CN106188094B - Isoxazole ring analog derivative and its preparation method and application - Google Patents
Isoxazole ring analog derivative and its preparation method and application Download PDFInfo
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- CN106188094B CN106188094B CN201610576415.2A CN201610576415A CN106188094B CN 106188094 B CN106188094 B CN 106188094B CN 201610576415 A CN201610576415 A CN 201610576415A CN 106188094 B CN106188094 B CN 106188094B
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- camptothecin derivative
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- camptothecin
- derivative
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- 235000011164 potassium chloride Nutrition 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
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- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
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- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses camptothecin derivative, preparation method and the application in preparing tumor, which has general structure below,In formula, R1For the alkyl of H, C1~C4, or (CH3)2‑N‑CH2-；R2It is no more than 8 pharmaceutically acceptable hydrophilic radical for H or total carbon atom number.Inventor passes through 9,10,20 upper progress structural modifications in camptothecine, under the premise of keeping the stability of camptothecine new derivative, its bioactivity is improved, increases its water solubility, and toxicity is reduced, final realize improves its internal antitumor high efficiency and the application as drug.
Description
Technical field
The invention belongs to the field of chemical synthesis, are related to isoxazole ring camptothecin derivative and its preparation method and application.
Background technology
Cancer is the number one killer of current human health.The Ministry of Public Health in 2010 announce statistical data show, malignant tumour
The primary cause of the death of Chinese is had become, the patient for dying of tumour every year is more than 1,000,000.And counted according to the World Health Organization (WHO),
Die of the person nearly 7,000,000 of malignant tumour every year on average in the whole world, new cases about 8,700,000, and is also constantly increasing every year,
The death rate occupies second, is only second to cardiovascular and cerebrovascular disease.Therefore, the treatment of cancer is very urgent.
Camptothecine (Camptothecin, CPT) is a kind of cytotoxicity extracted from Nyssaceae plant camptotheca acuminata for 1966
Alkaloid, structural formula are as follows：
Camptothecine belongs to tryptophan-terpenes Alkaloid, proves that this tryptophan-terpenes Alkaloid has through tumor experiment
There is apparent antitumor activity, it is especially stronger to tumor in digestive tract, leukaemia, carcinoma of urinary bladder isoreactivity, but it easily causes marrow to press down
System, vomiting and the side effects such as blood urine, and its is not soluble in water and be insoluble in fat, is not easy to that suitable dosage form is made, further limits
Its application.Until researchs in 1985 confirm that CPT is the specific inhibitor of topoisomerase I, making it again becomes anti-swollen
The hot spot of tumor medicine research.By the way that CPT rings 7,9,10,11 structure of modification (see camptothecine structural formula), topology can be obtained
For the antitumor activities such as health and Irinotecan, Lurtotecan, hydroxycamptothecin higher, the lower camptothecin derivative of toxicity.
Two kinds of camptothecin derivatives, topotecan and Irinotecan are respectively used to Small Cell Lung Cancer/ovum in worldwide
The treatment (table 1) of nest cancer and cancer of colon, although stronger compared to the dissolubility of camptothecine both drugs, their toxicity
And the effect of adverse reaction is still very strong, including diarrhea, blood urine, vomiting, nausea etc., and which limits them and dosage, at present
Also it is untapped go out a kind of oral preparation.But even so, both drugs global marketing volume in 2005 is still very huge：Yi Li
For health, one line drug of cancer of colon, sales volume is up to 900,000,000 U.S. dollars；Topotecan, oophoroma and Small Cell Lung Cancer two wires drug,
Sales volume is up to 200,000,000 U.S. dollars.
The introduction of table 1 topotecan and Irinotecan
The World Health Organization is using the research of camptothecin derivative as one of main direction of anticancer drug, section of various countries
Scholar is falling over each other to synthesize new camptothecin derivative (CPTs) and screen.Current many structure of modification to camptothecine
It mainly on 7,9,10, or is changed on A rings, or E rings opening, ring expansion and derivatization, to be imitated
The better compound of fruit, but existing structure of modification is also to be optimized.
Invention content
The purpose of the present invention is to provide a kind of isoxazole ring camptothecin derivatives.
The purpose of the present invention is in the preparation method for providing isoxazole ring camptothecin derivative.
The present invention also aims to provide isoxazole cyclisation class camptothecin derivative and its salt, composition to prepare anti-swell
Application in tumor medicine.
The technical solution that the present invention takes is：
Inventor is keeping the steady of camptothecine new derivative by 9,10,20 upper progress structural modifications in camptothecine
Under the premise of qualitative, its bioactivity is improved, increases its water solubility, and reduce toxicity, it is antitumor in vivo that final realization improves it
High efficiency and application as drug.
Camptothecin derivative, shown in the chemical structure of general formula such as formula (1) of the camptothecin derivative：
In formula (1), R1For the alkyl of H, C1~C4, or (CH3)2-N-CH2-；R2It is no more than 8 for H or total carbon atom number
Pharmaceutically acceptable hydrophilic radical.
As a further improvement on the present invention, R2For polynary alcohol radical and its ester, hydrophilic amino-acid residue and its salt and ester,
These groups include but not limited to following group：
Camptothecin derivative or its pharmaceutical salts and ester, shown in the chemical structure of general formula such as formula (2) of the camptothecin derivative：
In formula (2), R1For the alkyl of H, C1~C4, or (CH3)2-N-CH2-。
The preparation method of camptothecin derivative, includes the following steps：
1) 10-Hydroxycamptothecin is reacted with hexa obtains 9 aldehyde radical 10-Hydroxycamptothecins, then aldehyde
Base is reacted with hydroxylamine hydrochloride generates 9- aldoximes -10-Hydroxycamptothecin, in the work of diisopropyl azodiformate and triphenylphosphine
Under, 9 aldoximes and 10 hydroxyl reaction cyclization isoxazoles generate 9,10 Wei isoxazole camptothecines；
2) 20 hydroxyls of 9,10 isoxazole camptothecines BOC- glycine is esterified, after sloughing BOC protecting groups, sweet ammonia
The amino terminal of acid obtains connecting 9,10 Wei isoxazole camptothecin derivatives of hydrophilic radical at 20 with succinic anhydride acylation again,
Ji isoxazole ring camptothecin derivatives
Reaction step is as follows：
The application of above-mentioned camptothecin derivative or its pharmaceutical salts and ester in preparing tumor.
Preferably, the tumour is selected from (non-) Small Cell Lung Cancer, liver cancer, gastric cancer, cancer of pancreas, carcinoma of mouth, the carcinoma of the rectum, mammary gland
Cancer, neuroblastoma, lymph cancer.
A kind of composition for treating tumour, the active constituent in the composition include above-mentioned camptothecin derivative and its medicinal
Salt and ester.
Preferably, the tumour is selected from (non-) Small Cell Lung Cancer, liver cancer, gastric cancer, cancer of pancreas, carcinoma of mouth, the carcinoma of the rectum, mammary gland
Cancer, neuroblastoma, lymph cancer.
A method of it treats tumour, including continues or interruption gives patient and contains above-mentioned camptothecin derivative and its medicinal
The Pharmaceutical composition of salt and ester.
The beneficial effects of the invention are as follows：
1) camptothecin derivative of the invention has in inhibition liver cancer (HepG-2), breast cancer (MDA-MB-231) on better than
The Bioactivity of city's drug topotecan, while its toxicity is lower.The camptothecin derivative of the present invention is as a kind of low
Malicious, efficient new drug candidates, which are applied, has extensive foreground.
2) present invention breaks its intramolecular hydrogen bond by the hydroxyl with hydrophilic radical esterification topotecan 20 so that happiness
Setting alkali/topotecan derivative open loop possibility in blood plasma reduces, and helps to maintain its closed loop so that camplotheca acuminata of the present invention
Alkali derivant is maintained the binding ability of target spot-Topoisomerase I, while being cyclized 9,10 by isoxazole, most
Reach the bioactivity for improving this analog derivative eventually and reduces toxicity.
Description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 1 product of embodiment (Rngn-YH-006)；
Fig. 2 is the carbon-13 nmr spectra figure of 1 product of embodiment (Rngn-YH-006)；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of 1 product of embodiment (Rngn-YH-010)；
Fig. 4 is the carbon-13 nmr spectra figure of 1 product of embodiment (Rngn-YH-010)；
Fig. 5 is Rngn-YH-010, Rngn-YH-006 and topotecan in vitro to the inhibition of 10 kinds of tumour cells；
Specific implementation mode
Term used in the present invention is defined as follows：
The alkyl of C1~C4：Refer to the saturated hydrocarbyl containing 1~4 carbon, especially methyl, ethyl, n-propyl, normal-butyl.
The pharmaceutical salts of the claimed compound of the present invention include but is not limited to alkaline-earth metal, alkaline metal salt, especially
It is its calcium salt, magnesium salts, sodium salt, sylvite, lithium salts, zinc salt, molysite etc..
Lower member ester：Refer to the esters that total carbon atom number is no more than 8, including substitution and non-substituted saturated ester.
The medicinal ester of the claimed compound of the present invention is its lower member ester, the preferably saturated ester of C1~C4, especially first
Ester, ethyl ester.
It is pharmaceutically come-at-able, refer to that some researches show that compound itself or its cylinder metabolism-ures to the basic nonhazardous of human body
Effect.
Camptothecin derivative, shown in the chemical structure of general formula such as formula (1) of the camptothecin derivative：
In formula (1), R1For the alkyl of H, C1~C4, or (CH3)2-N-CH2-；R2It is no more than 8 medicine for H or total carbon atom number
Acceptable hydrophilic radical on.
As a further improvement on the present invention, R2For polynary alcohol radical and its ester, hydrophilic amino-acid residue and its salt and ester,
These groups include but not limited to following group：
.Hydrophilic amino-acid residue is preferably natural hydrophilic amino acid residue.
Camptothecin derivative or its pharmaceutical salts and ester, shown in the chemical structure of general formula such as formula (2) of the camptothecin derivative：
In formula (2), R1For the alkyl of H, C1~C4, or (CH3)2-N-CH2-。
The preparation method of camptothecin derivative, includes the following steps：
3) 10-Hydroxycamptothecin is reacted with hexa obtains 9 aldehyde radical 10-Hydroxycamptothecins, then aldehyde
Base is reacted with hydroxylamine hydrochloride generates 9- aldoximes -10-Hydroxycamptothecin, in the work of diisopropyl azodiformate and triphenylphosphine
Under, 9 aldoximes and 10 hydroxyl reaction cyclization isoxazoles generate 9,10 Wei isoxazole camptothecines；
4) 20 hydroxyls of 9,10 isoxazole camptothecines BOC- glycine is esterified, after sloughing BOC protecting groups, sweet ammonia
The amino terminal of acid obtains connecting 9,10 Wei isoxazole camptothecin derivatives of hydrophilic radical at 20 with succinic anhydride acylation again,
Ji isoxazole ring camptothecin derivatives
Reaction step is as follows：
The application of above-mentioned camptothecin derivative or its pharmaceutical salts and ester in preparing tumor.
Preferably, the tumour is selected from (non-) Small Cell Lung Cancer, liver cancer, gastric cancer, cancer of pancreas, carcinoma of mouth, the carcinoma of the rectum, mammary gland
Cancer, neuroblastoma, lymph cancer.
A kind of composition for treating tumour, the active constituent in the composition include above-mentioned camptothecin derivative and its medicinal
Salt and ester.
Preferably, the tumour is selected from (non-) Small Cell Lung Cancer, liver cancer, gastric cancer, cancer of pancreas, carcinoma of mouth, the carcinoma of the rectum, mammary gland
Cancer, neuroblastoma, lymph cancer.
A method of it treats tumour, including continues or interruption gives patient and contains above-mentioned camptothecin derivative and its medicinal
The Pharmaceutical composition of salt and ester.
1. dosage form：
The present invention provides the methods for treating or preventing cancer, including formulate the therapeutically effective amount of patient, compound
Or composition, compound and its composition, pharmaceutically acceptable carrier, excipient or diluent.The compound of the invention and its
Composition can treat or prevent cancer and include but are not limited to, such as lymphangioendothelial sarcoma, colon cancer, cancer of pancreas, breast cancer, ovum
Nest cancer, prostate cancer, squamous cell carcinoma, gland cancer, clear-cell carcinoma, liver cancer, cervix cancer, lung cancer, Small Cell Lung Cancer, carcinoma of urinary bladder,
Malignant mela noma, leukaemia, acute lymphoblastic leukemia and acute myelocytic leukemia (granulocyte, progranulocyte,
Granulocyte, monocyte and leukaemia)；Chronic leukemia (chronic myelocytic leukemia (grain) and the white blood of chronic lymphocytic
Disease), lymph cancer (Huo Qijin disease and non-Hodgkin's disease), Huppert's disease etc..
The compound of the present invention and composition can continuously or intermittently any mode compatible with other molecules be administered,
Oral or parenteral mode absorbs, including intramuscular injection, abdominal cavity, vein, subcutaneous, intranasal, Epidural cavity, oral, sublingual, ridge
In column, intra-ventricle, in intrathecal, brain pond, intracapsular, vagina, transdermal, rectum, by sucking or being applied with, especially ear, nose, eye
Eyeball or skin etc..It is also likely to be to work with another bioactivator one.Its effect can be whole body or part.Different
Delivery system includes to be packaged in liposome, particulate, microcapsules, capsule etc..
The present invention can also be by using inhalator or sprayer, and aerosol is made, or by being poured in fluorine carbon compound
Object or the Curosurf of synthesis.The compound of the present invention is alternatively arranged as suppository, with traditional adhesive and carrier such as glycerine
Three esters.
Listed by " pharmaceutically acceptable " universally recognized pharmacopeia in animals, more particularly carrier refers on mankind
Diluent, auxiliary agent, auxiliary material.This carrier can such as water and oil.Animal, vegetables or synthesis source, such as peanut oil, soybean oil,
Mineral oil, sesame oil etc.Carrier can also be physiological saline, Arabic gum, gelatin, gelatinized corn starch, talcum powder, cutin, colloid
Silica etc..In addition.Adjuvant, stabilizer, thickener, lubricant, colorant can use.When giving patient's medication
When, the chemical composition and pharmaceutically acceptable carrier of invention, excipient or diluent are preferably sterile.When intravenously administrable,
Water is the carrier that the compound of the present invention is first choice.The solution of salt, glucose and glycerine also can be used as liquid carrier, especially note
In the scheme penetrated.Suitable pharmaceutical carrier further includes such as supplementary product starch, glucose, lactose, sucrose, gelatin, malt, rice,
Flour, silica gel, odium stearate, glycerol monostearate, talcum powder, sodium chloride, skim milk, glycerine, propylene glycol, water, ethyl alcohol etc..
Compound and composition at present can also include if the need arises suitable wetting agent or emulsifier or pH buffer.
It includes suspended matter that current compound and composition, which can take the form of solution,.Emulsion, tablet, pill,
Particle equipped with liquid, capsule, powder, long controlled release preparation, suppository, emulsion.Aviation colloidal sol, spray, suspended matter or it is any its
His form is suitble to use.
Invention compound and constituent oral medication may be in tablet, lozenge, the form or oiliness suspended matter of water,
Grain, powder, lotion, capsule, syrup.Compound and constituent Oral administration can also formulate food and food is mixed
It closes.In addition it can postpone to disintegrate in tablet or the chemical composition of pill form and be absorbed in gastrointestinal tract, continue one to provide
The effect of longer term.Time delay material includes such as glyceryl monostearate or glycerol stearate.Oral compositions may include
The carrier of standard pharmaceutical rank such as mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate etc..
1.1 combination therapy
The compound of the present invention can be used for mammal, the especially mankind simultaneously with one or more other medicines.
When other treatment is used in combination, such as other anticancer compounds, the addition of the compound and therapeutic agent can be served as or preferably be assisted
Same-action.The compound of invention can be the combination for similarly forming or separating with other treatment drug, before or after
Application method.For many chronic disease therapies, the application method for being that a composite treatment and combination of interactions, example are embodied
Such as, to reduce specific drug toxicity to the greatest extent.In certain situations, when composition and another therapeutic agent or reagent use of invention can
The side effect that can be generated, include but are not limited to toxicity, can reduce dosage of therapeutic agent and be reached caused by reduction with being less than threshold value
Adverse side effect.
The anticancer drug that can be used for combining with the compound of the present invention includes but are not limited to：Acivicin；Accra is mould
Plain hydrochloric acid acodzole hydrochloric acid；Acronine；Adozelesin；Aldesleukin；Hemel；Ambomycin；Ametantrone vinegar
Acid；Amsacrine；Anastrozole；Anthramycin；L-Asparaginasum；Asperline；Azacitidine；Azetepa；Azotomycin；Bar
Ma Sita；Benzcarbimine；Bleomycin Sulphate；Brequinar sodium；Bropirimine；Busulfan；Carboplatin；Carmustine；Cis-platinum；Carat is bent
Shore；Cytarabine；Dacarbazine；Taxol；Docetaxel；Doxorubicin hydrochloride；Droloxifene citric acid；Floxuridine；Phosphoric acid
Fludarabine；Fluorouracil；Gemcitabine hydrochloric acid；Gemcitabine；Hydroxycarbamide；Idarubicin hydrochloride；Cyclophosphamide；Yi Li is replaced
Health；Lanreotide acetic acid song azoles；Lomustine；Megestrol acetate；The human relations of acetic acid U.S.；Melphalan；Methotrexate sodium；Thiophene urethane is rattled away
Azoles；Purine hydrochloric acid；Streptonigrin；Teniposide；Vinblastine sulfate；Eldisine sulfuric acid；Vinorelbine tartrate etc..
With reference to specific embodiment, the present invention is further illustrated, embodiment this hair only for illustration
Bright technical solution does not constitute the limitation to technical solution of the present invention.
Embodiment 1
Camptothecine isoxazole derivatives (quino isoxazole compound), the chemical constitution of the not no hydrophilic radical in No. 20 positions
Formula is as follows, and chemistry is entitled：(S)-8-ethyl-8-hydroxy-8H-isoxazolo[4,5-f]pyrano[3',4':6,7]
indolizino[1,2-b]quinoline-9,12(11H,14H)-dione
No. 20 positions are entitled with hydrophilic radical isoxazole ring camptothecin derivatives chemicals：(S)-4-((2-((8-
ethyl-9,12-dioxo-9,11,12,14-tetrahydro-8H-isoxazolo[4,5-f]pyrano[3',4':6,7]
indolizino[1,2-b]Quinolin-8-yl) oxy) -2-oxoethyl) amino) -4-oxobutanoic acid, change
It is as follows to learn structural formula：
The preparation method of above-mentioned camptothecin derivative includes the following steps, synthetic route is as follows：
Specific synthesis step is as follows：
1) 10-hydroxycamptothecine in TFA (trifluoroacetic acid) (10ml) (1,100 milligrams, 0.27 mM of compound)
It is heated to reflux under argon gas 20 hours with the solution of hexa (HMTA, 80 milligrams, 0.55 mM).It then will reaction
Mixture concentrates, and 20ml distilled water is added and stirs 1 hour.After adding part distilled water, pH is adjusted to by sodium bicarbonate
8-9.PH is adjusted to 1.5 by water phase after being washed with EA (ethyl acrylate), and EA is used in combination to extract (20mL × 5).By combined organic phase
Respectively with 1N HCl, H2O and saturation NaCl aqueous solutions washing, it is dried over sodium sulfate, it filters and concentrates.By residue through chromatographically pure
Change (methanol：DCM (dichloromethane)=1：50) compound 5 is obtained.Compound 5 determines that structure is coincide by nucleus magnetic hydrogen spectrum and carbon spectrum；
2) to compound 5 (50 milligrams, 0.13 mM) and hydroxylamine hydrochloride (11 milligrams, 0.15 mM) in ethyl alcohol (10
Milliliter) in solution in be slowly added to TEA (15 microlitres, 0.15 mM).Then it is small that mixture 20 is stirred to react under 95 degree
When.Reactant is concentrated, residue is extracted with EA and water.Combined organic layer is washed with water, it is dried over sodium sulfate and concentrate.
By residue through chromatogram purification (methanol：DCM=1：50) compound 10 is obtained.Compound 10 determines knot by nucleus magnetic hydrogen spectrum and carbon spectrum
Structure coincide；
3) it is slowly added into THF (tetrahydrofuran) (10mL) solution of (48 milligrams, 0.12 mM) of compound 10
After diisopropyl azodiformate (Diisopropyl azodicarboxylate, DIAD, 25 milligram, 0.12 mM) again plus
Enter PPh3(triphenylphosphine) (32 milligrams, 0.12 mM).Reaction mixture is stirred at room temperature 5 hours.Solvent is removed, it is remaining
Object uses methanol by chromatogram purification：DCM(1：50) compound 11 (Rngn-YH-006) is afforded；
4) solution (120 milligrams, 026 mM) of compound 11, scandium (OTF)3(trifluoromethane sulfonic acid scandium) (78 milligrams,
0.16 mM) and DMAP (4-dimethylaminopyridine) (94 milligrams, 0.78 mM) stirred in the mixture room temperature of dry DCM
After mixing 30min, BOC- glycine (136 milligrams, 0.78 mM) is added.It is added after being stirred to react mixture at room temperature 30 minutes
DCC (dicyclohexylcarbodiimide) (272 milligrams, 1.3 mMs), is stirred overnight at room temperature, then simultaneously by diatomite filtering
Concentration.By residue through chromatogram purification (methanol：DCM=1：100) compound 12, is obtained.Compound 12 is by nucleus magnetic hydrogen spectrum and carbon
Spectrum determines that structure is coincide；
5) it toward addition TFA (1 milliliter) in solution of the compound 12 (95 milligrams, 0.15 mM) in DCM, stirs at room temperature
It is to remove solvent after 30 minutes to mix, and residue is dissolved in 2mL DMF (dimethylformamide), be added succinic anhydride (97 milligrams,
0.97 mM) and 4- picolines (73 milligrams, 0.81 mM).Reaction mixture is stirred at room temperature to stay overnight.Solvent is removed, it will
Residue is through chromatogram purification (methanol：DCM=1：50) Rngn-YH-010, two-step reaction yield 49% are obtained.
(Rngn-YH-006) structure of compound 11 is determined that nucleus magnetic hydrogen spectrum, carbon spectrogram divide by nucleus magnetic hydrogen spectrum and carbon modal data
Do not see Fig. 1 and Fig. 2, determines that structure is coincide by nucleus magnetic hydrogen spectrum and carbon spectrum, characterize data is as follows：
1H NMR (500MHz, DMSO) δ 9.89 (s, 1H), 9.12 (s, 1H), 8.33 (d, J=9.3Hz, 1H), 8.25 (d,
J=9.3Hz, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 5.41 (s, 2H), 5.34 (s, 2H), 1.87 (qd, J=14.1,
7.3Hz, 2H), 0.88 (t, J=7.3Hz, 3H)
13C NMR(101MHz,DMSO)δ172.93,161.84,157.20,152.07,150.48,147.12,146.48,
145.74,133.19,132.20,128.07,122.44,119.45,116.94,115.01,97.04,72.84,65.70,
50.87,30.77,8.24。
Compound R ngn-YH-010 structures are determined that nucleus magnetic hydrogen spectrum, carbon spectrogram are shown in respectively by nucleus magnetic hydrogen spectrum and carbon modal data
Fig. 3 and Fig. 4, characterize data are as follows：
1H NMR (400MHz, DMSO) δ 12.06 (s, 1H), 9.90 (s, 1H), 9.11 (s, 1H), 8.44 (t, J=
5.1Hz, 1H), 8.32 (t, J=10.3Hz, 1H), 8.25 (d, J=9.4Hz, 1H), 7.15 (s, 1H), 5.48 (d, J=
8.6Hz, 2H), 5.34 (s, 2H), 4.17 (dd, J=17.8,5.8Hz, 1H), 4.00 (dd, J=17.9,5.6Hz, 1H), 2.42
(t, J=4.5Hz, 2H), 2.40-2.35 (m, 2H), 2.16 (dd, J=14.7,7.4Hz, 2H), 0.92 (t, J=7.4Hz,
3H).
13C NMR(400MHz；DMSO-d6)δ7.96,29.36,30.12,30.88,50.81,66.77,76.63,
95.60,115.00,116.94,119.35,122.50,128.07,132.17,133.08,145.58,146.23,146.44,
147.11,151.88,156.89,161.85,167.50,169.58,172.07,174.12。
Effect experiment
The activity of the compounds of this invention is further described with reference to experiment, but is not so limited.
The anti tumor activity in vitro of the camptothecine being prepared/topotecan derivative is tested
Experimental principle：MTT analytic approach is measured based on living cells metabolin reducing agent MTT tetrazolium bromides using microplate reader
Optical density OD values at 490nm, to reflect number of viable cells, to measure the fragmentation effect of compound on tumor cell.
Experimental procedure：
1) logarithmic phase cell is collected, concentration of cell suspension is adjusted, 100 μ L are added per hole, bed board makes the cell density to be measured be
1000-10000/hole (edge hole is filled with sterile PBS)；
2) 96 orifice plates are placed on 5%CO2, it is incubated in 37 DEG C of incubators, until cell monolayer is paved with bottom hole, concentration gradient is added
Drug, in principle, after cell is adherent can dosing or two hours or time half a day, but we often evening before that day spread
Plate, the dosing of morning next day.General 5-7 gradient, per 5 μ L of hole, if 3-5 parallel hole；5%CO2, 37 DEG C are incubated 16-48 hours,
It is observed under inverted microscope；
3) 20 μ L MTT solution (5mg/ml, i.e. 0.5%MTT) are added per hole, continue to cultivate 4h.If drug can with MTT
Reaction, can first centrifuge and discard culture solution afterwards, carefully rush 2-3 after with PBS, add the culture solution containing MTT；Culture is terminated, it is small
The heart sucks culture solution in hole；150 μ L dimethyl sulfoxide (DMSO)s are added per hole, sets low-speed oscillation 10min on shaking table, keeps crystal fully molten
Solution, microplate reader measure the light absorption value (OD values) in each hole at 490nm.
Calculation formula is as follows：
Inhibiting rate=(mean OD value-administration group mean OD value)/(control group mean OD value) × 100%.
3 kinds of drugs are respectively used to the inhibiting tumor cell activity of 10 kinds of tumour cells of detection, respectively：
1) Rngn-YH-010 (compound 12)；2) Rngn-YH-006 (compound 11)；3) topotecan.
10 kinds of tumour cells are：1)A549,Lung Cancer；2)MCF-7,Breast Cancer；3)PANC-1,
Pancreatic Cancer；4)MDA-MB-231,Human Breast；5)HepG-2,Liver Cancer；6)KB,Oral
Carcinoma；7)BEL-7402,Liver Cancer；8)MGC803,Gastric Cancer；9)SK-N-SH,Human
Neuroblastoma；10)HuT-78,Human T cell lymphoma.
Experimental result is as shown in following table and Fig. 5.
The anti tumor activity in vitro IC50 (ng/ml) of 2 camptothecin derivative of table
Fig. 5 shows that Rngn-YH-010, Rngn-YH-006 and the external inhibition of the different tumours of 10 kinds of topotecan pair live
Property, ordinate IC50, by upper table and Fig. 5 it is found that external MTT testing inspection 10 kinds of primary tumor cells of these compounds pair
The antitumor activity of strain.Rngn-YH-010 is to two kinds of tumours of breast cancer cell (MDA-MB-231) and liver cancer cells (HepG-2)
It all shows the activity for being better than topotecan, and is also equal to listing medicine topotecan to the antitumor activity of other cells.
The antitumor activity of Rngn-YH-006 pairs of 10 kinds of tumour cells is essentially identical to listing medicine topotecan.
Data above and analysis confirm freshly prepd Rngn-YH-010, Rngn-YH-006 camptothecin derivative compared to
The topotecan of listing has better anti-tumor biological, especially in anti-liver cancer and anti-(HepG-2) and breast cancer (MDA-MB-
231) very promising new drug candidates will be can be used as.
Claims (6)
1. camptothecin derivative, shown in the chemical structure of general formula such as formula (1) of the camptothecin derivative：
In formula (1), R1For the alkyl of H, C1~C4, or (CH3)2-N-CH2-；R2For H.
2. camptothecin derivative or its pharmaceutical salts, shown in the chemical structure of general formula such as formula (2) of the camptothecin derivative：
In formula (2), R1For the alkyl of H, C1~C4, or (CH3)2-N-CH2-。
3. the preparation method of camptothecin derivative, includes the following steps：
1) 10-Hydroxycamptothecin reacted with hexa obtain 9 aldehyde radical 10-Hydroxycamptothecins, then aldehyde radical with
Hydroxylamine hydrochloride reaction generates 9- aldoximes -10-Hydroxycamptothecin, under the action of diisopropyl azodiformate and triphenylphosphine,
9 aldoximes and 10 hydroxyl reaction cyclization isoxazoles generate 9,10 Wei isoxazole camptothecines；
2) 20 hydroxyls of 9,10 isoxazole camptothecines BOC- glycine is esterified, after sloughing BOC protecting groups, glycine
Amino terminal obtains connecting 9,10 Wei isoxazole camptothecin derivatives of hydrophilic radical at 20 with succinic anhydride acylation again, i.e., different
Oxazole ring camptothecin derivative
Reaction step is as follows：
4. application of the camptothecin derivative in preparing tumor, wherein camptothecin derivative is claims 1 or 2
Camptothecin derivative pharmaceutical salts described in the camptothecin derivative or claim 2.
5. application according to claim 4, it is characterised in that：Tumour is selected from Small Cell Lung Cancer, non-small cell lung cancer, liver
Cancer, gastric cancer, cancer of pancreas, carcinoma of mouth, the carcinoma of the rectum, breast cancer, neuroblastoma, lymph cancer.
6. a kind of composition for treating tumour, the active constituent in the composition includes that camptothecine described in claim 1 derives
Camptothecin derivative described in object or claim 2 and its pharmaceutical salts.
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