CN109553589A - A kind of synthetic method preparing natural products Kanamienamide and its derivative - Google Patents
A kind of synthetic method preparing natural products Kanamienamide and its derivative Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
Abstract
The present invention relates to the derivatives of natural products Kanamienamide shown in formula (I), and/or its pharmaceutically acceptable salt, and/or its stereoisomer, and/or its solvate and its synthetic method, it further include the pharmaceutical composition containing formula (I) compound and their purposes in the preparation of antitumor drugs.
Description
Technical field
The invention belongs to organic synthesis and field of pharmaceutical chemistry technology, be related to natural products Kanamienamide and its
The application of the synthetic route of derivative and such compound in anticancer drug.
Background technique
In new drug development, the importance of natural products is just gradually highlighted.Between 1981-2010,1073 small point is shared
Sub- drug is granted.Wherein, although 66% drug be it is fully synthetic obtain, wherein 16% include natural products source medicine
Effect group, there are also 14% analogies from natural products, therefore only 36% drug is unrelated with natural products.Except 66%
Outside synthetic drug, in addition 34% drug is entirely from natural products or the natural products of modification.
Ocean cyanobacteria is the source of a kind of very important biologically active secondary metabolite, is especially being made
Medicine field.Nature has antitumor, anti-inflammatory and antibacterial activity ocean cyanobacteria with a variety of.Its metabolite quilt at present
It studies extensively and is applied to antitumor clinical research2。
2016, chemist's isolated natural products from marine cyanobacterium Moorea bouillonii
Kanamienamide, and pass through nuclear-magnetism, mass spectrum, monocrystalline has determined its structure.Kanamienamide is a kind of structure novel
Ring type polypeptide class natural products.It is presently found first natural products with enamine structure.It is anti-swollen by screening it
Tumor activity discovery, Kanamienamide have very strong anti-tumor activity.It has preferable growth inhibition to Hela cell
Activity, IC50=2.5Um, and have the function of inducing cell apoptosis.In view of its unique chemical structure, good life
Object activity.We have carried out fully synthetic research for the first time to it, and are explored to its structure-activity relationship.
Summary of the invention
The present invention has multiple embodiments, and an embodiment of the invention provides change shown at least one Formulas I
Object and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its solvate are closed,
Wherein:
R1It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Heteroaryl
Base, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle be it is unsubstituted or
Hydrogen, halogen, C are optionally independently selected from by one or more1-6Alkyl, C1-6The group of alkoxy, hydroxyl and halogenated alkyl replaces；
R2It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Heteroaryl
Base, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle be it is unsubstituted or
Hydrogen, halogen, C are optionally independently selected from by one or more1-6Alkyl, C1-6The group of alkoxy, hydroxyl and halogenated alkyl replaces；
R3It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Aralkyl
Base, C6-14Heteroaryl, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle is not
It is substituted or optional hydrogen, halogen, C are independently selected from by one or more1-6Alkyl, C1-6Alkoxy, hydroxyl and alkyl halide
The group of base replaces；
R4It is independently selected from hydrogen, C1-6Alkyl, C3-8Naphthenic base, hydroxyl, C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle；
R5It is independently selected from hydrogen, C1-6Alkyl, C3-8Naphthenic base, hydroxyl, C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle；
R6It is independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C6-14Aryl, C6-14Heteroaryl, C4-14Heterocycle
Base, alkenyl and halogenated alkyl；
R7It is independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C6-14Aryl, C6-14Heteroaryl, C4-14Heterocycle
Base, alkenyl and halogenated alkyl；
L1And L2It is independently selected from C1-6Alkylidene, C3-8Cycloalkylidene, C6-14Arlydene, C6-14Sub- heterocycle；
M, n are independently selected from 1,2,3,4,5 and 6.
In another embodiment, provides and a kind of pharmaceutical composition is provided, it includes at least one formula (I) compounds, and/
Or its pharmaceutically acceptable salt and/or its stereoisomer and/or its solvate and one or more pharmaceutical carriers
And/or pharmaceutical preparation made of diluent, it is pharmaceutically acceptable any dosage form.
In another embodiment, a kind of pharmaceutical composition is provided, at least one compound comprising claim 1-11,
And/or its pharmaceutically acceptable salt and/or stereoisomer and/or its solvate, and at least one can pharmaceutically connect
The carrier received.
In another embodiment, a kind of pharmaceutically acceptable dosage form is provided, it includes at least one formula (I) compound,
And/or its pharmaceutically acceptable salt and/or its stereoisomer and/or its solvate and one or more medicinal loads
Body and/or diluent.
In another embodiment, provide a kind of by least one formula (I) compound and/or its is pharmaceutically acceptable
Salt and/or its stereoisomer and/or its solvate are used to manufacture the purposes of anti-tumor drug.
Term definition
To keep the purposes, technical schemes and advantages of embodiment clearer, the technical solution of embodiment is carried out below clear
Chu is fully described by.Obviously, described embodiment is a part of the embodiments of the present invention, instead of all the embodiments.
Based on described the embodiment of the present invention, those of ordinary skill in the art are obtained under the premise of being not necessarily to creative work
Every other embodiment, shall fall within the protection scope of the present invention.
" halogen " includes fluorine atom, chlorine atom, bromine atom and iodine atom.
" alkyl " refers to that the paraffin section containing 1-18 carbon atom removes linear chain or branched chain derived from a hydrogen atom
Alkyl, the example includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary fourth
Base, n-pentyl, isopentyl, 2- methyl butyl, 3- methyl butyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, neopentyl,
1- ethyl propyl, n-hexyl, isohesyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 1,1- dimethylbutyl, 1,
2- dimethylbutyl, 1,3- dimethylbutyl, 2,2- dimethylbutyl, 2,3- dimethylbutyl, 3,3- dimethylbutyl, 1-
Ethyl-butyl, 2- ethyl-butyl, 1,1,2- thmethylpropyl, 1,2,2- thmethylpropyl, 1- ethyl -1- methyl-propyl and 1-
Ethyl-2-Methyl propyl etc..Term " C1-18Alkyl ", " C1-6Alkyl ", " C1-4Alkyl ", " C1-3Alkyl " refers in examples detailed above
Specific example containing 1-18,1-6,1-4,1-3 carbon atoms.
" alkenyl " refers to the linear chain or branched chain or cricoid alkene that the carbon atom number containing at least one double bond is 2-8
Base, including such as " C2-8Alkenyl, " C2-6Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl ", " C3-6Cycloalkenyl " etc., example include but
It is not limited to: vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyl, 3- cyclobutenyl, 2- methyl-1-propylene base, 1- methyl -2-
Acrylic, 1- pentenyl, 2- pentenyl, 3- pentenyl, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl -3- fourth
Alkenyl, 1,1- dimethyl -2- acrylic, 1- ethyl -2- acrylic, 2- hexenyl, 3- hexenyl, 2- methyl-1-pentene alkenyl,
3- methyl-1-pentene alkenyl, 1- methyl -2- pentenyl, 3- methyl -2- pentenyl, 2- methyl-3-pentenyl, 1- methyl -4- penta
Alkenyl, 3- methyl -4- pentenyl, 1,1- dimethyl -3- cyclobutenyl, 1,2- dimethyl -3- cyclobutenyl, 1,3- dimethyl -2- fourth
Alkenyl, 2,2- dimethyl -3- cyclobutenyl, 2,3- dimethyl -2- cyclobutenyl, 2,3- dimethyl -1- cyclobutenyl, 2- ethyl -1- fourth
Alkenyl, 2- ethyl -3- cyclobutenyl, 2- heptenyl, 3- heptenyl, 4- heptenyl, 1- octenyl, 3- octenyl, 4- octenyl,
1,3- butadienyl, 2,4- pentadienyl, 1,4- hexadienyl, 2,4- hexadienyl, 1,5- heptadiene base, 2,5- heptadiene
Base, 2,6- octadienyl, cyclopentenyl, 1,3- cyclopentadienyl group, cyclohexenyl group, 1,4- cyclohexadienyl, cycloheptenyl, 1,
4- cycloheptadiene base, cyclo-octene base etc..Term " C2-4Alkenyl " refers to the specific example containing 2-4 carbon atom in examples detailed above.
" the C3-8Naphthenic base " refers to that the paraffin section of 3-8 carbon atom removes ring-type alkane derived from a hydrogen atom
Base, the example include but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
" C of the present invention6-14Aryl " refers to the aromatic series ring type group of carbon atom number 6 to 14, specifically, for example
Benzene, pentalene, indenes, naphthalene, azulene, heptalene, biphenylene, two indenes of benzo, acenaphthene
Alkene, fluorenes, phenalene, phenanthrene, anthracene etc..
" the C5-14Heteroaryl " refers to that annular atom number is 5 to 14, and the atomic species for constituting the ring of ring type group includes 1
The heteroatomic aromatic ring type group such as a above nitrogen-atoms, sulphur atom and oxygen atom.Specifically, such as pyrrole ring, pyrrole
Phenazine ring, pyridone ring, pyridazine ring, pyrimidine ring, pyridine ring, pyrazole ring, imidazole ring, triazole ring, tetrazole ring, indole ring, different Yin
Diindyl ring, indolizine ring, purine ring, indazole ring, quinoline ring, isoquinolin ring, quinolizine ring, phthalazines ring, naphthyridines ring, quinoxaline ring, quinoline
Oxazoline ring, cinnolines ring, pteridine ring, imidazopyridine ring, imidazo-triazine ring, pyrazine and pyridazine ring, acridine ring, phenanthridines ring, click
Azoles ring, hexahydro carbazole ring, perimidine ring, phenanthroline ring, azophenlyene ring, oxadiazoles ring, benzimidazole, pyrrolo-
The nitrogenous heteroaromatics such as pyridine ring, Pyrrolopyrimidin phenazine ring, Pyridopyrimidine ring；The sulfur-bearings such as thiphene ring, benzothiophene ring fragrance
Race's heterocycle；The oxygen-containing aromatic series such as furan nucleus, pyranoid ring, cyclopenta pyranoid ring, benzofuran ring, isobenzofuran ring are miscellaneous
Ring；Thiazole ring, Thiadiazole, isothiazole ring, benzoxazole ring, benzothiazole ring, diazosulfide ring, phenthazine ring, isoxazole
Ring, azophenlyene ring, pyrazoloazole coupler ring, Imidazothiazole ring, thienofuran ring, furans and pyrrole ring, pyrido piperazine ring, furans
And pyridine ring, Furanopyrimidines ring, Thienopyrimidine ring, oxazole ring etc. contain 2 selected from nitrogen-atoms, sulphur atom and oxygen atom
A above heteroatomic heteroaromatic.
" the C4-14Heterocycle " refers to that the atomicity for constituting the ring of ring type group is 4 to 14, constitutes ring type group
The atomic species of ring includes the ring type group of the heteroatomic non-aromatic such as at least one nitrogen-atoms, sulphur atom and oxygen atom.Tool
For body, such as pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, N methyl piperazine base, imidazolinyl, pyrazolidinyl, miaow
Oxazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, THP trtrahydropyranyl, azetidinyl, oxetanyl, oxa-
Tiacyclopentane base (oxathiolanyl), pyridone ring, 2-Pyrrolidone ring, ethylidene-urea ring, 1,3-dioxolane, 1,
The non-aromatic heterocyclic groups such as 3- dioxane, Isosorbide-5-Nitrae-dioxane, phthalimide ring, succinimide ring.
" hetero atom " specific such as oxygen atom, sulphur atom, nitrogen-atoms, phosphorus, arsenic, antimony, silicon, germanium, tin, lead, boron, mercury
Deng.
" the C1-6Alkoxy " refers to above-mentioned " C1-6The substituent group that alkyl " obtains in conjunction with oxygen atom, the example include but
Be not limited to methoxyl group, ethyoxyl, n- propoxyl group, i- propoxyl group, n- butoxy, i- butoxy, sec- butoxy, t- butoxy,
N- amoxy, i- amoxy, sec- amoxy, t- amoxy, neopentyl oxygen, 1- methyl butoxy, 2- methyl butoxy, 1,
1- dimethyl propylene oxygroup, 1,2- dimethyl propylene oxygroup, n- hexyloxy, i- hexyloxy, 1- methyl amoxy, 2- methyl amoxy,
3- methyl amoxy, 1,1- dimethyl butyrate oxygroup, 1,2- dimethyl butyrate oxygroup, 2,2- dimethyl butyrate oxygroup, 1,3- dimethyl butyrate
Oxygroup, 2,3- dimethyl butyrate oxygroup, 3,3- dimethyl butyrate oxygroup, 1- ethyl-butoxy, 2- ethyl-butoxy, 1,1,2- front three
Base propoxyl group, 1,2,2- trimethyl propoxyl group, 1- ethyl -1- methyl propoxyl group, 1- Ethyl-2-Methyl propoxyl group etc..
" the C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl,
C1-6Alkyl sulfonyl amino, C1-6Alkyl amino sulfonyl, (C1-6Alkyl)2Amino-sulfonyl, C1-6Alkyl sulphonyl, C1-6Alkyl
Carbonyl oxygroup " refers to C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2-N-、C1-6Alkyl-S-, C1-6Alkyl-C
(O)-、C1-6Alkyl-SO2NH-、C1-6Alkyl-NHSO2-、(C1-6Alkyl)2-NSO2-、C1-6Alkyl-SO2-、 C1-6Alkyl-C (O)-
The group that O- mode is formed, wherein " C1-6Described in alkyl " text as defined above.
" the halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, hydroxyl C2-8Alkene
Base, carboxyl C2-8Alkenyl, hydroxyl C2-8Alkynyl, carboxyl C2-8Alkynyl, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, C1-6Alkoxy
C1-6Alkoxy, hydroxyl C1-6Alkyl amino " refers to one or more, such as 1-4,1-3,1-2 halogen atom, hydroxyl, ammonia
Base, carboxyl, C1-6Alkoxy replaces C respectively1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkoxy, C1-6Hydrogen in alkyl amino
Atom is formed by group.
" halogenated alkyl " refers to the C replaced by least one halogen1-6Alkyl；Particularly relate to monohaloalkyl alkyl, dihalo-
Substituted alkyl, tri haloalkyl, the example include but is not limited to: methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethane
Base, trichloromethyl, trichloromethyl, pentafluoroethyl group, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, bis-fluoro ethyls, difluoro third
Base, Dichloroethyl and two chloropropyls.
The salt used in pharmaceutical composition is officinal salt, but other salt can be used for producing formula (1) compound and its
Officinal salt.For example, officinal salt of the invention includes the acid-addition salts of formula defined above (1) compound, which changes
The alkalinity for closing object is enough to form the acid-addition salts.This acid-addition salts include the nothing for example with the pharmaceutically acceptable anion of offer
The salt that machine or organic acid are formed, for example, with hydrogen halides (especially hydrochloric acid or hydrobromic acid, wherein particularly preferred hydrochloric acid), sulfuric acid,
The salt that phosphoric acid, trifluoroacetic acid, citric acid or maleic acid are formed.Suitable salt includes hydrochloride, hydrobromate, phosphate, sulfuric acid
Salt, disulfate, alkylsulfonate, arylsulphonate, acetate, benzoate, citrate, maleate, fumaric acid
Salt, succinate, lactate and tartrate.In addition, when formula (I) compound has enough acid, can with provide can
The inorganic or organic base of medicinal cation forms officinal salt.For example, this salt formed with inorganic or organic base includes alkali gold
Belong to salt, such as sodium salt or sylvite, alkali salt, such as calcium salt or magnesium salts, ammonium salt or for example with methylamine, dimethylamine, trimethylamine, piperazine
The salt that pyridine, morpholine or three-(2- ethoxy) amine are formed.
Preferred salt includes acid-addition salts, for example, hydrochloride, hydrobromate, phosphate, acetate, fumarate, horse
Come hydrochlorate, tartrate, citric acid, oxalates, mesylate or tosilate or alkali metal salt, such as sodium salt or sylvite.
When signified compound of the invention is alkali, need to prepare its salt at least one pharmaceutically acceptable non-toxic acid,
These acid are selected from inorganic and organic acid.For example, it is selected from acetic acid, and benzene sulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethane sulfonic acid,
Fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane
Sulfonic acid, glactaric acid, nitric acid flutter acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-methyl benzenesulfonic acid.In some embodiments,
These acid may be selected, such as: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, tartaric acid.
" leaving group " refers in the art it is well known that referring for example to " Advanced Organic Chemistry (Advanced
OrganicChemistry), " Jie Ruimaqi (Jerry March), the 5th edition, 351- page 357, John Wei Li father and son goes out
Version company (John Wiley and Sons), New York (N.Y).The leaving group include but is not limited to halogen, alkoxy,
Sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenyl sulfonyloxy, optionally substituted aryl
Sulfonyloxy, acyl group and diazo-moieties.The example of suitable leaving group includes chlorine, iodine, bromine, fluorine, acetoxyl group, methane sulphur
Acyloxy (mesyloxy), tosyloxy, trifluoro-methanesulfonyl oxy, nitro _ phenylsulfonyloxy group (nitrobenzene sulphonyl
Oxygroup) and bromine _ phenylsulfonyloxy group (bromophenylsulfonyl oxygroup).
" protecting group " (Pg) refer to it is a kind of for functional group reactions other on compound and obstruct or protect particular functional
The substituent group of group.Obstruct or protect amido functional group on compound to take for example, " amino protecting group " refers to be connected on amino
Dai Ji.Suitable amido protecting group includes acetyl group, three fluorine-based, tertbutyloxycarbonyls (BOC), benzyloxycarbonyl group (CBZ) and chloromethane
Acid -9- fluorenyl methyl ester (Fmoc).Equally, " hydroxyl protection base " refers to that a kind of hydroxyl substituent can effectively stop or protect hydroxyl
Function.Protecting group appropriate includes acetyl group and silicyl." carboxyl-protecting group " refers to that a kind of carboxyl substituent can effectively hinder
The function of gear or protection carboxyl.Common carboxyl-protecting group includes-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl,
2- (trimethylsilyl) ethoxyl methyl, 2- (para toluene sulfonamide) ethyl, 2- (p-nitrophenyl sulfenyl) ethyl, 2- (diphenyl
Phosphine)-ethyl, nitro-ethyl etc..For the general description and operation instruction of protecting group, see reference document: T.W.Greene,
Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991。
" composition " include: the special component comprising specific quantity product and it is any directly or indirectly these specific quantities
Special component the product being composed.Pharmaceutical compositions include: comprising effective component and as the inert fraction of carrier
Product and any two or more than two ingredients are direct or indirect, by combination, the compound or manufactured product of aggregation,
Or the product generated by one or more ingredient breakdowns, or other types reaction is occurred by one or more ingredients
Or the product that interaction generates.
" giving " or " administration " at least one compound and/or its at least one pharmaceutically acceptable salt refer to for needs
The individual for the treatment of provides at least one compound and/or its at least one pharmaceutically acceptable salt.
Term language treats (treat), " treatment (treating) " and " treatment (treatment) is referred to mitigation or gone
The method for falling disease and/or its attached symptom.
Term " prevention (prevent)., " prevention (preventing) and " prevention (prevention) refers to prevention
The method of the generation (onset) of disease and/or its attached symptom, or the method for preventing subject from suffering from disease.Such as this paper institute
, " prevention (prevent) examination, " prevention (preventing) has and " it further includes delaying disease that prevention (prevention), which has,
And/or the risk of generation and reduction subject with disease of its attached symptom.
" effective dose " refers to that at least one compound and/or its at least one pharmaceutically acceptable salt can cause carefully
Born of the same parents, tissue, system, animals or humans appearance can be studied what personnel, animal doctor, clinician or other clinical staffs were observed
The dosage of biology or medical response.
" pharmaceutically acceptable " refer to it is compatible with other components in preparation, and to user without unacceptable murder by poisoning.
Term " adjusting " refers to that compound increases or decreases the function or active ability of kinases.Various shapes used herein
" adjusting " of formula includes active antagonism relevant to kinases, agonism, partial antagonism and/or partial agonist
Effect.Kinase inhibitor is following compounds, for example, partially or completely retardance stimulation, reduces, prevents, delaying to activate, making
Signal transduction inactivation, passivation are adjusted downwards.Kinase activation agent is following compounds, for example, stimulating, improving, open, swashing
Living, promotion increases activation, and signal transduction is made to be sensitized or be adjusted up.
Terms used herein " composition " include the product containing specific amount of concrete component, and directly or indirectly
Ground is obtained from any product of the combination of specific amount of concrete component." pharmaceutically acceptable " refers to that carrier, diluent or excipient must
And adverse effect must not be will cause to its recipient with other components of preparation not contradiction.
" patient " as defined herein includes animal, such as mammal, including but not limited to: primate (for example, people),
Ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc..In preferred embodiments, patient is people.
Compound
Geometric isomer can reside in the compound of the present invention.The compound of the present invention can be containing with E or Z configuration
Carbon-to-carbon double bond or carbon-to-nitrogen double bond, wherein it is described as according to determined by Cahn-Ingold-Prelog priority rule
Term " substituent group for indicating advanced sequence is first advised in the opposite side of carbon-to-carbon or carbon-to-nitrogen double bond, and the term " double bond table
Show the substituent group of advanced sequence on the same side of carbon-to-carbon or carbon-to-nitrogen double bond.The compound of the present invention is also used as " double bond
" " mixture of key isomers exists.Substituent group around naphthenic base or Heterocyclylalkyl be also referred to as be it is cis- or
Anti-configuration.
The compound of the present invention can be containing with the carbon atom of the Asymmetrical substitute of R or S configuration, the wherein term " sum of type
" " if IUPAC 1974 is for the part E, basic stereoscopic chemistry is recommended, Pure Appl.Chem. (1976) 45,13-10
Defined in.The compound of carbon atom with Asymmetrical substitute and R the and S configuration with identical quantity is in those carbon original
Sub- place is racemic.A kind of configuration is referred to as relative to the excessive atom of another configuration with configuration existing for higher amount, excellent
With about 85%-90% excess, more preferably from about 95%-99% is excessive for choosing, and also more preferably more than about 99% it is excessive higher
Measure existing configuration.Therefore, the present invention includes racemic mixture, opposite and absolute stereoisomer and opposite
With the mixture of absolute stereoisomer.
Formula (I) compound can contain the atom of one or more Asymmetrical substitutes.Formula (I) compound is also used as respectively
A stereoisomer (including enantiomter and diastereoisomer) and its mixture exist.The each of formula (I) compound stands
Body isomers can be prepared in synthesis from commercially available comprising asymmetric or chiral centre starting material, or pass through system
Then standby racemic mixture splits each stereoisomer using method known to persons of ordinary skill in the art to prepare.
The example of fractionation is that enantiomeric mixture is connect by such as (i) with chiral accessory, is separated by recrystallization or chromatography
Then resulting non-enantiomer mixture discharges optics pure products；Or (ii) separation mapping on chiral chromatographic column is different
The mixture of structure body or diastereoisomer.
Formula (I) compound can also include various geometric isomers and its mixture, by substituent group is placed on carbon-to-carbon
Caused by around double bond, carbon-to-nitrogen double bond, naphthenic base or Heterocyclylalkyl.Substituent group around carbon-to-carbon double bond or carbon-to-nitrogen double bond
Referred to as Z or E configuration, and the substituent group around naphthenic base or Heterocyclylalkyl is known as cis or trans configuration.
In the present invention, it should be understood that compounds as disclosed herein can show tautomerism, and own
Tautomer be included within the scope of the invention.
Therefore, the formula in this specification (I) compound can only indicate possible tautomerism, geometry or alloisomerism shape
One of formula.It should be understood that the present invention includes any tautomerism, geometry or stereoisomeric forms in any ratio and its mixture, and
Used any one tautomerism, geometry or stereoisomeric forms in any ratio in formula (I) compound should not be limited to only.
Isotope enrichment or label compound
The compound of the present invention can exist in the form of isotope-label or-enrichment, contain one or more and had
Some atomic masses or mass number are different from the atomic mass of most abundant discovery or the atom of mass number in nature.Isotope
It can be radioactivity or non radioactive isotope.The isotope of atom such as hydrogen, carbon, phosphorus, sulphur, fluorine, chlorine and iodine includes, but unlimited
In,2H、 3H、13C、14C、15N、18O、32P、35S、18F、36Cl and125I.Other isotopes containing these and/or other atoms
Compound within the scope of the invention.
In another embodiment, the compound of the isotope labelling contain deuterium (2H), tritium (3H) or14C isotope.This
The compound of the isotope labelling of invention can be prepared by conventional method known to a person of ordinary skill in the art.It can facilitate
Ground with the reagent for the isotope labelling being easy to get by replacing unmarked reagent to carry out embodiment disclosed herein and scheme
(Schemes) the step of disclosed in, to prepare the compound of such isotope labelling.It in some cases, can be with together
The reagent processing compound of position element label is to exchange normal atom with its isotope, such as passes through deuterium acid, such as D2SO4/D2O's
Effect, can be exchanged into deuterium for hydrogen.Except above in addition to these, such as in Lizondo, J et al., Drugs Fut, 21 (11), 1116
(1996)；Brickner, S J et al., J Med Chem, 39 (3), 673 (1996)；Mallesham, B et al., Org Lett,
5 (7), 963 (2003)；PCT publication WO1997010223, WO2005099353, WO1995007271, WO2006008754；
United States Patent (USP) Nos.7538189；7534814；7531685；7528131；7521421；7514068；7511013；It is special with the U.S.
Sharp application publication object Nos.20090137457；20090131485；20090131363；20090118238；20090111840；
20090105338；20090105307；20090105147；20090093422；20090088416；In 20090082471
Correlation step and intermediate are disclosed, these methods are incorporated herein by reference.
The compound of isotope labelling of the invention can be used as measuring BET bromine structural domain inhibitor in combining detection
The reference substance of effect.Compound containing isotope is for by assessing isotope-labeled parent in study of pharmacy
The mechanism of action of compound and metabolic pathway come study the compound internal metabolic fate (Blake et al.,
J.Pharm.Sci.64,3,367-391 (1975)).Such metabolism is studied
Important, because delivering medicine to the active compound in vivo of patient or because the metabolin generated by parent compound is proved to be
Toxic or carcinogenic (Foster et al., Advances in Drug Research Vol.14, the 2-36 pages, Academic
Press, London, 1985；Kato et al., J.Labelled Comp.Radiopharmaceut., 36 (10): 927-932
(1995)；Kushner et al., Can.J.Physiol.Pharmacol., 77,79-88 (1999)).
In addition, the drug containing non radioactive isotope, the deuterate drug for being such as referred to as " weight medicine " can be used for treating and BET
The relevant disease of bromine domain activity and illness.By the amount of isotope present in compound be increased to its natural abundance with
It is upper to be referred to as enrichment.The example of enriching quantity include from about 0.5,1,2,3,4,5,6,7,8,9,10,12,16,21,25,29,
33,37,42,46,50,54,58,63,67,71,75,79,84,88,92,96 to about 100 moles of %.In mammal, packet
It includes in rodent and canine the normal atom of realization heavy isotope substitution for up to about 15% and is kept for a couple of days to number
During week, minimum side effect (Czajka D M and Finkel AJ, Ann.N.Y.Acad.Sci.1960 observed
84:770；1960 84:736 of Thomson J F, Ann.New York Acad.Sci；Czakja D M et al.,
Am.J.Physiol.1961 201:357).The acute replacement of deuterium that 15%-23% is up in human body fluid does not find to cause
Toxicity (Blagojevic N et al., in " Dosimetry&Treatment Planning for Neutron Capture
In Therapy ", Zamenhof R, Solares G and Harling O Eds.1994.Advanced Medical
The 125-134 pages of Publishing, Madison Wis.；Diabetes Metab.23:251 (1997)).
Its physicochemical properties can be changed in the stable isotope labeling of drug, such as pKa and fat-soluble.If isotopic
The region involved in ligand-receptor interaction is acted on, then the pharmacodynamics that these effects and variation can influence drug molecule is rung
It answers.Although some physical properties of the molecule of stable isotope labeling be different from it is unlabelled those, chemistry and biology
Matter be it is identical, an important exception is: due to the quality of the raising of heavy isotope, being related to heavy isotope and another atom
Any key will be more stronger than the same keys between light isotope and the atom.Therefore, it is incorporated in the site of metabolism or enzymatic conversion method
Isotope will slow down the reaction, potentially change pharmacokinetics spectrum or effect compared with heterotope compound.
Specific embodiment
In some embodiments, at least one general formula (I) compound represented is provided, and/or its is pharmaceutically acceptable
Salt, and/or its stereoisomer and/or its solvate:
Wherein:
R1It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Heteroaryl
Base, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle be it is unsubstituted or
Hydrogen, halogen, C are optionally independently selected from by one or more1-6Alkyl, C1-6The group of alkoxy, hydroxyl and halogenated alkyl replaces；
R2It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Heteroaryl
Base, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle be it is unsubstituted or
Hydrogen, halogen, C are optionally independently selected from by one or more1-6Alkyl, C1-6The group of alkoxy, hydroxyl and halogenated alkyl replaces；
R3It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Aralkyl
Base, C6-14Heteroaryl, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle is not
It is substituted or optional hydrogen, halogen, C are independently selected from by one or more1-6Alkyl, C1-6Alkoxy, hydroxyl and alkyl halide
The group of base replaces；
R4It is independently selected from hydrogen, C1-6Alkyl, C3-8Naphthenic base, hydroxyl, C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle；
R5It is independently selected from hydrogen, C1-6Alkyl, C3-8Naphthenic base, hydroxyl, C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle；
R6It is independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C6-14Aryl, C6-14Heteroaryl, C4-14Heterocycle
Base, alkenyl and halogenated alkyl；
R7It is independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C6-14Aryl, C6-14Heteroaryl, C4-14Heterocycle
Base, alkenyl and halogenated alkyl；
L1And L2It is independently selected from C1-6Alkylidene, C3-8Cycloalkylidene, C6-14Arlydene, C6-14Sub- heterocycle；
M, n are independently selected from 1,2,3,4,5 and 6.
In some embodiments, R1Selected from methyl, ethyl, isopropyl and cyclopropyl；
In some embodiments, R2Selected from methyl, ethyl, isopropyl and cyclopropyl；
In some embodiments, R3Independently selected from isobutyl group, neopentyl, phenyl and benzyl；
In some embodiments, R4It is methyl；
In some embodiments, R5It is methyl；
In some embodiments, R6Independently selected from methyl, ethyl, isopropyl and cyclopropyl；
In some embodiments, R7It is methyl；
In some embodiments, L1And L2It is methylene respectively；
In some embodiments, m=1；
In some embodiments, n=1.
At least one compound and/or its pharmaceutically acceptable salt and/or its stereoisomer and/or its solvent
Object is closed, is selected from:
Since provided compound has pharmaceutical active, the compounds of this invention in the mankind and non-human animal's body
It is useful.The compounds of this invention can be used as drug for antitumor.
On the other hand, it is related to a kind of pharmaceutical composition, the composition includes any one above-mentioned reality as active constituent
Apply the compound of example and modification.In a specific modification, the composition is suitable for the solid pharmaceutical preparation of oral administration.?
In another specific modification, the composition is adapted for the liquid preparation of oral administration.It, should in another specific modification
Composition is tablet.In another specific modification, composition is the liquid preparation suitable for parenterai administration.
On the other hand, it is related to a kind of pharmaceutical composition, the composition includes any one above-described embodiment and modification
Compound, wherein composition is suitable for different administration routes, including oral, parenterally, in cavum peritoneale, and intravenously, intra-arterial,
Transdermal, sublingual, intramuscular, rectum, cheek, intranasally, liposome, via sucking, vagina intraocularly (such as passes through via local delivery
Conduit or bracket), subcutaneous injection, fat is interior to be injected, intra-articular injection and intrathecal injection.
On the other hand, it is related to a kind of medicine box (kit), which includes the chemical combination of any one above-described embodiment and modification
Object, and the operation instruction including one or more composition informations, including being suitable for the morbid state introduction for taking composition, group
Close object storage information, drug administration information and the explanation for how using the composition.In a specific modification, the medicine box packet
Include multiple dosage forms of compound.
On the other hand, it is related to a kind of product, compound and packing timber including any one above-described embodiment and modification
Material.In a kind of modification, packaging material includes the container for accommodating compound.In a kind of specific modification, container includes mark
Label, label information include be suitable for the morbid state introduction for taking composition, storage information, drug administration information and how using should
The explanation of composition.In another modification, product includes a variety of dosage forms of compound.
On the other hand, it is related to a kind for the treatment of method, this method includes giving any one above-described embodiment of subject
With the compound of modification.
On the other hand, it is related to a kind of antineoplastic method, this method includes giving any one above-mentioned implementation of patient
The compound of example and modification.
Embodiment
There are many at least one formula (I) compounds represented or its at least one pharmaceutically acceptable salt synthetic method.?
What is enumerated in this example is representative method.It should be noted, however, that the compound of at least one formula (I) or
Its at least one pharmaceutically acceptable salt may also synthesize to obtain by other synthetic routes.
In certain compound shown in formula (I), the connection between atom and atom may cause that there are special alloisomerisms
Body (such as chiral centre).There may be not for the compound or its at least one pharmaceutically acceptable salt for synthesizing at least one formula (I)
The mixture of same isomers (enantiomter, diastereoisomer).It is some specific spatial configuration unless stated otherwise,
Cited compound includes its all stereoisomer that may be present.
Its pharmaceutically acceptable acid-addition salts can be made at least one formula (I) compound represented, for example, pass through by
The free alkali form of the compounds of this invention and pharmaceutically acceptable inorganic or organic acid reaction.Or by formula (I) institute of the present invention
The free acid form of the compound shown is reacted with pharmaceutically acceptable inorganic or organic base, is made into pharmaceutically acceptable alkali
Addition salts.It is suitable for preparing the inorganic and organic bronsted lowry acids and bases bronsted lowry of the pharmaceutically acceptable salt of formula (I) compound in this specification
Definition part is described.In addition, formula (I) compound represented salt form can also be by using starting material or intermediate
Salt prepared.
The free acid or free alkali of formula (I) compound represented can pass through its corresponding base addition salts or acid-addition salts
It is prepared.For example, passing through the acid addition salt form thereof of formula (I) compound represented with suitable alkali (such as ammonium hydroxide
Solution, sodium hydroxide etc.) processing can convert it into corresponding free alkali.By the alkali addition of formula (I) compound represented
Salt form, which passes through, can be translated into corresponding free acid with suitable sour (such as hydrochloric acid) processing.
The N- oxide of at least one formula (I) compound represented or its at least one pharmaceutically acceptable salt can pass through this
Conventional method known to field is made.For example, N- oxide can pass through the non-oxide shape of formula (I) compound represented
Formula under conditions of close to 0~80 DEG C with oxidant (such as trifluoro peracetic acid, peroxy maleic acid, benzoyl hydroperoxide, peroxide second
Acid, metachloroperbenzoic acid etc.) it is obtained in the middle reaction of inert organic solvents (such as methylene chloride halogenated hydrocarbon).In addition, compound
N- oxide can also be prepared by the N- oxide of starting material.
The non-oxidised form of formula (I) compound represented can be by by its N- oxide and reducing agent (such as sulphur, titanium dioxide
Sulphur, triphenyl phosphorus, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide etc.) under conditions of 0~80 DEG C corresponding
Reaction is made in inert organic solvents (such as acetonitrile, ethyl alcohol, dioxane aqueous solution etc.).
The protection derivative of formula (I) compound represented can be prepared by method well known in the art.It closes
It describes in the detailed technology of addition and the removal of blocking group referring to Wuts, Peter G.M., Greene's Protective
Groups in Organic Synthesis,5th Edition,John Wiley&Sons,Inc.2014。
Mark and common sense used in these reactions, chart is consistent with existing scientific literature with case, for example,
Journal of the American Chemical Society or journal of biological chemistry.Unless otherwise indicated, in the L- construction single-letter of Plays or triliteral
Abbreviation is often referred to amino acid residue.Unless otherwise indicated, all starting materials used can buy commercially available from market supply,
It is not further purified when use.For example, can all use following abbreviation in example and the whole instruction: g (gram), mg (milli
Gram), L (liter), mL (milliliter), μ L (microlitre), psi (pound per square inch), M (mole), mM (mM), i.v. (vein note
Penetrate), Hz (hertz), MHz (megahertz), mol (mole), mmol (mM), RT (room temperature), min (minute), h (hour), mp
(fusing point), TLC (thin-layered chromatography), Rt (retention time), RP (reverse phase), MeOH (methanol), NEt3(triethylamine), TFA (three
Fluoroacetic acid), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DCM (methylene chloride), MeCN (second
Nitrile), DMF (n,N-Dimethylformamide), AcOH (acetic acid), BOC (tertbutyloxycarbonyl), Ac (acetyl group), atm (atmospheric pressure),
TIPS (tri isopropyl silane), TBS (t-Butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe
(methoxyl group), Et (ethyl), t-Bu (tert-butyl), HPLC (high performance liquid chromatography), TBAF (tetrabutyl ammonium fluoride),
TosMIC (to Methyl benzenesulfonyl methyl isocyanide), TIPSCl (tri isopropyl chlorosilane), TBTU (O- benzotriazole-N, N,
N', N'- tetramethylurea tetrafluoro boric acid), NBS (N-bromosuccinimide), n-BuLi (n-BuLi), DIPEA (diisopropyl
Base ethamine), LDA (lithium diisopropylamine), NosCl (m-nitrobenzene sulfonyl chloride), NHP (n-Hydroxyphthalimide),
Con.HCl (concentrated hydrochloric acid).
Ether or Et2O each means ether；Salt water then refers to saturation NaCl aqueous solution.Unless otherwise indicated, all temperature are equal
Refer to a DEG C temperature (degree Celsius), all reactions are reacted in inert atmosphere at room temperature.
1H H NMR spectroscopy is recorded using (600MHz) nuclear magnetic resonance spectrometer of Bruker-AM 600.Chemical shift is with ppm table
Show.Coupling constant (Hz) as unit of hertz.Apparent diversity is described with Fractionation regimen, and is set to s (unimodal), d is (double
Peak), t (triplet), q (quartet), quin (quintet), sex (sextet), sept (heptet), m (multiplet), br
(general peak).
Low Resolution Mass Spectra (MS) and compound purity data come from the list of Shimadzu LC-MS chromatography (LCMS-2020)
Grade quadrupole lever system.
Synthetic route
For example following route of the preparation method of compound of the present invention and embodiment are illustrated, and starting material is business
Source can exemplary method preparation according to known methods or herein.
In some cases to guarantee that reaction is able to carry out or avoid to occur side reaction, the implementation reacted shown in above-mentioned route is suitable
Sequence can be adjusted.Following embodiment is not to be regarded as any limitation of the invention for fully understanding the present invention.
This 2,5,6 three segment of synthesis point carries out, and realizes natural products Kanamienamide with raw material simple and easy to get
And the synthesis of its derivative.
The synthesis of segment 2 is raw material with reported compound 21, and by hydrolysis, condensation reaction obtains target segment
2。
The synthesis of segment 5 is starting material with reported compound 12, through peroxidization, Witting reaction, hydroxyl
Deprotection, oxidation alcoholic extract hydroxyl group obtain target segment 5.
The synthesis of segment 6 is starting material with reported compound 18, and by ester condensation reaction, amino is deprotected to obtain
Target segment 6.
The amide condensed reaction of segment 5 and 6 that will be obtained, obtains critical segment 4.
By segment 4 by Grubbs olefin metathesis reaction, reduction reaction, then hydroxyl Deprotection, is aoxidized,
Stork-Zhao-Wittig reacts to obtain critical segment 3.Obtained segment 3 and segment 2 are obtained by Heck coupling reaction
To natural products Kanamienamide.
Embodiment 1
Step 1
The preparation of intermediate 5
Compound 10 (1.95g, 12.41mmol) be dissolved in 20mL tetrahydrofuran 0 DEG C be added dropwise LDA (12.41mL,
2.0M, 24.82mmol), reaction solution is stirred at room temperature one hour.HMPA (4.50mL, 25.86mmol) is added at -78 DEG C, then
The tetrahydrofuran solution of compound 7 (3.0g, 10.34mmol) is added, stirs at -78 DEG C one hour and is then slowly risen in 3 hours
It is reacted again to room temperature one hour.Add ammonium chloride solution to be quenched, ethyl acetate extract organic phase, by silica gel column separating purification (3:
2PE:EtOAc, Rf=0.2) colorless oil 11 (2.67g, 81%): [α] is obtainedD 27–48.3(c 0.27,CH2Cl2)；
{lit.11a[α]D 27–50.0 (c 5.2,CH2Cl2)}；1H NMR(400MHz,CDCl3)δ7.35–7.28(m,5H),5.21
(br s, 1H), 4.47 (q, J=8.0Hz, 2H), 4.21-4.15 (m, 1H), 3.65-3.22 (m, 6H), 2.73-2.64 (m,
1H),1.98–1.92(m,1H), 1.88–1.66(m,3H),1.61–1.49(m,2H),1.47–1.40(m,1H),1.10(d,J
=6.8Hz, 3H), 0.92 (d, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ178.4,138.5,128.3,127.7,
127.5,76.3,73.1,67.7, 61.0,47.6,38.0,35.8,31.5,28.2,24.4,17.8,17.5；HRMS(ESI)
m/z:[M+Na]+Calcd for C19H29NO3Na 342.2039,found 342.2037。
Compound 11 (2.5g, 7.83mmol) is dissolved in 1N HCl (60mL) and is heated to reflux 6 hours, is cooled to room temperature, second
Acetoacetic ester extraction, organic phase drying are concentrated to give crude product 12a.This crude product is added to LiAlH at 0 DEG C4(0.59g,
20mL in tetrahydrofuran solution 15.50mmol).Reaction solution is slowly increased to room temperature and stirs 2 hours.Water quenching is added to go out, acetic acid second
Ester extracts organic phase, passes through silica gel column separating purification (4:1PE:EtOAc, Rf=0.2) obtain colorless oil 12 (1.66g,
96%) .12a:[α]D 27–13.7 (c 0.22,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.40–7.26(m,5H),
4.53(s,2H),3.39–3.32(m, 2H),2.59(m,1H),1.94–1.86(m,1H),1.66–1.52(m,2H),1.20
(d, J=7.0Hz, 3H), 0.97 (d, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ183.4,138.5,128.4,
127.6,127.5,75.6,73.1,37.6, 37.2,31.4,17.1,17.0；HRMS(ESI)m/z:[M+Na]+Calcd for
C14H20O3Na 259.1304,found 259.1303；12:[α]D 27–13.7(c 0.22,CHCl3)；1H NMR(400MHz,
CDCl3)δ7.41–7.23(m,5H), 4.51(s,2H),3.49–3.39(m,2H),3.33–3.26(m,2H),1.96–1.84
(m, 1H), 1.79-1.74 (m, 1H), 1.29-1.16 (m, 2H), 0.92 (d, J=6.7Hz, 3H), 0.90 (d, J=6.7Hz,
3H)；13C NMR(101MHz,CDCl3) δ138.6,128.3,127.5,127.4,76.6,73.0,68.8,37.2,33.0,
30.6,17.0,16.3；HRMS(ESI)m/z:[M+ Na]+Calcd for C14H23O2 223.1692,found 223.1689。
Compound 12 (1.50g, 6.75mmol) and NaHCO3(1.21g, 16.89mmol) is dissolved in 30mL methylene chloride.
This Martin reagent (4.30g, 10.13mmol) is worn in addition.React at room temperature two hours.Reaction solution filtering, add methylene chloride extraction
It takes, is concentrated to give yellow oily crude product.Compound 13 (7.02g, 20.18mmol) is dissolved in tetrahydrofuran, and NaHMDS is added under ice bath
(18.83 mL, 1M in THF, 18.83mmol) is stirred 20 minutes at this temperature, is then warmed to room temperature and stirs 1 hour.Again
Crude product obtained by upper step is added in reaction solution by ice bath 1, falls back within 2 hours.Ethyl acetate extracts organic phase, Guo Zhufen
From purifying to obtain object 14 (1.26g, 86%): [α]D 27–5.8(c 0.44,CHCl3)；1H NMR(400MHz,CDCl3)δ
7.50-7.22 (m, 5H), 5.73 (ddd, J=17.5,10.1,7.7Hz, 1H), 5.04-4.99 (m, 2H), 4.52 (q, J=
2.7Hz, 2H), 3.37 (dd, J=9.0,5.4Hz, 1H), 3.32-3.20 (m, 1H), 2.29-2.19 (m, 1H), 1.95-1.80
(m, 1H), 1.41-1.34 (m, 1H), 1.20-1.13 (m, 1H), 0.98 (d, J=7.0Hz, 3H) 0.97 (d, J=7.0Hz,
3H)；13C NMR(101 MHz,CDCl3)δ145.1,138.8,128.3,127.5,127.4,112.2,75.8,72.9,40.7,
35.2,31.0,20.1,17.6； ESI MS m/z:219.2[M+H]+。
Naphthalene (5.63g, 44.03mmol) is dissolved in 10mL tetrahydrofuran, and lithium particle (0.38g, 55.04mmol) room temperature is added
Stir 30 minutes formation naphthalene lithium reagents.The tetrahydrofuran solution of compound 14 (1.20g, 5.50mmol) is added at -20 DEG C
In above-mentioned reaction solution, it is warmed to room temperature stirring 1.5 hours.Reaction solution adds ammonium chloride saturated solution slightly to go out, ether extraction, Guo Zhuchun
Change (4:1PE:Et2O, Rf=0.30) object 15 (0.58g, 83%): [α] is obtainedD 27–4.8(c 0.17,CHCl3)；1H
NMR(400MHz,CDCl3) δ 5.81-5.56 (m, 1H), 5.04-4.80 (m, 2H), 3.50 (dd, J=10.5,5.3Hz, 1H),
3.38 (dd, J=10.3,6.7Hz, 1H), 2.22 (dt, J=14.1,7.1Hz, 1H), 1.72-64 (m, 1H), 1.34-1.27
(m, 1H), 1.12 (dt, J=13.9,7.4 Hz, 1H), 0.95 (d, J=6.7Hz, 3H), 0.90 (d, J=6.7Hz, 3H)；13C
NMR(101MHz,CDCl3)δ145.0, 112.3,68.0,40.1,35.1,33.2,20.0,16.9；ESI MS m/z:129.2
[M+H]+。
Compound 15 (250mg, 1.95mmol) is dissolved in acetone soln, and Jones reagent (2.54mL, 2.3M are added at 0 DEG C
in water, 5.85mmol).Reaction is warmed to room temperature after 30 minutes reacts 2.5 hours again.Hypo solution is added to be quenched, second
Acetoacetic ester extraction, crosses column purification (2:3EtOA:PE, Rf=0.5) object 5 (216mg, 78%) is obtained: [α]D 27–15.0(c
0.13,CHCl3)；1H NMR(400MHz,CDCl3) δ 5.64 (ddd, J=18.0,10.1,8.1Hz, 1H), 4.98 (dd, J=
18.6,13.8Hz, 2H),2.58–2.49(m,1H),2.27–2.16(m,1H),1.76–1.69(m,1H),1.37–1.29(m,
1H), 1.18 (d, J=7.0Hz, 3H), 1.00 (d, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ183.6,
143.5,113.7,40.4, 37.4,36.1,20.5,17.7；HRMS(ESI)m/z:[M–H]–Calcd for C8H13O2
141.0921,found 141.0920。
Step 2
The preparation of intermediate 6
Vinyl Grignard Reagent (5.37mL, 1.0M in THF, 5.37mmol) be added to compound 16 (0.9g,
In tetrahydrofuran solution 3.58mmol), room temperature is stirred 2 hours.Ammonium chloride solution is added to be quenched, ethyl acetate extracts organic phase, mistake
Column purification (9:1PE:EtOAc, Rf=0.5) object 17 (0.73g, 93%) is obtained:1H NMR(400MHz,CDCl3)δ7.36–
7.19 (m, 5H), 6.32 (ddd, J=17.7,10.5,0.9Hz, 1H), 6.17 (d, J=17.7Hz, 1H), 5.77 (d, J=
10.5Hz, 1H), 4.48 (s, 2H), 3.47 (t, J=5.8Hz, 2H), 2.59 (t, J=7.1Hz, 2H), 1.76-1.60 (m,
4H)；13C NMR(101MHz,CDCl3) δ200.6,138.5,136.5,128.3,127.9,127.6,127.5,72.9,
70.0,39.2,29.2,20.7；ESI MS m/z:219.1 [M+H]+。
(R)-CBS catalyst (0.18mL, 1.0M in toluene, 0.18mmol) is dissolved in THF (5mL) and is down to -40
DEG C be added BH3·Me2S(0.91mL,2M in THF,1.83mmol).The compound 17 for being dissolved in 2mL tetrahydrofuran is added
(200mg, 0.91mmol), -40 DEG C of stirring 8h. add methanol to be quenched, and column purification (2:8PE:EtOAc, R are crossed in ethyl acetate extractionf
=0.3) object 18 (180mg, 89%) is obtained: [α]D 27+4.0(c 0.44,CHCl3)；{lit.17[α]D 27+3.8(c
1.0,CHCl3)}；1H NMR(400MHz,CDCl3) δ 7.38-7.23 (m, 5H), 5.85 (ddd, J=16.9,10.4,6.2Hz,
1H), 5.24-5.06 (m, 2H), 4.50 (s, 2H), 4.08 (m, 1H), 3.48 (t, J=6.5Hz, 2H), 1.70-1.50 (m,
6H)；13C NMR(101 MHz,CDCl3)δ141.2,138.5,128.3,127.7,127.5,114.6,73.0,72.9,70.2,
36.7,29.6,22.0；HRMS (ESI)m/z:[M+Na]+Calcd for C14H20O2Na 243.1355,found
243.1355。
Compound 18 (0.35g, 1.59mmol) and amino acid 9 (0.40g, 1.67mmol) are dissolved in CH2Cl2In (20mL), add
Enter EDCIHCl (0.37mg, 1.90mmol) and DMAP (10mg) is stirred overnight at room temperature, adds 1N HCl (15mL) to be quenched, second
Acetoacetic ester extraction, crosses column purification (9:1PE:EtOAc, Rf=0.6) object 19 (0.62g, 88%) is obtained: [α]D 27–15.4(c
0.55, CHCl3)；1H NMR(400MHz,CDCl3) δ 7.36-7.23 (m, 5H), 5.75 (ddd, J=16.8,9.9,6.4Hz,
1H), 5.29-5.10 (m, 2H), 4.93-4.80 (m, 1H), 4.63 (dd, J=10.8,4.4Hz, 1H), 4.48 (s, 2H),
3.45 (t, J=6.5Hz, 2H), 2.77 (d, J=11.8Hz, 3H), 1.71-1.54 (m, 7H), 1.45 (d, J=4.9Hz,
9H),1.42–1.35(m, 2H),0.94(m,6H)；13C NMR(101MHz,CDCl3)δ171.8,171.5,156.2,155.7,
138.5,136.2,128.3, 127.6,127.5,116.8,116.7,80.1,79.8,75.3,75.2,72.9,70.0,70.0
57.1,56.1,37.7,37.4,34.0,30.3, 30.1,29.7,29.4,28.3,24.9,24.6,23.3,21.74,
21.67,21.4,21.1；HRMS(ESI)m/z:[M+Na]+Calcd for C21H41O5Na 470.2876,found
470.2870。
Compound 19 (0.50g, 1.11mmol) is dissolved in CH2Cl2In (5mL), 0 DEG C adds TFA (1mL) to be stirred at room temperature one hour
To fully reacting, ethyl acetate extraction is concentrated to give object 6 (0.38g, 99%): [α]D 27+1.7(c 0.18,CHCl3)；1H
NMR (400MHz,CDCl3)δ7.38–7.24(m,5H),5.84–5.71(m,1H),5.34–5.14(m,3H),4.49(s,
2H), 3.46 (t, J=6.2Hz, 2H), 3.16 (t, J=6.9Hz, 1H), 2.35 (s, 3H), 1.67 (m, 5H), 1.51-1.35
(m, 4H), 0.92 (d, J=6.8Hz, 3H), 0.89 (d, J=6.6Hz, 3H)；13C NMR(101MHz,CDCl3)δ175.1,
138.5, 136.3,128.3,127.6,127.5,117.2,74.9,72.9,70.0,62.0 42.7,34.7,34.0,29.4,
24.9,22.6,22.5,21.9； HRMS(ESI)m/z:[M+Na]+Calcd for C26H34NO3Na 348.2533,found
348.2535。
Step 3
The preparation of intermediate 2
Compound 21 (0.5g, 3.47mmol) is dissolved in THF (20mL) and LiOHH is added2O(0.89g,20.83mmol)
Aqueous solution, 60 DEG C are stirred 24 hours.Acid adding tune pH=3, ether extraction cross column purification and obtain object 14 (0.36g, 80%)1H
NMR (400MHz,CDCl3) δ 4.97 (s, 1H), 3.65 (s, 3H), 2.75 (q, J=7.5Hz, 2H), 1.11 (t, J=7.5Hz,
3H)；13C NMR(101MHz,CDCl3)δ180.0,173.3,89.5,55.7,25.7,11.7；ESI MS m/z:131.1[M+
H]+.Compound 22 (200mg, 1.53mmol) is dissolved in .0 DEG C of addition methylamine solution (1.16mL, 2.0M in THF (10mL)
THF, 2.30mmol), then it is added EDCIHCl (368mg, 1.92mmol) reaction solution stirring at normal temperature 24 hours.Acetic acid second
Ester extraction, crosses column purification (PE:EtOAc=1:1, Rf=0.2) target compound 2 (180mg, 82%) yield is obtained:1H NMR
(400 MHz,CDCl3)δ5.36(br s,1H),4.80(s,1H),3.56(s,3H),2.92–2.71(m,5H),1.21–0.98
(m,3H)；13C NMR(101MHz,CDCl3)δ173.9,167.8,91.9,54.9,26.1,25.0,12.0；ESI MS m/z:
144.2[M+ H]+。
Step 4
The synthesis of Kanamienamide
Compound 6 (0.32g, 0.92mmol), compound 5 (0.13g, 0.92mmol) are dissolved in DMF (12mL), are added
HATU (0.38g, 1.01mmol), DIPEA (0.38mL, 1.93mmol) are reacted at room temperature six hours, add ethyl acetate to extract, mistake
Column purification obtains target compound 4 (0.35g, 80%): [α]D 27–40.6(c 0.166,CHCl3)；1H NMR(400MHz,
CDCl3) δ 7.37-7.26 (m, 5H), 5.73 (ddd, J=17.0,10.5,6.3Hz, 1H), 5.59 (m, 1H), 5.40 (dd, J
=10.7,5.3Hz, 1H), 5.25-5.11 (m, 3H), 4.96-4.82 (m, 2H), 4.48 (s, 2H), 3.45 (t, J=6.4Hz,
2H),2.86(s,3H), 2.79–2.67(m,1H),2.06–1.99(m,1H),1.94–1.87(m,1H),1.74–1.57(m,
6H), 1.49-1.33 (m, 3H), 1.23-1.14 (m, 1H), 1.07 (d, J=6.9Hz, 3H), 0.97 (d, J=6.8Hz, 3H),
0.95 (d, J=7.0Hz, 3H), 0.93 (d, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ177.0,171.5,
144.9,138.5,136.1,128.3, 127.6,127.5,116.8,113.1,75.4,72.9,70.0,54.1,41.2,
37.1,36.9,34.00,33.98,30.9,29.4,25.0, 23.4,21.8,21.4,21.2,18.0；HRMS(ESI)m/z:
[M+Na]+Calcd for C29H45NO4Na 494.3240,found 494.3242。
Compound 4 (0.13g, 0.27mmol) is dissolved in CH2Cl2In (138mL), second generation Grubbs ' catalyst is added
(23.4mg, 0.027mmol), heated overnight at reflux, concentration of reaction solution, adds ethyl acetate to dilute and that Pd-C (20mg) is added is normal
Overnight, filtering collects filtrate concentration, crosses column purification (1:1PE:EtOAc, R for temperature reactionf=0.2) target compound 23 is obtained
(65mg, 67%): [α]D 27–55.0(c 0.1,CHCl3)；1H NMR(400MHz,CDCl3)δ5.04–4.97(m,1H),4.55–
4.48 (m, 1H), 3.59 (t, J=6.4Hz, 2H), 2.84 (s, 3H), 2.83-2.76 (m, 1H), 1.96 (br s, 1H),
1.80-1.86 (m, 4H), 1.72 (t, J=11.2Hz, 1H), 1.59-1.42 (m, 6H), 1.37-1.29 (m, 3H), 1.27-
1.24 (m, 1H), 1.07 (d, J=6.7 Hz, 3H), 0.96 (d, J=6.7Hz, 3H), 0.92 (d, J=6.5Hz, 3H), 0.83
(d, J=5.8Hz, 3H)；13C NMR(101 MHz,CDCl3)δ178.9,172.8,77.2,62.4,58.3,43.1,38.2,
35.2,34.1,33.6,32.3,31.3,30.6,28.8, 24.6,23.2,22.2,21.4,20.7,18.6；HRMS(ESI)m/
z:[M+H]+Calcd for C20H38NO4 356.2795, found 356.2794。
Compound 23 (42mg, 0.11mmol) is dissolved in CH2Cl2In (5mL), DMP (75.2mg, 0.17mmol) is added and room
Temperature stirring 2 hours.Add NaHCO3Solution (5mL) simultaneously uses CH2Cl2(10mL) extracts.It is concentrated and dried to obtain crude product.It will at 0 DEG C
NaHMDS (0.28mL of 1.0M in THF, 0.28mmol) is added to P (Ph)3CHI2The tetrahydro of (179mg, 0.33mmol)
In tetrahydrofuran solution (10mL), -78 DEG C are cooled to, crude product (37.4mg, 0.4mmol) before is dissolved in THF (2mL) and dropwise
Is added to react 3 hours, adds ammonium chloride solution to quench, ethyl acetate is added to extract, crosses column purification (9:1PE:EtOAc, Rf=0.2)
It obtains target compound 3 (39.1mg, 69%): [α]D 27–46.3(c 0.11,CHCl3)；1H NMR(400MHz,CDCl3)δ6.22
(d, J=7.4Hz, 1H), 6.16-6.12 (m, 1H), 5.07-5.01 (m, 1H), 4.58-4.49 (m, 1H), 2.87 (s, 3H),
2.85-2.78 (m, 1H), 2.16-2.11 (m, 2H), 1.91-1.82 (m, 3H), 1.75 (t, J=11.3Hz, 1H), 1.68-
1.50 (m, 6H), 1.45-1.31 (m, 4H), 1.10 (d, J=7.7Hz, 3H), 0.98 (d, J=6.7Hz, 3H), 0.94 (d, J
=6.5Hz, 3H), 0.86 (d, J=5.8Hz, 3H)；13C NMR(101MHz,CDCl3)δ178.8,172.9,140.4,83.1,
58.3,43.1, 38.3,34.8,34.3,34.2,33.6,31.4,30.5,29.7,28.9,24.7,23.6,23.2,22.2,
20.7,18.6；HRMS(ESI) m/z:[M+H]+Calcd for C21H36INO3 478.1812,found 478.1813。
CuI (6.0mg, 0.03mmol, 1.0eq) is added in tube sealing, segment 2 (13.4mg, 0.095mmol, 3.0eq),
Cs2CO3The protection of (30.7mg, 0.094mmol, 3.0eq) argon gas, addition N, N'- dimethyl amine (6.1 μ L, 0.062mmol,
2.0eq), the segment 3 (15mg, 0.03mmol) being dissolved in 2.0mL toluene solution is added, 36h is reacted in 90 DEG C of heating.Reaction solution
Filtering, adds ethyl acetate to extract, by preparing thin layer chromatography (7:3PE:EtOAc, Rf=0.2) natural products is obtained
Kanamienamide (6.43mg, 42%).[α]D 27–42.7(c 0.044,CHCl3),lit.4[α]D 26.8- 47.0 (c=
0.15, CHCl3)；1H NMR(600MHz,C6D6) δ 5.92 (br s, 1H), 5.20 (s, 1H), 4.96 (dt, J=11.0,
5.5Hz, 1H), 4.89 (q, J=7.4Hz, 1H), 4.40 (dd, J=11.4,3.7Hz, 1H), 3.15 (s, 3H), 3.11 (q, J
=7.2Hz, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.60 (dt, J=10.5,5.2Hz, 1H), 2.01 (t, J=
11.9Hz, 1H), 1.90 (td, J=12.0,9.9,3.8Hz, 1H), 1.87 (m, 1H), 1.67 (m, 1H), 1.50 (m, 1H),
1.40 (m, 1H), 1.36 (m, 1H), 1.31 (t, J=7.4 Hz, 3H), 1.22 (m, 1H), 1.20 (m, 1H), 1.13 (dd, J=
6.8,10.1Hz, 2H), 1.04 (d, J=6.6Hz, 3H), 0.99 (dd, J=14.1,8.8Hz, 2H), 0.94 (m, 1H), 0.91
(d, J=6.6Hz, 3H), 0.88 (d, J=7.5Hz, 1H), 0.79 (m, 1H), 0.79 (d, J=6.7Hz, 3H), 0.75 (d, J
=6.6Hz, 3H)13C NMR(101MHz,C6D6)δ177.95, 174.68,172.67,166.60,130.99,126.01,
91.34,76.80,58.45,54.56,43.64,38.46,35.42,34.85, 34.52,33.65,31.78,30.87,
28.67,27.09,25.95,24.99,24.73,23.23,22.52,20.82,19.01,12.55. HRMS(ESI)m/z:[M+
Na]+Calcd for C28H48IN2O5Na 515.3455,found 515.3456。
Embodiment 2
24 synthesis
According to the synthetic route of embodiment 1, compound 7 (S)-((the iodo- 2- methyl of 3-) benzyl) propyl ether of step 1 is replaced
(S)-((the iodo- 2- ethyl of 3-) benzyl) propyl ether is changed into, by the same way up to compound 24, MS (ESI) m/z:[M+H]+
=521.
Embodiment 3
25 synthesis
According to the synthetic route of embodiment 1, by compound 9 (S) -2- ((tertiary fourth oxygen formoxyl) (methyl) ammonia of step 2
Base) -4- methylvaleric acid replaces with (S) -2- ((tertiary fourth oxygen formoxyl) (methyl) amino) butyric acid.By the same way up to change
Close object 25, MS (ESI) m/z:[M+H]+=465.
Embodiment 4
27 synthesis
According to the synthetic route of embodiment 1, by compound 9 (S) -2- ((tertiary fourth oxygen formoxyl) (methyl) ammonia of step 2
Base) -4- methylvaleric acid replaces with (S) -2- ((tertiary fourth oxygen formoxyl) (methyl) amino) benzenpropanoic acid.By the same way to obtain the final product
Compound 27, MS (ESI) m/z:[M+H]+=527.
Embodiment 5
28 synthesis
According to the synthetic route of embodiment 1, by compound 9 (S) -2- ((tertiary fourth oxygen formoxyl) (methyl) ammonia of step 2
Base) -4- methylvaleric acid replaces with (S) -2- ((tertiary fourth oxygen formoxyl) (methyl) amino) -3 Methylbutanoic acid.By the same way
Up to compound 28, MS (ESI) m/z:[M+H]+=507.
Embodiment 6
30 synthesis
According to the synthetic route of embodiment 1, the amyl- 2- enamine of compound 2 (E) -3- methoxy-. N-methyl of step 3 is replaced
It is changed to (E) -3- methoxyl group -5- methyl-N-methyl hex- 2- enamine.By the same way up to compound 30, MS (ESI) m/z:
[M+H]+=521.
Anti-tumor biological measurement
MTT colorimetric bio activation measurement is to A549, MCF7, the inhibitory activity measuring method of A375 cell Proliferation.
By tumor cell line A549 (ATCC), MCF7 (ATCC) and A375 (ATCC) cell with 5000 cells/every hole
Density is inoculated on 96 orifice plates.At 37 DEG C after plating cells, 5%CO2Overnight incubation 18h in incubator.By cell testedization
Close serial dilution processing of the object in culture medium (ultimate density containing 0.3%DMSO).The test-compound of each concentration is equal
Do two parallel holes.Control wells are that the maximum concentration of doubling dilution is respectively 5 μM/L (A549), 1 μM/L (A375), 5 μM/L
(MCF7) the diluted DOX solution of DMEM culture medium.Cell after dosing continues at 37 DEG C, 5%CO2It is cultivated in incubator
72h.Microscopically observation cell activity situation after culture, microplate reader measures absorbance after MTT colorimetric determination, calculates
Median lethal dose (IC of each compound in different tumour cells50), it is as a result as follows:
Claims (21)
1. at least one Formulas I compound represented and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate,
Wherein:
R1It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Heteroaryl, C4-14
Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle is unsubstituted or optionally by one
It is a or multiple be independently selected from hydrogen, halogen, C1-6Alkyl, C1-6The group of alkoxy, hydroxyl and halogenated alkyl replaces；
R2It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Heteroaryl, C4-14
Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle is unsubstituted or optionally by one
It is a or multiple be independently selected from hydrogen, halogen, C1-6Alkyl, C1-6The group of alkoxy, hydroxyl and halogenated alkyl replaces；
R3It is independently selected from hydrogen, halogen, C1-6Alkyl, C3-8Naphthenic base, C1-6Alkoxy, hydroxyl, C6-14Aryl, C6-14Aralkyl, C6-14
Heteroaryl, C4-14Heterocycle, alkenyl, halogenated alkyl, wherein C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle is unsubstituted
Or optional hydrogen, halogen, C are independently selected from by one or more1-6Alkyl, C1-6The base of alkoxy, hydroxyl and halogenated alkyl
Group replaces；
R4It is independently selected from hydrogen, C1-6Alkyl, C3-8Naphthenic base, hydroxyl, C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle；
R5It is independently selected from hydrogen, C1-6Alkyl, C3-8Naphthenic base, hydroxyl, C6-14Aryl, C6-14Heteroaryl and C4-14Heterocycle；
R6It is independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C6-14Aryl, C6-14Heteroaryl, C4-14Heterocycle, alkene
Base and halogenated alkyl；
R7It is independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C6-14Aryl, C6-14Heteroaryl, C4-14Heterocycle, alkene
Base and halogenated alkyl；
L1And L2It is independently selected from C1-6Alkylidene, C3-8Cycloalkylidene, C6-14Arlydene, C6-14Sub- heterocycle；
M, n are independently selected from 1,2,3,4,5 and 6.
2. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein R1、R2Separately it is selected from methyl, ethyl, isopropyl and cyclopropyl.
3. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein R3Independently selected from isobutyl group, neopentyl, phenyl and benzyl.
4. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein R4It is methyl.
5. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein R5It is methyl.
6. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein R6Independently selected from methyl, ethyl, isopropyl and cyclopropyl.
7. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein R7It is methyl.
8. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein L1And L2It is methylene respectively.
9. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its
Solvate, wherein m=1.
10. compound as described in claim 1 and/or its pharmaceutically acceptable salt and/or stereoisomer, and/or
Its solvate, wherein n=1.
11. at least one compound and/or its pharmaceutically acceptable salt and/or stereoisomer and/or its solvent close
Object is selected from:
12. a kind of pharmaceutical composition, comprising at least one compound of claim 1-11 and/or its is pharmaceutically acceptable
Salt and/or stereoisomer and/or its solvate, and at least one pharmaceutically acceptable carrier.
13. at least one compound and/or its pharmaceutically acceptable salt and/or stereoisomer of claim 1-11,
And/or pharmaceutical preparation made of its solvate and one or more pharmaceutical carriers and/or diluent, it is pharmaceutically acceptable
Any dosage form.
14. compound and/or its pharmaceutically acceptable salt and/or stereoisomer as described in claim 1-11, and/
Or its solvate, purposes in the preparation of antitumor drugs.
15. a kind of synthetic method of the compound as shown in Formula II (Kanamienamide), described method includes following steps:
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
16. synthetic method as described in claim 15, it is characterised in that with compound 12 be starting material, through peroxidation
Answer, Witting reaction, hydroxyl deprotection, oxidation alcoholic extract hydroxyl group obtain intermediate 5.
17. synthetic method as described in claim 15, it is characterised in that it with reported compound 18 is starting material, warp
Ester condensation reaction is crossed, amino is deprotected to obtain title intermediate 6.
18. synthetic method as described in claim 15, it is characterised in that with reported compound 21 be raw material, by water
Solution reaction, condensation reaction obtain title intermediate 2.
19. synthetic method as described in claim 15, it is characterised in that obtained intermediate 5 and intermediate 6 are passed through acyl
Amine condensation reaction obtains intermediate 4.
20. such as the synthetic method stated in claim 15, it is characterised in that obtained intermediate 4 is passed through Grubbs alkene subdivision
Solution reaction, reduction reaction, then hydroxyl Deprotection, oxidation, Stork-Zhao-Wittig react to obtain key intermediate 3.
21. synthetic method as described in claim 15, it is characterised in that by obtained intermediate 3 and intermediate 2, pass through
Heck coupling reaction obtains natural products Kanamienamide.
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