CN110028439A - Phthalimide analog derivative and its preparation method and application - Google Patents
Phthalimide analog derivative and its preparation method and application Download PDFInfo
- Publication number
- CN110028439A CN110028439A CN201910339789.6A CN201910339789A CN110028439A CN 110028439 A CN110028439 A CN 110028439A CN 201910339789 A CN201910339789 A CN 201910339789A CN 110028439 A CN110028439 A CN 110028439A
- Authority
- CN
- China
- Prior art keywords
- unsubstituted
- substituted
- compound
- alkyl
- yuan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to phthalimide analog derivatives and its preparation method and application, belong to chemical medicine.The present invention provides I compound represented of formula or its pharmaceutically acceptable salts.The present invention also provides the preparation method of the compound and purposes.Biological experiment shows, the compounds of this invention shows apparent inhibiting effect to PARP, can be used as potential anti-cancer sensitization agent and uses, and, the proliferation of pancreatic cancer cell can be effectively suppressed in part of compounds in the case where exclusive use, and new medication selection is provided for clinical treatment tumour.
Description
Technical field
The present invention relates to phthalimide analog derivatives and its preparation method and application, belong to chemical medicine.
Background technique
Tumour is the mutation and function that body cell leads to its gene level in the case where inside and outside tumorigenesis factor acts synergistically for a long time
Regulation is abnormal, to promote cell hypelproliferative and cause to occur to convert and the neoformation of formation.China is new every year at present
Raw about 212.7 ten thousand people of tumor patient sum or so, wherein have 1,000,000 or so malignant tumour new life patient every year；Meanwhile entirely
There are about the existing patients of 268.5 ten thousand or so tumour for state, wherein the existing patient of malignant tumour about 148.5 ten thousand or so, benign tumour is existing
There is patient about 1,200,000 or so.There are about 1,540,000 people or so every year for national tumor mortality number, that is to say, that tumor patient crowd is just
It is expanded with the speed of about 600,000 people every year.Main means currently used for oncotherapy have operation, radiotherapy, chemotherapy and biology to control
It treats, other effective means further include endocrine therapy, traditional Chinese medical herbal treatment, thermotherapy and radiofrequency ablation therapy etc..Due to existing each
Kind treatment means respectively have its optimal adaptation disease, also respectively there is its deficiency, so, in order to improve cure rate, it is safe and effective to still need to exploitation
Targeted therapies.
Poly adenosine diphosphate-ribose polymerase-1 (poly (ADP-ribose) polymerases, PARPs) is to be present in eukaryon
A kind of ribozyme in cell is a novel targets of current treatment of cancer, can be catalyzed ADP- ribose unit from nicotinoyl amine gland
Purine dinucleotides (nicotinamide adenine dinucleotide, NAD+) it is transferred to various receptor proteins.PARP ginseng
With DNA reparation and transcriptional control, not only there is key effect in adjusting cell survival and death process, while being also tumour hair
Central transcription factor in exhibition and inflammation generating process.PARP is in the DNA single stranded gaps (SSBs) of base excision repair are repaired
With key effect, inhibit its activity that can enhance the effect of radiotherapy and DNA damage based chemotherapy drug.
PARP-1 inhibitor has prospect in two field performances very much.First is to treat as sensitizer to improve anticancer drug
Effect, since most of antineoplastic is all to inhibit cancer cell to increase to cause the mechanism of DNA damage, and PARP-1 can be repaired
The DNA of damage makes repressed cell generate certain drug resistance, to influence antitumous effect.Pass through PARP-1 inhibitor and its
The mode of the use in conjunction of his radiotherapy or chemotherapy class drug can have the function that reduce dosage and heighten the effect of a treatment.Certainly,
There is antitumous effect of the preclinical study observation PARP-1 inhibitor as single formulation in BRCA-1/2 (-/-) cell strain.
Second is the treatment to cell ischemia injury.In ischemia injury, PARP-1 consumes a large amount of ATP by excessive activation,
Cell is set to occur the reaction such as to crack and cause inflammation.Two protection processes can be induced in the presence of PARP-1 inhibitor, on the one hand
Store a certain amount of NAD+And ATP, so that periphery cell can reparation of the spontaneous completion to DNA in the case where there is damage situations；Another party
Face plays certain anti-inflammatory effect again, avoids accelerating the damage to cell because of immune response.
Therefore, the drug inhibited to PARP is developed, is had for the treatment of tumour and cell ischemia injury
Significance.
Summary of the invention
The purpose of the present invention is to provide phthalimide analog derivatives and its preparation method and application.
The present invention provides I compound represented of formula or its pharmaceutically acceptable salts:
R1、R2、R3Independently selected from-H or halogen；
R4、R5Independently selected from-H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy；
R6Selected from substituted or unsubstituted aryl, substituted or unsubstituted alicyclic ring；
N is 0 or 1.
Further, R1、R2、R3Independently selected from-H or-F.
Preferably, R1、R2、R3It is-H, alternatively, R1、R3For-H, R2For-F.
Further, R4、R5Independently selected from-H, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~
C6 alkoxy.
Preferably, R4、R5Independently selected from-H, unsubstituted C1~C6 alkyl or unsubstituted C1~C6 alkoxy.
Preferably, R4、R5Independently selected from-H ,-CH3Or-OCH3。
Preferably, R4、R5Independently selected from-H or-OCH3。
Preferably, R4、R5It is-H, alternatively, R4For-H, R5For-OCH3。
Further, R6For substituted or unsubstituted aryl, n 0.
Preferably, R6For substituted or unsubstituted 5~10 yuan of aryl.
Preferably, R6For substituted or unsubstituted 6 yuan of aryl.
Preferably, R6For substituted or unsubstituted phenyl.
Preferably, the substituted phenyl contains at least one substituent group selected from the group below: halogen, substituted or unsubstituted
Alkyl, substituted or unsubstituted alkoxy ,-NO2, substituted or unsubstituted naphthenic base, substituted or unsubstituted aryl.
Preferably, the substituted phenyl contains at least one substituent group selected from the group below: halogen, substituted or unsubstituted
C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy ,-NO2, substituted or unsubstituted 5~6 yuan of naphthenic base, replace or
Unsubstituted 5~6 yuan of aryl；Wherein, the naphthenic base contains 0~2 hetero atom, and the hetero atom is oxygen or nitrogen；The virtue
Base contains 0~2 hetero atom, and the hetero atom is oxygen or nitrogen.
Preferably, the substituted phenyl contains at least one substituent group selected from the group below: halogen, unsubstituted C1~C6
C1~C6 alkoxy ,-NO that alkyl, C1~C6 alkyl of halogen substitution, unsubstituted C1~C6 alkoxy, halogen replace2, not
6 yuan of naphthenic base, the alkyl-substituted 6 yuan of naphthenic base, the alkyl-substituted methyl of 5 member rings, unsubstituted 5 yuan of aryl replaced, wherein
6 yuan of naphthenic base contain 2 hetero atoms, and 5 yuan of naphthenic base contain 1 hetero atom, and the aryl contains 2 hetero atoms.
Preferably, alkyl-substituted 6 yuan of naphthenic base areWherein, R7For substituted or unsubstituted alkane
Base.
Preferably, R7For substituted or unsubstituted C1~C6 alkyl.
Preferably, R7For unsubstituted C1~C6 alkyl.
Preferably, the substituted phenyl contains at least one substituent group selected from the group below :-F, tert-butyl ,-CF3、-
OCH3、-OCF3、-NO2、
Further, R6It is selected from:
Most preferably, R6For
Further, R6For substituted or unsubstituted 6~10 yuan of alicyclic rings, n is 0 or 1.
Preferably, the alicyclic ring contains 0~1 hetero atom, and the hetero atom is nitrogen.
Preferably, R6It is selected fromSubstituted or unsubstituted cyclohexyl, substitution or
The alkyl that unsubstituted adamantyl, adamantyl replace；Wherein, R8The methyl, substituted or unsubstituted replaced selected from aryl
Naphthenic base, substituted or unsubstituted aryl,R10Selected from substituted or unsubstituted alkyl, R11It is selected from
Substituted or unsubstituted alkyl；R9Selected from-H, substituted or unsubstituted alkyl.
Preferably, R6It is selected fromUnsubstituted cyclohexyl, unsubstituted Buddha's warrior attendant
C1~C6 alkyl that alkyl, adamantyl replace.
Preferably, R8Selected from 5~10 yuan of aryl replace methyl, substituted or unsubstituted 5~6 yuan of naphthenic base, replace or
Unsubstituted 5~10 yuan of aryl,R10Selected from substituted or unsubstituted C1~C6 alkyl, R11Selected from taking
Generation or unsubstituted C1~C6 alkyl, and n is 0.
Preferably, R8Selected from 6 yuan of aryl replace methyl, halogen replace 6 yuan of naphthenic base, unsubstituted 6 yuan of aryl,R10Selected from unsubstituted C1~C6 alkyl, R11Selected from unsubstituted C1~C6 alkyl.
Preferably, R9Selected from-H, substituted or unsubstituted C1~C6 alkyl, and n is 1.
Preferably, R9Selected from-H or unsubstituted C1~C6 alkyl.
Further, R6It is selected from:
Preferably, R6ForAnd n is 0, alternatively, R6ForAnd n is 1.Further, institute
Compound is stated to be selected from:
The present invention provides the preparation methods of the compound or its pharmaceutically acceptable salt, include the following steps:
A, the dehydration of benzenetricarboxylic acid 1 obtains intermediate 2:
B, intermediate 2 is reacted with primary amine derivatives 3, obtains intermediate 4:
C, intermediate 4 and compound 5 are through amidation process to get I compound represented of formula:
Further, the preparation method meets at least one of following:
The method of dehydration described in step a are as follows: heat benzenetricarboxylic acid 1 in 150 DEG C；
Preferably, heating time 6h；
Preferably, make benzenetricarboxylic acid 1 in reaction vessel in adherent shape before heating；
Preferably, make benzenetricarboxylic acid 1 in adherent shape using following methods: benzenetricarboxylic acid 1 and molten being added in round-bottomed flask
Agent shakes up, and removes solvent；
Preferably, solvent is removed by the way of vacuum distillation；
Preferably, the solvent is THF；
Step b intermediate 2: the molar ratio of primary amine derivatives 3 is 10:12；
The reaction dissolvent of step b is acetic acid；
The reaction temperature of step b is 120 DEG C；
The reaction time of step b is 1.5h；
Condensing agent EDCI and HOAt are added into reaction system by step c；
Preferably, the molar ratio of intermediate 4:EDCI:HOAt is 1:1.8:1.8；
Acid binding agent is also added into the reaction system of step c；
Preferably, the acid binding agent is NMM；
Preferably, intermediate 4: the molar ratio of acid binding agent is 1:5；
The reaction dissolvent of step c is CHCl3；
Preferably, the operating method of step c are as follows: intermediate 4, EDCI, HOAt and acid binding agent are added in reaction dissolvent,
Sufficiently reaction, adds compound 5, reaction terminate to get；
Preferably, 1h is reacted in the abundant reaction under normal temperature conditions；
Preferably, 5h is reacted under normal temperature conditions after compound 5 being added.
The present invention provides the compounds or its pharmaceutically acceptable salt in preparing PARP inhibitor class drug
Purposes.
Preferably, the drug is PARP-1 inhibitor.
The present invention provides the compounds or its pharmaceutically acceptable salt to prepare the purposes in anticancer drug.
Preferably, the cancer is cancer of pancreas.
Preferably, the compound or its pharmaceutically acceptable salt are radiotherapy and/or chemotherapeutics sensitizer.
Preferably, the chemotherapeutics is the drug for causing DNA damage.
The present invention provides the pharmaceutical compositions of anticancer, it is with the compound or its pharmaceutically acceptable salt for work
Property ingredient, is added the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
The present invention provides the combination medicines of anticancer, it contains the said medicine combination for being administered simultaneously or respectively
Object and other chemotherapeutics.
Preferably, other chemotherapeutics are the drugs for causing DNA damage.
Term definition:
Compound and derivative provided by the invention can according to IUPAC (International Union of Pure and Applied Chemistry) or
The name of CAS (chemical abstracts service, Columbus, OH) naming system.
Term " alkyl " is the group of linear or branched saturated hydrocarbon base.C1~C6The example of alkyl includes but is not limited to first
Base (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), normal-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl group
(C4), n-pentyl (C5), 3- amyl (C5), amyl (C5), neopentyl (C5), 3- methyl -2- butyl (C5), tertiary pentyl (C5) and just
Hexyl (C6)。
Term " alkoxy " refers to group-OR, and wherein R is alkyl defined above.C1~C6The example of alkoxy includes
But be not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy,
Positive hexyloxy and 1,2- dimethyl butyrate oxygroup.
Term " aryl " refers to includes or the group not comprising heteroatomic 4n+2 aromatics ring system in aromatics ring system,
In, hetero atom is selected from nitrogen, oxygen and/or sulphur.
Term " alicyclic ring " refers to the unsaturated cyclic hydrocarbon group of saturation or part.
It includes or the cyclic hydrocarbon group not comprising heteroatomic saturation that can be single ring architecture that term " naphthenic base ", which refers to,
It is also possible to more than two rings, wherein hetero atom is selected from phosphorus, sulphur, oxygen and/or nitrogen.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual
In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " pharmaceutically acceptable salt " refers to the acid that the compounds of this invention and inorganic and/or organic bronsted lowry acids and bases bronsted lowry are formed
And/or basic salt, also include amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.These salt, which can be, to be changed
Close being finally separating and directly obtaining in purifying for object.It is also possible to by the way that above compound and a certain number of acid or alkali is appropriate
(such as equivalent) is obtained by mixing.These salt may be formed precipitating in the solution and be collected with filter method, or molten
It recycles and obtains after agent evaporation, or be freeze-dried and be made after reacting in an aqueous medium.Heretofore described salt can be compound
Hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, acetate, propionate, fourth two
Hydrochlorate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing: (a) filler or solubilizer, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
Pharmaceutically acceptable auxiliary material of the present invention refers in addition to the active ingredient (s include substance in dosage form.
Pharmaceutically acceptable complementary ingredient of the present invention, it has certain physiological activity, but the addition of the ingredient
The leading position of aforementioned pharmaceutical compositions in the course of disease treatment will not be changed, and only play auxiliary effect, these auxiliary
Effect is only the utilization to the ingredient known activity, is the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary
Ingredient is used cooperatively with pharmaceutical composition of the present invention, still should belong to the scope of protection of the invention.
The present invention provides the phthalimide derivatives of a kind of structure novel.Biological experiment shows this kind ofization
It closes object and apparent inhibiting effect is shown to PARP, can be used as potential anti-cancer sensitization agent and use, moreover, part of compounds is in list
The proliferation of pancreatic cancer cell can be effectively suppressed in the case where only use, new medication selection is provided for clinical treatment tumour.
Specific embodiment
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it described technology or conditions or is carried out according to the literature in the art according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
Embodiment 1 compound H1:2- (4- morpholino phenyl) -1,3- dioxoisoindole -4- formamide
The first step, the preparation of 3- carboxyl phthalic anhydride (2)
1,2,3- benzenetricarboxylic acid (1) 2.1g (10mmol) and THF 30mL are added in 100mL single necked round bottom flask, shake
And it shakes up.It is evaporated under reduced pressure out solvent, so that raw material is in adherent shape.Round-bottomed flask opening is put into dry combustion method 6h in 150 DEG C of oil bath pans,
Being clearly visible in bottle wall in the process has droplet generation.Room temperature is down in reaction after completion of the reaction and obtains white solid 21.9g, yield
99%；1H NMR(400MHz,DMSO-d6) δ: 7.77 (d, J=7.7Hz, 2H), 7.44 (t, J=7.7Hz, 1H)；13C NMR
(101MHz,DMSO-d6)δ:169.92,169.07,136.26,131.57,129.04。
Second step, the preparation of 2- (4- morpholino phenyl) -1,3- dioxoisoindole -4- formic acid (3a)
Raw material 21.92g (10mmol), 4- (4- morpholinyl) aniline and acetic acid 15mL are added in 50mL round-bottomed flask, rises
Temperature is to 120 DEG C of reflux 1.5h.TLC is monitored after the reaction was completed, and reaction solution is poured into 30mL ice water, has a large amount of solids to be precipitated.
Filtering, filter cake are simultaneously stirred with methanol eddy and wash 2h, filtered while hot, filter cake is dried under reduced pressure again, obtains brown solid 3a 0.98g, yield
27%；1H NMR(400MHz,DMSO-d6) δ: 7.71~7.61 (m, 2H), 7.52 (dd, J=6.7,2.1Hz, 1H), 7.25~
.19 (m, 2H), 7.08~7.01 (m, 2H), 3.76 (t, J=4.8Hz, 4H), 3.17 (t, J=4.8Hz, 4H).
Third step, the synthesis of 2- (4- morpholino phenyl) -1,3- dioxoisoindole -4- formamide (H1)
Raw material 0.35g (1mmol) is added in 50mL round-bottomed flask, EDCI 0.34g (1.8mmol), HOAt 0.24g
(1.8mmol), NMM 0.5g (5mmol) and CHCl3After 20mL, stirring at normal temperature 1h, the methanol solution 1mL of the ammonia of 7M is added, it is molten
Liquid is become cloudy by clarifying, and continues stirring at normal temperature 5h.After TLC monitors fully reacting, reaction solution is poured into 30mL water, stirs 15min
After stand liquid separation, water layer is extracted with methylene chloride (2 × 20mL), combining extraction liquid, successively uses water 50mL saturated salt solution 50mL
Washing, anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure obtains crude compound, through thin-layer chromatography [solvent DCM/MeOH (V/V=
15/1) 0.12g, yield 34.3%] are purified to obtain.1H NMR(400MHz,DMSO-d6) δ: 8.51 (s, 1H), 8.10 (d, J=
7.7Hz, 1H), 8.03 (d, J=7.2Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.87 (s, 1H), 7.31~7.21 (m,
2H), 7.10~7.00 (m, 2H), 3.76 (t, J=4.7Hz, 4H), 3.18 (t, J=4.8Hz, 4H)；13C NMR(101MHz,
DMSO-d6)δ:168.21,167.08,166.80,138.41,135.15,134.55,134.22,134.09,133.61,
130.14,129.48,125.22,120.54,60.54,53.92；HR-MS (ESI-TOF) m/z:Calcd for C19H17N3O4
{[M+H]+352.1292, found352.1230.
2 compound H2:2- of embodiment (4- (4- methylpiperazine-1-yl) phenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H2 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material with 4- (4- methyl piperazine) aniline.Solid (yield 39.2%).1H NMR(400MHz,Chloroform-d)δ:9.98
(s, 1H), 8.76 (dd, J=8.0,1.2Hz, 1H), 8.13 (dd, J=7.3,1.2Hz, 1H), 7.92 (t, J=7.7Hz, 1H),
7.27 (d, J=6.9Hz, 2H), 7.07~7.00 (d, J=8.9Hz, 2H), 6.00 (s, 1H), 3.29 (t, J=5.1Hz, 4H),
2.61~2.56 (m, 4H), 2.37 (s, 3H)；13C NMR(101MHz,DMSO-d6)δ:168.11,167.08,166.88,
138.55,135.21,134.57,134.41,134.21,133.68,130.24,129.51,125.42,120.77,57.54,
53.92,44.32；HR-MS (ESI-TOF) m/z:Calcd for C20H20N4O3{[M+H]+365.1608,
found365.1610。
3 compound H3:2- of embodiment (4- (trifluoromethoxy) phenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H3 is similar with the good H1 of compound, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 4- trifluoro-methoxyaniline are raw material.Solid (yield 47.3%).1H NMR(400MHz,DMSO-d6)δ13.40(s,
1H), 8.39 (s, 1H), 8.35-8.23 (m, 2H), 7.91 (dd, J=8.6,1.4Hz, 1H), 7.48 (s, 2H), 7.25 (d, J=
5.1Hz, 1H), 7.14 (t, J=7.8Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.88 (t, J=1.9Hz, 1H), 6.74 (s,
2H), 6.53 (dd, J=8.0,2.2Hz, 1H), 5.66 (d, J=5.1Hz, 1H), 2.76 (d, J=4.9Hz, 3H)13C NMR
(101MHz,DMSO-d6)δ164.34,164.15,159.51,150.68,143.03,142.06,138.03,135.62,
131.25,129.60,122.25,121.43,119.98,119.92,114.78,112.44,109.64,109.27,106.78,
30.30.HRMS(ESI-TOF)m/z Calcd for C20H19N6[M+H]+:343.1672,found:343.1678。
4 compound H4:2- of embodiment (4- (pyrrolidin-1-yl methyl) phenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H4 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material with 4- (1- pyrrolidinylmethyl) aniline.Solid (yield 31.5%).1H NMR(400MHz,DMSO-d6)δ:10.89
(s, 1H), 8.08 (d, J=7.3Hz, 1H), 7.97 (t, J=6.9Hz, 1H), 7.92 (d, J=7.5Hz, 1H), 7.68 (d, J=
8.1Hz, 2H), 7.35 (d, J=8.2Hz, 2H), 3.70 (s, 2H), 2.61~2.57 (m, 4H), 1.75 (q, J=3.8,
3.3Hz,4H)；13C NMR(101MHz,DMSO-d6)δ:169.64,169.00,163.26,138.26,134.94,134.55,
134.11,134.07,133.45,129.74,129.48,125.05,119.93,59.24,53.79,23.49；HR-MS(ESI-
TOF) m/z:Calcd for C20H19N3O3{[M+H]+350.1499, found350.1508.
5 compound H5:2- of embodiment (4- (oxazole -2- base) phenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H5 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material with 4- (oxazole -2- base) aniline.Solid (yield 31.1%).1H NMR(400MHz,DMSO-d6)δ:8.50(s,1H),
8.42 (d, J=3.9Hz, 1H), 8.11 (dd, J=7.7,1.1Hz, 1H), 8.07 (dd, J=7.5,1.1Hz, 1H), 7.97 (t,
J=7.6Hz, 1H), 7.90 (d, J=8.6Hz, 2H), 7.78 (s, 1H), 7.58 (d, J=8.6Hz, 2H)；13C NMR
(101MHz,DMSO-d6)δ:167.11,166.58,166.20,152.67,150.37,135.17,135.13,134.55,
132.38,132.14,128.46,128.14,127.58,125.30,125.03,123.27；HR-MS (ESI-TOF) m/z:
Calcd for C18H11N3O4{[M+Na]+356.0642, found356.0648.
Embodiment 6 compound H6:2- (4- fluorophenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H6 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material, solid (yield 45.2%) with 4- fluoroaniline.1H NMR(400MHz,DMSO-d6)δ:8.45(s,1H),8.11(d,J
=7.7Hz, 1H), 8.06 (d, J=7.3Hz, 1H), 7.96 (t, J=7.6Hz, 1H), 7.89 (s, 1H), 7.51 (dd, J=
8.7,5.1Hz, 2H), 7.39 (t, J=8.7Hz, 2H)；13C NMR(101MHz,DMSO-d6)δ:167.31,166.69,
166.11,163.18,160.74,135.13,134.44,132.42,130.23,130.14,128.39,128.17,125.31,
116.46,116.23；HR-MS (ESI-TOF) m/z:Calcd for C15H9FN2O3{[M+Na]+307.0495,
found307.0547。
7 compound H7:2- of embodiment (the fluoro- 3- nitrobenzene of 4-) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H7 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material with the fluoro- 3- nitroaniline of 4-.Solid (yield 25.9%).1H NMR(400MHz,DMSO-d6)δ:11.62(s,1H),
11.20 (s, 1H), 8.71~8.58 (m, 1H), 8.06 (d, J=7.4Hz, 1H), 7.98 (dt, J=10.9,5.5Hz, 3H),
7.64 (t, J=10.1Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:169.11,168.81,164.18,152.56,
149.98,136.90,135.88,135.11,134.24,133.41,129.55,127.43,125.34,119.50,116.48；
HR-MS (ESI-TOF) m/z:Calcd for C18H8F3O5{[M+K]+368.0085, found 368.0117.
8 compound H8:2- of embodiment (4- methoxyl group -3- (trifluoromethyl) phenyl) -1,3- dioxoisoindole -4- formyl
Amine
The reaction condition of prepare compound H8 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material with 4- methoxyl group -3- 5-trifluoromethylaniline.Solid (yield 32.9%).1H NMR(400MHz,DMSO-d6)δ:8.45
(s, 1H), 8.12 (d, J=7.7Hz, 1H), 8.06 (d, J=7.3Hz, 1H), 7.96 (t, J=7.6Hz, 1H), 7.90 (s,
1H), 7.74 (d, J=15.4Hz, 2H), 7.45 (d, J=8.8Hz, 1H), 3.97 (s, 3H)13C NMR(101MHz,DMSO-
d6)δ:167.40,166.73,166.07,157.19,135.15,135.12,134.38,133.94,132.47,128.20,
126.63,126.58,125.32,125.08,124.33,114.01,57.04；HR-MS (ESI-TOF) m/z:Calcd for
C17H11F3N2O4{[M+Na]+387.0569, found 387.0568.
9 compound H9:2- of embodiment (4- (tert-butyl) phenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H9 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic anhydride
It is raw material with 4- tertbutyl-aniline.Solid (yield 42.1%).1H NMR(400MHz,DMSO-d6)δ:8.47(s,1H),8.13
~8.07 (m, 1H), 8.05 (dd, J=7.5,1.2Hz, 1H), 7.95 (t, J=7.6Hz, 1H), 7.88 (s, 1H), 7.61~
7.52 (m, 2H), 7.40~7.33 (m, 2H), 1.34 (s, 9H)；13C NMR(101MHz,DMSO-d6)δ:167.45,166.85,
166.17,151.29,135.08,135.06,134.42,132.42,129.51,128.18,127.47,126.19,125.24,
34.97,31.56；HR-MS (ESI-TOF) m/z:Calcd for C19H18N2O3{[M+Na]+345.1215, found
345.1211。
Embodiment 10 compound H10:2- (3,5- Dimethoxyphenyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H10 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 3,5- dimethoxyaniline are raw material, solid (yield 40.4%).1H NMR(400MHz,DMSO-d6)δ:8.45(s,
1H), 8.10 (d, J=7.7Hz, 1H), 8.05 (d, J=7.3Hz, 1H), 7.95 (t, J=7.6Hz, 1H), 7.88 (s, 1H),
6.67~6.57 (m, 3H), 3.77 (s, 6H)；13C NMR(101MHz,DMSO-d6)δ:167.15,166.53,166.14,
160.87,135.09,134.45,133.75,132.39,128.10,125.26,106.56,100.66,55.96；HR-MS
(ESI-TOF) m/z:Calcd for C17H14N2O5{[M+Na]+349.0800, found 349.0800.
11 compound H11:2- of embodiment (1- Acetylpiperidin -4- base) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H11 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 1- Acetylpiperidin -4- amine are raw material, solid (yield 43.4%).1H NMR(400MHz,DMSO-d6)δ:8.47(s,
1H), 8.03 (dd, J=7.7,1.2Hz, 1H), 7.94 (dd, J=7.5,1.3Hz, 1H), 7.90~7.82 (m, 2H), 4.59~
4.45 (m, 1H), 4.28 (tt, J=12.2,4.1Hz, 1H), 4.00~3.86 (m, 1H), 3.13 (dd, J=13.7,2.6Hz,
1H), 2.60 (td, J=13.0,2.7Hz, 1H), 2.21 (qd, J=12.5,4.3Hz, 1H), 2.04 (m, 4H), 1.81~1.66
(m,2H)；13C NMR(101MHz,DMSO-d6)δ:168.52,168.01,167.42,166.14,134.84,134.79,
134.09,132.28,127.99,124.83,48.89,45.72,40.87,29.50,28.75,21.73；HR-MS(ESI-
TOF) m/z:Calcd for C16H17N4O4{[M+Na]+338.1192, found338.1117.
12 compound H12:2- of embodiment (1- benzyl piepridine -4- base) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H12 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 1- benzyl piepridine -4- amine are raw material.Solid (yield 40.4%).1H NMR(400MHz,DMSO-d6)δ:8.49(s,1H),
8.04 (d, J=7.6Hz, 1H), 7.94 (d, J=7.3Hz, 1H), 7.90~7.83 (m, 2H), 7.44~7.18 (m, 5H),
4.02 (t, J=12.1Hz, 1H), 3.53 (s, 2H), 2.94 (d, J=11.3Hz, 2H), 2.34 (tt, J=12.7,7.3Hz,
2H), 2.06 (t, J=11.8Hz, 2H), 1.72~1.54 (m, 2H)；13C NMR(101MHz,DMSO-d6)δ:168.09,
167.49,166.14,138.94,134.82,134.75,134.05,132.29,129.21,128.65,127.97,127.37,
124.79,62.32,53.09,49.42,28.85；HR-MS (ESI-TOF) m/z:Calcd for C21H21N3O3{[M+H]+}
364.1656, found364.1661.
13 compound H13:2- of embodiment (1- (4,4- difiuorocyclohexyl) piperidin-4-yl) -1,3- dioxoisoindole -4-
Formamide
The reaction condition of prepare compound H13 is similar with compound H1.Second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 1- (4,4- difiuorocyclohexyl) piperidines -4- amine are raw material.Solid (yield 46.3%).1H NMR(400MHz,DMSO-d6)
δ: 8.49 (s, 1H), 8.03 (dd, J=7.7,1.3Hz, 1H), 7.93 (dd, J=7.4,1.3Hz, 1H), 7.90~7.81 (m,
2H), 3.97 (ddd, J=15.8,9.6,4.1Hz, 1H), 2.94 (d, J=9.0Hz, 2H), 2.47~2.55 (m, 1H), 2.38
~2.17 (m, 4H), 2.04 (q, J=10.9,9.5Hz, 2H), 1.91~1.72 (m, 4H), 1.71~1.61 (m, 2H), 1.61
~1.46 (m, 2H)；13C NMR(101MHz,DMSO-d6)δ:168.10,167.50,166.14,134.82,134.75,
134.04,132.31,127.98,124.79,60.21,49.73,49.02,32.71,32.47,32.24,29.34,24.63,
24.54；HR-MS (ESI-TOF) m/z:Calcd for C20H23F2N3O3 { [M+H]+392.1780, found392.1785.
14 compound H14:2- of embodiment (1- Phenylpiperidine -4- base) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H14 is similar with compound H1.Second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 1- Phenylpiperidine -4- amine are raw material.Solid (yield 42.1%).1H NMR(400MHz,DMSO-d6)δ13.49(s,1H),
8.42 (m, 1H), 8.36 (d, J=8.5Hz, 1H), 8.27 (d, 1H), 8.07-8.02 (d, J=5.4Hz, 1H), 7.91 (d,
1H), 7.80 (s, 1H), 7.69 (d, 1H), 7.42 (d, J=8.5Hz, 1H), 6.94 (d, J=5.4Hz, 1H), 6.90 (s, 1H),
6.71(s,2H),4.46(s,3H)；13C NMR(101MHz,DMSO-d6)δ164.15,163.19,155.01,150.94,
149.14,146.37,143.09,142.31,137.58,135.24,134.64,125.39,124.18,122.37,121.86,
115.65,108.62,37.27；HRMS(ESI-TOF)m/z Calcd for C20H17N10[M+H]+:397.1638,found:
397.1631。
Embodiment 15 compound H15:2- (1- methyl sulphonyl) piperidin-4-yl) -1,3- dioxoisoindole -4- formyl
Amine
The reaction condition of prepare compound H15 is similar with compound H1.Second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 1- methanesulphonylpiperidine -4- amine are raw material.Solid (yield 32.7%).1H NMR(400MHz,DMSO-d6)δ:8.48(s,
1H), 8.05 (d, J=7.6Hz, 1H), 7.95 (d, J=7.3Hz, 1H), 7.92~7.83 (m, 2H), 4.18 (tt, J=12.4,
4.0Hz, 1H), 3.76~3.63 (m, 2H), 2.95~2.82 (m, 5H), 2.33 (qd, J=12.8,4.4Hz, 2H), 1.83
(dd, J=13.3,3.9Hz, 2H)；13C NMR(101MHz,DMSO-d6)δ:167.98,167.40,166.12,134.86,
134.80,134.07,132.29,127.99,124.86,48.22,45.67,35.15,28.40；HR-MS (ESI-TOF) m/z:
Calcd for C15H17N3O5S{[M+Na]+374.0787, found374.0860.
16 compound H16:2- of embodiment ((1R) -1- ((1R, 3R, 5S)-adamantane -1- base) ethyl) -1,3- dioxo
Iso-indoles -4- formamide
The reaction condition of prepare compound H16 is similar with compound H1.Second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and rimantadine are raw material.Solid (yield 35.6%).1H NMR(400MHz,DMSO-d6) δ: 8.52 (d, J=
19.7Hz, 1H), 8.03 (dd, J=7.1,4.8Hz, 1H), 7.89 (ddt, J=19.8,17.0,10.0Hz, 3H), 3.92 (qd,
J=7.3,3.9Hz, 1H), 1.93 (s, 4H), 1.60 (m, 12H), 1.42 (d, J=7.3Hz, 3H)；13C NMR(101MHz,
DMSO-d6)δ:169.07,168.46,166.34,134.90,134.68,134.10,132.47,128.19,124.84,
56.76,39.36,37.72,36.78,28.27,11.79；HR-MS (ESI-TOF) m/z:Calcd for C21H24N2O3{[M+
Na]+375.1685, found375.1685.
17 compound H17:2- of embodiment ((1R, 3R, 5S)-adamantane -1- base) -1,3- dioxoisoindole -4- formyl
Amine
The reaction condition of prepare compound H17 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and amantadine are raw material.Solid (yield 37.6%).1H NMR(400MHz,DMSO-d6)δ:11.58(s,1H),8.87
(s, 1H), 8.06 (m, 1H), 7.89 (dd, J=, 1H), 7.85 (d, J=7.4Hz, 1H), 2.12~2.02 (m, 9H), 1.68
(d, J=2.8Hz, 6H)；13C NMR(101MHz,DMSO-d6)δ:170.42,168.98,162.95,135.01,134.77,
134.66,133.52,129.23,124.78,52.17,41.18,36.53,29.30；HR-MS (ESI-TOF) m/z:Calcd
for C19H20N2O3{[M+Na]+347.1372, found347.1376.
Embodiment 18 compound H18:2- (cyclohexyl methyl) -1,3- dioxoisoindole -4- formamide
The reaction condition of prepare compound H17 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and cyclohexyl methylamine are raw material.Solid (yield 47.2%).1H NMR(400MHz,Chloroform-d)δ:10.01(s,1H),
8.69 (dd, J=8.1,1.2Hz, 1H), 8.03 (dd, J=7.3,1.2Hz, 1H), 7.86 (t, J=7.7Hz, 1H), 6.07 (s,
1H), 3.58 (d, J=7.2Hz, 2H), 1.88~1.60 (m, 6H), 1.31-1.13 (m, 3H), 1.12~0.96 (m, 2H)；13C
NMR(101MHz,Chloroform-d)δ:170.47,167.28,164.31,137.82,134.31,132.44,131.30,
128.34,126.47,44.71,36.91,30.79,26.15,25.61；HR-MS (ESI-TOF) m/z:Calcd for
C16H18N2O3{[M+Na]+309.1287, found 309.1215.
19 compound H19:2- of embodiment ((4- methyl -2- oxygen -1,2,5,6,7,8- hexahydro quinoline -3- base) methyl)-two
Oxo isoindole -4- formamide
The reaction condition of prepare compound H19 is similar with compound H1, and second step reaction uses 3- carboxyl phthalic acid
Acid anhydride and 3- (amine methyl) -4- methyl -5,6,7,8- tetrahydroquinolones are raw material.Solid (yield 27.2%).1H NMR
(400MHz,DMSO-d6) δ: 11.14 (s, 1H), 8.62 (s, 1H), 8.05 (dt, J=7.6,1.7Hz, 1H), 7.92 (dd, J=
7.5,1.2Hz, 1H), 7.89~7.84 (m, 1H), 7.84 (s, 1H), 3.57 (s, 2H), 2.42 (d, J=5.4Hz, 2H), 2.35
(q, J=6.1Hz, 2H), 2.13 (s, 3H), 1.64 (dd, J=8.1,4.7Hz, 4H)；13C NMR(101MHz,DMSO-d6)δ:
168.03,166.98,165.95,161.40,150.55,141.28,134.88,134.71,133.81,132.55,128.00,
124.91,120.05,112.32,35.35,26.96,24.33,22.75,21.45,15.86；HR-MS (ESI-TOF) m/z:
Calcd for C20H19N3O4{[M+Na]+388.1273, found388.1277.
20 compound H20:2- of embodiment (1- (4,4- difiuorocyclohexyl) piperidin-4-yl)-N- methoxyl group 1,3- dioxo
Iso-indoles -4- formamide
The reaction condition of prepare compound H20 is similar with compound H13, and third step reaction uses 2- (1- (4,4- difluoro rings
Hexyl) piperidin-4-yl)-N- methoxyl group 1,3- dioxoisoindole -4- formic acid and methoxy amine hydrochlorate be raw material.Solid (is received
Rate 40.1%).1H NMR (400MHz, Chloroform-d) δ 12.83 (s, 1H), 8.71 (dt, J=8.0,2.1Hz, 1H),
8.01 (dd, J=7.4,1.2Hz, 1H), 7.88 (t, J=7.7Hz, 1H), 4.16 (tt, J=12.2,4.2Hz, 1H), 3.04
(d, J=11.2Hz, 2H), 2.51 (qd, J=12.2,3.6Hz, 3H), 2.32 (td, J=12.0,2.2Hz, 2H), 2.16 (q, J
=10.2,9.2Hz, 2H), 1.85 (d, J=12.6Hz, 4H), 1.78-1.58 (m, 4H)；13C NMR(101MHz,
Chloroform-d)δ170.58,166.67,160.84,137.29,134.69,132.03,129.26,127.49,126.39,
77.22,64.29,60.98,50.43,49.03,32.87,32.63,32.38,32.07,29.29,24.51,24.42；HR-MS
(ESI-TOF) m/z:Calcd for C20H19N3O4 { [M+H]+422.1886, found422.1891.
21 compound H21:2- of embodiment (1- (4,4- difiuorocyclohexyl) piperidin-4-yl) fluoro- different Yin of 1,3- dioxo of -6-
Diindyl -4- formamide
The reaction condition of prepare compound H21 is similar with compound H13, and the first step reacts 5- fluoro- 1,2,3- benzenetricarboxylic acids
For raw material.Solid (yield 44.5%).1H NMR(400MHz,DMSO-d6) δ: 8.79 (s, 1H), 8.33 (dd, J=10.9,
1.3Hz, 1H), 8.01 (dd, J=7.4,1.3Hz, 1H), 7.90 (s, 1H), 4.10 (ddd, J=15.8,9.6,4.1Hz, 1H),
2.95 (d, J=9.0Hz, 2H), 2.47~2.44 (m, 1H), 2.38~2.17 (m, 4H), 2.04 (q, J=10.9,9.5Hz,
2H), 1.91~1.72 (m, 4H), 1.71~1.61 (m, 2H), 1.60~1.49 (m, 2H)；13C NMR(101MHz,DMSO-d6)
δ:168.29,167.61,166.31,164.79,134.92,134.85,134.23,132.44,128.15,60.22,49.73,
49.01,32.70,32.48,32.24,29.35,24.61,24.53；HR-MS (ESI-TOF) m/z:Calcd for
C20H23F2N3O3{[M+H]+411.1686, found411.1689.
It should be noted that particular features, structures, materials, or characteristics described in this specification can any one or
It can be combined in any suitable manner in multiple embodiments.In addition, without conflicting with each other, those skilled in the art can incite somebody to action
The feature of difference embodiment described in this specification and different embodiments is combined.
Beneficial effects of the present invention are proved below by way of biological experiment.
The biological experiment of 1 the compounds of this invention of test example
One, laboratory apparatus and material
Instrument used in Bioexperiment is as follows in the present invention, the safe and sound life of superclean bench BHC-1000IIA/B3: Su Jing
Object technology company；Constant water bath box PolyScience 9505:PolyScience company；Autoclave MLS-3780:SANYO is public
Department；Baking oven: Binder company；Ultrapure water instrument Milli-Q Integral 10:Millipore company；Microplate reader
MultiscanMK3, cell incubator, low speed centrifuge Sorvall ST1:Thermofisher company；
Cell strain of the present invention is public purchased from U.S. ATCC (American Type Culture Collection)
Department, and saved and cultivated by Sichuan University biological therapy National Key Laboratory technical staff.6,24,96 holes of cell culture
Plate, 15mL, 50mL centrifuge tube, 25cm2Cultivate square vase and 75cm2Culture bottle is purchased from Chengdu A Biding company.The purchase of 10mL culture dish
From WHB company.Physiological saline is purchased from Cologne pharmaceutical Co. Ltd.
Two, experimental method
1, vitro enzyme active testing
Vitro kinase inhibition analysis is completed using the enzyme testing service that Reaction Biology company provides.Testing principle
It is to combine detection based on radioisotopic filter membrane, mixes labelled with radioisotope in the substrate captured on filter membrane
NAD+, in free NAD+It is detected after wash-off.Experimental method is summarized as follows: in freshly prepd reaction buffer (50mM Tris-
HCl(pH 8.0),50mM NaCl,10mM MgCl2, 1mM DTT, 1%DMSO, and 20g/ml activated dna) in preparation instruction
Substrate；PARP is put into substrate solution, is gently mixed；With instrument Acoustic Technology (Echo 550, LabCyte
Inc.Sunnyvale, CA) untested compound for being dissolved in DMSO is put into reaction mixture；Incubation at room temperature 20 minutes；It will32P-
NAD+It is put into reaction solution, starting reaction；It is incubated at room temperature 2 hours；Reaction solution is put on filter membrane and clear with phosphate buffer
It is detected after washing；Data are analyzed with Excel and GraphPad Prism and inhibiting rate or IC50 value is calculated.
2, cell culture
It is removed from liquid nitrogen the tumour cell for freezing conservation, 37 DEG C of water bath with thermostatic control rewarmings is immediately placed in and melts, in sterile item
It is washed 1 time under part with culture medium.Then with complete culture medium inoculated in culture bottle, at 37 DEG C, 5%CO2It is cultivated in incubator,
Second day displacement fresh cell medium.The passage of suspension growth cell: after cell culture 2~3 days, training is taken out from incubator
Bottle is supported, collects cell suspension in centrifuge tube, 1500rpm/min is centrifuged 3min, goes supernatant, cell precipitation training completely
It supports base weight to hang and blow and beat uniformly, then divides to 3~5 bottles and cultivate.It passes on 1 time within general 3~4 days；The passage of adherent growth cell: thin
Born of the same parents are adherent to cover with to 80% or so of bottom of bottle, and culture bottle is taken out from incubator, sucks culture medium, washs 1 with 0.25% pancreatin
It is secondary, 0.25% pancreatin digestive juice digestion is then added, after observation cellular contraction is rounded, complete medium is added and terminates digestion,
And blowing and beating makes cell dispersion fall off, and collects cell suspension, 1500rpm/min is centrifuged 3min, removes supernatant, and cell precipitation is used
Complete medium is resuspended and blows and beats uniformly, then divides to 3~5 bottles of bottle cultures.It passes on 1 time within general 3~4 days.
3, cell growth inhibition assay (mtt assay)
The cell of logarithmic growth phase is collected, with every hole 2.5 × 103~1 × 104A quantity is inoculated in 96 orifice plates, 37
DEG C, 5%CO2Cell incubator in overnight incubation 24 hours, drug to be measured is diluted using DMEM culture medium and is added to 96 holes
In plate, 8 gradients of every kind of drug, each gradient contains 3 multiple holes.In dosing group, by gradient (final concentration is respectively 30,10,
0.33,0.11,0.036,0.012 μM) culture medium solutions of 100 μ L compounds is added in every hole, and each concentration sets 3 multiple holes；Yin
Property the every hole of control group in the 100 μ L of blank cultures for containing 1 ‰ DMSO, totally 6 multiple holes are added；It is only added in the every hole of blank control group
100 μ L culture mediums.Plate is placed in 37 DEG C, 5%CO2Culture 72 hours in cell culture incubator.Drug-treated group, stealthy control group
20 μ LMTT solution (5mg/mL) are added with the every hole of blank group, continue culture 2-4 hours, after first a ceremonial jade-ladle, used in libation is formed, terminates culture, inclines
It goes to every hole after supernatant to add 150 μ L DMSO (being then directly added into 50 μ L 20%SDS solution for suspension cell), is shaken on shaking table
15~20 minutes.Every hole cell absorbance (OD 570) is detected under 570nm wavelength with microplate reader, takes its average value record knot
Fruit.Cell proliferation inhibition rate=(control group OD570Experimental group OD570)/(control group OD 570- blank OD570) × 100%.Most
Afterwards, half-inhibitory concentration is fitted using GraphpadPrism software.
Three, experimental result
1, the inhibiting effect of compound on tumor cell
The IC of 1 compound of table inhibition tumour cell50Valuea(μmol/L)
| Compound | Capan-1 | MDA-MB-231 |
| H1 | >30 | >30 |
| H2 | 27.45 | >30 |
| H3 | 17.23 | >30 |
| H4 | >30 | >30 |
| H5 | >30 | >30 |
| H6 | 8.91 | >30 |
| H7 | 20.17 | >30 |
| H8 | 1.37 | >30 |
| H9 | >30 | >30 |
| H10 | 14.32 | >30 |
| H11 | 4.43 | >30 |
| H12 | 21.41 | >30 |
| H13 | 11.95 | >30 |
| H14 | 0.48 | >30 |
| H15 | 5.68 | >30 |
| H16 | 3.44 | 21.02 |
| H17 | 5.95 | >30 |
| H18 | 0.19 | >30 |
| H19 | 2.32 | >30 |
| H20 | 4.39 | >30 |
| H21 | 3.98 | >30 |
| Olaparib | 0.09 | 5.39 |
aEach compound is tested 2 times, and numerical value indicates average value in table.Wherein, Capan-1 is human pancreatic cancer cell,
MDA-MB-231 is human breast cancer cell.
2 compound of table is to the active inhibiting rate of PARP-1a
aIt is single hole inhibiting rate under 1 μm of ol/L, it is specified that 75-100% range is A that each compound, which surveys concentration to PARP-1,
50-75% range is B, and 25-50% is that range is C, and 0-25% range is D.
As can be seen from Table 1 and Table 2, the compounds of this invention has shown apparent inhibition to PARP-1 and pancreatic cancer cell
Effect.Wherein, compound H8, H14, H18, H19, H20, H21 can reach the inhibiting rate of PARP-1 under the concentration of 1 μm of ol/L
To 50-75%, prompt these compounds that can become potential anti-cancer sensitization agent.Preferably, the anticancer of compound H8, H14, H18
Effect is the most significant, and the proliferation of pancreatic cancer cell can be effectively suppressed in they in the case where exclusive use.
Claims (14)
1. I compound represented of formula or its pharmaceutically acceptable salt:
R1、R2、R3Independently selected from-H or halogen；
R4、R5Independently selected from-H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy；
R6Selected from substituted or unsubstituted aryl, substituted or unsubstituted alicyclic ring；
N is 0 or 1.
2. compound as described in claim 1, it is characterized in that:
R1、R2、R3Independently selected from-H or-F；
Preferably, R1、R2、R3It is-H, alternatively, R1、R3For-H, R2For-F.
3. compound as claimed in claim 1 or 2, it is characterized in that:
R4、R5Independently selected from-H, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy；
Preferably, R4、R5Independently selected from-H, unsubstituted C1~C6 alkyl or unsubstituted C1~C6 alkoxy；
Preferably, R4、R5Independently selected from-H ,-CH3Or-OCH3；
Preferably, R4、R5Independently selected from-H or-OCH3；
Preferably, R4、R5It is-H, alternatively, R4For-H, R5For-OCH3。
4. the compound as described in claims 1 to 3 any one, it is characterized in that:
R6For substituted or unsubstituted aryl, n 0；
Preferably, R6For substituted or unsubstituted 5~10 yuan of aryl；
Preferably, R6For substituted or unsubstituted 6 yuan of aryl；
Preferably, R6For substituted or unsubstituted phenyl；
Preferably, the substituted phenyl contains at least one substituent group selected from the group below: halogen, substituted or unsubstituted alkane
Base, substituted or unsubstituted alkoxy ,-NO2, substituted or unsubstituted naphthenic base, substituted or unsubstituted aryl；
Preferably, the substituted phenyl contains at least one substituent group selected from the group below: halogen, substituted or unsubstituted C1~
C6 alkyl, substituted or unsubstituted C1~C6 alkoxy ,-NO2, substituted or unsubstituted 5~6 yuan of naphthenic base, replace or do not take
5~6 yuan of aryl in generation；Wherein, the naphthenic base contains 0~2 hetero atom, and the hetero atom is oxygen or nitrogen；The aryl contains
There is 0~2 hetero atom, the hetero atom is oxygen or nitrogen；
Preferably, the substituted phenyl contains at least one substituent group selected from the group below: halogen, unsubstituted C1~C6 alkane
C1~C6 alkoxy ,-NO that base, C1~C6 alkyl of halogen substitution, unsubstituted C1~C6 alkoxy, halogen replace2, do not take
6 yuan of naphthenic base in generation, alkyl-substituted 6 yuan of naphthenic base, the alkyl-substituted methyl of 5 member rings, unsubstituted 5 yuan of aryl, wherein institute
It states 6 yuan of naphthenic base and contains 2 hetero atoms, 5 yuan of naphthenic base contain 1 hetero atom, and the aryl contains 2 hetero atoms；
Preferably, alkyl-substituted 6 yuan of naphthenic base areWherein, R7For substituted or unsubstituted alkyl；
Preferably, R7For substituted or unsubstituted C1~C6 alkyl；
Preferably, R7For unsubstituted C1~C6 alkyl；
Preferably, the substituted phenyl contains at least one substituent group selected from the group below :-F, tert-butyl ,-CF3、-OCH3、-
OCF3、-NO2、
5. compound as claimed in claim 4, it is characterized in that: R6It is selected from:
Most preferably, R6For
6. the compound as described in claims 1 to 3 any one, it is characterized in that:
R6For substituted or unsubstituted 6~10 yuan of alicyclic rings, n is 0 or 1；
Preferably, the alicyclic ring contains 0~1 hetero atom, and the hetero atom is nitrogen；
Preferably, R6It is selected fromSubstituted or unsubstituted cyclohexyl, substitution do not take
The alkyl that adamantyl, the adamantyl in generation replace；Wherein, R8Methyl, the substituted or unsubstituted cycloalkanes replaced selected from aryl
Base, substituted or unsubstituted aryl,R10Selected from substituted or unsubstituted alkyl, R11Selected from substitution
Or unsubstituted alkyl；R9Selected from-H, substituted or unsubstituted alkyl；
Preferably, R6It is selected fromUnsubstituted cyclohexyl, unsubstituted adamantane
C1~C6 alkyl that base, adamantyl replace；
Preferably, R8It is the methyl that replaces selected from 5~10 yuan of aryl, substituted or unsubstituted 5~6 yuan of naphthenic base, substituted or unsubstituted
5~10 yuan of aryl,R10Selected from substituted or unsubstituted C1~C6 alkyl, R11Selected from substitution or not
Substituted C1~C6 alkyl, and n is 0；
Preferably, R8Selected from 6 yuan of aryl replace methyl, halogen replace 6 yuan of naphthenic base, unsubstituted 6 yuan of aryl,R10Selected from unsubstituted C1~C6 alkyl, R11Selected from unsubstituted C1~C6 alkyl；
Preferably, R9Selected from-H, substituted or unsubstituted C1~C6 alkyl, and n is 1；
Preferably, R9Selected from-H or unsubstituted C1~C6 alkyl.
7. compound as claimed in claim 6, it is characterized in that: R6It is selected from:
Preferably, R6ForAnd n is 0, alternatively, R6ForAnd n is 1.
8. the compound as described in claim 1~7 any one, it is characterized in that: the compound is selected from:
9. the preparation method of compound described in claim 1~8 any one or its pharmaceutically acceptable salt, it is characterized in that:
Include the following steps:
A, the dehydration of benzenetricarboxylic acid 1 obtains intermediate 2:
B, intermediate 2 is reacted with primary amine derivatives 3, obtains intermediate 4:
C, intermediate 4 and compound 5 are through amidation process to get I compound represented of formula:
10. preparation method as claimed in claim 9, it is characterized in that: meeting at least one of following:
The method of dehydration described in step a are as follows: heat benzenetricarboxylic acid 1 in 150 DEG C；
Preferably, heating time 6h；
Preferably, make benzenetricarboxylic acid 1 in reaction vessel in adherent shape before heating；
Preferably, make benzenetricarboxylic acid 1 in adherent shape using following methods: benzenetricarboxylic acid 1 and solvent being added in round-bottomed flask, shakes
It is even, remove solvent；
Preferably, solvent is removed by the way of vacuum distillation；
Preferably, the solvent is THF；
Step b intermediate 2: the molar ratio of primary amine derivatives 3 is 10:12；
The reaction dissolvent of step b is acetic acid；
The reaction temperature of step b is 120 DEG C；
The reaction time of step b is 1.5h；
Condensing agent EDCI and HOAt are added into reaction system by step c；
Preferably, the molar ratio of intermediate 4:EDCI:HOAt is 1:1.8:1.8；
Acid binding agent is also added into the reaction system of step c；
Preferably, the acid binding agent is NMM；
Preferably, intermediate 4: the molar ratio of acid binding agent is 1:5；
The reaction dissolvent of step c is CHCl3；
Preferably, the operating method of step c are as follows: intermediate 4, EDCI, HOAt and acid binding agent are added in reaction dissolvent, sufficiently
Reaction, adds compound 5, reaction terminate to get；
Preferably, 1h is reacted in the abundant reaction under normal temperature conditions；
Preferably, 5h is reacted under normal temperature conditions after compound 5 being added.
11. compound described in claim 1~8 any one or its pharmaceutically acceptable salt are in preparation PARP inhibitor class medicine
Purposes in object；Preferably, the drug is PARP-1 inhibitor.
12. compound described in claim 1~8 any one or its pharmaceutically acceptable salt are preparing the use in anticancer drug
On the way；Preferably, the cancer is cancer of pancreas；Preferably, the compound or its pharmaceutically acceptable salt are radiotherapy and/or change
Treat drug sensitizer；Preferably, the chemotherapeutics is the drug for causing DNA damage.
13. the pharmaceutical composition of anticancer, it is characterized in that: it is with compound described in claim 1~8 any one or its pharmacy
Upper acceptable salt is active constituent, and the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared is added.
14. the combination medicine of anticancer, it is characterized in that: it contains described in the claim 12 for being administered simultaneously or respectively
Pharmaceutical composition and other chemotherapeutics；Preferably, other chemotherapeutics are the drugs for causing DNA damage.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910339789.6A CN110028439B (en) | 2019-04-25 | 2019-04-25 | Phthalimide derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910339789.6A CN110028439B (en) | 2019-04-25 | 2019-04-25 | Phthalimide derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110028439A true CN110028439A (en) | 2019-07-19 |
| CN110028439B CN110028439B (en) | 2020-11-13 |
Family
ID=67240282
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910339789.6A Active CN110028439B (en) | 2019-04-25 | 2019-04-25 | Phthalimide derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110028439B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014365A1 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Phthalimide derivatives as matrix metalloproteinase inhibitors |
| CN1534035A (en) * | 2003-03-27 | 2004-10-06 | \ | Water soluble thalidomide derivrative |
| CN1844118A (en) * | 2005-04-07 | 2006-10-11 | 天津和美生物技术有限公司 | Piperidine-2,6-dione derivatives capable of inhibiting cell from releasing tumor necrosis factor |
| CN101500563A (en) * | 2006-06-19 | 2009-08-05 | 赛福伦公司 | Cycloalkanopyrolocarbazole derivatives and the use thereof as PARP, VEGFR2 and MLK3 inhibitors |
| CN107257800A (en) * | 2014-12-23 | 2017-10-17 | 达纳-法伯癌症研究所股份有限公司 | The method that target protein is degraded is induced by bifunctional molecule |
-
2019
- 2019-04-25 CN CN201910339789.6A patent/CN110028439B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014365A1 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | Phthalimide derivatives as matrix metalloproteinase inhibitors |
| CN1534035A (en) * | 2003-03-27 | 2004-10-06 | \ | Water soluble thalidomide derivrative |
| CN1844118A (en) * | 2005-04-07 | 2006-10-11 | 天津和美生物技术有限公司 | Piperidine-2,6-dione derivatives capable of inhibiting cell from releasing tumor necrosis factor |
| CN101500563A (en) * | 2006-06-19 | 2009-08-05 | 赛福伦公司 | Cycloalkanopyrolocarbazole derivatives and the use thereof as PARP, VEGFR2 and MLK3 inhibitors |
| CN107257800A (en) * | 2014-12-23 | 2017-10-17 | 达纳-法伯癌症研究所股份有限公司 | The method that target protein is degraded is induced by bifunctional molecule |
Non-Patent Citations (1)
| Title |
|---|
| 孙道安等: ""抗肿瘤药物帕玛度胺类似物的合成"", 《现代生物医学进展》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110028439B (en) | 2020-11-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104230827B (en) | 1-(aryl methyl) quinazoline-2,4 (1H, 3H)-diketone is as PARP inhibitor and application thereof | |
| TWI804933B (en) | Compounds and uses thereof as CDK7 kinase inhibitors | |
| CN103946231B (en) | Oleanolic acid amidated derivative, and its preparation method and application | |
| CN106967070A (en) | It is used as the compound of JAK inhibitor | |
| KR20180041748A (en) | PARP inhibitors, processes for preparing crystalline forms and uses thereof | |
| JP5938400B2 (en) | Pyrrolyl-substituted dihydroindol-2-one derivatives, preparation methods and uses thereof | |
| CN105683166A (en) | Substituted pyrimidine Bmi-1 inhibitors | |
| TW202019913A (en) | Necroptosis inhibitors, and preparation and use of the same | |
| CN109982687A (en) | Conjoint therapy | |
| CN107759600A (en) | Crystallization as the Pyrrolopyrimidine compounds of JAK inhibitor | |
| CN107245075A (en) | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines | |
| CN103044395A (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN108069954B (en) | The quinazolinones of the donor containing NO | |
| CN106831812A (en) | Heterocycle containing biaryl amide structure and pyrimidine or pyrazine compounds and its application | |
| CN106565685A (en) | Tubulin inhibitor | |
| CN102268000A (en) | Novel spiroheterocyclic compound and application of same serving as therapeutic agent | |
| CN107141284B (en) | Coptisine analog derivative, preparation method, pharmaceutical composition and anticancer usage | |
| CN110028439A (en) | Phthalimide analog derivative and its preparation method and application | |
| CN104402861A (en) | Benzene sulfonamide derivatives, preparation method, and treatment application | |
| CN110437140A (en) | It is a kind of inhibit SREBP-1 target spot compound and its application | |
| CN102827160B (en) | PI3K or PI3K/m-TOR pathway inhibitor and the purposes in pharmacy thereof | |
| CN105998018A (en) | Application of pirfenidone derivative to pharmacy | |
| CN105198787B (en) | N- benzenesulfonyl -3- acetylindole acylhydrazone, preparation method and application | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN101544634B (en) | 2-phenyl-3-substituted pyrazolo[1,5-a]pyridine derivatives, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |