CN110357897A - A kind of camptothecin derivative with anti-tumor activity and its preparation method and application - Google Patents
A kind of camptothecin derivative with anti-tumor activity and its preparation method and application Download PDFInfo
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- CN110357897A CN110357897A CN201910683067.2A CN201910683067A CN110357897A CN 110357897 A CN110357897 A CN 110357897A CN 201910683067 A CN201910683067 A CN 201910683067A CN 110357897 A CN110357897 A CN 110357897A
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- 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
- C07D491/22—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 four or more hetero rings
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Abstract
The present invention relates to a kind of camptothecin derivatives with anti-tumor activity and its preparation method and application, the camptothecin derivative is compound or its pharmaceutically acceptable salt, enantiomter, diastereoisomer, tautomer, solvate, polymorph or prodrug with structure shown in logical formula (I):
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of camptothecin derivative with anti-tumor activity and its system
Preparation Method and application.
Background technique
Camptothecine is a kind of botanical anticancer drug, extracts and obtains from the camplotheca acuminata of Central-South, the southwestern distribution of China.Camptothecine pair
Intestines and stomach and head-neck carcinoma etc. have a better effect, but have the side effect of hematuria to a few patients.The anticancer of 10-hydroxycamptothecine
Activity is more than camptothecine, also has obvious curative effects to liver cancer and head-neck carcinoma.But long-term clinical application practice discovery, camptothecine
Class drug toxic side effect with higher, such as gastrointestinal tract, reproductive system, hematological system side effect are particularly evident, in addition camplotheca acuminata
The chemical stability of bases drug, thermal stability and physicochemical property are bad, all limit camptothecin clinically extensive
Using.
Thus, it is found that and it is still current for finding efficient, low toxicity novel camptothecin analog derivative as anti-tumor drug
One big hot spot.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide one kind to have antitumor work
The camptothecin derivative and its preparation method and application of property.
The in-depth study by long-term, the present invention are prepared for a kind of camptothecin with structure novel shown in formula (I)
Derivative, and find its with preferable anti-tumour cell proliferative activity, and the compound extremely low concentration (≤
50nmol/L), inhibitory activity can be generated to specific tumors cell, and selective property is quite excellent, it is contemplated that shown in logical formula (I)
Camptothecin derivative side effect can be substantially reduced than tripterygium wilfordii itself, thus can be used for treating specific tumors.Based on above-mentioned
It was found that completing the present invention.
The purpose of the present invention can be achieved through the following technical solutions:
A kind of camptothecin derivative with anti-tumor activity, the camptothecin derivative are with structure shown in logical formula (I)
Compound or its pharmaceutically acceptable salt, enantiomter, diastereoisomer, tautomer, solvate, more
Crystal form object or prodrug:
In formula:
CPT is camptothecin derivative, including 10-hydroxycamptothecine, 7-Ethyl-10-hydroxycamptothecin or 7-N, N- bis-
Methylmethylene -10-hydroxycamptothecine or its pharmaceutically acceptable salt, enantiomter, diastereoisomer, tautomerism
The one of which of body, solvate, polymorph or prodrug；
R1Selected from the one or more of hydrogen, alkyl, naphthenic base, Heterocyclylalkyl, alkenyl, alkynyl, aryl or heteroaryl；R2、
R3、R4、R5It is each independently selected from hydrogen, halogen, cyano, sulfuryl, sulfoxide group, azido, alkyl, naphthenic base, Heterocyclylalkyl, hydroxyl
Base, amino, carbonyl, sulfonyl, ether, aryl or heteroaryl it is one or more；And R2With R3, R4With R5, R1With R2Or R4
Between can each independently with adjacent group formed saturation or the unsaturated cyclic group in part；
One or more hydrogen atoms on above-mentioned any group can be replaced by substituent group selected from the group below: including but not
It is limited to deuterium, halogen, hydroxyl, amino, nitro, cyano, sulfuryl or sulfoxide group, C1-C8Alkyl, C1-C8Alkoxy, C1-C8Alkylamino,
C2-C6Alkenyl, C2-C6Alkynyl, C2-C6Acyl group or sulfonyl, 5-8 member aryl or heteroaryl, 4-8 member naphthenic base or Heterocyclylalkyl；
Wherein, the heteroaryl includes 1-3 hetero atoms selected from the group below: N, O or S, and the Heterocyclylalkyl includes 1-3 and is selected from
The hetero atom of the following group: N, O, P or S.
It is further, described,
R1Selected from hydrogen or C1-C6Alkyl；
R2、R3、R4Independently selected from the one or more of hydrogen, halogen, alkyl, hydroxyl, amino or alkoxy；
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkene
Base, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl it is one or more；
And R2With R3, R4With R5, R1With R2Or R4Between can each independently with adjacent group formed saturation or part
Unsaturated cyclic group.
It is further, described,
R1Selected from hydrogen or C1-C6Alkyl；
R2Selected from the one or more of hydrogen, halogen, alkyl or alkoxy；
R3、R4Independently selected from hydrogen or halogen；
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkene
Base, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl it is one or more.
Further, the R2、R3、R4For hydrogen；
That is the structure of the derivative as shown in logical formula (II),
In formula (II),
R1Selected from hydrogen or C1-C3Alkyl；
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkene
Base, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are one or more.
Further, the R1For hydrogen or methyl；
I.e. shown in such as logical formula (III) of the structure of the derivative or (IV),
In formula (III) or (IV),
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkene
Base, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are one or more.
Further, the specific structure of the compound is as follows:
It is a kind of camptothecin derivative with anti-tumor activity and its pharmaceutically acceptable salt, enantiomter, non-right
Reflect the preparation method of isomers, tautomer, solvate, polymorph or prodrug, this method are as follows: by molar ratio be 0.5-
It is intermediate general formula (A) compound of 2:1 and raw material of camptothecine (B) or its pharmaceutically acceptable salt, enantiomter, diastereomeric
Isomers, tautomer, solvate, polymorph or prodrug use under the conditions of solvent appropriate and base catalyst
Mitsunobu reaction obtain as lead to camptothecin derivative and its pharmaceutically acceptable salt shown in formula (I), enantiomter,
Diastereoisomer, tautomer, solvate, polymorph or prodrug；
The solvent includes ethylene glycol monomethyl ether, N-Methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, two
Chloromethanes, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, one kind of n,N-dimethylacetamide or dioxane or
It is a variety of；The alkali includes pyridine, triethylamine, n,N-diisopropylethylamine, DBU (1,8- diazabicylo [5.4.0] 11
Carbon -7- alkene), two silicon substrate lithium of hexamethyl, two silicon substrate sodium of hexamethyl or lutidines it is one or more.
A kind of preparation method of camptothecin derivative with anti-tumor activity, reaction process are as follows:
Specifically includes the following steps:
(1) mass volume ratio is molten for 3- hydroxybenzoic acid, the dimethylamine tetrahydrofuran of 3g:8-12mL:4-6g:8-12mL
In liquid, HATU and methylene chloride mixing, 8-12h is stirred at room temperature；After reaction, it is extracted with dichloromethane, organic phase is used respectively
Dilute hydrochloric acid, distillation water washing, it is dry, it is concentrated under reduced pressure to give compound 3- hydroxy-n, N- dimethyl benzamide is anti-for lower step
It answers；
(2) under nitrogen protection, the 3- hydroxy-n for being 2g:2-3g:12-20mL:3-5g by mass volume ratio, N- dimethyl
Benzamide, raw material 1, DMF and Anhydrous potassium carbonate mixing, react 2-h at 70-100 DEG C, are cooled to room temperature, methylene chloride extraction
It takes, organic phase is dry, and concentration, methyl tertiary butyl ether(MTBE) crystallizes to obtain intermediate 1；The raw material 1 includes the fluoro- 4- nitrobenzoyl of 3-
Aldehyde or the fluoro- 4- nitro-acetophenone of 3-, the intermediate 1 include 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- dimethyl benzene first
Amide or 3- (5- acetyl group -2- nitro-phenoxy)-N, N- dimethyl benzamide；
(3) under ice cooling, 4, by mass volume ratio be the intermediate 1 of 1.8g:25-35mL:0.5-2g, anhydrous methanol and
Sodium borohydride solids mixing, is stirred at room temperature 2-4h, and TLC display reaction terminates；Reaction solution is quenched with saturated aqueous ammonium chloride, is subtracted
Pressure concentration, ethyl acetate dilution, organic phase use water and saturated common salt to wash respectively, dry concentration, concentrate methyl tertbutyl
Ether is beaten to obtain intermediate 2；The intermediate 2 includes 3- (5- (methylol) -2- nitro-phenoxy)-N, N- dimethyl benzene first
Amide or 3- (5- (ethoxy) -2- nitro-phenoxy)-N, N- dimethyl benzamide；
(4) by molar ratio be 0.5-2:1 intermediate 2 and camptothecin derivative in solvent appropriate and base catalyst condition
Under, it is reacted using Mitsunobu and prepares chromatographic separation and purification and obtain camptothecin derivative with anti-tumor activity；Described
Camptothecin derivative includes 10-hydroxycamptothecine, 7-Ethyl-10-hydroxycamptothecin or 7-N, N- dimethylmethylene -10- hydroxyl
Base camptothecine it is one or more；The solvent includes ethylene glycol monomethyl ether, N-Methyl pyrrolidone, dimethyl sulfoxide, tetrahydro
Furans, toluene, methylene chloride, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide or dioxy
Six rings it is one or more；The alkali includes pyridine, triethylamine, n,N-diisopropylethylamine, DBU (1,8- diazabicylo
[5.4.0] 11 carbon -7- alkene), two silicon substrate lithium of hexamethyl, two silicon substrate sodium of hexamethyl or lutidines it is one or more.
A kind of application of camptothecin derivative with anti-tumor activity, the compound are used to prepare tumor therapeutic agent；
The tumour includes non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, breast cancer, prostate cancer, liver cancer, skin
Skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, the cancer of the brain, leukaemia, lymph cancer, nasopharyngeal carcinoma or cancer of pancreas it is one or more.
Further, the pharmaceutical composition includes: (i) camptothecin derivative or its pharmacy as shown in logical formula (I)
Upper acceptable salt, enantiomter, diastereoisomer, tautomer, solvate, polymorph or prodrug；(ii)
Pharmaceutically acceptable carrier.
Compared with prior art, the invention has the following advantages that
(1) camptothecin derivative of the present invention can specifically inhibit the proliferation of kinds of tumor cells；
(2) camptothecin derivative of the present invention is extremely low to the inhibiting effect of normal cell；
(3) camptothecin derivative of the present invention can be used as the specific tumour medicine of completely new mechanism of action
Object.
Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology
The normally understood connotation of personnel is identical.All patents, patent application, the public material being cited in full text herein are whole by reference
Body is incorporated herein.
It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without appointing to present subject matter
What is limited.In the present invention, unless otherwise expressly specified, otherwise using odd number when also include plural number.
It has to be noticed that otherwise singular used includes institute in the present specification unless clear explanation
The plural form of self-explanatory characters' object.It shall yet further be noted that unless otherwise stated, "or" used, "or" indicate "and/or".In addition, institute
With term " includes " and other forms, for example, it is "comprising", " containing " and " containing " and non-limiting.
It can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH
ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms.
Unless otherwise stated, using the conventional method within the scope of art technology, as mass spectrum, NMR, IR and UV/VIS spectroscopic methodology and
Pharmacological method.
Unless proposing to be specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and drug and pharmaceutical chemical
Term in relation to using in description is known in the art.Can in chemical synthesis, chemical analysis, medicine preparation, preparation and delivering,
And in the treatment of patient use standard technique.For example, using manufacturer to the operation instruction of kit, or according to ability
Mode well known to domain or explanation of the invention are implemented to react and be purified.
Usually can according in this specification quote and discuss multiple summary and more specific document in description, according to
Conventional method well known in the art implements above-mentioned technology and methods.In the present specification, base can be selected by those skilled in the art
Group and its substituent group are to provide stable structure division and compound.
When the conventional chemical formulas by writing from left to right describes substituent group, which similarly includes from right to left
Write obtained equivalent substituent group in chemistry when structural formula.For example ,-CH2O- is equal to-OCH2-。
Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme
System.All documents or literature department quoted in the present invention point include but is not limited to patent, patent application, article, books, manipulator
Volume and paper are integrally incorporated herein by reference.
The certain chemical groups defined herein indicate carbon atom present in the group previously by symbol is simplified
Sum.For example, C1-6Alkyl refers to the alkyl as defined below with 1 to 6 carbon atom in total.Simplify the carbon in symbol
Total atom number does not include the carbon being likely to be present in the substituent group of the group.
In addition to aforementioned, when in for specification of the invention, unless otherwise specified, otherwise following term has
Meaning as follows.
In the present invention, term " halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH group.
" hydroxy alkyl " refers to the alkyl as defined below replaced by hydroxyl (- OH).
" carbonyl " refers to-C (=O)-group.
" nitro " refers to-NO2。
" cyano " refers to-CN.
" amino " refers to-NH2。
" substituted amino " refers to by one or two alkyl as defined below, alkyl-carbonyl, aralkyl, heteroaryl alkane
The amino that base replaces, for example, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroarylalkyl amino.
" carboxyl " refers to-COOH.
In the present invention, " optional " or " optionally " indicate that the event then described or situation may occur may not also
Occur, and the description includes the case where that the event or situation occur and do not occur simultaneously.For example, " aryl being optionally substituted "
Indicate that aryl is substituted or unsubstituted, and the description includes simultaneously substituted aryl and unsubstituted aryl.
Terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer in molecule
Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.
" stereoisomer " refers to be made of same atoms, is bonded by identical key, but with different three-dimensional structures
Compound.The present invention will cover various stereoisomers and its mixture.
When containing alkene double bond in the compound of the present invention, unless otherwise stated, the compound of the present invention is intended to wrap
Containing E- and Z- geometric isomer.
" tautomer " refers to another atom from an atom transfer of molecule to identical molecule of proton and is formed
Isomers.All tautomeric forms of the compound of the present invention also will within the scope of the present invention.
The compound of the present invention and its pharmaceutically acceptable salt may contain one or more asymmetric carbon atoms, and therefore
It can produce enantiomter, diastereoisomer and other stereoisomeric forms in any ratio.Each asymmetric carbon atom can be based on three-dimensional
It learns and is defined as (R)-or (S)-.
The present invention is intended to include all possible isomers and its racemic modification and optical voidness forms.Change of the invention
The preparation for closing object can choose racemic modification, diastereoisomer or enantiomter as raw material or intermediate.Optical activity
Isomers chiral synthon or chiral reagent can be used to prepare, or split using routine techniques, for example, by using
The methods of crystallization and chiral chromatogram.
The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or make
With such as chiral hplc resolution of racemic body (or racemic modification of salt or derivative), Gerald see, for example,
Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,
Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,
Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF
PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical
Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128.
In the present invention, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used
The base addition salts of receiving.
" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects
, salt is formed by with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulfate, nitric acid
Salt, phosphate etc.；Acylate includes but is not limited to formates, acetate, 2,2- dichloroacetate, trifluoroacetate, propionic acid
Salt, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, sebacate, adipic acid
Salt, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, citrate, palm
Hydrochlorate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate, aspartic acid
Salt, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylate, 4- ammonia
Base salicylate, napadisilate etc..These salt can be prepared by method known in the art.
" pharmaceutically acceptable base addition salts " refer to the biological effectiveness for being able to maintain free acid and without other side effects
, with inorganic base or organic base be formed by salt.Salt derived from inorganic base includes but is not limited to sodium salt, sylvite, lithium salts, ammonium
Salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Preferred inorganic salts are ammonium salt, sodium salt, sylvite, calcium salt and magnesium
Salt.Salt derived from organic base includes but is not limited to salt below: primary amine class, secondary amine class and tertiary amines, substituted amine, packet
Include natural substituted amine, cyclic amine and deacidite, such as ammonia, isopropylamine, trimethylamine, diethylamine, three
Ethamine, tripropyl amine (TPA), ethanol amine, diethanol amine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2- lignocaine second
Alcohol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, glycine betaine, ethylenediamine, gucosamine,
Methyl glucose osamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin etc..Preferred organic base includes isopropyl
Amine, diethylamine, ethanol amine, trimethylamine, dicyclohexylamine, choline and caffeine.These salt can pass through method known in the art
Preparation.
" polymorph " refer to certain compounds of the invention in the solid state due to there are two or more not
The different solid crystal phases generated with molecules align.Certain compounds of the invention may exist more than one crystal form, this hair
It is bright to be intended to include various crystal forms and its mixture.
In general, crystallization effect can generate the solvate of the compounds of this invention.Term " solvation used in the present invention
Object " refers to the aggregation comprising one or more the compounds of this invention molecules and one or more solvent molecules.Solvent can be
Water, solvate in this case are hydrate.Alternatively, solvent can be organic solvent.Therefore, the compound of the present invention can be with
Exist with hydrate, including monohydrate, dihydrate, semihydrate, times semihydrate, trihydrate, tetrahydrate etc., with
And corresponding solvation form.The compounds of this invention can form true solvate, but in some cases, can also only protect
Indefinite water or water is stayed to add the mixture of the indefinite solvent in part.The compound of the present invention can react in a solvent or from
It Precipitation or is crystallized out in solvent.The solvate of the compounds of this invention is also contained within the scope of the present invention.
The invention also includes the prodrugs of above compound.In the present invention, term " prodrug " expression can be in physiological conditions
Compound lower or that bioactive compound of the invention is converted to by solvolysis.Therefore, term " prodrug " refers to
The pharmaceutically acceptable metabolic precursor thereof of the compound of the present invention.When being given individual in need, prodrug can not have
Activity, but it is converted to reactive compound of the invention in vivo.Prodrug usually conversion rapidly in vivo, and generate of the invention
Parent compound, such as realized by hydrolyzing in blood.Prodrug compound usually provides in mammalian organism molten
The advantages of Xie Du, histocompatbility or sustained release.Prodrug includes known amino protecting group and carboxyl-protecting group.Specific prodrug system
Preparation Method can refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994,4,1985-1990；
Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
In the present invention, " pharmaceutical composition " refers to that the compounds of this invention is used to live biology with what this field usually received
Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable carrier.Drug
The purpose of composition is to promote the administration of organism, plays bioactivity in turn conducive to the absorption of active constituent.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity or property for not influencing the compounds of this invention
Substance (such as carrier or diluent), and relative nontoxic, the i.e. substance can be applied to individual without causing undesirable biological respinse
Or it is interacted in a manner of bad with any component for including in composition.
In the present invention, " pharmaceutically acceptable carrier " includes but is not limited to any to be permitted by relevant government administration section
It can be acceptable adjuvant, carrier, excipient, glidant, sweetener, diluent, the preservative, dye used for the mankind or domestic animal
Material/colorant, corrigent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
" tumour " of the present invention, " cell Proliferation exception related disease " etc. include but is not limited to leukaemia, gastro-intestinal stromal
Tumor, histiocytic lymphoma, non-small cell lung cancer, Small Cell Lung Cancer, cancer of pancreas, lung squamous cancer, adenocarcinoma of lung, breast cancer, forefront
Gland cancer, liver cancer, cholangiocarcinoma, gallbladder cancer, cutaneum carcinoma, cell carcinoma, cervical carcinoma, oophoroma, intestinal cancer, nasopharyngeal carcinoma, the cancer of the brain, bone
The diseases such as cancer, cancer of the esophagus, melanoma, kidney, carcinoma of mouth.
Terms used herein " prevention ", " prevention " and " preventing " includes the generation or evil for so that sufferer is reduced disease or illness
A possibility that change.
The term as used herein " treatment " includes following meanings with other similar synonyms:
(i) prevent disease or illness to occur in mammals, especially when this kind of mammal be susceptible to the disease or
Illness, but when being not yet diagnosed as having suffered from the disease or illness；
(ii) inhibit disease or illness, that is, contain its development；
(iii) alleviate disease or illness, that is, the state of the disease or illness is made to subside；Or
(iv) mitigate symptom caused by the disease or illness.
Term " effective quantity ", " therapeutically effective amount " or " pharmacy effective dose " used herein, which refers to, takes metapedes at certain
Alleviate at least one medicament of one or more symptoms of treated disease or illness or the amount of compound in degree.Its result
It can be sign, the abatement of symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for controlling
" effective quantity " treated is the composition needed for clinically providing significant remission effect comprising compound is disclosed herein
Amount.The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.
Terms used herein " taking ", " application ", " administration " etc. are to refer to for compound or composition to be delivered to progress
The method in the required site of biological effect.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note
Penetrate (including in intravenous, subcutaneous, peritonaeum, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.This field
It can be used for the application technique of Compounds and methods for described herein known to technical staff, such as in Goodman and Gilman, The
Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,
It is discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa
Those of.In preferred embodiments, the compound and composition being discussed herein pass through oral administration.
Term " pharmaceutical composition " used herein, " drug combination ", " applying other treatments ", " applies it at " drug combination "
Its therapeutic agent " etc. refers to the drug therapy obtained and mixing or combining more than one active constituent comprising active constituent
Fix and be not fixed combination.Term " fixed Combination ", which refers to, to be administered simultaneously in the form of single entity or single dosage form to patient
At least one compound as described herein and at least one collaboration medicament.Term " being not fixed combination " refers to the shape with corpus separatum
Formula is administered simultaneously to patient, share or sequentially apply at least one compound as described herein and at least with variable interval time
A kind of collaboration preparation.These are also applied in cocktail therapy, such as apply three or more active constituents.
It should also be appreciated by one skilled in the art that midbody compound functional group may need in method discussed below
It to be protected by protecting group appropriate.Such functional group includes hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protection base packet
Include trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, tert-butyl diphenyl first
Silylation or trimethyl silyl), THP trtrahydropyranyl, benzyl etc..The protecting group of suitable amino, amidino groups and guanidine radicals includes uncle
Butoxy carbonyl, benzyloxycarbonyl group etc..Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " is alkyl, aryl or aralkyl),
To methoxy-benzyl, trityl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl esters.
Protecting group can be introduced and be removed according to standard technique well known by persons skilled in the art and as described herein.It protects
The use of shield base is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi
Synthesis, (1999), in 4th Ed., Wiley.Protecting group can also be fluoropolymer resin.
The Mitsunobu, which reacts, to be referred to, work of the alcoholic extract hydroxyl group in DEAD (diethylazodicarboxylate) and triphenylphosphine
Replaced with lower by nucleopilic reagent, while being flipped with the connected carbon atom configuration of hydroxyl, overall reaction equation is as follows:
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1 synthesizes compound (a)
(1) 3- hydroxybenzoic acid (3g), dimethylamine tetrahydrofuran solution (10mL) and HATU (5g) are dissolved in methylene chloride
In (10mL), it is stirred overnight at room temperature.After reaction, methylene chloride extracts, and organic phase uses dilute hydrochloric acid, distillation water washing respectively,
It is dry, it is concentrated under reduced pressure to give compound 3- hydroxy-n, N- dimethyl benzamide (2.1g, white solid) is directly used in lower step
Reaction；
(2) by 3- hydroxy-n, N- dimethyl benzamide (2g) and the fluoro- 4- nitrobenzaldehyde (2.5g) of 3- are dissolved in anhydrous
In DMF (15mL), Anhydrous potassium carbonate powder (4g) is added under nitrogen protection；3h is reacted at 80 DEG C, is cooled to room temperature, methylene chloride
Extraction, organic phase is dry, and concentration, methyl tertiary butyl ether(MTBE) crystallizes to obtain compound 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- bis-
Methyl benzamide (1.8g, white solid)；
(3) 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- dimethyl benzene first are added in dry 100mL round-bottomed flask
Sodium borohydride solids (1g) is added portionwise under ice bath is cooling in amide (1.8g) and anhydrous methanol (30mL).3h, TLC is stirred at room temperature
Display reaction terminates.Reaction solution is quenched with saturated aqueous ammonium chloride, is concentrated under reduced pressure, and ethyl acetate dilution, organic phase is used respectively
Water and saturated common salt washing, dry concentration, concentrate are beaten to obtain 3- (5- (methylol) -2- nitrobenzene with methyl tertiary butyl ether(MTBE)
Oxygroup)-N, N- dimethyl benzamide (1.2g, white solid)；LC-MS (M+H): 317.1；
(4) by molar ratio be 0.5:1 3- (5- (methylol) -2- nitro-phenoxy)-N, N- dimethyl benzamide with
10-hydroxycamptothecine, which is reacted using Mitsunobu and prepared chromatographic separation and purification, obtains compound (a), LC-MS (M+H):
663.2。
Embodiment 2 synthesizes compound (b)
(1) 3- hydroxybenzoic acid (3g), dimethylamine tetrahydrofuran solution (8mL) and HATU (4g) are dissolved in methylene chloride
In (12mL), 8h is stirred at room temperature.After reaction, methylene chloride extracts, and organic phase uses dilute hydrochloric acid, distillation water washing respectively, does
It is dry, it is concentrated under reduced pressure to give compound 3- hydroxy-n, N- dimethyl benzamide is directly used in the next step；
(2) 3- hydroxy-n, N- dimethyl benzamide (2g) and the fluoro- 4- nitrobenzaldehyde (2g) of 3- are dissolved in anhydrous DMF
In (12mL), Anhydrous potassium carbonate powder (5g) is added under nitrogen protection；4h is reacted at 70 DEG C, is cooled to room temperature, methylene chloride extraction
It takes, organic phase is dry, and concentration, methyl tertiary butyl ether(MTBE) crystallizes to obtain compound 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- diformazan
Yl-benzamide (1.8g, white solid)；
(3) 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- dimethyl benzene first are added in dry 100mL round-bottomed flask
Sodium borohydride solids (2g) is added portionwise under ice bath is cooling in amide (1.8g) and anhydrous methanol (25mL).2h, TLC is stirred at room temperature
Display reaction terminates.Reaction solution is quenched with saturated aqueous ammonium chloride, is concentrated under reduced pressure, and ethyl acetate dilution, organic phase is used respectively
Water and saturated common salt washing, dry concentration, concentrate are beaten to obtain 3- (5- (methylol) -2- nitrobenzene with methyl tertiary butyl ether(MTBE)
Oxygroup)-N, N- dimethyl benzamide (1.2g, white solid)；
(4) 3- (5- (methylol) -2- nitro-phenoxy)-N, N- dimethyl benzamide and 7- for being 1:1 by molar ratio
Ethyl-10-hydroxycamptothecin, which is reacted using Mitsunobu and prepared chromatographic separation and purification, obtains compound (b), LC-MS (M+
H): 691.1.
H1- NMR (400MHz, DMSO) 8.16 (d, J=6.8Hz, 1H), 8.09 (d, J=3.2Hz, 1H), 7.54-7.58
(m, 3H), 7.47 (t, J=6.4Hz, 1H), 7.39 (s, 1H), 7.27 (s, 1H), 7.23 (d, J=6.4Hz, 1H), 7.12-
7.14(m,1H),7.08(s,1H),6.49(s,1H),5.46(s,2H),5.42(s,2H),5.30(s,2H),3.13-3.17
(m, 2H), 2.91 (s, 3H), 2.87 (s, 3H), 1.83-1.89 (m, 2H), 1.23 (t, J=6.0Hz, 3H), 0.84-0.88 (m,
3H)。
Embodiment 3 synthesizes compound (c) and its enantiomter (d) and (e)
(1) 3- hydroxybenzoic acid (3g), dimethylamine tetrahydrofuran solution (12mL) and HATU (6g) are dissolved in methylene chloride
In (8mL), 12h is stirred at room temperature.After reaction, methylene chloride extracts, and organic phase uses dilute hydrochloric acid, distillation water washing respectively, does
It is dry, it is concentrated under reduced pressure to give compound 3- hydroxy-n, N- dimethyl benzamide is directly used in the next step；
(2) 3- hydroxy-n, N- dimethyl benzamide (2g) and the fluoro- 4- nitro-acetophenone (3g) of 3- are dissolved in anhydrous DMF
In (20mL), Anhydrous potassium carbonate powder (3g) is added under nitrogen protection；2h is reacted at 100 DEG C, is cooled to room temperature, methylene chloride extraction
It takes, organic phase is dry, and concentration, methyl tertiary butyl ether(MTBE) crystallizes to obtain compound 3- (5- acetyl group -2- nitro-phenoxy)-N, N- bis-
Methyl benzamide (1.8g, white solid)；
(3) 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- dimethyl benzene first are added in dry 100mL round-bottomed flask
Sodium borohydride solids (0.5g) is added portionwise under ice bath is cooling in amide (1.8g) and anhydrous methanol (35mL).4h is stirred at room temperature,
TLC display reaction terminates.Reaction solution is quenched with saturated aqueous ammonium chloride, is concentrated under reduced pressure, ethyl acetate dilution, organic phase difference
It is washed with water and saturated common salt, dry concentration, concentrate is beaten to obtain 3- (5- (ethoxy) -2- nitro with methyl tertiary butyl ether(MTBE)
Phenoxy group)-N, N- dimethyl benzamide (1.2g, white solid)；
(4) by molar ratio be 1.5:1 3- (5- (methylol) -2- nitro-phenoxy)-N, N- dimethyl benzamide with
7-Ethyl-10-hydroxycamptothecin, which is reacted using Mitsunobu and prepared chromatographic separation and purification, obtains compound (c), LC-MS (M+
H): 705.1 and its enantiomter (d) LC-MS (M+H): 705.3 and (e), LC-MS (M+H): 705.3.
Embodiment 4 synthesizes compound (f)
(1) 3- hydroxybenzoic acid (3g), dimethylamine tetrahydrofuran solution (12mL) and HATU (6g) are dissolved in methylene chloride
In (8mL), 12h is stirred at room temperature.After reaction, methylene chloride extracts, and organic phase uses dilute hydrochloric acid, distillation water washing respectively, does
It is dry, it is concentrated under reduced pressure to give compound 3- hydroxy-n, N- dimethyl benzamide is directly used in the next step；
(2) 3- hydroxy-n, N- dimethyl benzamide (2g) and the fluoro- 4- nitro-acetophenone (3g) of 3- are dissolved in anhydrous DMF
In (20mL), Anhydrous potassium carbonate powder (3g) is added under nitrogen protection；2h is reacted at 100 DEG C, is cooled to room temperature, methylene chloride extraction
It takes, organic phase is dry, and concentration, methyl tertiary butyl ether(MTBE) crystallizes to obtain compound 3- (5- acetyl group -2- nitro-phenoxy)-N, N- bis-
Methyl benzamide (1.8g, white solid)；
(3) 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- dimethyl benzene first are added in dry 100mL round-bottomed flask
Sodium borohydride solids (0.5g) is added portionwise under ice bath is cooling in amide (1.8g) and anhydrous methanol (35mL).4h is stirred at room temperature,
TLC display reaction terminates.Reaction solution is quenched with saturated aqueous ammonium chloride, is concentrated under reduced pressure, ethyl acetate dilution, organic phase difference
It is washed with water and saturated common salt, dry concentration, concentrate is beaten to obtain 3- (5- (ethoxy) -2- nitro with methyl tertiary butyl ether(MTBE)
Phenoxy group)-N, N- dimethyl benzamide (1.2g, white solid)；
(4) 3- (5- (methylol) -2- nitro-phenoxy)-N, N- dimethyl benzamide and 7- for being 2:1 by molar ratio
N, N- dimethylmethylene -10-hydroxycamptothecine, which are reacted using Mitsunobu and prepared chromatographic separation and purification, obtains compound
(f), LC-MS (M+H): 734.2.
Embodiment 5, the present invention test the proliferation inhibition activity of different tumour cells
The exponential phase tumour cell A549 (source of people lung cancer cell line) of in vitro culture, according to the cell density in 8000/ hole, connects
For kind after 96 orifice plates, overnight incubation, cell is exposed to test-compound processing, and compound exposure concentrations are followed successively by 10000,
2500,625,156,39,9.77nM, after acting on 72h, detection reagent, CCK8 colour developing is added.After being incubated for 2h, microplate reader read plate, root
According to OD value, the inhibiting rate of cell proliferation after compound effects under each concentration is calculated, inhibiting rate (%)=[(control group is flat
Equal OD value-experimental group mean OD value)]/[(control group mean OD value-blank control group mean OD value)] × 100%, specific data
It is as shown in the table:
Based on the inhibiting rate under each concentration of compound, the IC for acquiring compound is calculated using Prism software50Value.IC50
Value, camptothecine 303nM, the compound (c) that embodiment 3 synthesizes are 750.8nM, it is seen that the present invention has tumour cell very strong
Inhibiting effect.
Claims (10)
1. a kind of camptothecin derivative with anti-tumor activity, which is characterized in that the camptothecin derivative is with logical formula (I)
The compound of shown structure or its pharmaceutically acceptable salt, enantiomter, diastereoisomer, tautomer, solvent
Compound, polymorph or prodrug:
In formula:
CPT is camptothecin derivative, including 10-hydroxycamptothecine, 7-Ethyl-10-hydroxycamptothecin or 7-N, N- dimethyl
Methylene -10-hydroxycamptothecine or its pharmaceutically acceptable salt, enantiomter, diastereoisomer, tautomer,
One of solvate, polymorph or prodrug；
R1Selected from the one or more of hydrogen, alkyl, naphthenic base, Heterocyclylalkyl, alkenyl, alkynyl, aryl or heteroaryl；
R2、R3、R4、R5It is each independently selected from hydrogen, halogen, cyano, sulfuryl, sulfoxide group, azido, alkyl, naphthenic base, heterocycle alkane
Base, hydroxyl, amino, carbonyl, sulfonyl, ether, aryl or heteroaryl it is one or more；And R2With R3, R4With R5, R1With R2
Or R4Between can each independently with adjacent group formed saturation or the unsaturated cyclic group in part；
One or more hydrogen atoms on above-mentioned any group can be replaced by substituent group selected from the group below: include but is not limited to
Deuterium, halogen, hydroxyl, amino, nitro, cyano, sulfuryl or sulfoxide group, C1-C8Alkyl, C1-C8Alkoxy, C1-C8Alkylamino, C2-C6
Alkenyl, C2-C6Alkynyl, C2-C6Acyl group or sulfonyl, 5-8 member aryl or heteroaryl, 4-8 member naphthenic base or Heterocyclylalkyl；Wherein,
The heteroaryl includes 1-3 hetero atoms selected from the group below: N, O or S, and the Heterocyclylalkyl includes 1-3 and is selected from the group
Hetero atom: N, O, P or S.
2. a kind of camptothecin derivative with anti-tumor activity according to claim 1, which is characterized in that it is described,
R1Selected from hydrogen or C1-C6Alkyl；
R2、R3、R4Independently selected from the one or more of hydrogen, halogen, alkyl, hydroxyl, amino or alkoxy；
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkenyl, alkynes
Base, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl it is one or more；
And R2With R3, R4With R5, R1With R2Or R4Between saturation can be formed with adjacent group each independently or part is unsaturated
Cyclic group.
3. a kind of camptothecin derivative with anti-tumor activity according to claim 2, which is characterized in that it is described,
R1Selected from hydrogen or C1-C6Alkyl；
R2Selected from the one or more of hydrogen, halogen, alkyl or alkoxy；
R3、R4Independently selected from hydrogen or halogen；
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkenyl, alkynes
Base, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl it is one or more.
4. a kind of camptothecin derivative with anti-tumor activity according to claim 3, which is characterized in that the R2、
R3、R4For hydrogen；
That is the structure of the derivative as shown in logical formula (II),
In formula (II),
R1Selected from hydrogen or C1-C3Alkyl；
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkenyl, alkynes
Base, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are one or more.
5. a kind of camptothecin derivative with anti-tumor activity according to claim 4, which is characterized in that the R1
For hydrogen or methyl；
I.e. shown in such as logical formula (III) of the structure of the derivative or (IV),
In formula (III) or (IV),
R5Selected from hydrogen, halogen, cyano, azido, amino, hydroxyl, alkoxy, amino, sulfuryl, sulfoxide group, alkyl, alkenyl, alkynes
Base, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are one or more.
6. a kind of camptothecin derivative with anti-tumor activity according to claim 5, which is characterized in that the camptothecine
The structural formula of derivative is one of the following:
7. a kind of preparation method of camptothecin derivative with anti-tumor activity as claimed in claim 6, which is characterized in that
This method are as follows:
By intermediate general formula (A) compound and raw material of camptothecine (B) that molar ratio is 0.5-2:1 or its is pharmaceutically acceptable
Salt, enantiomter, diastereoisomer, tautomer, solvate, polymorph or prodrug, in solvent appropriate and
Under the conditions of base catalyst, reacting to obtain using Mitsunobu can pharmaceutically be connect as led to camptothecin derivative shown in formula (I) or its
Salt, enantiomter, diastereoisomer, tautomer, solvate, polymorph or the prodrug received；
The solvent includes ethylene glycol monomethyl ether, N-Methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane
Alkane, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide or dioxane it is one or more；
The base catalyst includes pyridine, triethylamine, n,N-diisopropylethylamine, DBU (1,8- diazabicylo [5.4.0]
11 carbon -7- alkene), two silicon substrate lithium of hexamethyl, two silicon substrate sodium of hexamethyl or lutidines it is one or more.
8. the preparation method of camptothecin derivative with anti-tumor activity according to claim 7, which is characterized in that logical
Formula (A) compound is 3- (5- aldehyde radical -2- nitro-phenoxy)-N, N- dimethyl benzamide or 3- (5- acetyl group -2- nitrobenzene
Oxygroup)-N, N- dimethyl benzamide is prepared especially by following procedure:
Or,
9. camptothecin derivative with anti-tumor activity as described in claim 1 answering in preparation tumor
With.
10. application of the camptothecin derivative according to claim 9 in preparation tumor, which is characterized in that
It is the drug camptothecin derivative as shown in logical formula (I) that includes: (i) or its pharmaceutically acceptable salt, enantiomter, non-
Enantiomter, tautomer, solvate, polymorph or prodrug；(ii) pharmaceutically acceptable carrier.
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