CN105061316B - Thick cyclics, preparation method and purposes - Google Patents
Thick cyclics, preparation method and purposes Download PDFInfo
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- CN105061316B CN105061316B CN201510423552.8A CN201510423552A CN105061316B CN 105061316 B CN105061316 B CN 105061316B CN 201510423552 A CN201510423552 A CN 201510423552A CN 105061316 B CN105061316 B CN 105061316B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention discloses thick cyclics, preparation method and purposes, it has the compound of the brand-new condensed cyclic structure of structure shown in Formulas I for one kind, and find that it has preferable ERs inhibitory activity, inhibitory action can be produced to a series of tumor cell proliferation of hormone dependants, and can preferably overcome resistance caused by TAM.
Description
Technical field
The invention belongs to drug field, in particular it relates to a kind of preparation and its application of thick cyclics.
Background technology
Estrogen is to maintain female pathology and endogenous active substance necessary to mental health, therefore for women because each
Estrogen level caused by kind of reason it is low and its caused by endocrine, biology anomalous variation and the female of various clinical symptoms swash
Plain supplementary therapy a, it has also become important field of research.SERM (SERMs) can be with estrogen
Acceptor combines the combination for preventing estrogen, or is combined with ERs cause its destruction so cause cell inner estrogen by
Body is horizontal to be declined.SERM is mainly used in preventing and treating the breast cancer of estrogen receptor positive, female
Property the related disease of the hormone such as climacteric metancholia, osteoporosis.
TAM is the first-line drug of estrogen receptor positive breast cancer patients endocrine therapy.TAM drug resistance
Generation and the recurrence of tumour be the clinical significant challenge faced, there is no effective medicine at present.Therefore, find and find energy
The new prevention and treatment medicine of TAM resistance is enough resisted, is still the important research neck of current academia and industrial quarters
Domain.
The content of the invention
The purpose of this part is to summarize some aspects of embodiments of the invention and briefly introduce some preferably to implement
Example.It may do a little simplified or be omitted to avoid making our department in this part and the description of the present application summary and denomination of invention
Point, the purpose of specification digest and denomination of invention obscure, and this simplification or omit and cannot be used for limiting the scope of the present invention.
In view of problem present in the preparation and its application of above-mentioned and/or existing thick cyclics, it is proposed that the present invention.
Therefore, it is an object of the present invention to provide a kind of compound of brand-new condensed cyclic structure, it has preferably female sharp
Plain receptor inhibiting activity, inhibitory action can be produced to a series of tumor cell proliferation of hormone dependants.
In order to solve the above technical problems, the invention provides following technical scheme：A kind of thick cyclics, its feature exist
In：Its chemical structural formula as shown in following formula I,
Wherein,
R1 is one kind in hydrogen, halogen or alkyl；
R2 is one kind in substituted or unsubstituted hydroxyl, amino, ester group or azanol；
M is CH2Or O；
Ar1 and Ar2 is separately selected from 5~10 yuan of fragrant or miscellaneous aromatic groups, and above-mentioned group can be by one
Or multiple substituent substitutions.
As a kind of preferred scheme of thick cyclics of the present invention, wherein：The R1 is hydrogen or fluorine.
As a kind of preferred scheme of thick cyclics of the present invention, wherein：The Ar1 and Ar2 are respectively benzene
Ring or pyridine ring, and phenyl ring or pyridine ring can be substituted by one or more alkyl, alkoxy, amino or halogen.
The another two purpose of the present invention is to provide a kind of preparation method of thick cyclics.
In order to solve the above technical problems, the invention provides following technical scheme：A kind of preparation side of thick cyclics
Method, it is mixed by raw material A with solvent, is carried out substitution reaction with halo alkynes under the catalysis of alkali, is obtained compound B；Chemical combination
Thing B reacts with aryl halide under transition metal-catalyzed, obtains intermediate C；Intermediate C issues life in simple substance catalysis of iodine
Ring closure reaction, obtain intermediate D-1 and D-2；Intermediate D-1 and D-2 and aryl boric acid, reacted under transition metal-catalyzed
Obtain target compound E-1 and E-2；Wherein,
The chemical structural formula of the raw material A is：
The chemical structural formula of the compound B is：
The chemical structural formula of the intermediate C is：
The chemical structural formula of the intermediate D-1 is：
The chemical structural formula of the intermediate D-2 is：
The chemical structural formula of the target compound E-1 is：
The chemical structural formula of the target compound E-2 is：
The solvent is water, methanol, ethanol, isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrochysene furan
Mutter, toluene, dichloromethane, 1,2- dichloroethanes, acetonitrile, DMF, DMA, dioxane
In one or more；
The alkali includes inorganic base and organic base, is sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, fluorine
Change caesium, potassium phosphate, potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, or its composition；Or pyridine, triethylamine, N, N- bis-
Wopropyl ethyl amine, the carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0] 11, the silicon substrate lithium of hexamethyl two, the silicon substrate of hexamethyl two
Sodium, the one or more in lutidines；
The transition metal is three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd
(PPh3)4), palladium, palladium bichloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [1,1'- is double
(diphenylphosphino) ferrocene] palladium chloride, double (three adjacent benzyl phosphines) palladium chlorides, 1,2- bis- (diphenylphosphino) ethane two
One or more in palladium bichloride.
In order to solve the above technical problems, the invention provides following technical scheme：A kind of preparation side of thick cyclics
Method, it reacts to obtain intermediate G by multistep functional group conversions in a solvent by raw material F；Intermediate G is under simple substance catalysis of iodine
Generation ring closure reaction obtains intermediate H-1 and H-2；Intermediate H-1 and H-2 and aryl boric acid, in transition metal-catalyzed lower generation
Reaction obtains target compound I-1 and I-2；Wherein,
The chemical structural formula of the raw material F is：
The chemical structural formula of the intermediate G is：
The chemical structural formula of the intermediate H-1 is：
The chemical structural formula of the intermediate H-2 is：
The chemical structural formula of the target compound I-1 is：
The chemical structural formula of the target compound I-2 is：
As a kind of preferred scheme of the preparation method of thick cyclics of the present invention, wherein：The solvent is
Water, methanol, ethanol, isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane,
One or more in 1,2- dichloroethanes, acetonitrile, DMF, DMA, dioxane.
As a kind of preferred scheme of the preparation method of thick cyclics of the present invention, wherein：The transition gold
Belong to for three (dibenzalacetone) two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd (PPh3)4), palladium, palladium bichloride, two
Chlorine two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [double (diphenylphosphino) ferrocene of 1,1'-] dichloride
One or more in palladium, double (three adjacent benzyl phosphines) palladium chlorides, 1,2- bis- (diphenylphosphino) ethane palladium chloride.
The present invention, which a further object is, provides a kind of pharmaceutical composition.
In order to solve the above technical problems, the invention provides following technical scheme：A kind of pharmaceutical composition, it includes, thick
Cyclics, or its pharmaceutically acceptable salt or its enantiomter, diastereoisomer, dynamic isomer, solvation
Thing, polymorph or prodrug；And pharmaceutically acceptable carrier.
A kind of thick cyclics are preparing prevention or are treating the disease related to estrogen receptor activity or expression quantity
Medicine, the application in terms of the prevention and treatment of particularly existing estrogenic agents resistance relevant disease.
Beneficial effects of the present invention：The present invention is prepared for the chemical combination of a kind of brand-new condensed cyclic structure with structure shown in Formulas I
Thing, and find that it has preferable ERs inhibitory activity, a series of tumor cell proliferation of hormone dependants can be produced
Inhibitory action, and can preferably overcome resistance caused by TAM.
Embodiment
In order to facilitate the understanding of the purposes, features and advantages of the present invention, with reference to specific embodiment pair
The embodiment of the present invention is described in detail.
Many details are elaborated in the following description to facilitate a thorough understanding of the present invention, still the present invention can be with
It is different from other manner described here using other to implement, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention is not limited by following public specific embodiment.
Secondly, " one embodiment " or " embodiment " referred to herein refers to may be included at least one realization side of the present invention
Special characteristic, structure or characteristic in formula." in one embodiment " that different places occur in this manual not refers both to
Same embodiment, nor the single or selective embodiment mutually exclusive with other embodiment.
It should be understood that, within the scope of the present invention in, the present invention above-mentioned each technical characteristic and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to forming new or preferable technical scheme.As space is limited, exist
This no longer tires out one by one states.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that, these embodiments be merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are percentage by weight and weight
Number.
The reaction principle of the present invention：
1)
2)
Universal method is：
The first step：By I-Ar2-R (1mmol), two (triphenylphosphine) palladium chlorides (0.1mmol), cuprous iodide
(0.05mmol), triethylamine (3mmol) and tetrahydrofuran (5mL) are placed in two-mouth bottle, are well mixed, in nitrogen protective condition
Under, indazole alkynes (1mmol) is slowly added dropwise, 40 DEG C are reacted 10~20 hours, and TLC detection raw material reactions are complete, add into mixed liquor
Water quenching reaction, adds ethyl acetate extraction, merges organic layer, and remove what solvent obtained with anhydrous sodium sulfate drying, revolving
Residue carries out silica gel column chromatography, obtains yellow solid product alkynyl compounds.
Second step：Above-mentioned alkynyl compounds (1mmol), sodium acid carbonate (2mmol) are dissolved in acetonitrile (10mL), added in batches
Enter elemental iodine (3mmol), react at room temperature 10 hours, after the completion of reaction, into mixed liquor plus saturated sodium thiosulfate solution is quenched
Reaction, ethyl acetate extraction is added, merge organic layer, and the residue that solvent obtains is removed with anhydrous sodium sulfate drying, revolving
Silica gel column chromatography is carried out, obtains white solid product alkenyl iodide.
3rd step：By above-mentioned alkenyl iodide (1mmol), aryl boric acid (3mmol), tetrakis triphenylphosphine palladium
(0.03mmol), potassium carbonate (3mmol) and dioxane/water (15mL:5mL) it is placed in two-mouth bottle, under nitrogen protective condition,
95 DEG C are reacted 5 hours, after the completion of question response, are filtered, and filtrate adds water and ethyl acetate to extract, and merge organic layer, and with anhydrous sulphur
Sour sodium is dried, and revolving removes the residue that solvent obtains and carries out silica gel column chromatography, obtains white solid matter.
It is sequentially prepared to obtain following target compound using above-mentioned general preparative methods：
Test case proliferation of breast cancer MCF-7 cells Inhibition test
MCF-7 cell growth inhibition assays use CellTiter-Luminescent Cell Viability
Assay methods determine.Experiment suppresses Mcf- on human breast carcinoma Mcf-7 cells, by CellTiter method detection compound
The effect of 7 cells propagation, in detection process, the selection of test-compound initial concentration is 10 μM, and each embodiment compound selects 9
Individual gradient dilution concentration, gradient dilution multiple are 3 times, are detected per 2 multiple holes of concentration.
Testing procedure：1. normally culture human breast cancer cell Mcf-7, after digestion, by every 675 cell density kind plates in hole in
384 orifice plates；2. after kind of plate 1d, one block of plate is used for surveying background Celltiter values, is designated as ControlD1.Remaining plate dosing：Set
Cell controls group.Test-compound initial concentration is 10 μM, successively 9 gradient dilution concentration, and gradient dilution multiple is 3 times, often
2 multiple holes of concentration are detected.3. test-compound adds 25ul CellTiter detection liquid, vibration per hole after handling 7 days
2min is fully mixed, centrifugation, is stood balance and is detected after 10 minutes, record fluorescence signal, medicine group is designated as Drug D7, cell pair
Control D7 are designated as according to group.4. Log (inhibitor) is carried out to data using Graphpad Prism 5.0
Vs.response-Variable slope (four parameters) curve matching, calculates corresponding IC50.
Test result indicates that compound of the embodiment of the present invention has the work of strong suppression proliferation of breast cancer MCF-7 cells
Property, IC50 are respectively less than 100nM, and section Example compound (such as embodiment 1,2,13,15,18,19,25 etc.) IC50 is less than
10nM, therefore novel condensed ring compound of the present invention can have higher as the prevention and treatment medicine of estrogen relative diseases
Clinical value.
It should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to preferable
The present invention is described in detail embodiment, it will be understood by those within the art that, can be to the technology of the present invention
Scheme is modified or equivalent substitution, and without departing from the spirit and scope of technical solution of the present invention, it all should cover in this hair
Among bright right.
Claims (8)
- A kind of 1. thick cyclics, it is characterised in that：Its chemical structural formula as shown in following formula I,Wherein,R1 is one kind in hydrogen, halogen or methyl；R2 is one kind in unsubstituted hydroxyl, amino, methoxyl group or azanol；M is CH2 or O；The Ar1 and Ar2 are respectively phenyl ring or pyridine ring, and phenyl ring or pyridine ring can be by one or more methyl, methoxies Base, amino or halogen are substituted.
- 2. thick cyclics as claimed in claim 1, it is characterised in that：The R1 is hydrogen or fluorine.
- A kind of 3. preparation method of thick cyclics as described in any one of claim 1 or 2, it is characterised in that：Raw material A with Solvent mixes, and carries out substitution reaction with halo alkynes under the catalysis of alkali, obtains compound B；Compound B exists with aryl halide Reacted under transition metal-catalyzed, obtain intermediate C；Intermediate C issues raw ring closure reaction in simple substance catalysis of iodine, obtains centre Body D-1 and D-2；Intermediate D-1 and D-2 and aryl boric acid, react to obtain target compound E-1 under transition metal-catalyzed And E-2；Wherein,The chemical structural formula of the raw material A is：The chemical structural formula of the compound B is：The chemical structural formula of the intermediate C is：The chemical structural formula of the intermediate D-1 is：The chemical structural formula of the intermediate D-2 is：The chemical structural formula of the target compound E-1 is：The chemical structural formula of the target compound E-2 is：The solvent is water, methanol, ethanol, isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, In toluene, dichloromethane, 1,2- dichloroethanes, acetonitrile, DMF, DMA, dioxane One or more；The alkali includes inorganic base and organic base, be sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, Potassium phosphate, potassium carbonate, saleratus, sodium carbonate, sodium acid carbonate, or its composition；Or pyridine, triethylamine, N, N- diisopropyls Base ethamine, the carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0] 11, the silicon substrate lithium of hexamethyl two, the silicon substrate sodium of hexamethyl two, two One or more in picoline；The transition metal be three (dibenzalacetone) two palladium (Pd2 (dba) 3), tetrakis triphenylphosphine palladium (Pd (PPh3) 4), Palladium, palladium bichloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, the [double (diphenylphosphines of 1,1'- Base) ferrocene] palladium chloride, double (three adjacent benzyl phosphines) palladium chlorides, in 1,2- bis- (diphenylphosphino) ethane palladium chloride One or more.
- A kind of 4. preparation method of thick cyclics as described in any one of claim 1 or 2, it is characterised in that：Raw material F exists React to obtain intermediate G by multistep functional group conversions in solvent；Intermediate G issues raw ring closure reaction in simple substance catalysis of iodine and obtained Intermediate H-1 and H-2；Intermediate H-1 and H-2 and aryl boric acid, react to obtain target chemical combination under transition metal-catalyzed Thing I-1 and I-2；Wherein,The chemical structural formula of the raw material F is：The chemical structural formula of the intermediate G is：The chemical structural formula of the intermediate H-1 is：The chemical structural formula of the intermediate H-2 is：The chemical structural formula of the target compound I-1 is：The chemical structural formula of the target compound I-2 is：
- 5. the preparation method of thick cyclics as claimed in claim 4, it is characterised in that：The solvent is water, methanol, second Alcohol, isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, the chloroethenes of 1,2- bis- One or more in alkane, acetonitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dioxane.
- 6. the preparation method of the thick cyclics as described in claim 4 or 5, it is characterised in that：The transition metal is three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, palladium, palladium bichloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid Palladium, triphenylphosphine palladium acetate, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, double (three adjacent benzyl phosphines) dichlorides One or more in palladium, 1,2- bis- (diphenylphosphino) ethane palladium chloride.
- A kind of 7. pharmaceutical composition, it is characterised in that：Including, thick cyclics as claimed in claim 1 or 2, or its medicine Acceptable salt or its dynamic isomer and pharmaceutically acceptable carrier on.
- 8. a kind of thick cyclics as claimed in claim 1 or 2 prepare prevention or treatment and estrogen receptor activity or Purposes in the medicine of the related disease of expression quantity.
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