amyloid polypeptide；It is excellent
Selection of land, described disease or illness are selected from Alzheimer disease, amyloidosis angiosis, kuru and Down's syndrome
Any one is various.
7. the compound or pharmaceutically acceptable salt thereof described in claim 1 or 2 is in the medicine or reagent that suppress beta-secretase is prepared
Purposes.
8. the compound or pharmaceutically acceptable salt thereof described in claim 1 or 2 is in the medicine for preparing the generation for reducing or blocking A β
Purposes.
9. the change described in a kind of claim 1 or 2 of method for suppressing beta-secretase in vivo or in vitro, including use effective dose
The step of compound or its officinal salt.
10. a kind of method of the generation for reducing in vivo or in vitro or blocking A β, including the claim 1 or 2 for using effective dose
The step of described compound or pharmaceutically acceptable salt thereof.
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| CN111533694A (en) * | 2020-06-05 | 2020-08-14 | 河南牧业经济学院 | Synthetic method of 2-imido hydantoin compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101233113A (en) * | 2005-07-29 | 2008-07-30 | 惠氏公司 | Cycloalkyl amino-hydantoin compounds and use thereof for beta-secretase modulation |
| CN101273018A (en) * | 2005-09-26 | 2008-09-24 | 惠氏公司 | Amino-5- [4- (difluoromethoxy) phenyl] -5-phenylimidazolone compounds as inhibitors of the beta-secretase (BACE) |
| CN102627609A (en) * | 2003-12-15 | 2012-08-08 | 先灵公司 | Heterocyclic aspartyl protease inhibitors |
-
2015
- 2015-11-25 CN CN201510827740.7A patent/CN106749033A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102627609A (en) * | 2003-12-15 | 2012-08-08 | 先灵公司 | Heterocyclic aspartyl protease inhibitors |
| CN101233113A (en) * | 2005-07-29 | 2008-07-30 | 惠氏公司 | Cycloalkyl amino-hydantoin compounds and use thereof for beta-secretase modulation |
| CN101273018A (en) * | 2005-09-26 | 2008-09-24 | 惠氏公司 | Amino-5- [4- (difluoromethoxy) phenyl] -5-phenylimidazolone compounds as inhibitors of the beta-secretase (BACE) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533694A (en) * | 2020-06-05 | 2020-08-14 | 河南牧业经济学院 | Synthetic method of 2-imido hydantoin compound |
| CN111533694B (en) * | 2020-06-05 | 2023-03-14 | 河南牧业经济学院 | Synthetic method of 2-imido hydantoin compound |
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