CN108640916A - One kind has the thio indolizine class compound and its derivative of active anticancer - Google Patents
One kind has the thio indolizine class compound and its derivative of active anticancer Download PDFInfo
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- CN108640916A CN108640916A CN201810583904.XA CN201810583904A CN108640916A CN 108640916 A CN108640916 A CN 108640916A CN 201810583904 A CN201810583904 A CN 201810583904A CN 108640916 A CN108640916 A CN 108640916A
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- 0 *c([n](cccc1)c1c1)c1-c(cc1)ccc1[N+]([O-])=O Chemical compound *c([n](cccc1)c1c1)c1-c(cc1)ccc1[N+]([O-])=O 0.000 description 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The present invention relates to a kind of thio indolizine class compounds and its derivative with active anticancer.It is with as follows：
Description
Technical field
The present invention relates to a kind of thio indolizine class compound or its stereoisomer or its pharmaceutically acceptable salt or
Its solvate.The invention further relates to the pharmaceutical compositions containing at least the above compound, are used for treating cancer.
Background technology
Cancer is one of the important diseases that current serious threatens human health, and treatment and prevention cause to pay attention to extensively.Mesh
Preceding therapy has operation excision, radiotherapy, chemotherapy etc., but still mainly based on chemotherapy.When
Before be clinically used for treating cancer chemicals type it is more, such as platinum class, nitrogen mustards, triazole type, but most drugs due to
Toxicity is big, adverse reaction is more, bioavilability is low and its application is made to be restricted.Therefore, anticarcinogen efficiently, less toxic is found
Object has become one of current medical chemical field emphasis research topic.
In view of potential application of the indolizine kind anti-cancer drugs object in treatment of cancer, and author has no that domestic and foreign literature is specially reported
R＆D course of the indolizine derivative in entire anticancer drug field summarizes indolizine class herein in conjunction with the research work in this laboratory
Compound is as anticancer drug in radiosensitizer, farnesyl transferase inhibitor, cytochrome P 450 inhibitors, angiogenesis
Inhibitor, topoisomerase enzyme inhibitor, period element dependent protein kinase inhibitor and tumor drug resistance reversal agent etc. are most
Recent studies on and development progress.
The present invention relates to a new class of indolizine class compounds, can effectively inhibit all kinds of cancers or tumour.
Invention content
The present invention provides a kind of thio indolizine class compound and its derivative with active anticancer.
Purpose of the present invention is to the compounds for treating various cancers or tumour or its stereoisomer, tautomerism
Body, pharmaceutically acceptable salt, solvate or its prodrug.
Present invention provides prepare the compounds of this invention or its stereoisomer, tautomer, be subjected on drug
Salt, solvate or its prodrug method and intermediate.
Present invention provides different including pharmaceutically acceptable carrier and at least one the compounds of this invention or its solid
The pharmaceutical composition of structure body, tautomer, pharmaceutically acceptable salt, solvate or its prodrug.
Present invention provides treatment tumour or the methods of cancer, including according to treatment needs, bestowing treatment to host has
At least one the compounds of this invention or its stereoisomer of effect amount, tautomer, pharmaceutically acceptable salt, solvation
Object or its prodrug.
Preferred embodiment is the various tumours for the treatment of or cancer.
Present invention provides the compounds or its stereoisomer, tautomer, drug for treatment
Acceptable salt, solvate or its prodrug.
Present invention provides the compound or its stereoisomers, tautomer, pharmaceutically acceptable salt, molten
Agent compound or its prodrug, are used to prepare the drug for the treatment of cancer.
These and other features of the invention will continue to explain in more detailed manner.
The present invention provides selected from compound of formula I a general formula compound or its stereoisomer or its drug on can
The salt of receiving or its solvate, as follows：
Wherein
R1-R3It is independent to be selected from hydrogen, deuterium, halogen ,-CN ,-C (O)-OEt ,-S-R0, substituted or unsubstituted C1-6Alkyl takes
Generation or unsubstituted C1-6Halogenated alkyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substitution or not
Substituted C3-10Naphthenic base, substituted or unsubstituted C6-10Aryl, the heteroatomic substitution or not in N, O and S containing 1-4
Substituted 5-10 circle heterocyclic rings, or contain 1-4 substituted or unsubstituted 5-10 unit's heteroaryls heteroatomic in N, O and S；
R0It is independent to be selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Halogenated alkyl, substitution or not
Substituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10It is naphthenic base, substituted or unsubstituted
C6-10Aryl is selected containing 1-4 substituted or unsubstituted 5-10 circle heterocyclic rings heteroatomic in N, O and S, or containing 1-4
The heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls from N, O and S.
Preferably, wherein described is substituted, refer to corresponding group by halogen, NH2、OH、C1-6Alkyl, C2-6Alkene
Base, C2-6Alkynyl, C3-10Naphthenic base, C6-10Aryl contains one in 1-4 5-10 unit's heteroaryls heteroatomic in N, O and S
It is a or multiple replaced.
Preferably, the aryl is selected from phenyl, naphthalene, anthryl or phenanthryl.
Preferably, the heteroaryl is selected from indolinyl, benzothiazolyl, Pyrazolopyridine base, benzisothia oxazolyl, three
Azoles and pyridyl group, indolizine and pyridyl group, benzoxazolyl, triazolo pyridyl, indolizine and pyridyl group, pyrido-pyrazine base, quinoline
Oxazoline base, pyrido-pyrazine base, Ben Bing oxadiazolyl, diazosulfide base, benzo indolizine base.
Preferably, following compounds are selected from：
The present invention also provides the preparation methods of the compound comprising following step：
Substitution benzazole and substitution mercaptan are prepared in oil bath pan reaction；
A kind of composition comprising above-mentioned as being subjected in I compounds represented or its stereoisomer or its drug
Salt or its solvate and pharmaceutically acceptable auxiliary agent, carrier or diluent.
Preferably, the dosage form of the composition be selected from plain piece, thin membrane coated tablet, sugar coated tablet, casing piece, dispersible tablet, capsule,
Granule, oral administration solution or oral administration mixed suspension.
It is described such as I compounds represented or its stereoisomer or its pharmaceutically acceptable salt or its solvate
Can be used for preparing treatment tumour or cancer drug, the tumour or cancer be gastric cancer, adenocarcinoma of the uterine cervix, colon cancer, lung cancer, liver cancer,
Glioma, cancer of the esophagus, intestinal cancer, nasopharyngeal carcinoma, breast cancer, lymph cancer, kidney, cancer of pancreas, carcinoma of urinary bladder, oophoroma, uterine cancer, bone
Cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, squamous carcinoma, cutaneum carcinoma, hemangioma, lipoma,
Cervical carcinoma and thyroid cancer.
Present invention provides prepare the compounds of this invention, its stereoisomer, tautomer, pharmaceutically acceptable
The method and intermediate of salt, solvate or prodrug.
Present invention provides the method for the treatment of tumour or cancer (or the compound of the present invention or its stereoisomers, mutually
Tautomeric, pharmaceutically acceptable salt, solvate or prodrug are used to prepare the purposes for treating these disease medicaments), including
According to treatment needs, at least one the compounds of this invention or its stereoisomer, the mutually variation of therapeutically effective amount are bestowed to host
Structure body, pharmaceutically acceptable salt, solvate or its prodrug.
Present invention provides the method for the treatment of disease (or the compound of the present invention or its stereoisomer, tautomerisms
Body, pharmaceutically acceptable salt, solvate or prodrug are used to prepare the purposes for treating these disease medicaments), including according to controlling
The compound of formula I for needing that therapeutically effective amount is bestowed to patient is treated, wherein the disease is gastric cancer, adenocarcinoma of the uterine cervix, colon cancer, lung
Cancer, liver cancer, glioma, cancer of the esophagus, intestinal cancer, nasopharyngeal carcinoma, breast cancer, lymph cancer, kidney, cancer of pancreas, carcinoma of urinary bladder, oophoroma, son
Palace cancer, osteocarcinoma, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, squamous carcinoma, cutaneum carcinoma, hemangioma,
Lipoma, cervical carcinoma and thyroid cancer.
Include the formula for needing to bestow therapeutically effective amount according to treatment to patient present invention provides the method for the treatment of disease
Compound I or its pharmaceutically acceptable salt, are used in combination with other therapeutic reagents.
Present invention provides the compound or its stereoisomers, tautomer, pharmaceutically acceptable salt, molten
Agent compound or prodrug are for treating.
In another specific implementation mode, compound of formula I is selected from the combination or herein of example compound or example compound
Other specific implementation modes.
In another specific implementation mode, present invention aims at including formula (I) compound and one or more activearms
The pharmaceutical composition divided.
The term " alkyl " used herein be include the branch and straight chain saturation alkane base with given number carbon atom.Such as
“C1-10Alkyl " (or alkylidene) purpose is C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl.In addition, such as " C1-6Alkane
Base " indicates the alkyl with 1 to 6 carbon atoms.Alkyl can be non-substituted or substitution, so that its one or more hydrogen atom quilt
Other chemical group substitutions.The embodiment of alkyl includes but not limited to methyl (Me), ethyl (Et), propyl (such as n-propyl and different
Propyl), butyl (such as normal-butyl, isobutyl group, tertiary butyl), amyl (such as n-pentyl, isopentyl, neopentyl) and the like.
" alkenyl " is both to have included the hydrocarbon of straight or branched structure, and appear in any stable point in chain with one or more
Carbon-to-carbon double bond.Such as " C2-6Alkenyl " (or alkenylene) purpose be include C2, C3, C4, C5 and C6 alkenyl.The example packet of alkenyl
Include but be not limited to vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyls, 3- cyclobutenyls, 2- pentenyls, 3- pentenyls, 4- amylenes
Base, 2- hexenyls, 3- hexenyls, 4- hexenyls, 5- hexenyls, 2- methyl -2- acrylic, 4- methyl-3-pentenyls and its class
Like object.
" alkynyl " is both to have included the hydrocarbon of straight or branched structure, and appear in any stable point in chain with one or more
Three key of carbon-to-carbon.Such as " C2-6Alkynyl " (or alkynylene) purpose be include C2, C3, C4, C5 and C6 alkynyl；Such as acetenyl, third
Alkynyl, butynyl, pentynyl, hexin base and the like.
When mentioning substituted alkenyl, alkynyl, alkylidene, alkenylene or alkynylene, these groups are with as described above one to three
The substituent group of a substitution alkyl.
The term " substituted " used herein refers to any one or more hydrogen atoms on specified atom or group
Replaced with the specified group of selection, on condition that no more than the general chemical valence of specified atom.When substituent group be oxygen or ketone (i.e.=
O), then 2 hydrogen atoms on atom are substituted.Ketone substituent group is not present in fragrant segment.If without other explanation, substitution
Base is named to division center.For example, it is to be understood that when (naphthenic base) alkyl is possible substituent group, the substituent group to center
The tie point of structure is in moieties.Ring double bond used herein is formed at two double bonds closed between annular atom
(such as C=C, C=N or N=N).
The combination of substituent group and/or variable is allowed, only when these combinations generate stable compound or useful synthesis
Intermediate.When stable compound or rock-steady structure implies that the compound is separated with useful purity from reaction mixture
It is sufficiently stable, prepares form effective therapeutic reagent therewith.Preferably, the compound does not include N- halogens, S at present
(O)2H or S (O) H bases.
Term " naphthenic base " refers to naphthenic base, including mono-, double-or polycyclic system.C3-7The purpose of naphthenic base be include C3,
C4, C5, C6 and C7 naphthenic base.Examples of cycloalkyl includes but not limited to cyclopropyl, goes back butyl, cyclopenta, cyclohexyl, norborny
And the like." carbocyclic ring " used herein or " carbocyclic ring is remaining " refers to any stablizing 3,4,5,6 or 7- unit monocycles or bicyclic
Or the first double or tricyclics of 7,8,9,10,11,12 or 13-, can be saturation, part unsaturation, insatiable hunger and/or armaticity.These carbon
Ring example includes but not limited to cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, pentenyl, cyclohexyl, cyclohexenyl group, cycloheptyl
Base, cycloheptenyl, adamantyl, cyclooctyl, cyclo-octene base, cyclo-octadiene, [3.3.0] double-octane, [4.3.0] bicyclic nonyl
Alkane, [4.4.0] bicyclic decane, [2.2.2] double-octane, fluorenyl, phenyl, naphthalene, indanyl, adamantyl, anthryl and tetrahydrochysene
Naphthalene (tetralin).As described above, bridged ring is also contained in the definition of carbocyclic ring (such as [2.2.2] double-octane).If not other
Illustrate, preferred carbocyclic ring is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and phenyl.When use term " carbocyclic ring ", it is therefore an objective to wrap
It includes " aryl ".There is bridged ring when one or more carbon atoms connect two non-carbon atoms that close on.Preferred bridge is one or two
Carbon atom.It is bicyclic to be pointed out that bridge always converts monocycle to.When ring is bridging, the substituent group of ring exists on bridge.
Term " aryl " is referred in monocycle or Bicyclic alkyl that loop section has 6 to 12 carbon atoms, such as phenyl
And naphthalene, it each can be substituted.
Term " halogen " or " halogen " refer to chlorine, bromine, fluorine and iodine.
Term " halogenated alkyl " refers to the substitution alkyl with one or more halogenic substituents.Such as " halogenated alkyl "
Including single, double and trifluoromethyl.
Term " heteroaryl " refer to substitution and non-substituted fragrant 5 or 6 unit monocycle group, 9- or 10- membered bicyclic groups, and
11 to 14 membered tricyclic groups have at least one hetero atom (O, S or N) at least one ring, described excellent containing heteroatomic ring
Choosing has 1,2 or 3 hetero atom in O, S and N.Each ring containing heteroatomic heteroaryl can contain one or two oxygen or
Sulphur atom and/or by 1 to 4 nitrogen-atoms, on condition that heteroatomic sum is 4 or less in each ring, and each ring is with extremely
A few carbon atom.Carbon atom can only be contained by completing bicyclic and three cyclic groups fused rings, and can be saturation, fractional saturation or
It is unsaturated.Nitrogen and sulphur atom can optionally be aoxidized and nitrogen-atoms can be optionally quaternized.Bicyclic or tricyclic heteroaryl must wrap
At least one full aromatic rings is included, the other fused rings of nitrogen can be armaticity or nonaromatic.Heteroaryl can be in any of any ring
Using being connected on nitrogen or carbon atom.When chemical valence allow, if other rings are naphthenic base or heterocycle, in addition optionally with
=O (oxygen) replaces.
Exemplary monocyclic heteroaryl includes pyrrole radicals, pyrazolyl, pyrazolinyl, imidazole radicals, oxazolyl, isoxazolyls, thiophene
Oxazolyl, thiadiazolyl group, furyl, thienyl, oxadiazolyls, pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, triazine radical and its class
Like object.
Exemplary bicyclic heteroaryl include indyl, benzothiazolyl, benzodioxole base, benzoxazolyl,
Benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base, benzo furan
It mutters base, chromone base, cumarin base, benzopyranyl, cinnoline base, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluorinated pyridine
Base, dihydro-iso indolyl, tetrahydric quinoline group and the like.
If without other explanations, the compound of the present invention is interpreted as including free state and its salt.Term " salt " indicate with
Inorganic and/or organic bronsted lowry acids and bases bronsted lowry forms acid and/or basic salt.In addition, " salt may include amphoteric ion (inner salt) to term, such as work as
Compound of formula I contains basic moiety such as amine or pyridine or imidazole ring and acid segment such as carboxylic acid.It is pharmaceutically acceptable (i.e. non-
It is toxicity, physiologically acceptable) salt is preferred, such as acceptable metal and amine salt, wherein cation does not have notable contribution
The bioactivity of toxicity or salt.However, other salt can be useful, isolated or purified step is used such as in preparation process, because
This is also contained in the scope of the invention.The salt of compound of formula I can be formed such as compound of formula I and a certain amount of acid or alkali, such as
Amount, in medium as salt wherein is precipitable or its it is water-borne in, then carry out lyophilization.
Illustrative acid addition salt include acetate (such as being formed with acetic acid or three halogen acetic acid, such as trifluoroacetic acid), oneself
Diacid salt, alginates, ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, borate, butyrate,
Citrate, camsilate, cipionate, double gluconates, lauryl sulfate, esilate, prolongs camphor hydrochlorate
Fumarate salt, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochloride (being formed with hydrochloric acid), hydrogen bromine
Hydrochlorate (being formed with hydrobromic acid), hydriodate, 2- isethionates, lactate, maleate (being formed with maleic acid), methylsulphur
Hydrochlorate (being formed with methanesulfonic acid), 2- naphthalene sulfonates, nicotinate, nitrate, oxalates, pectate, persulfate, 3- phenyl third
Hydrochlorate, phosphate, picrate, Pivalate, propionate, salicylate, succinate, sulfate with sulfuric acid (as formed
Those), sulfonate those of (as referenced herein), tartrate, rhodanate, toluene fulfonate such as toluene fulfonate, 11
Hydrochlorate and the like.
Exemplary basic salts include ammonium salt, alkali metal salt such as sodium, lithium and sylvite；Alkali salt such as calcium and magnesium salts；Barium, zinc
And aluminium salt；The salt (such as organic amine) such as trialkylamine such as triethylamine, procaine, dibenzylamine, N- benzyls-β-formed with organic base
Phenyl ethylamine, 1- ephenamines, N, the bis- benzyl ethylenediamines of N '-, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexyl amine or similar medicine
Acceptable amine and with the salt such as arginine, lysine of amino acid and the like on object.Basic nitrogenous group can be with reagent season
Ammonium such as elementary alkyl halide (such as methyl, ethyl, propyl and butyl chloride, bromine and iodide), dialkyl sulfate (such as diformazan
Base, diethyl, dibutyl and diamyl sulfate), long chain halide (such as decyl, dodecyl, myristyl and octadecyl
Chlorine, bromine and iodide), aralkyl halide (such as benzyl and phenylethyl bromide) and other materials.Preferred salt includes mono-salt
Hydrochlorate, disulfate, mesylate, phosphate or nitrate.
Phrase " pharmaceutically acceptable " refers to those compounds, material, composition and/or dosage form, in intact doctor
Treat range of value in, contacted suitable for the tissue with human and animal, without additional toxicity, stimulation, allergic reaction or
Other problems or complication have the reasonable benefit/risk ratio to match.
" the pharmaceutically acceptable salt " used herein refers to the derivative of open compound, wherein paternal compound is
With acid or the modification of its basic salt.The example of drug acceptable salt includes but not limited to the inorganic or organic acid of alkali formula group such as amine
Formula salt；With the alkali or organic salt of acidic groups such as carboxylic acid.Pharmaceutically acceptable salt includes traditional non-toxic salt or paternal lineization
It closes object and forms quaternary ammonium salt, such as by non-toxic inorganic or organic acid.For example, these traditional non-toxic salts, which include those, is derived from nothing
Machine acid such as hydrochloric acid, hydrobromic acid, thiosulfonic acid, sulfamic acid, phosphoric acid and nitric acid；With salt such as acetic acid, propionic acid, the amber prepared by organic acid
Amber acid, hydroxyacetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pa not acid, maleic acid, hydroxyl horse
Come sour, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- ethoxies benzoic acid, fumaric acid, toluenesulfonic acid, first
Sulfonic acid, ethane disulfonic acid, oxalic acid and isethionic acid and the like.
The pharmaceutically acceptable salt of the present invention can pass through conventional chemical by the paternal compound containing alkali formula or acid segment
Method synthesizes.Normally, these salt can be by the free acid or alkali form of these compounds and the suitable alkali or acid of stoichiometric ratio
It is prepared in water or organic solvent or its two kinds of mixtures；Normally, it is non-it is water-borne such as ether, it is ethyl acetate, ethyl alcohol, different
Propyl alcohol or acetonitrile are preferred.
All stereoisomers of the compounds of this invention be it is considered, both by mixture or it is pure or substantially pure in the form of.
Stereoisomer may include the compound of the substituted optical isomer by one or more chiral atoms, and pass through limitation
The optical isomer compound of the one or more keys (atropisomer) of rotation.The definition of the compounds of this invention includes being possible to
Stereoisomer and its mixture.It especially including racemic form and has especially active separating optical isomers.Pass through
Physical method resolution of racemic form, such as fractional crystallisation, separation or the crystallization of alloisomerism derivative or pass through chiral column color
Spectrum separation.The salt that independent optical isomer is such as formed with optically active acid is obtained by racemic salt by conventional method, so
After crystallize.
The prodrug and solvate of the compounds of this invention are also considered.Term " prodrug " indicates compound, based on applying
Receptor is given, compound of formula I and/or salt and/or its solvate are generated by metabolic or chemical method experience chemical reaction.
Convert in vivo with any compound that bioactive agents (i.e. compound of formula I) are provided be in scope and spirit of the present invention before
Medicine.For example, the compound containing carboxyl can form the physiology hydrolyzable ester as prodrug, by hydrolyzing production I in vivo
Combound itself.The preferred oral administration of these prodrugs, under the influence of appearing in digestive ferment substantially due to the hydrolysis under the conditions of many.
Usable parenteral is bestowed, and ester itself is active, and in those examples, hydrolysis appears in blood.The physiology of compound of formula I
It includes C to learn hydrolysis ester example1-6Alkyl benzyl, 4- methoxy-benzyls, indanyl, phthalyl, methoxy, C1-6Chain
Alkanoyloxy-C1-6Alkyl such as acetyl-o-methyl, pivaloyloxymethyl or the third oxygen methyl, C1-6Alkyl oxy carbonyl oxygen-C1-6Alkyl, such as
Methoxycarbonyl group-oxygen methyl or ethyoxyl carbonyl oxygen methyl, glycyl oxygen methyl, hydroxyphenylglycyl oxygen methyl, (oxygen -1 5- methyl -2-,
3- Dioxol-4 -yls)-methyl and other well known physiology hydrolysis esters used, such as in penicillin and
In the fields cephalogensporin.These esters can be prepared by routine techniques well known in the prior art.Diversified forms
Prodrug be in the prior art known to.
" pharmaceutically acceptable carrier " generally referred to as usually receives in this field, can transmit bioactive agents
To animal, especially mammal.Acceptable carriers on compounding pharmaceutical, according to many well known to those of ordinary skill in the art
Factor.These include that there is no limit the types and characteristic for the active agent being formulated；The receptor bestowed containing reagent composition；Combination
Object bestows approach；It is indicated with targeted therapy.Pharmaceutically acceptable carrier includes aqueous and nonaqueous liquid medium and a variety of
Solid-state and semisolid dosage form.These carriers include many different components and additive, other than active agent, these additional sets
Point be contained in formula due to many reasons, such as active agent, adhesive stability, this is those of ordinary skill in the art
Known.
Any suitable mode that formula Compound I can treat symptom is bestowed, and is depended on site-specific and is treated or pass
The amount of drug delivery.The generally preferable skin related disease of topical administration, the systemic treatment of carcinous or carcinous preceding symptom, but other biographies
The pattern of passing is also to consider.Such as oral administration of Compound, such as with tablet, capsule, particle, powder or including the liquid of syrup
Form of formulations；Part is such as with solution, suspension, gel or ointment；Sublingual administration；Cheek；Parenteral such as by it is subcutaneous,
Intravenous injection, intramuscular injection or breastbone inner injection or perfusion art (such as sterile water or non-aqueous solution or suspension)；Intranasal as logical
Cross sucking spraying；Locally such as with lotion or ointment；Rectally such as with suppository form；Or liposome.It can bestow and contain
The dosage unit formulations of excipient or diluent are subjected in non-toxic, drug.It can release immediately or delay the form of release
Bestow the compound.Release immediately or delay the pharmaceutical composition that release can be suitble to obtain, in the reality of portion retards release
In example, equipment such as subcutaneous transplantation or osmotic pumps are used.
The exemplary composition of oral administration includes suspension, contains the microcrystalline cellulose being such as used for transmission, conduct
The alginic acid or sodium alginate of suspending agent, the methylcellulose as viscosity intensifier and those sweet tastes well known in the prior art
Agent or flavoring agent；The tablet released immediately can contain such as microcrystalline cellulose, di(2-ethylhexyl)phosphate calcium salt, starch, magnesium stearate and/or lactose
And/or other excipient, adhesive, swelling agent, disintegrant, diluent and lubricant it is as be known in the art those.This
Invention compound can also bestow carry out oral delivery by sublingual and/or cheek, such as pressing mold, compression or freeze-drying tablet.It is exemplary
Composition may include rapidly-soluble diluent such as mannitol, lactose, sucrose and/or cyclodextrin.Including in these formulations
It can also be high molecular weight excipients such as celluloseOr macrogol (PEG)；The figuration for contributing to mucous membrane to adhere to
Agent such as hydroxypropyl cellulose (HPC), hypromellose (HPMC), sodium carboxymethylcellulose (SCMC) and/or maleic anhydride
Copolymer is (such as)；The reagent such as acrylic copolymer discharged with control is (such as).
Lubricant, glidant, fragrance, colorant and stabilizer, which can be added, to be helped to prepare and use.
The exemplary composition that spray-on process or sucking are bestowed includes solution, and the solution can contain benzyl alcohol or other suitable
Preservative, the sorbefacient for improving absorbability and/or bioactivity, and/or other soluble or dispersible agents are for example existing
It is those of known in technology.
The exemplary composition of parenteral administration includes injection solution or suspension, containing as suitable non-toxic,
Stomach is subjected to diluent or solvent, as mannitol, 1,3-BDO, water, Ge Linshi solution, isotonic sodium chlorrde solution or its
Its suitable dispersion or wetting and flotation reagents, including the list of synthesis or di-glycerides and aliphatic acid include oleic acid.
The exemplary composition of rectally includes suppository, can be contained such as suitable non-irritating excipient, as cocoa butter,
Synthetic glycerine esters or macrogol class are at normal temperatures solid, but dissolve and/or dissolve in and discharge drug in stomach.
The compounds of this invention of therapeutically effective amount can be determined by those of ordinary skill in the art, and be wrapped for mammal
Exemplary dose is included about from 0.05 to 1000mg/kg；1-1000mg/kg；1-50mg/kg；5-250mg/kg；250-1000mg/
Kg can be bestowed according to reactive compound amount per kg body weight per day by single dose or in the form of individual separate doses,
As daily from 1 to 4 times.Depend on it is understood that disease can be changed in the special dosage level and medicament frequency for special receptor
In many factors, including use special compound activity, the compound metabolism stability and action length, race, the age,
Weight, general health, receptor gender and diet bestow pattern and time, discharge rate, pharmaceutical composition and special disease
Severity.Preferred receptor for treatment includes animal, most preferably lactation the race such as mankind and poultry animal such as dog, cat, horse
And the like.
Embodiment
Below by embodiment, the invention will be further described.It should be understood that the method for the embodiment of the present invention
It is only used for illustrating the present invention, rather than limiting the invention, to preparation side of the invention under the concept thereof of the present invention
The simple modifications of method belong to the scope of protection of present invention.All raw materials and solvent used in embodiment are purchased from
Sigma Biochemical and Organic Compounds for Research and Diagnostic Clinical
Reagents companies.
Embodiment 1：2- phenyl -3- (propyl thioether) indolizine (yield 84%)
A stirrer is added in the test tube of 25mL, adds 0.4mmol 2- phenyl indolizine (1a), 0.2mmol third
Mercaptan (2a), 0.04mmol HOAc, 0.01mmol CuI, 0.4mmol TBHP, 2mL DMSO.Reaction is placed in 60 DEG C of oil cauldrons and stirs
Reaction is mixed, monitor reaction by thin layer chromatography board stops reacting completely until 1a is consumed.Then by reaction mixture second
Acetoacetic ester and water dilution, extraction take ethyl acetate layer.Organic layer is washed with brine, through Mg2SO4It is dry, it is evaporated under reduced pressure.It is thick mixed
Object is closed to purify by thin-layer chromatography silica gel plate.
44.9mg.IR(KBr)：3048,2965,1609,756,712cm-1；1H NMR (400MHz, CDCl3) δ 8.53 (d,
J=7.2Hz, 1H), 7.84 (d, J=9.6Hz, 2H), 7.45 (t, J=7.6Hz, 2H), 7.40 (d, J=8.8Hz, 1H), 7.34
(t, J=7.2Hz, 1H), 6.84-6.80 (m, 1H), 6.69 (s, 1H), 6.67-6.63 (m, 1H), 2.56-2.51 (m, 2H),
1.42-1.35 (m, 2H), 0.83 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 135.8,135.4,134.9,
129.1,128.1,126.7,123.8,118.8,118.7,110.7,109.3,99.7,37.7,22.8,13.1.ESI-MS m/
Z (%) 267 (100) [M+H]+；Anal.Calcd for C17H17NS C, 76.36；H, 6.41；N, 5.24；Found：C,
76.48；H, 6.43；N, 5.22.
With the preparation method similar to embodiment 1, only following compound are prepared with different raw materials
Embodiment 2：3- (ethyl sulfide) -2- phenyl indolizine (yield 86%)
43.5mg.IR(KBr)：3047,2897,1608,774,708cm-1；1H NMR (400MHz, CDCl3) δ 8.55 (d,
J=7.2Hz, 1H), 7.86 (d, J=8.0Hz, 2H), 7.46 (t, J=6.8Hz, 2H), 7.41 (d, J=8.8Hz, 1H), 7.35
(t, J=6.8Hz, 1H), 6.85-6.79 (m, 1H), 6.71 (s, 1H), 6.65 (t, J=6.8Hz, 1H), 2.61 (q, J=
7.2Hz, 2H), 1.05 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 135.8,135.5,134.9,129.1,
128.1,126.7,123.9,118.9,118.7,110.7,109.0,99.7,29.8,14.6.ESI-MS m/z (%) 253
(100)[M+H]+；Anal.Calcd for C16H15NS C, 75.85；H, 5.97；N, 5.53；Found：C, 75.67；H, 5.98；
N, 5.52.
Embodiment 3：3- (butyl thioether) -2- phenyl indolizine (yield 76%)
42.7mg.IR(KBr)：3077,2880,1588,786,719cm-1；1H NMR (400MHz, CDCl3) δ 8.53 (d,
J=7.2Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.45 (t, J=7.6Hz, 2H), 7.40 (d, J=8.8Hz, 1H), 7.34
(t, J=6.8Hz, 1H), 6.87-6.77 (m, 1H), 6.69 (s, 1H), 6.65 (t, J=7.2Hz, 1H), 2.56 (t, J=
7.2Hz, 2H), 1.36-1.30 (m, 2H), 1.26 (dd, J=14.8,7.2Hz, 2H), 0.74 (t, J=7.2Hz, 3H)13C
NMR (100MHz, CDCl3) δ 135.8,135.4,134.9,129.1,128.1,126.7,123.8,118.8,118.7,
110.7,109.3,99.7,35.4,31.3,21.6,13.5.ESI-MS m/z (%) 281 (100) [M+H]+；Anal.Calcd
for C18H19NS C, 76.82；H, 6.81；N, 4.98；Found：C, 76.97；H, 6.83；N, 4.99.
Embodiment 4：3- (isopropyl thioether) -2- phenyl indolizine (yield 60%)
32.1mg.IR(KBr)：3031,2904,1507,753,689cm-1；1H NMR (400MHz, CDCl3) δ 8.57 (d,
J=7.2Hz, 1H), 7.85 (d, J=9.6Hz, 2H), 7.43 (t, J=6.8Hz, 2H), 7.38 (d, J=8.8Hz, 1H), 7.32
(t, J=7.6Hz, 1H), 6.83-6.78 (m, 1H), 6.69 (s, 1H), 6.62 (t, J=6.8Hz, 1H), 3.04 (m, 1H),
1.05 (d, J=6.8Hz, 6H)13C NMR (100MHz, CDCl3) δ 136.0,135.8,135.0,129.2,128.1,126.6,
124.1,118.9,118.6,110.5,109.2,99.8,40.4,23.0,23.0.ESI-MS m/z (%), 267 (100) [M+H
]+；Anal.Calcd for C17H17NS C, 76.36；H, 6.41；N, 5.24；Found：C, 76.49；H, 6.40；N, 5.23.
Embodiment 5：3- (benzyl thioether) -2- phenyl indolizine (yield 41%)
25.8mg.IR(KBr)：3073,2952,1603,786,707cm-1；1H NMR (400MHz, CDCl3) δ 8.24 (d,
J=7.2Hz, 1H), 7.71 (d, J=7.6Hz, 2H), 7.41 (t, J=7.2Hz, 2H), 7.34 (t, J=8.8Hz, 2H), 7.09
(d, J=6.4Hz, 3H), 6.90 (d, J=7.2Hz, 2H), 6.79-6.73 (m, 1H), 6.65 (s, 1H), 6.48 (t, J=
6.8Hz, 1H), 3.73 (s, 2H)13C NMR (100MHz, CDCl3) δ 137.5,135.9,135.6,135.1,129.0,
128.7,128.2,128.1,126.9,126.7,123.7,119.1,118.5,110.5,108.3,99.8,40.5.ESI-MS
M/z (%) 315 (100) [M+H]+；Anal.Calcd for C21H17NS C, 79.96；H, 5.43；N, 4.44；Found：C,
79.84；H, 5.44；N, 4.43.
Embodiment 6：3- ((4- fluorophenyls) thioether) -2- phenyl indolizine (yield 48%)
30.6mg.IR(KBr)：3047,2973,1603,846,775,713cm-1；1H NMR (400MHz, CDCl3)δ
8.25 (d, J=7.6Hz, 1H), 7.73 (d, J=8.0Hz, 2H), 7.48 (d, J=8.8Hz, 1H), 7.42 (t, J=7.6Hz,
2H), 7.33 (t, J=6.8Hz, 1H), 6.93-6.86 (m, 5H), 6.81 (s, 1H), 6.62 (t, J=6.8Hz, 1H)13C NMR
(100MHz, CDCl3) δ 162.3 (J=243.1Hz), 136.9,135.9,135.0,132.1 (J=3.0Hz), 130.5,
128.9,128.3,127.2,126.9 (J=7.8Hz), 119.9,118.8,116.4 (J=22.1Hz), 111.4,104.8,
100.2.ESI-MS m/z (%) 319 (100) [M+H]+；Anal.Calcd for C20H14FNS C, 75.21；H, 4.42；N,
4.39；Found：C, 75.42；H, 4.41；N, 4.38.
Embodiment 7：3- (propyl thioether) -2- (p- tolyls) indolizine (yield 73%)
41.0mg.IR(KBr)：3073,2952,1603,1484,842cm-1；1H NMR (400MHz, CDCl3)δ8.49
(d, J=6.0Hz, 1H), 7.77-7.68 (m, 2H), 7.39-7.32 (m, 1H), 7.26-7.22 (m, 2H), 6.81-6.73 (m,
1H), 6.67-6.57 (m, 2H), 2.55-2.48 (m, 2H), 2.41 (s, 3H), 1.42-1.34 (m, 2H), 0.85-0.78 (m,
3H).13C NMR (100MHz, CDCl3) δ 136.3,135.3,134.8,132.8,128.9,128.9,123.8,118.7,
118.6,110.5,109.1,99.5,37.7,22.8,21.2,13.2.ESI-MS m/z (%) 281 (100) [M+H]+；
Anal.Calcd for C18H19NS C, 76.82；H, 6.81；N, 4.98；Found：C, 76.64；H, 6.83；N, 4.99.
Embodiment 8：2- (4- methoxyphenyls) -3- (propyl thioether) indolizine (yield 93%)
55.24mg.IR(KBr)：3083,2942,1603,1434,837cm-1；1H NMR (400MHz, CDCl3)δ8.55
(d, J=8.0Hz, 1H), 7.47 (d, J=20.0Hz, 2H), 7.42-7.36 (m, 2H), 6.92 (d, J=8.8Hz, 1H),
6.86-6.80 (m, 1H), 6.71 (s, 1H), 6.65 (t, J=6.8Hz, 1H), 3.91 (s, 3H), 2.57 (t, J=7.2Hz,
2H), 1.41 (dt, J=14.4,7.2Hz, 2H), 0.86 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 159.3,
137.1,135.0,134.8,129.0,123.8,121.5,118.8,118.7,114.5,112.3,110.7,109.3,99.7,
55.2,37.7,22.8,13.2.ESI-MS m/z (%) 297 (100) [M+H]+；Anal.Calcd for C18H19NOS C,
72.69；H, 6.44；N, 4.71；Found：C, 72.56；H, 6.43；N, 4.73.
Embodiment 9：4- (3- (propyl thioether) indolizine -2- bases) cyanophenyl (yield 88%)
51.4mg.IR(KBr)：3045,2897,2247,1606,833cm-1；1H NMR (400MHz, CDCl3)δ8.50
(d, J=8.0Hz, 1H), 7.96 (d, J=8.4Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 7.40 (d, J=8.8Hz, 1H),
6.88-6.79 (m, 1H), 6.73-6.61 (m, 2H), 2.55-2.46 (m, 2H), 1.34 (q, J=7.2Hz, 2H), 0.81 (t, J
=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 140.5,135.1,133.0,131.9,129.3,123.8,119.4,
119.2,118.9,111.4,109.9,99.6,37.6,22.7,13.0.ESI-MS m/z (%) 292 (100) [M+H]+；
Anal.Calcd for C18H16N2S C, 73.94；H, 5.52；N, 9.58；Found：C, 73.67；H, 5.51；N, 9.54.
Embodiment 10：2- (4- fluorophenyls) -3- (propyl thioether) indolizine (yield 87%)
49.6mg.IR(KBr)：3033,2957,1583,1491,836cm-1；1H NMR (400MHz, CDCl3)δ8.53
(d, J=8.0Hz, 1H), 7.86-7.77 (m, 2H), 7.40 (d, J=8.8Hz, 1H), 7.18-7.12 (m, 2H), 6.85-6.80
(m, 1H), 6.66 (t, J=7.6Hz, 2H), 2.53 (t, J=7.2Hz, 2H), 1.39 (dt, J=14.4,7.2Hz, 2H), 0.84
(t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 163.2 (J=244.2Hz), 134.9 (J=44.7Hz), 131.8
(J=3.2Hz), 130.6 (J=7.7Hz), 123.8,118.9 (J=22.7Hz), 115.1 (J=21.1Hz), 110.8,
109.1,99.5,37.6,22.7,13.1.ESI-MS m/z (%) 285 (100) [M+H]+；Anal.Calcd for C17H16FNS
C, 71.55；H, 5.65；N, 4.91；Found：C, 71.36；H, 5.66；N, 4.92.
Embodiment 11：2- (4- nitrobenzophenones) -3- (propyl thioether) indolizine (yield 52%)
32.4mg.IR(KBr)：3056,2893,1592,1463,848cm-1；1H NMR (400MHz, CDCl3)δ8.51
(d, J=8.0Hz, 1H), 8.27 (d, J=8.8Hz, 2H), 8.02 (d, J=9.2Hz, 2H), 7.41 (d, J=8.8Hz, 1H),
6.90-6.81 (m, 1H), 6.72 (s, 1H), 6.68 (d, J=7.2Hz, 1H), 2.57-2.49 (m, 2H), 1.35 (q, J=
7.2Hz, 2H), 0.81 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 146.3,142.7,135.2,132.6,
129.4,123.9,123.5,119.6,119.1,111.6,110.2,99.8,37.7,22.7,13.1.ESI-MS m/z (%)
312(100)[M+H]+；Anal.Calcd for C17H16N2O2S C, 65.36；H, 5.16；N, 8.97；Found：C, 65.60；
H, 5.17；N, 8.99.
Embodiment 12：2- (3,4- dichlorophenyl) -3- (propyl thioether) indolizine (yield 87%)
58.5mg.IR(KBr)：3075,2946,1611,1481,764cm-1；1H NMR (400MHz, CDCl3)δ8.51
(d, J=8.0Hz, 1H), 7.99 (d, J=2.0Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.49 (d, J=8.4Hz, 1H),
7.38 (d, J=8.8Hz, 1H), 6.87-6.80 (m, 1H), 6.70-6.62 (m, 2H), 2.59-2.48 (m, 2H), 1.43-1.35
(m, 2H), 0.86 (t, J=7.2Hz, 3H)13C NMR (100MHz, CDCl3) δ 135.9,134.9,132.5,132.0,
130.5,130.0,128.1,123.8,119.2,118.8,111.1,109.5,99.4,37.7,22.8,13.1.ESI-MS m/
Z (%) 336 (100) [M+H]+；Anal.Calcd for C17H15Cl2NS C, 60.72；H, 4.50；N, 4.17；Found：C,
60.53；H, 4.51；N, 4.19.
Toxicity test：
Healthy Kunming mouse is selected, is provided by Guangdong pharmaceutical university experimental center.Mouse feeder in non-toxic plastic box,
It is female, male to divide cage per 5, box, 1 bedding and padding is changed daily, freely ingests and drinks water, and room temperature is kept for 18-20 DEG C, natural lighting.Drug
It is dissolved with 0.9% sodium-chloride water solution, tested material dosage is indicated with mg/kg.By following dosage intraperitoneal injection, volume is administered
For 0.1mL/10g, it is administered according to following dosage：50、100、150、200、300mg/kg.Animal is observed and recorded after administration daily
Appearance, spirit, diet, sleep, activity condition and dead distribution day by day, are observed continuously 10 days, LD50 are calculated by Bliss methods.
After the administration of high concentration group, mouse is apathetic, and dead preceding excrement is shapeless, becomes thin, erects hair, atrophy of uniting is motionless.
As can be seen from the above table, compound of formula I of the invention has low toxicity.
Inhibiting effect of the compound of formula I to tumour cell：
Logarithmic growth phase cell, digestion count, and are inoculated in 96 well culture plates, per 100 μ L of hole.After culture for 24 hours, with
Various concentration compound handles tumour cell.After drug effect 72h, supernatant is removed, 100 μ L MTT (1mg/mL) are added per hole, after
Continuous culture 4h, abandons supernatant, 100 μ L DMSO is added per hole, vibrate mixing, absorbance value is measured at 570nm with microplate reader.Meter
Calculate inhibiting rate.Calculation formula：Inhibiting rate (%)=(control group absorbance value-administration group absorbance value)/(control group absorbance
Value-blank group absorbance value) × 100%.Using IC50Software for calculation (China Medicine University) finds out half-inhibition concentration
(IC50).The unit of data is a μm ol/L in table.
Experimental tumor strain includes gastric carcinoma cells BGC, people's adenocarcinoma of the uterine cervix cell HeLa, human colon cancer cell HCT116, people
Human umbilical vein endothelial cell, human lung carcinoma cell NCI-H460, Human Prostate Cancer Cells DU-145, human breast cancer cell MDA-MB-
231.Cell is purchased from Guangdong Province's Culture Collection cell bank.The experimental results are shown inthe following table.
Claims (9)
1. a kind of compound shown in formula I or its stereoisomer or its pharmaceutically acceptable salt or its solvate,
It is characterized in that as follows：
Wherein
R1-R3It is independent to be selected from hydrogen, deuterium, halogen ,-S-R0, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6Halogen
Substituted alkyl, substituted or unsubstituted C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Naphthenic base,
Substituted or unsubstituted C6-10Aryl contains 1-4 substituted or unsubstituted 5-10 circle heterocyclic rings heteroatomic in N, O and S,
Or contain 1-4 substituted or unsubstituted 5-10 unit's heteroaryls heteroatomic in N, O and S；
R0It is independent to be selected from substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C1-6It is halogenated alkyl, substituted or unsubstituted
C2-6Alkenyl, substituted or unsubstituted C2-6Alkynyl, substituted or unsubstituted C3-10Naphthenic base, substituted or unsubstituted C6-10Aryl,
Containing 1-4 substituted or unsubstituted 5-10 circle heterocyclic rings heteroatomic in N, O and S, or containing 1-4 in N, O and S
Heteroatomic substituted or unsubstituted 5-10 unit's heteroaryls.
2. compound according to claim 1 or its stereoisomer or its pharmaceutically acceptable salt or its solvation
Object, it is characterised in that：Wherein described is substituted, refers to corresponding group by halogen, NH2、OH、C1-6Alkyl, C2-6Alkenyl,
C2-6Alkynyl, C3-10Naphthenic base, C6-10Aryl contains one in 1-4 5-10 unit's heteroaryls heteroatomic in N, O and S
Or multiple replaced.
3. compound according to claim 1 or 2 or its stereoisomer or its pharmaceutically acceptable salt or its is molten
Agent compound, it is characterised in that：The aryl is selected from phenyl, naphthalene, anthryl or phenanthryl.
4. compound according to claim 1 or 2 or its stereoisomer or its pharmaceutically acceptable salt or its is molten
Agent compound, it is characterised in that：The heteroaryl is selected from indolinyl, benzothiazolyl, Pyrazolopyridine base, benzisothiazole
Base, triazolo pyridyl, indolizine and pyridyl group, benzoxazolyl, triazolo pyridyl, indolizine and pyridyl group, pyrido-pyrazine
Base, quinazolyl, pyrido-pyrazine base, Ben Bing oxadiazolyl, diazosulfide base, benzo indolizine base.
5. compound according to claim 1 or 2 or its stereoisomer or its pharmaceutically acceptable salt or its is molten
Agent compound, it is characterised in that be selected from following compounds：
6. the preparation method of any compounds of claim 1-5, it is characterised in that include the following steps：
Substitution indolizine and substitution mercaptan are prepared in oil bath pan reaction.
7. a kind of composition, it is characterised in that including any described such as the I compounds represented of claim 1-5 or it is three-dimensional
Isomers or its pharmaceutically acceptable salt or its solvate and pharmaceutically acceptable auxiliary agent, carrier or diluent.
8. composition according to claim 7, it is characterised in that：Its dosage form be selected from plain piece, thin membrane coated tablet, sugar coated tablet,
Casing piece, dispersible tablet, capsule, granule, oral administration solution or oral administration mixed suspension.
9.1-6 any described such as I compounds represented or its stereoisomer or its pharmaceutically acceptable salt or its is molten
Agent compound is used to prepare treatment tumour or the purposes of cancer drug, the tumour or cancer be gastric cancer, adenocarcinoma of the uterine cervix, colon cancer,
Lung cancer, liver cancer, glioma, cancer of the esophagus, intestinal cancer, nasopharyngeal carcinoma, breast cancer, lymph cancer, kidney, cancer of pancreas, carcinoma of urinary bladder, oophoroma,
Uterine cancer, osteocarcinoma, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngocarcinoma, leukemia, prostate cancer, brain tumor, squamous carcinoma, cutaneum carcinoma, blood vessel
Tumor, lipoma, cervical carcinoma and thyroid cancer.
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| Title |
|---|
| COLONNA, MARTINO等: "Electron-transfer processes. Trans-sulfenylation of electron-rich systems with sulfonamides", 《GAZZETTA CHIMICA ITALIANA》 * |
| LI, BIN 等: "Transition-Metal-Free Regioselective Cross-Coupling: Controlled Synthesis of Mono- or Dithiolation Indolizines", 《ORG. LETT.》 * |
| MIREK, JULIAN 等: "The reaction of indolizines and acetylindolizines with trifluoromethylsulfenyl chloride", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
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