CN102558178B - Tabersonine derivative, pharmaceutical compositions, preparing method and medical application thereof - Google Patents
Tabersonine derivative, pharmaceutical compositions, preparing method and medical application thereof Download PDFInfo
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- 0 COC(C1C(C(/C=C/C2)N)=CCC3)C2=C(*2)C13c1c2cccc1 Chemical compound COC(C1C(C(/C=C/C2)N)=CCC3)C2=C(*2)C13c1c2cccc1 0.000 description 5
- NZLHJVZJGDBFOY-UHFFFAOYSA-N CCC(C)(CC(C(OC)=O)=C(C12CC3)N(C(C)=O)c4c1cccc4)C2[NH+]3[O-] Chemical compound CCC(C)(CC(C(OC)=O)=C(C12CC3)N(C(C)=O)c4c1cccc4)C2[NH+]3[O-] NZLHJVZJGDBFOY-UHFFFAOYSA-N 0.000 description 1
- DCMGTXCKJHMKAA-UHFFFAOYSA-N CCC1(C2)C=CC(C#C)N(CC3)C1C3(c(cccc1)c1N1)C1=C2C(OC)=O Chemical compound CCC1(C2)C=CC(C#C)N(CC3)C1C3(c(cccc1)c1N1)C1=C2C(OC)=O DCMGTXCKJHMKAA-UHFFFAOYSA-N 0.000 description 1
- RKOGRIAHKZIERJ-KOENEWCDSA-N CC[C@@](C)(C1)C2N(CC)CCC2(c(cccc2)c2N2C(C)=O)C2=C1C(OC)=O Chemical compound CC[C@@](C)(C1)C2N(CC)CCC2(c(cccc2)c2N2C(C)=O)C2=C1C(OC)=O RKOGRIAHKZIERJ-KOENEWCDSA-N 0.000 description 1
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Abstract
The invention provides antineoplastic active ingredient tabersonine derivative shown in formula (I), pharmaceutical compositions, and a preparing method and the medical application thereof.
Description
Technical field:
The invention belongs to technical field of pharmaceuticals, particularly, relate to monoterpenoid indole alkaloid compounds tabersonine (tabersonine) derivative of novel skeleton and organic and inorganic acid salt thereof, with the pharmaceutical composition that it is effective ingredient, its preparation method and they preparation treatment or preventing cancer medicine in application.
Background technology:
Tumour is world-famous puzzle.At China's newly-increased 1,600,000 tumor patients in heilongjiang every year, there are 1,300,000 tumor patients in heilongjiang dead every year.Although the chemotherapeutics used clinically at present has certain curative effect, bring the painful and stress of the huge human body because its toxicity is large to patient, new determined curative effect and the discovery of the relatively little antitumor drug of toxic side effect is extremely urgent.Tabersonine (tabersonine) derivative is the chemical synthetic derivative coming from tabersonine in natural phant.Do not report about the medical active of this compound before this.
Be separated first from 1818 and obtain vauqueline so far, find more than 3000 indole alkaloid altogether, relate to more than 40 skeletons, have more than 50 compounds at present in clinical middle application as antitumor drug vinealeucoblastine(VLB), camptothecine two series (camptothecin); Hypertension and anti-arrhythmic raubasine (ajmalicine) and Ajmaline (ajmaline).Antihypertensive drug reserpine (reserpine) and deserpidine (deserpidine).Be used for the treatment of the Strychnine (strychnine) of hemiplegia, paralysis etc.The successful discovery of said medicine proves that indole alkaloid is the class that researches on natural drugs Chinese patent medicine coefficients comparison is high.
Also get the Green Light in a cancer therapy drug sum about 130-150 molecule of use in world community invention, the mechanism of action that indole alkaloid derivative vinealeucoblastine(VLB), camptothecine two series are clear and definite and target spot, good formulation properties (alkaloid salt solves the water-soluble of injection) makes it become one of focus of antitumor drug research always.
Vindesine (VDS), Vinorelbine (NVB) are semisynthetic cancer therapy drugs on vinca compound structure basis, by reducing the toxicity of vinca, thus improve comprehensive therapeutic index.Hycamtin (topotecan) and irinotecan (irinotecan) are basic synthesizing water-solubility derivatives in camptothecine structure.The chloroquine of basis synthesis in quinine (quinine) structure, primary amine quinoline, Mefloquine hydrochloride are important anti-malaria medicaments (Kaufman, T.S., 2005).The new drug development carried out as guide's molecule still in continuation, as being in anticancer drug candidate F 81097 (AVLB) and the Vinflunine (VLF) of II-III phase.
Summary of the invention:
The object of the invention is to: monoterpenoid indole alkaloid compounds tabersonine (tabersonine) derivative is provided, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.); Its preparation method; Its pharmaceutical composition formed with pharmaceutically acceptable carrier or vehicle as effective constituent; And tabersonine (tabersonine) derivative and pharmaceutical salts thereof the purposes in the medicine of preparation prevention or Hepatoma therapy, leukemia, colorectal carcinoma, mammary cancer and lung cancer.
Above-mentioned purpose of the present invention is achieved by the following technical solutions:
Monoterpene Benzazole compounds tabersonine (tabersonine) derivative shown in formula (I) or its pharmaceutical salts,
Wherein R
1be selected from halogen atom, cyano group, hydroxyl, C
1-10alkyl, C
2-10thiazolinyl, C
2-10alkynyl; C
1-10alkoxyl group, C
2-10alkene oxygen base, C
2-10alkynyloxy group; C
2-10ketone group, C
6-15arone base; C
1-10ester group; C
3-C
10cycloalkyl; C
3-C
10cycloalkyl-C
1-C
10alkyl; 6 to 10 yuan of aryl; 6 to 10 yuan of heteroaryls; Or 6 to 10 yuan of aryl-C
1-C
10alkyl;
R
2be selected from H, C
1-10alkyl, C
1-10acyl group.
In formula
represent singly-bound or double bond.
Wherein said C
1-10alkyl, C
2-10thiazolinyl, C
2-10alkynyl, C
1-10alkoxyl group, C
2-10alkene oxygen base, C
2-10alkynyloxy group, C
3-C
10cycloalkyl, 6 to 10 yuan of aryl or 6 to 10 yuan of heteroaryls are optionally by 1 ~ 3 halogen, hydroxyl, C
1-10alkoxyl group replaces.
Wherein, R is worked as
2when being H, R
1not-CH
2cOCH
3or-CH (COCH
3)
2.
Pharmaceutical composition, comprises formula as above (I) compound or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier and/or vehicle.
The application of formula (I) compound or pharmaceutically acceptable salt thereof in treatment or preventing cancer medicine.
Described cancer includes but not limited to mammary cancer, respiratory cancer, neural system cancer, genital cancer, digestive tract cancer, urinary tract cancer, cancer eye, liver cancer, skin carcinoma, head and neck cancer, vascular tumor, bone tumor, vascular fibroma, jaw knurl, thyroid carcinoma, parathyroid carcinoma etc.
The example of mammary cancer includes, but not limited to invasive duct carcinoma, invasive lobular carcinoma, ductal carcinoma in situ and LCIS.
The example of respiratory cancer includes, but not limited to lung cancer, small cell lung cancer, nonsmall-cell lung cancer, bronchial adenoma and pleura pulmonary blastoma.
The example of neural system cancer includes, but not limited to brain stem and hypothalamus neurospongioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma, schwann's sheath cancer and neuroderm and Pinealoma.
Male reproductive organ tumour includes, but not limited to prostate cancer, carcinoma of testis.Female reproductive organ's tumour includes, but not limited to carcinoma of endometrium, carcinoma of uterine body, cervical cancer, ovarian cancer, carcinoma of vagina, carcinoma vulvae and sarcoma of uterus.
Digestive tract tumor includes, but not limited to anus cancer, colorectal carcinoma, colorectal carcinoma, esophagus cancer, carcinoma of gallbladder, cancer of the stomach, duodenal cancer, carcinoma of the pancreas, the rectum cancer, carcinoma of small intestine, tongue cancer and glandula cancer.
Urinary tract cancer includes, but not limited to bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter and urethral carcinoma.
Cancer eye includes, but not limited to intraocular melanoma and retinoblastoma.
Liver cancer includes, but not limited to hepatocellular carcinoma (being with or without the hepatocellular carcinoma of layer of fibers varient), cholangiocarcinoma (hepatic bile pipe cancer) and Combination liver cell cholangiocarcinoma.
Skin carcinoma includes, but not limited to squamous cell carcinoma, Kaposi sarcoma, Kaposi sarcoma, malignant melanoma, Merkel cell skin cancer and non-malignant skin carcinoma.
Head and neck cancer include, but not limited to larynx/hypopharynx/nasopharynx/oropharynx cancer, and lip and oral carcinoma.
Lymphoma includes, but not limited to malignant lymphoma, aids related lymphoma, non-Hodgkin lymphoma, cutaneous T cell lymphoma, Hodgkin's disease and central nervous system lymphoma.
Sarcoma includes, but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, leiomyosarcoma and rhabdosarcoma.
Leukemia includes, but not limited to acute myelogenous leukemia, Acute Lymphoblastic Leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia.
Preferably, described cancer is liver cancer, leukemia, carcinoma of the pancreas, mammary cancer or lung cancer.
Except as otherwise noted, the term " alkyl " that the present invention uses refers to the saturated monovalent hydrocarbon of straight chain or side chain, and wherein alkyl can optionally be replaced by one or more substituting group.Term " alkyl " also comprises straight chain and branched-chain alkyl, unless otherwise mentioned.In some embodiments, alkyl has 1 to 20 (C
1-20), 1 to 15 (C
1-15), 1 to 12 (C
1-12), 1 to 10 (C
1-10) or 1 to 6 (C
1-6) monovalent hydrocarbon that the straight chain of individual carbon atom is saturated, or there are 3 to 20 (C
3-20), 3 to 15 (C
3-15), 3 to 12 (C
3-12), 3 to 10 (C
3-10) or 3 to 6 (C
3-6) the saturated monovalent hydrocarbon of side chain of individual carbon atom.The straight chain C that the present invention uses
1-6with side chain C
3-6alkyl is also referred to as " low alkyl group ".The embodiment of alkyl includes but not limited to methyl, ethyl, propyl group (comprising all isomeric forms), n-propyl group, sec.-propyl, butyl (comprising all isomeric forms), n-butyl, isobutyl-, t-butyl, amyl group (comprising all isomeric forms) and hexyl (comprising all isomeric forms).Such as, C
1-6alkyl refers to have the saturated monovalent hydrocarbon of straight chain of 1 to 6 carbon atoms or has the saturated monovalent hydrocarbon of side chain of 3 to 6 carbon atoms.
Unless otherwise mentioned, the term " thiazolinyl " that the present invention uses refers to the straight chain or side chain monovalent hydrocarbon that comprise one or more carbon-carbon double bond (in one embodiment 1 to 5).Thiazolinyl can optionally be replaced by one or more substituting group.Term " thiazolinyl " also comprises the group of " cis (cis) " and " trans (trans) " structure, or " E " and " Z " formula structure that those of ordinary skill in the art understand.Unless otherwise mentioned, the term " thiazolinyl " that the present invention uses comprises straight chain and branched-chain alkenyl.Such as, C
2-6thiazolinyl refers to the unsaturated monovalent hydrocarbon of side chain of the unsaturated monovalent hydrocarbon of the straight chain of 2 to 6 carbon atoms or 3 to 6 carbon atoms.In some embodiments, thiazolinyl is 2 to 20 (C
2-20), 2 to 15 (C
2-15), 2 to 12 (C
2-12), 2 to 10 (C
2-10) or 2 to 6 (C
2-6) the straight chain monovalent hydrocarbon of individual carbon atom, or 3 to 20 (C
3-20), 3 to 15 (C
3-15), 3 to 12 (C
3-12), 3 to 10 (C
3-10) or 3 to 6 (C
3-6) the side chain monovalent hydrocarbon of individual carbon atom.The embodiment of thiazolinyl includes but not limited to vinyl, propylene-1-base, propylene-2-base, allyl group, butenyl and 4-methyl butene base.
Unless otherwise mentioned, the term " alkynyl " that the present invention uses refers to the straight chain or side chain monovalent hydrocarbon that comprise one or more carbon carbon triple bond (in one embodiment 1 to 5).Alkynyl can optionally be replaced by one or more substituting group.Unless otherwise mentioned, term " alkynyl " also comprises straight chain and branch alkynyl.In some embodiments, alkynyl is 2 to 20 (C
2-20), 2 to 15 (C
2-15), 2 to 12 (C
2-12), 2 to 10 (C
2-10) or 2 to 6 (C
2-6) the straight chain monovalent hydrocarbon of individual carbon atom, or 3 to 20 (C
3-20), 3 to 15 (C
3-15), 3 to 12 (C
3-12), 3 to 10 (C
3-10) or 3 to 6 (C
3-6) monovalent hydrocarbon of side chain of individual carbon atom.The embodiment of alkynyl includes but not limited to ethynyl (-C ≡ CH) and propargyl (-CH
2c ≡ CH).Such as, C
2-6alkynyl refers to the unsaturated monovalent hydrocarbon of side chain of the unsaturated monovalent hydrocarbon of the straight chain of 2 to 6 carbon atoms or 3 to 6 carbon atoms.
Unless otherwise mentioned, the term " cycloalkyl " that the present invention uses refers to the monovalent hydrocarbon of the saturated bridge of ring-type and/or non-bridge, and it can optionally be replaced by one or more substituting group of the present invention.In some embodiments, cycloalkyl has from 3 to 20 (C
3-20), from 3 to 15 (C
3-15), from 3 to 12 (C
3-12), from 3 to 10 (C
3-10) or from 3 to 7 (C
3-7) individual carbon atom.The embodiment of cycloalkyl group includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, decahydro naphthyl and adamantyl.
Unless otherwise mentioned, the present invention uses term " assorted alkyl ", " assorted thiazolinyl " and " alkynyl of mixing " refer to alkyl, alkenyl and alkynyl that one or more carbon atom is replaced by heteroatoms respectively.
Unless otherwise mentioned, the term " heteroatoms " that the present invention uses refers to other any atoms except carbon or hydrogen.In some embodiments, term " heteroatoms " refers to N, O, S, Si or P.In other embodiments, term " heteroatoms " refers to N, O or S.
Unless otherwise mentioned, the term " ketone group " that the present invention uses refers to that wherein optional position inserts the straight or branched alkyl of ketone carbonyl, such as " C
2-10ketone group " refer to the straight or branched alkyl with 1 to 9 carbon atom and insert ketone carbonyl in its optional position, it has general formula-C
nalkyl-CO-C
malkyl, wherein m is the integer of 1 ~ 9, n be 0 ~ 8 integer and m+n≤9.C of the present invention
2-10the example of ketone group includes but not limited to ethyl ketone base (-COCH
3), acetonyl (-COCH
2cH
3or-CH
2cOCH
3) etc.
Unless otherwise mentioned, the term " aryl " that the present invention uses refers to monocyclic aryl and/or comprises the polycyclic monovalent aryl of at least one aromatic hydrocarbon ring.In some embodiments, aryl has from 6 to 20 (C
6-20), from 6 to 15 (C
6-15) or from 6 to 10 (C
6-10) individual annular atoms.The embodiment of aryl includes but not limited to phenyl, naphthyl, fluorenyl, Azulene base (azulenyl), anthryl, phenanthryl, pyrenyl, xenyl and terphenyl.Aryl also refers to that one of them ring is aromatic and other rings can be saturated, the carbocyclic ring of part undersaturated or aromatic two rings or three rings, such as dihydro naphthyl, indenyl, dihydro indenyl or tetralyl (tetralin base (tetralinyl)).In some embodiments, aryl also can optionally be replaced by one or more substituting group.
Unless otherwise mentioned, the present invention use term " arylalkyl " or " aralkyl " refer to aryl replace monovalent alkyl.In some embodiments, alkyl and aryl are optionally replaced by one or more substituting group.
Unless otherwise mentioned, the term " arone base " that the present invention uses refers to the monoradical with aryl and ketone carbonyl, and aryl moiety wherein has the identical implication of aforementioned definitions.In some embodiments, C
6-15arone base comprises C
6-10aryl-carbonyl-C
1-4alkyl, C
6-10aryl-C
1-4alkyl-carbonyl.The example of arone base includes but not limited to benzophenone base, phenacyl etc.
Unless otherwise mentioned, the term " pharmacy acceptable salt " that the present invention uses refers to the salt be prepared from by pharmaceutically acceptable nontoxic acid, comprises mineral acid and organic acid.Described organic acid includes but not limited to tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, citric acid, aspartic acid, benzene Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, succsinic acid, tartrate, sulfocyanic acid, p-tosylate and undecane hydrochlorate, described mineral acid includes but not limited to hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
General preparation method:
The general preparation method of the monoterpene Benzazole compounds shown in formula (I) one of comprises the following steps:
(1) compound 1 is converted into formula II, then formula II is converted into formula I '
Or
(2) tabersonine 1 is converted into formula III, then formula III is converted into formula I '
Or
(3) tabersonine 1 is directly used NBS and methyl ketone reflow treatment in the basic conditions;
And alternatively,
(4) if needed, formula I ' or I " can be changed into other formula I;
Wherein R
1and R
2having identical meanings mentioned above, R " is C
1-8alkyl or phenyl.
Preferably, the step that compound 1 is converted into formula II by step (1) can comprise:
A, by compound 1 at organic solvent CCl
4middle AIBN, NBS process, obtains tabersonine bromo derivative 2, or obtains methoxylation derivative 3 in presence of methyl alcohol, then makes 2 or 3 and R
1-L is obtained by reacting formula II compound:
Or
B, 21 N are oxidized to obtain compound 4 by compound 1 mcpba, then obtain compound 5 or 6 with trifluoro-acetic anhydride catalysis, then make 5 or 6 and R
1-L is obtained by reacting formula II compound:
Or
C, by after the double bond epoxidation of 3,4 in compound 1, obtaining compound 7 through series reaction, then making 7 and R
1-L reacts, and finally obtains formula III compound:
Wherein, R
1and R
2have identical meanings mentioned above, L represents H, Li or MgX, and X represents halogen.
Preferably, the step that formula III is converted into formula I ' by step (2) comprises:
A, by formula III compound at organic solvent CCl
4middle AIBN, NBS process, obtains formula IV, or obtains methoxylation derivative V in presence of methyl alcohol, then makes IV or V and R
1-L is obtained by reacting formula II compound:
Or
B, 21 N are oxidized to obtain formula VI by formula III mcpba, then obtain formula VII or VIII with trifluoro-acetic anhydride catalysis, then make VII or VIII and R
1-L is obtained by reacting formula I ' compound:
Or
C, by after the double bond epoxidation of 3,4 in compound III, then be translated into compound VI I, then make VII and R
1-L is obtained by reacting formula I ' compound:
Wherein, R
1and R
2have identical meanings mentioned above, L represents H, Li or MgX, and X represents halogen.
Preferably, in above-mentioned steps (1) or (2), step formula II being converted into formula I ' or compound 1 being converted into formula III comprises: formula II or compound 1 are reacted with acid anhydrides or alkylating reagent and obtained.
Wherein said acid anhydrides is the acid anhydrides that the carboxylic acid with 1 to 10 carbon atom is formed, the acid anhydrides that the carboxylic acid preferably with 1 to 6 carbon atom is formed, the example of described acid anhydrides includes but not limited to formic anhydride, diacetyl oxide, propionic anhydride, butyryl oxide, isobutyric anhydride, valeric anhydride etc.Described alkylating reagent has C
1-10moieties, preferably has C
1-6moieties, the example of described alkylating reagent includes but not limited to.
For
the compound representing singly-bound can be prepared as follows: under 0 DEG C of condition, is being dissolved with the CH of tabersonine
2cl
2in add bromine water, and with acetic acid catalysis, obtain compound 8, after add TBAF and slough bromo, and introduce hydroxyl on 3-C.
Composition of the present invention can be any suitable form, such as solid, semi-solid, liquid or aerosol form.Generally, medicine contains compound of the present invention or extract as activeconstituents, with applicable outside, enteron aisle, or the organic or inorganic carrier of administered parenterally or mixed with excipients.Activeconstituents can be compound, such as, can accept carrier and/or vehicle make tablet, piller, capsule, suppository, vaginal suppository, solution, emulsion, suspension and be applicable to other forms of using with conventional non-toxic pharmaceutical.The pharmaceutical acceptable carrier used in the composition comprises, such as, water, glucose, lactose, gum arabic, gelatin, mannitol, starch, Magnesium Trisilicate, talcum, W-Gum, Keratin sulfate, colloidal silica, yam starch, and be adapted at preparing other carriers used in the preparation of solid, semisolid, liquid or aerosol form.Composition can contain stablizer, thickening material in addition, and/or tinting material and spices.
Utilize the additive method previously used for low-solubility drug also can prepare composition of the present invention.Such as, compound of the present invention can be mixed with emulsion with vitamin-E or its PEGization derivative.Typically, compound dissolution, in the aqueous solution containing ethanol (being preferably less than 1%w/v), then adds vitamin-E or PEGization vitamin-E.Then remove ethanol, emulsion before being formed, it can be mixed with for intravenously or oral administration.Or compound of the present invention can make capsule in liposome.
In some embodiments, composition of the present invention can contain polymkeric substance, biological example polymkeric substance or physiologically acceptable (synthesis or naturally occurring) polymkeric substance.Bioavailable polymer can be categorized as biodegradable and not biodegradable.Biodegradable polymers degradation in vivo is chemical composition, preparation method, and/or the function of implant structure.The example of the detailed description of synthetic polymer comprises, such as, and polyanhydrides, polyhydroxy acid class, such as poly(lactic acid), polyglycolic acid and multipolymer thereof, polyester, polyamide-based, poly-former ester class and some group of polyphosphazenes.The example of the detailed description of naturally occurring polymkeric substance comprises protein and polysaccharide, such as collagen, hyaluronic acid, albumin and gelatin.
In other embodiments, compound of the present invention can with enhancing water miscible polymkeric substance coupling.The representative example of the polymkeric substance of this object be applicable to comprises polyoxyethylene glycol, poly-(d-L-glutamic acid), poly-(1-L-glutamic acid), poly-(d-aspartic acid), poly-(1-aspartic acid), and their multipolymer.
Compound tabersonine (tabersonine) derivative of the present invention or its salt can per os or without mouth administration, dosage is had nothing in common with each other because medicine is different, and concerning adult, every day, 1-1000mg was proper.
During oral administration administration, first make compound mix as vehicle, disintegrating agent, tamanori, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc. with conventional medicinal adjuvant, be made into the form administrations such as granule, capsule, tablet; Can the form administration such as injection liquid, infusion solution or suppository during non-oral administration.When preparing above-mentioned preparation, conventional preparation technique can be used.
Embodiment:
Test example below, embodiment and example of formulations can illustrate in greater detail the present invention, but do not limit the present invention in any form.
Test example 1:
The compounds of this invention tabersonine (tabersonine) derivative has obvious anti-tumor activity, experimental technique and result as follows:
One, materials and methods:
1. sample and preparation:
Sample is colourless, and dimethyl sulfoxide (DMSO) (DMSO) is dissolved the stock solution being formulated as 10mg/ml concentration and kept in Dark Place for subsequent use.
2. cell strain:
MCF-7, Breast cancer lines
SMMC7721, human hepatoma cell strain
HL-60, human leukemia cell line
SW-480, human colon cancer cell strain
A549, human lung carcinoma cell line
3. experimental technique:
(1). inoculating cell: be made into individual cells suspension with the nutrient solution (DMEM or RMPI1640) containing 10% foetal calf serum, 96 orifice plates are inoculated into every hole 10000-20000 cell, every pore volume 100ul, attached cell shifts to an earlier date 12 hours inoculation culture.
(2). add testing compound solution (compound monomer fixed concentration 40uM primary dcreening operation, crude extract 100ug/ml primary dcreening operation, suppress the compound near 50% to establish 5 concentration to enter gradient in this concentration to growth of tumour cell to sieve again), every hole final volume 200ul, 3 multiple holes are all established in often kind of process.
(3). colour developing: cultivate after 48 hours for 37 degrees Celsius, every hole adds MTT solution 20ul.Continue to hatch 4 hours, stop cultivating, careful suction abandons in hole that culture supernatant 100ul is to avoid cell loss, and every hole adds the SDS100ul of 20%, and night incubation (temperature 37 DEG C), makes crystallisate fully melt.
(4). colorimetric: select 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad 680) reads each hole absorbance value, record result, take concentration as X-coordinate, cell survival rate is that ordinate zou draws cell growth curve, the IC50 value of application two-point method (Reed and Muench method) computerized compound.
(5). positive control: cis-platinum
Two, result:
Under this experiment condition, the tabersonine derivative prepared by following embodiment 1-9 is to the half-inhibition concentration (IC comprising Breast cancer lines (SK-BR-3), human hepatoma cell strain (SMMC7721), human leukemia cell line (HL-60), human colon cancer cell strain (SW480) and/or human lung carcinoma cell line (A549) above and grow
50) lower than 50 μMs, be preferably lower than 10 μMs, more preferably between 0.23-5 μM.About the compounds of this invention activity data (IC more specifically
50) see table 1.
Half-inhibition concentration (the IC that table 1. tabersonine (tabersonine) derivative grows human tumor cell line
50, μM)
Three, conclusion:
According to Chinese Journal of Pharmaceuticals 1993,24:455-457, the improvement mtt assay of the evaluation antitumorigenic substance activity that Zhou Jianjun etc. propose is reached a conclusion: above-mentioned data presentation goes out tabersonine derivative of the present invention and has the effect significantly suppressing cancer, by introducing substituting group of the present invention at 3, the anti-tumor activity of tabersonine can be significantly improved.
The preparation of tabersonine (tabersonine) derivative
Embodiment 1:
The preparation of methoxytabersonine and acetonyl tabersonine:
Tabersonine, benzoyl hydroperoxide acid anhydride, NBS and 5eq methyl alcohol are dissolved in CCl4, reflux 5h under anhydrous and oxygen-free condition, obtains tabersonine first oxidized derivatives, be then dissolved in acetonitrile by first oxidized derivatives, silver trifluoromethanesulfonate and methyl ketone, react 10h under room temperature, obtain acetone derivatives.ESI：393[M+1]
+，
1H-NMR(CDCl3，500MHz)δ：7.34(m，H-12)，7.13(m，H-10)，7.02(t，H-11)，6.86(dd，H-9)，5.86(m，H-14)，5.72(m，H-15)，4.04(m，H-3)，3.68(-OCH3)，3.30(d，-CH2-)，3.01-2.78(m，H-5)，2.61(s，H-21)，2.58-2.04(dddd，H-17)，2.16(COCH3)，2.01(m。H-6)，0.91(m，H-19)，0.67(m，H-18)。
Embodiment 2.:
Prepare the alternative method of acetonyl tabersonine:
By AIBN, NBS, 5eq acetone, and do alkali with salt of wormwood or cesium carbonate, be dissolved in methylene dichloride, reflux under anhydrous and oxygen-free condition, obtain target compound.ESI：393[M+1]
+。
(1)
Embodiment 3:
The preparation of bromo tabersonine and the conversion to acetonyl tabersonine:
By tabersonine, NBS, benzoyl hydroperoxide acid anhydride, at CCl
4middle backflow one night, obtain bromo derivative, after in trifluoroacetic acid catalysis, silver trifluoromethanesulfonate does alkali, and bromo derivative and acetone are dissolved in methylene dichloride, obtain target compound.Bromo derivative: ESI:415 [M+1]
+.Acetone derivatives: ESI:393 [M+1]
+.
The following derivative of tabersonine can be prepared according to similar method:
Phenacyl tabersonine:
Ethynyl tabersonine:
Embodiment 4:
The preparation of 1-ethanoyl-3-acetonyl tabersonine:
Tabersonine, tosic acid are dissolved in diacetyl oxide; 48h is reacted under normal temperature; 1-N is acetylation; obtain compd A 2, then with mcpba, 21 N are oxidized under 0 DEG C of condition, obtain formula A3 compound; then; by A3 compound under-78 DEG C of conditions, obtain intermediate formula A4 with triethylamine and trifluoro-acetic anhydride catalysis, then add acetone conversion and become target compound: ESI:393 [M+1]
+.
Alkylating reagent such as methyl-sulfate is adopted to replace diacetyl oxide can obtain 1-methyl-3-acetonyl tabersonine
Embodiment 5:
The preparation of dimerization tabersonine:
Concrete steps, with embodiment 4, just change triethylamine into 2,6-lutidine catalysis in the 3rd step.Dimer: ESI:671 [M+1]
+.Tripolymer: ESI:1006 [M+1]
+.
Embodiment 6:
The preparation of 1-ethanoyl-3-methoxytabersonine:
Concrete steps, with embodiment 4, just add free radical inhibitors Cu in the third step, suppress dimeric generation.First oxidized derivatives: ESI:367 [M+1]
+.
Embodiment 7:
The preparation of 1-ethanoyl-3-acetoxyl group tabersonine:
Concrete steps, with embodiment 4, just add buffered soln, thus obtain target compound in the 4th step.Acetonyl ester radical derivative: ESI:395 [M+1]
+.
Embodiment 8:
The preparation of 1-ethanoyl-3-cyano group tabersonine:
Concrete steps, with embodiment 4, add TFA and KCN in the third step, after half an hour, add salt of wormwood, thus obtain target product.Cyano derivative: ESI:404 [M+1]
+,
1H-NMR(CDCl3，500MHz)δ：7.90(m，H-12)，7.32(m，H-10)，7.25(t，H-11)，7.10(dd，H-9)，5.92(m，H-14)，5.83(m，H-15)，4.46(m，H-3)，3.78(-OCH3)，2.56(m，H-5)，3.09(s，H-21)，3.05-2.89(dddd，H-17)，2.27(COCH3)，2.12-1.91(m。H-6)，1.01(m，H-19)，0.62(m，H-18)
Embodiment 9:
The reduction of double bond:
Under 0 DEG C of condition, in the CH2Cl2 being dissolved with tabersonine, add bromine water, and with acetic acid catalysis, obtain compound 8, after add TBAF and slough bromo, and introduce hydroxyl on 3-C.Hydroxy derivatives: ESI:353 [M+1]
+.
Embodiment 9:
The epoxidation of double bond:
Under 0 DEG C of condition, add mcpba, by double bond epoxidation, after four with reference to specific exampless 4, after adding acetophenone groups, reduced by triatomic ring with palladium carbon, rear triphenyl phosphorus sloughs double bond, thus obtains target product: ESI:455 [M+1]
+.
Example of formulations 1:
By method first obtained tabersonine (tabersonine) derivative of embodiment 1, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) salt made, inject with water routinely, essence filter, injection liquid is made in embedding sterilizing.
Example of formulations 2:
By method first obtained tabersonine (tabersonine) derivative of embodiment 1, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), be dissolved in sterile water for injection, stirring makes molten, filters with aseptic suction funnel, more aseptic essence filter, be sub-packed in 2 ampoules, after frozen drying, aseptic sealing by fusing obtains powder injection.
Example of formulations 3:
By be separated and obtain tabersonine (tabersonine) derivative, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), the ratio being 9: 1 with excipient weight ratio adds vehicle, makes pulvis.
Example of formulations 4:
By method first obtained tabersonine (tabersonine) derivative of embodiment 1, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), the ratio being 1: 5-1: 10 in itself and excipient weight ratio adds vehicle, pelletizing press sheet.
Example of formulations 5:
By method first obtained tabersonine (tabersonine) derivative of embodiment 1, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) salt made, oral liquid method for making makes oral liquid routinely.
Example of formulations 6:
By method first obtained tabersonine (tabersonine) derivative of embodiment 1, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), the ratio being 5: 1 in itself and excipient weight ratio adds vehicle, makes capsule or granule or electuary.
Example of formulations 7:
By method first obtained tabersonine (tabersonine) derivative of embodiment 1, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), the ratio being 3: 1 in itself and excipient weight ratio adds vehicle, makes capsule or granule or electuary.
Claims (14)
1. the monoterpenoid indole alkaloid shown in formula (I) or its pharmaceutical salts,
Wherein R
1be selected from C
1-10alkoxyl group or C
2-10ketone group;
Wherein, described C
2-10ketone group has general formula-C
nalkyl-CO-C
malkyl, wherein m is the integer of 1 ~ 9, n be 0 ~ 8 integer and m+n≤9;
R
2be selected from H, C
1-10alkyl, C
1-10acyl group;
In formula
represent singly-bound or double bond;
Wherein, R is worked as
2when being H, R
1not-CH
2cOCH
3.
2. the monoterpenoid indole alkaloid shown in formula (I) or its pharmaceutical salts,
Wherein R
1be selected from methoxyl group ,-CH
2cOCH
3, phenacyl; R
2be selected from H or C
1-10acyl group;
Wherein, R is worked as
2when being H, R
1not-CH
2cOCH
3.
3. be selected from following compound or pharmaceutically acceptable salt thereof:
4. the pharmaceutical salts as described in any one of claim 1-3, refers to pharmacy acceptable salt.
5. pharmaceutical salts as claimed in claim 4, described pharmacy acceptable salt is the salt that described compound and organic acid or mineral acid are formed.
6. pharmaceutical salts as claimed in claim 5, wherein said organic acid is selected from tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, citric acid, aspartic acid, benzene Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, succsinic acid, tartrate, sulfocyanic acid, p-toluenesulphonic acids and undecanoic acid, described mineral acid is selected from hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid.
7. the preparation method of the monoterpene Benzazole compounds tabersonine derivative as shown in claim 1 formula (I), one of comprises the following steps:
(1) compound 1 is converted into formula II, then formula II is converted into formula I '
Or
(2) tabersonine 1 is converted into formula III, then formula III is converted into formula I '
Or
(3) tabersonine or formula III compound are directly used NBS and methyl ketone reflow treatment in the basic conditions:
Alternatively,
(4) if needed, above-mentioned formula I ' or I " can be changed into other formula I;
And alternatively,
(5) if needed, formula I can be changed into pharmacologically acceptable salt;
Wherein R
1and R
2having the implication that claim 1 is identical, R " is C
1-8alkyl or phenyl.
8. preparation method as claimed in claim 7, wherein the step that compound 1 is converted into formula II comprises by step (1):
A, by compound 1 at organic solvent CCl
4middle NBS process, obtains tabersonine bromo derivative 2, or obtains methoxylation derivative 3 in presence of methyl alcohol, then makes 2 or 3 and R
1-L is obtained by reacting formula II compound:
Or
B, 21 N are oxidized to obtain compound 4 by compound 1 mcpba, then obtain compound 5 or 6 with trifluoro-acetic anhydride catalysis, then make 5 or 6 and R
1-L is obtained by reacting formula II compound:
Or
C, by after the double bond epoxidation of 3,4 in compound 1, then be translated into compound 7, then make 7 and R
1-L
Reaction, finally obtains formula II compound:
Wherein, R
1and R
2have the implication that claim 1 is identical, L represents H, Li or MgX, and X represents halogen.
9. preparation method as claimed in claim 7, the step that wherein formula III is converted into formula I ' by step (2) comprises:
A, by formula III compound at organic solvent CCl
4middle NBS process, obtains formula IV, or obtains methoxylation derivative V in presence of methyl alcohol, then makes IV or V and R
1-L is obtained by reacting formula II compound:
Or
B, 21 N are oxidized to obtain formula VI by formula III mcpba, then obtain formula VII or VIII with trifluoro-acetic anhydride catalysis, then make VII or VIII and R
1-L is obtained by reacting formula I ' compound:
C, by after the double bond epoxidation of 3,4 in compound III, then be translated into compound VI I, then make VII and R
1-L reacts, and finally obtains formula I ' compound:
Wherein, R
1and R
2have the implication that claim 1 is identical, L represents H, Li or MgX, and X represents halogen.
10. the preparation method as described in any one of claim 7-9, the step wherein formula II being converted into formula I ' or compound 1 being converted into formula III comprises: formula II or compound 1 are reacted with acid anhydrides or alkylating reagent and obtained, wherein said acid anhydrides is the acid anhydrides that the carboxylic acid with 1 to 10 carbon atom is formed, and described alkylating reagent has C
1-6moieties.
11. pharmaceutical compositions, wherein containing formula (I) compound or pharmaceutically acceptable salt thereof described in any one of claim 1-4, and at least one pharmaceutically acceptable carrier and/or vehicle.
The application of compound or pharmaceutically acceptable salt thereof shown in 12. formulas (I) in preparation treatment or preventing cancer medicine:
Wherein R
1be selected from C
1-10alkoxyl group, C
2-10ketone group; Described C
2-10ketone group has general formula-C
nalkyl-CO-C
malkyl, wherein m is the integer of 1 ~ 9, n be 0 ~ 8 integer and m+n≤9;
R
2be selected from H, C
1-10alkyl, C
1-10acyl group;
In formula
represent singly-bound or double bond.
13. apply as claimed in claim 12, wherein said cancer selected from breast cancer, lung cancer, small cell lung cancer, nonsmall-cell lung cancer, bronchial adenoma and pleura pulmonary blastoma, brain stem and hypothalamus neurospongioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma, schwann's sheath cancer, neuroderm and Pinealoma, prostate cancer, carcinoma of testis, carcinoma of endometrium, carcinoma of uterine body, cervical cancer, ovarian cancer, carcinoma of vagina, carcinoma vulvae, sarcoma of uterus, anus cancer, colorectal carcinoma, colorectal carcinoma, esophagus cancer, carcinoma of gallbladder, cancer of the stomach, duodenal cancer, carcinoma of the pancreas, the rectum cancer, carcinoma of small intestine, tongue cancer, glandula cancer, bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter and urethral carcinoma, cancer eye, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, Combination liver cell cholangiocarcinoma, skin carcinoma, head and neck cancer, vascular tumor, bone tumor, lymphoma, vascular fibroma, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, leiomyosarcoma and rhabdosarcoma, jaw knurl, leukemia, thyroid carcinoma, parathyroid carcinoma.
14. apply as claimed in claim 13, and described cancer is selected from liver cancer, leukemia, colorectal carcinoma, mammary cancer and lung cancer.
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| CN109223781B (en) * | 2018-09-28 | 2020-11-06 | 郑士平 | Medicine for treating kidney injury caused by lithium salt and application thereof |
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| CN109908146A (en) * | 2019-04-12 | 2019-06-21 | 山西中医学院中西医结合医院(太原铁路中心医院) | Pseudo- strychnine inhibits the purposes of human colon cancer cells |
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|---|---|---|---|---|
| US4145552A (en) * | 1976-07-13 | 1979-03-20 | Parcor | Preparation of vincamine and related alkaloids |
| CN1063690A (en) * | 1990-12-18 | 1992-08-19 | 格德昂·理查德化学工厂股份公司 | New tabersonine derivative contains pharmaceutical composition of this compounds and preparation method thereof |
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2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4145552A (en) * | 1976-07-13 | 1979-03-20 | Parcor | Preparation of vincamine and related alkaloids |
| CN1063690A (en) * | 1990-12-18 | 1992-08-19 | 格德昂·理查德化学工厂股份公司 | New tabersonine derivative contains pharmaceutical composition of this compounds and preparation method thereof |
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| Title |
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