CN106478655B - Gambogic acid compounds with anti-tumor activity and its preparation method and application - Google Patents
Gambogic acid compounds with anti-tumor activity and its preparation method and application Download PDFInfo
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
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Abstract
The present invention relates to gambogic acid compounds with anti-tumor activity and its preparation method and application, belong to field of medicinal chemistry.For the present invention on the basis of fully realizing existing compound activity, design has synthesized a variety of gambogic acid-type derivatives, and carries out anti-tumor biological research to it, obtains improved antitumoral compounds.The present invention specifically provides logical formula (I) compound represented or its pharmaceutically acceptable salt, its pharmaceutical composition, preparation method and is used to prepare the purposes for treating or preventing the pharmaceutical composition of disease:
Description
Technical field
The present invention relates to active gambogic acid-type derivatives of a kind of new antitumoral and its preparation method and application, belong to medicine
Object chemical field.
Background technique
Gamboge, is dry resin secreted by Garcinia maingayii gamboge, and Chinese medicine tradition is used for detumescence, detoxification, hemostasis.
Recent study shows that gamboge also has antitumor action, and it is equal to be used clinically for treatment breast cancer, lymphosarcoma, cutaneum carcinoma
Certain curative effect is obtained, therefore is paid high attention to.
Gambogicacid (gambogic acid, GA) is chemical combination with anti-tumor activity isolated from Chinese medicine gamboge
Object has the characteristics that antitumor spectra compared with wide, toxicity is lower, can selectively kill cancer cell, and to normal hemopoietic system
It is influenced with leucocyte smaller.The compound and the anti-tumor drug as high-efficiency low-toxicity, can be played antitumor by different mechanisms
Effect, including inducing cell cycle arrest and Apoptosis inhibit Telomerase and topoisomerase active, Antineoplastic angiogenesis
And metastases, reverse multidrug drug resistance etc..However, there is also water-soluble poor, degradable and bioavilability is lower for gambogicacid
Deng the deficiency urgently improved.For this purpose, scientists show keen interest to the exploitation of gambogic acid-type derivative, to suchization
The exploration for closing object also deepens continuously.
For the present invention on the basis of fully realizing existing compound activity, design has synthesized a variety of gambogic acid-type derivatives,
And anti-tumor biological research is carried out to it, obtain improved antitumoral compounds.
Summary of the invention
The present invention provides logical formula (I) compound represented or its pharmaceutically acceptable salt:
Wherein, R1For H or selected from optionally by one or more RaSubstituted following groups: C1-6Alkyl-, C2-6Alkenyl-,
C3-10Naphthenic base-is selected from the heteroatomic 3-10 membered heterocycloalkyl of N, O and S, C comprising 1-36-14Aryl-is selected from comprising 1-3
N, the heteroatomic 5-14 unit's heteroaryl-of O and S ,-C (=O) Rb,-S (=O)2Rb;
R2Selected from O, S, OH, SH or optionally by one or more RaSubstituted following groups: C1-6Alkyl oxy-, C2-6Alkenyl
Oxygroup-, C3-10Cycloalkyl oxy-is selected from the heteroatomic 3-10 membered heterocycloalkyl oxygroup-of N, O and S, C comprising 1-36-14Aryl
Oxygroup-is selected from the heteroatomic 5-14 unit's heteroaryl oxygroup-of N, O and S, C comprising 1-31-6Alkyl sulfenyl-, C2-6Enylsulfanyl-,
C3-10Cycloalkylsulfanyl-is selected from the heteroatomic 3-10 membered heterocycloalkyl sulfenyl-of N, O and S, C comprising 1-36-14Artyl sulfo-,
The heteroatomic 5-14 unit's heteroaryl sulfenyl-of N, O and S ,-OC (=O) R are selected from comprising 1-3b,-OS (=O)2Rb, R2Between C-12
'sSingly-bound or double bond are indicated, wherein working as R2When for O or S, double bond is formed with C-12, works as R2For its in defined above
When its group, singly-bound is formed with C-12;
R3Selected from F, Cl, Br, I, OH, SH, CN or optionally by one or more RaSubstituted following groups: C1-6Alkyl-,
C2-6Alkenyl-, C3-C10Naphthenic base-, NRcRd, comprising 1-3 be selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C6-14Virtue
Base-is selected from the heteroatomic 5-14 unit's heteroaryl-of N, O and S ,-C (=O) R comprising 1-3b,-S (=O)2Rb,-OC (=O) Rb、-
OS (=O)2Rb;
R4Selected from-CHO ,-CH=N-OR5,-CH=N-OC (=O)-R6,-CH=N-OC (=O) O-R7,-CH=N-OC
(=O)-NH-R8,-C (=O) O-N=CH-R9;
R5Selected from H, OH or optionally by one or more RaSubstituted C1-6Alkyl oxy-;Connect R5C-4 and C-3 betweenSingly-bound or double bond are indicated, wherein working as R5When for H, C-4 and C-3 form double bond, work as R5When not being H, C-4 is formed with C-3
Singly-bound;
RaIndependently selected from F, Cl, Br, I, OH, SH, CN ,=O, NRcRd、C1-6Alkyl-, C2-6Alkenyl-, C3-C10Cycloalkanes
Base-is selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C comprising 1-36-14Aryl-is selected from N, O and S comprising 1-3
Heteroatomic 5-14 unit's heteroaryl-, C1-6Alkyl oxy-, C2-6Alkenyl oxygroup-, C3-C10Cycloalkyl oxy-includes 1-3 choosing
From the heteroatomic 3-10 membered heterocycloalkyl oxygroup-of N, O and S, C6-14Aryloxy-includes 1-3 heteroatomic selected from N, O and S
5-14 unit's heteroaryl oxygroup-,-C (=O) Rb,-S (=O)2Rb;
RbSelected from optionally by one or more RaSubstituted following groups: C1-6Alkyl-, C2-6Alkenyl-, C3-10Naphthenic base-,
NRcRd, comprising 1-3 be selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C6-14Aryl-is selected from N, O and S comprising 1-3
Heteroatomic 5-14 unit's heteroaryl-;
RcAnd RdIt is independently selected from H or optionally by one or more RaSubstituted following groups: C1-6Alkyl-, C2-6Alkene
Base-, C3-10Naphthenic base-is selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C comprising 1-36-14Aryl-includes 1-3
It is a to be selected from the heteroatomic 5-14 unit's heteroaryl-of N, O and S.
According to the present invention, R1Preferably H or optionally by one or more RaSubstituted following groups: C1-6Alkyl-, C2-6Alkene
Base-, C3-10Naphthenic base-,-C (=O) Rb,-S (=O)2Rb;
R2It is preferably selected from O, S, OH, SH or optionally by one or more RaSubstituted following groups: C1-6Alkyl oxy-, C2-6
Alkenyl oxygroup-, C3-C10Cycloalkyl oxy-, C1-6Alkyl sulfenyl-, C2-6Enylsulfanyl-, C3-C10Cycloalkylsulfanyl-,-OC (=
O)Rb,-OS (=O)2Rb, R2Between C-12Singly-bound or double bond are indicated, wherein working as R2When for O or S, with C-12 shape
At double bond, work as R2When for other groups, singly-bound is formed with C-12;
R3It is preferably selected from F, Cl, Br, I, OH, SH, CN or optionally by one or more RaSubstituted following groups: C1-6Alkane
Base-, C2-6Alkenyl-, C3-10Naphthenic base-, NRcRd, comprising 1-3 be selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C6-14
Aryl-is selected from the heteroatomic 5-14 unit's heteroaryl-of N, O and S ,-C (=O) R comprising 1-3b,-S (=O)2Rb,-OC (=O)
Rb,-OS (=O)2Rb。
According to the present invention, R1More preferably H or optionally by one or more RaSubstituted C1-6Alkyl-,-C (=O) Rb、-S
(=O)2Rb;
R2It is more preferably selected from O, S, OH, SH or optionally by one or more RaSubstituted following groups: C1-6Alkyl oxy-,
C1-6Alkyl sulfenyl-,-OC (=O) Rb,-OS (=O)2Rb, R2Between C-12Singly-bound or double bond are indicated, wherein working as R2
When for O or S, double bond is formed with C-12, works as R2When for other groups, singly-bound is formed with C-12;
R3It is more preferably selected from F, Cl, Br, OH, SH or optionally by one or more RaSubstituted following groups: C1-6Alkyl-,
C3-10Naphthenic base-, NRcRd, comprising 1-3 be selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C6-14Aryl-includes 1-3
It is a to be selected from the heteroatomic 5-14 unit's heteroaryl-of N, O and S ,-OC (=O) Rb,-OS (=O)2Rb;
Optionally, R1Selected from H, C1-6Alkyl-or by one or more RaSubstituted C1-6Alkyl-;
R2Selected from O ,-OH or C1-6Alkyl-;
R3Selected from optionally by one or more RaSubstituted following groups: C1-6Alkyl-, C3-10Naphthenic base-, NRcRd, include
1-3 are selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C6-14Aryl-includes 1-3 heteroatomic selected from N, O and S
5-14 unit's heteroaryl-or-OC (=O) Rb,-OS (=O)2Rb。
According to the present invention, following formula (I ') and (I ") compound represented can be selected from by leading to formula (I) compound:
Wherein, group R1To R5The definition being each independently selected from logical formula (I).
According to the present invention, following formula (II ')~(VII ') and formula (II ") can also be illustratively selected from by leading to formula (I) compound
~(VII ") compound represented:
Wherein, R1~R2And R5The separately definition in above-mentioned logical formula (I), R3Selected from F, Cl, Br, I, OH,
SH, CN or optionally by one or more RaSubstituted following groups: C1-6Alkyl-, C2-6Alkenyl-, C3-C10Naphthenic base-, NRcRd、
The heteroatomic 3-10 membered heterocycloalkyl-of N, O and S, C are selected from comprising 1-36-14Aryl-is selected from the miscellaneous original of N, O and S comprising 1-3
The 5-14 unit's heteroaryl-of son ,-C (=O) Rb,-S (=O)2Rb,-OC (=O) Rb,-OS (=O)2Rb;
R6、R7、R8、R9、R10It is independently from each other H ,-C (=O) Rb,-S (=O)2Rb, optionally by one or more RaIt takes
The C in generation1-6Alkyl-, C2-6Alkenyl-, C3-10Naphthenic base-, comprising 1-3 selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S,
C6-14Aryl-is selected from the heteroatomic 5-14 unit's heteroaryl-of N, O and S comprising 1-3;
Ra、Rb、Rc、RdSeparately with the definition in above-mentioned logical formula (I).
Preferably, chemical combination shown in the logical formula (I) of the present invention, (I '), (I "), (II ')~(VII ') and (II ")~(VII ")
Object includes its optical pure compound, stereoisomer mixture or its pharmaceutically acceptable salt.
Term definition and explanation
Term " C1-6Alkyl " is interpreted as the preferred linear or branching for indicating to have 1,2,3,4,5 or 6 carbon atom
It is saturated monovalent hydrocarbon, such as methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, isobutyl group, sec-butyl, tert-butyl, different
Amyl, 2- methyl butyl, 1- methyl butyl, 1- ethyl propyl, 1,2- dimethyl propyl, neopentyl, 1,1- dimethyl propyl, 4-
Methyl amyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 2- ethyl-butyl, 1- ethyl-butyl, 3,3- dimethyl butyrate
Base, 2,2- dimethylbutyl, 1,1- dimethylbutyl, 2,3- dimethylbutyl, 1,3- dimethylbutyl or 1,2- dimethyl butyrate
Base or their isomers.Particularly, the group has 1,2,3 or 4 carbon atom (" C1-4Alkyl "), such as methyl, second
Base, propyl, butyl, isopropyl, isobutyl group, sec-butyl, tert-butyl, more particularly, the group have 1,2 or 3 carbon atom
(“C1-3Alkyl "), such as methyl, ethyl, n-propyl or isopropyl.
Term " C2-6Alkenyl " is interpreted as preferably indicating linear or branching monovalent hydrocarbon, and it includes one or more
Double bond and have 2,3,4,5 or 6 carbon atom (" C of carbon atom, especially 2 or 32-3Alkenyl "), it should be appreciated that in the alkene
In the case that base includes more than one double bond, the double bond can be separated from each other or be conjugated.The alkenyl is such as vinyl, alkene
Propyl, (E) -2- methyl ethylene, (Z) -2- methyl ethylene, (E)-but-2-ene base, (Z)-but-2-ene base, (E)-butyl- 1-
Alkenyl, (Z)-but-1-ene base, amyl- 4- alkenyl, (E)-amyl- 3- alkenyl, (Z)-amyl- 3- alkenyl, (E)-amyl- 2- alkenyl, (Z)-
Amyl- 2- alkenyl, (E)-amyl- 1- alkenyl, (Z)-amyl- 1- alkenyl, hex- 5- alkenyl, (E)-hex- 4- alkenyl, (Z)-hex- 4- alkenyl,
(E)-hex- 3- alkenyl, (Z)-hex- 3- alkenyl, (E)-hex- 2- alkenyl, (Z)-hex- 2- alkenyl, (E)-hex- 1- alkenyl, (Z)-hex-
1- alkenyl, isopropenyl, 2- methyl propyl- 2- alkenyl, 1- methyl propyl- 2- alkenyl, 2- methyl propyl- 1- alkenyl, (E) -1- methyl propyl-
1- alkenyl, (Z) -1- methyl propyl- 1- alkenyl, 3- methyl butyl- 3- alkenyl, 2- methyl butyl- 3- alkenyl, 1- methyl butyl- 3- alkenyl, 3-
Methyl but-2-ene base, (E) -2- methyl but-2-ene base, (Z) -2- methyl but-2-ene base, (E) -1- methyl but-2-ene base,
(Z) -1- methyl but-2-ene base, (E) -3- methyl but-1-ene base, (Z) -3- methyl but-1-ene base, (E) -2- methyl but-1-ene
Base, (Z) -2- methyl but-1-ene base, (E) -1- methyl but-1-ene base, (Z) -1- methyl but-1-ene base, 1,1- dimethyl propylene -
2- alkenyl, 1- ethyl propyl- 1- alkenyl, 1- propyl ethylene base, 1- isopropyl-ethylene base.
Term " C3-10Naphthenic base " be understood to mean that saturation monovalent monocyclic or bicyclic hydrocarbon ring, have 3,4,5,6,7,
8,9 or 10 carbon atoms.The C3-10Naphthenic base can be monocycle alkyl, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring
Heptyl, cyclooctyl, cyclononyl or cyclodecyl or for example decahydronaphthalene naphthalene nucleus of bicyclic alkyl.
Term " 3-10 membered heterocycloalkyl " mean saturation monovalent monocyclic or bicyclic hydrocarbon ring, it includes 1-3 selected from N, O and
S hetero atom.The Heterocyclylalkyl can pass through any of described carbon atom or nitrogen-atoms (if present) and molecule
Rest part connection.Particularly, the Heterocyclylalkyl can include but is not limited to: 4 member rings, such as azetidinyl, oxa-
Cyclobutane base;5 member rings, such as tetrahydrofuran base, dioxa cyclopentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolin
Base;Or 6 member rings, such as THP trtrahydropyranyl, piperidyl, morpholinyl, dithianyl, thiomorpholine base, piperazinyl or trithiane base;Or 7
Member ring, such as Diazesuberane basic ring.Optionally, the Heterocyclylalkyl can be benzo-fused.The heterocycle can be
Bicyclic, such as, but not limited to 5,5 member rings, such as hexahydro cyclopentano [c] pyrroles -2 (1H)-basic ring or 5,6 membered bicyclics, such as six
Hydrogen pyrrolo- [1,2-a] pyrazine -2 (1H)-basic ring.The nitrogen atom ring can be that part is unsaturated, i.e., it may include
One or more double bonds, such as, but not limited to 2,5- dihydro -1H- pyrrole radicals, 4H- [1,3,4] thiadiazine base, 4,5- dihydro-oxazole
Base or 4H- [Isosorbide-5-Nitrae] thiazine basic ring, alternatively, it can be benzo-fused, such as, but not limited to dihydro-isoquinoline basic ring.
Term " C6-14Aryl " is interpreted as preferred one indicated with 6,7,8,9,10,11,12,13 or 14 carbon atoms
Monocyclic, bicyclic or tricyclic the hydrocarbon ring (" C of valence armaticity or partial aromatic6-14Aryl "), especially with the ring of 6 carbon atoms
(“C6Aryl "), such as phenyl;Or xenyl, or the ring (" C with 9 carbon atoms9Aryl "), such as indanyl or indenes
Base, or the ring (" C with 10 carbon atoms10Aryl "), such as tetrahydro naphthyl, ihydro naphthyl or naphthalene, or tool
There is the ring (" C of 13 carbon atoms13Aryl "), such as fluorenyl, or the ring (" C with 14 carbon atoms14Aryl "), such as
Anthryl.
Term " 5-14 unit's heteroaryl " is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring system, tool
There are 5,6,7,8,9,10,11,12,13 or 14 carbon atoms of annular atom, especially 5 or 6 or 9 or 10, and it includes at least one
A hetero atom (hetero atom is such as oxygen, nitrogen or sulphur) that can be identical or different, also, in addition at each occurrence may be used
It is benzo-fused.Particularly, heteroaryl is selected from thienyl, furyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrazoles
Base, isoxazolyl, isothiazolyl, oxadiazoles base, triazolyl, thiadiazolyl group, thiophene -4H- pyrazolyl etc. and their benzo spread out
Biology, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzo isoxazolyl, benzimidazolyl, benzotriazole base,
Indazolyl, indyl, isoindolyl etc.;Or pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical etc. and their benzene
And derivative, such as quinolyl, quinazolyl, isoquinolyl etc.;Or azocine base, indolizine base, purine radicals etc. and they
Benzo derivative;Or cinnoline base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridines base, pteridyl, carbazyl, acridinyl, azophenlyene
Base, phenothiazinyl, phenoxazine base etc..
Unless otherwise indicated, the heteroaryl or inferior heteroaryl include its all possible isomeric form, such as its position
Isomers.Therefore, for some illustrative non-limiting examples, term pyridyl group or sub-pyridyl group include pyridine -2- base, Asia
Pyridine -2- base, pyridin-3-yl, sub- pyridin-3-yl, pyridin-4-yl and sub- pyridin-4-yl;Alternatively, term thienyl or sub- thiophene
Pheno base includes thiophene -2- base, Asia thiophene -2- base, thiene-3-yl and sub- thiene-3-yl.
Term " substituted " means that one or more hydrogen on specified atom are replaced by listed group, and condition is not
More than specified atom normal atom valency in the current situation and the substitution forms stable compound.Substituent group
And/or the combination of variable is only just allowed when this combination forms stable compound.
Term " optionally quilt ... replace " refers to can be unsubstituted or to be replaced by listed group.
The substituent group of ring system refers to that the substituent group connecting with aromatics or non-aromatic ring system, such as the substituent group replace the ring
Fasten available hydrogen.
Term " one or many " used in the substituent group definition of each general formula compound of the present invention is understood to include one
It is secondary, twice, three times, four times or five times, especially once, twice, three times or four times, more particularly once, twice or thrice, example
As once or twice.
The present invention also provides gambogic acid-type derivative shown in formula (I) or the preparation method of its pharmaceutically acceptable salt, packets
Include the combination selected from following one or more steps:
Step 1):
Can be by methods known in the art, such as through over-churning, reduction, oxidation reaction, chemical combination is prepared by compound (a)
Object (b).Wherein:
In the esterification reaction, preferably in catalyst such as 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride
(EDCI) and in the presence of 4-dimethylaminopyridine (DMAP), by compound (a) and alcohol (such as C1-12Alcohol) reaction to prepare
The ester of compound (a);
In reduction reaction, the ester of compound (a) is reacted in the presence of a reducing agent, obtains corresponding reduzate,
The suffered preferred diisobutyl aluminium hydride of reducing agent;
In the oxidation reaction, reduzate is reacted in the presence of oxidant, obtains compound (b).
As an example, can be for example, by application number 201310682918.4, the Chinese invention of publication number CN103613602A
The method that patent specification [0004] to [0019] section is recorded carries out, and the content that the full text of this application is recorded is incorporated herein invention
Content.
Specific embodiment according to the present invention, step 1) include the following steps a)~c):
A): under the effect of the catalyst, compound (a) (such as gambogicacid) and alcohols (such as methanol) are condensed to yield compound
(a) ester (such as gamboge acid esters);
Reaction temperature can be such as -30 DEG C~30 DEG C, and reaction is preferably carried out under nitrogen protection in organic solvent, is had
The preferred methylene chloride of solvent, the preferred 1- ethyl-of catalyst (3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/
Or 4-dimethylaminopyridine (DMAP);
B): the ester of compound (a) reacts in the presence of a reducing agent in organic solvent, obtains corresponding reduzate;
Reaction temperature can be such as -78 DEG C~-40 DEG C, and reaction preferably carries out in organic solvent, and organic solvent is preferred
For methylene chloride, reducing agent is diisobutyl aluminium hydride;
C): the reduzate of step b) reacts in the presence of oxidant, obtains compound (b);
Reaction temperature can be such as -30 DEG C~30 DEG C, and reaction preferably carries out in organic solvent, and organic solvent is preferably
Methylene chloride, the preferred tetramethyl piperidine oxides of oxidant (TEMPO) and/or iodobenzene diacetate (BAIB).
If desired, carrying out step 2):
Wherein, the oxidation is carried out by any suitable reactions known in the art.As example, the oxidation can be selected
From such as Ao Benaoer oxidation, (Oppenauer Oxidation, oxidant are Al (O-i-Pr)3/ acetone), Dai Si-Martin's oxygen
Change reaction (Dess-Martin Oxidation, oxidant are that Dai Si-Martin crosses iodine alkane or DMP) or polite oxidation reaction
(Swern Oxidation, oxidant DMSO);
Or
Wherein, the etherificate is carried out by any appropriate method known in the art.As example, the etherificate can lead to
It crosses dehydration or Williamson synthesis (Williamson Synthesis) carries out.Such as by compound (b) and alcohol or mercaptan
It is dehydrated in presence of an acid, or converts compound (b) to after sodium alkoxide or mercaptan sodium compound and halogenated compound (such as alkyl halide
Hydrocarbon) reaction.
Step 3):
Wherein, the reaction preferably carries out under alkaline condition;It is highly preferred that the reaction carries out in the presence of base;
Step 4):
Wherein, each reaction preferably carries out under alkaline condition;It is highly preferred that the reaction carries out in the presence of base;
Or
It is described reaction preferably catalyst 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/
Or it is carried out in the presence of alkali;
Or use identical method, by following compounds (e ") and (f ") prepare corresponding compound (III ")~
(VII "):
And step 5):
Optionally, by step 1)~4) resulting compound reacts that prepare its pharmaceutically acceptable with acid appropriate or alkali
Salt;
Wherein, R1~R3、R5To R10It is respectively provided with the definition being independently selected from logical formula (I);
R2aSelected from OH or SH;
R2bSelected from O or S;
R2cSelected from optionally by one or more RaSubstituted following groups: C1-6Alkyl oxy-, C2-6Alkenyl oxygroup-, C3-
C10Cycloalkyl oxy-is selected from the heteroatomic 3-10 membered heterocycloalkyl oxygroup-of N, O and S, C comprising 1-36-14Aryloxy-, packet
The heteroatomic 5-14 unit's heteroaryl oxygroup-of N, O and S, C are selected from containing 1-31-6Alkyl sulfenyl-, C2-6Enylsulfanyl-, C3-C10Ring
Alkyl sulfenyl-is selected from the heteroatomic 3-10 membered heterocycloalkyl sulfenyl-of N, O and S, C comprising 1-36-14Artyl sulfo-includes 1-
3 are selected from the heteroatomic 5-14 unit's heteroaryl sulfenyl-of N, O and S ,-OC (=O) Rb,-OS (=O)2Rb, wherein RaAnd RbIndependent choosing
The group defined from formula (I);
X is selected from chlorine, bromine or iodine;
Z is selected from hydrogen, chlorine or bromine.
In the preparation process in accordance with the present invention, if it is desired, any suitable method that this field can be used will have instead
It is reacted again after answering active radical protection.As example, can be used as alcoholic extract hydroxyl group protecting group can be such as acetyl group, 2-
Methoxyl group ethoxymethyl ether, methoxyl methyl ether, to methoxy-benzyl ether, pivaloyl group, oxinane etc.;It can be used as amino
Protecting group can be such as benzyloxycarbonyl group, tertbutyloxycarbonyl, benzyl, p-methoxyphenyl;Can be used as carbonyl-protection base can
Think such as acetal and ketal, acylal, dithiane;Can be used as carboxyl-protecting group can be methyl ester base, benzyl ester
Base, tert-butyl ester group, silicon substrate ester group etc..
For example, can be by the R of step 1) compound (a)2bRadical protection is obtained using esterification, reduction, deprotection reaction
Compound (c).
Above steps can carry out in the presence of suitable solvent.The solvent is times inert at reaction conditions
What organic solvent, including being selected from for example following one or more mixtures: ketone, such as acetone and methyl ethyl ketone;It is acyclic
Ether and cyclic ethers, such as ether and tetrahydrofuran;Ester, such as ethyl acetate or butyl acetate;Hydrocarbon, such as benzene, first
Benzene, dimethylbenzene, hexane and hexamethylene;Chlorinated hydrocabon, such as monochloro methane, methylene chloride, chloroform, 1,2- dichloroethanes and chlorine
Benzene;Alcohol, such as methanol, ethyl alcohol, n-propanol, isopropanol, n-butanol or tert-butanol;Or other solvents, such as N, N-
Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP), acetonitrile or pyridine;
The alkali can be or mixtures thereof organic base, inorganic base, such as selected from alkali metal or alkaline earth metal carbonate
Or bicarbonate, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, saleratus, calcium bicarbonate;
Alkali metal alcoholates, such as tert-butanol sodium or potassium tert-butoxide;Alkali metal hydride, such as sodium hydride or hydrofining;Ammonification
Object, such as bis- (trimethyl silyl) lithium amides, bis- (trimethyl silyl) potassamides or lithium diisopropylamine
(LDA);Organic amine, such as triethylamine, N-methylmorpholine, N- methyl piperidine, n,N-diisopropylethylamine, 1,5- diazabicyclo
[4.3.0] nonyl- 5- alkene (DBN), 1,8- diazabicyclo [5.4.0] decyl- 7- alkene (DBU), pyridine or 4-N, N- dimethylamino
Yl pyridines;Or phosphonitrile alkali triethylamine, pyridine, piperidines, 4-dimethylaminopyridine (DMAP);
The alkali can specifically be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, saleratus, sodium hydroxide, hydrogen
One of potassium oxide, sodium hydride or a variety of mixtures;
Wherein, the acid can be or mixtures thereof organic acid, inorganic acid, such as selected from following one or more: carboxylic
Acid, such as acetic acid or trifluoroacetic acid;Sulfonic acid, such as methanesulfonic acid, trifluoro methylsulphur or p- toluenesulfonic acid;Hydrochloric acid, sulfuric acid, phosphoric acid,
Phosphonic acids or phosphoric acid.
Above steps can be carried out independently at suitable temperature, such as -30 DEG C~30 DEG C (such as room temperature).
As example, the compounds of this invention can be prepared by the combination selected from following one or more steps:
Wherein, R1~R3And R5The definition being each independently selected from logical formula (I);
R6、R7、R8、R9、R10It is independently from each other H ,-C (=O) Rb,-S (=O)2Rb, optionally by one or more RaIt takes
The C in generation1-6Alkyl-, C2-6Alkenyl-, C3-10Naphthenic base-, comprising 1-3 selected from the heteroatomic 3-10 membered heterocycloalkyl-of N, O and S,
C6-14Aryl-is selected from the heteroatomic 5-14 unit's heteroaryl-of N, O and S comprising 1-3.
As example, the preparation method of the compounds of this invention includes combining selected from following one or more steps:
Step a): in organic solvent, under nitrogen protection, under the action of oxidant, the oxidation of compound 8 obtains compound
2;The preferred methylene chloride of organic solvent, oxidant are preferably (1,1,1- triacetoxyl group) -1,1- dihydro -1,2- benzenesulfonyl -3
(1H) -one (Dess-Martin oxidant, DMP);
Step b): in organic solvent, under nitrogen protection, in the presence of alkali, compound 9 reacts to obtain with hydroxylamine hydrochloride
Compound 10;Organic solvent is preferably ethyl alcohol, and alkali is preferably pyridine, triethylamine;
Step c): in organic solvent, in the presence of alkali, compound 10 and halohydrocarbons reaction obtain oxime ethers chemical combination
Object 3;Organic solvent is preferably tetrahydrofuran (THF), dimethylformamide (DMF);Alkali is preferably sodium hydroxide (NaOH), hydrogenation
Sodium (NaH) etc.;
Step d): in organic solvent, under the action of alkali and catalyst, compound 10 and acyl chlorides or carboxylic acid reaction,
Obtain corresponding oxime ester compound 4;Organic solvent is preferably methylene chloride (DCM);The alkali can be organic base and nothing
Machine alkali, preferably pyridine, 4-dimethylaminopyridine (DMAP), sodium hydroxide etc., preferred 1- ethyl-(the 3- dimethylamino of catalyst
Base propyl) carbodiimide hydrochloride (EDCI);
Step e): in organic solvent, in the presence of alkali, compound 10 is reacted with chloro-formate, obtains corresponding carbon
Sour oxime ester compound 5;Organic solvent is preferably methylene chloride (DCM);The alkali can be organic base and inorganic base, preferably
For pyridine, 4-dimethylaminopyridine (DMAP), sodium hydroxide etc.;
Step f): in organic solvent, in the presence of alkali, compound 10 is reacted with isocyanates is replaced, and is obtained corresponding
Carbamide oxime ester compound 6;Organic solvent is preferably methylene chloride (DCM);The alkali can be organic base and inorganic
Alkali, preferably pyridine, 4-dimethylaminopyridine (DMAP), triethylamine etc.;
Step g): -30 DEG C~30 DEG C (such as room temperature) under the conditions of, in organic solvent, under the action of alkali and catalyst,
Gambogicacid is reacted with various oximes, obtains corresponding gambogicacid oxime ester compound 7;Organic solvent is preferably methylene chloride (DCM);
The alkali can be organic base and inorganic base, preferably pyridine, 4-dimethylaminopyridine (DMAP), sodium hydroxide etc., catalysis
The preferred 1- ethyl-of agent (3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI).
According to the present invention, those skilled in the art can also be by step 1)~5 each in above-mentioned preparation method) and each step a)~
G) arbitrary one or more steps and its actual conditions are combined or combine in, or with well known to a person skilled in the art steps
Rapid and actual conditions are combined or combine, and obtained method equally should be within the scope of the present invention.
The present invention also provides the pharmaceutical compositions comprising one or more the compounds of this invention or its pharmaceutically acceptable salt
Object.Desired pharmacotoxicological effect can be realized by being administered to patient with this need using these compositions.With regard to of the invention
For purpose, patient is the mammal including people for needing to treat specific conditions or diseases.Therefore, the present invention includes this
The pharmaceutical composition of sample, it includes the compound of the present invention of pharmaceutically acceptable carrier and pharmacy effective dose or its pharmaceutically
Acceptable salt.
The preferably such carrier of pharmaceutically acceptable carrier, with the consistent concentration of the effective active of active constituent
Under to patient's relative nontoxic and harmless so that any side effect as caused by the carrier will not destroy the active constituent
Beneficial effect.The pharmacy effective dose of compound or its pharmaceutically acceptable salt preferably generates the specific patient's condition being treated
Or the amount that has an impact as a result.Any effective conventional agent including quick-release, sustained release and time release formulation can be used
Unit form is measured, the compound of the present invention is given as follows together with pharmaceutically acceptable carrier well known in the art
Medicine: oral, parenteral, part, nasal cavity, eye, sublingual, rectum, vagina administration etc..
For oral administration, the compound or its pharmaceutically acceptable salt can be configured to solid or liquid preparation,
Such as capsule, pill, tablet, containing pastille (troche), pastille (lozenge), melten gel agent (melt), powder, solution, mixed
Suspension or emulsion, and can be prepared according to the method known in the art for being used to prepare pharmaceutical composition.Solid unit dosage form
It can be capsule, can be common ebonite bladder type or soft-capsule type, be filled including, for example, surfactant, lubricant and inertia
Agent (such as lactose, sucrose, calcium phosphate and cornstarch).
It in another embodiment, can be by the compound of the present invention or its pharmaceutically acceptable salt and conventional tablet bases
(such as lactose, sucrose and cornstarch) combines tabletted together and with following substance: adhesive (such as Arabic gum,
Cornstarch or gelatin), for tablet after adjunctive administration decomposition and dissolution disintegrating agent (such as potato starch, alginic acid, corn
Starch and guar gum, gum tragacanth, Arabic gum), the mobility for improving tablet granulation and prevent tablet material and piece
The lubricant (such as talcum, stearic acid or magnesium stearate, calcium stearate or zinc stearate) of the surface adhesion of agent mold and formed punch,
Dyestuff, colorant, and organoleptic properties for improving tablet and the flavoring agent for making them be easier to be accepted by patients (such as it is thin
Lotus oil, wintergreen or cherry essence).Suitable excipient for oral liquid dosage forms includes Dicalcium Phosphate and diluent, example
Such as water and alcohol (such as ethyl alcohol, benzyl alcohol and polyvinyl alcohol), pharmaceutically acceptable surfactant, suspending are added or not added
Agent or emulsifier.There may be various other substances as coating or for changing the physical form of dosage unit.Such as it can
Tablet, pill or capsule are coated with shellac, sugar or both.
Also the compound of the present invention can be subjected to parenteral administration with the injection dosage of the compound, i.e., subcutaneously, vein
Interior, intraocular, intrasynovial, intramuscular or Intraperitoneal medication, the injection dosage are preferably acceptable in the physiology containing pharmaceutical carrier
Diluent in, the pharmaceutical carrier can be the mixture of sterile liquid or liquid, the liquid such as water, salt water, glucose
Aqueous solution and relevant sugar juice, alcohol such as ethyl alcohol, isopropanol or hexadecanol, glycol such as propylene glycol or polyethylene glycol, glycerol
Ketal such as 2,2- dimethyl -1,1- dioxolanes -4- methanol, ether such as polyethylene glycol 400 (PEG400), oil, fatty acid, rouge
Fat acid esters or fatty glyceride or acetylated fatty acid glyceride, the diluent add or not added with pharmaceutically acceptable
Surfactant, such as soap or detergent, suspending agent for example pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or
Carboxymethyl cellulose or emulsifier and other pharmaceutical auxiliaries.
Exemplary surfactants for parenteral administration are polyethylene sorbitan fatty acid esters, such as de-
The high molecular weight adducts of water sorbitol monooleate and ethylene oxide and hydrophobic base, the hydrophobic base by
Propylene oxide and propylene glycol are condensed to be formed.
It can will be also administered in the form of the suppository of the rectally of composition of the invention to be used for drug.It can be by by drug
It is liquid under rectal temperature and therefore can dissolves in the rectum and discharge the drug with is at normal temperature solid
Suitable nonirritant excipient mixes to prepare these compositions.Substance of this kind is such as cocoa butter and polyethylene glycol.
Controlled release preparation for parenteral administration includes liposome microballoon, polymer microballoon and polymer known in the art
Gel preparation.
It may need or described pharmaceutical composition must be delivered to patient by mechanical delivery device.For delivering medicament
Mechanical delivery device construction and purposes be well known in the art.Such as the direct technology that drug is administered directly to brain is usual
It is related to drug delivery tube being placed in the ventricular system of patient around blood-brain barrier.
The compound of the present invention can be administered as single medicament or be administered with one or more other pharmaceutical agent combinations,
Described in combination will not cause unacceptable adverse reaction.The invention further relates to such combinations.For example, can be by change of the invention
Close object and known chemotherapeutics or anticancer agent (such as anti-hyperproliferative disease or the medicament of other indications etc.) and and it
Mixture and combination be combined.Other indication medicaments include but is not limited to anti-angiogenic agent, mitosis inhibition
Agent, alkylating agent, antimetabolite, DNA- are embedded in antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topology
Isomerase inhibitors, biological response modifier or antihormones.
In general, cytotoxic agent and/or cytostatics and the compound of the present invention or combination of compositions are used
It can play the role of following:
(1) compared with being administered alone any medicament reduce tumour growth or even be eliminated in tumour side generate it is more preferable
The effect of,
(2) allow to be administered lesser amount of chemotherapeutic agents be administered,
(3) chemotherapeutic agent is provided, is well tolerated by the patient and harmful pharmacology complication ratio for having is in list
It is few what is observed in one medicament chemotherapy and certain other combination treatments,
(4) allow the various cancers type of the wider array of mammal of therapeutic domain (especially people),
(5) higher response in subject is provided,
(6) the longer time-to-live is provided compared with the chemotherapeutic treatment of standard in subject,
(7) the longer tumor development time is provided, and/or
(8) combined with other cancer agents generate antagonistic effect known case compare, obtain at least with exclusive use
Medicament equally good effect and tolerance.
Another aspect of the present invention provides compound as described above and is used to prepare the medicine group for treating or preventing disease
Close the purposes of object.
The disease is by the growth of uncontrolled cell, proliferation and/or survival, unsuitable cellullar immunologic response or not
Disease caused by cellular inflammation response appropriate, or with the growth of uncontrolled cell, proliferation and/or survive, inappropriate
Cellullar immunologic response or unsuitable cellular inflammation response disease, particularly, the disease be such as neoplastic hematologic disorder, entity
Tumor and/or their transfer, as leukaemia and myelodysplastic syndrome, malignant lymphoma including brain tumor and brain metastes exist
Interior head and tumor colli, the breast tumor including non-fire power and small cell lung tumor, gastroenteric tumor,
Endocrine tumors, tumor of breast and other gynecological tumors, the urinary system including kidney neoplasms, bladder tumor and prostate tumor are swollen
Tumor, skin neoplasin and sarcoma, and/or their transfer.More particularly, the disease is cancer such as lung cancer.
In context of the invention, especially as used herein " unsuitable cellullar immunologic response is inappropriate
Cellular inflammation response " context in, term " unsuitable " be interpreted as it is preferred indicate it is weaker than normal response or it is stronger simultaneously
And the response of pathology that is related to the pathology of the disease, causing or lead to the disease.
Preferably, the purposes is the treatment or prevention for disease, wherein the disease is neoplastic hematologic disorder, solid tumor
And/or their transfer.
The present invention also provides the compound of the present invention and combinations thereof in the hyper-proliferative venereal disease for preparing treatment mammal
Purposes in the drug of disease.Can be inhibited using compound, block, reduce, reducing etc. cell Proliferations and/or cell division and/
Or cause apoptosis.Hyperproliferative disorders include but is not limited to psoriasis, keloid and other cutaneous hyperplasia, benign
Hyperplasia of prostate (BPH), solid tumor such as breast cancer, respiratory cancer, lung cancer, the cancer of the brain, genital cancer, digestive system cancer, uropoiesis
Road cancer, cancer eye, liver cancer, cutaneum carcinoma, head and neck cancer, thyroid cancer, parathyroid carcinoma and their far-end transfer.The illness is also
Including lymthoma, sarcoma and leukaemia.
These illnesss obtain good characterization in the mankind, but it is dynamic to be also present in other lactations with similar teiology
In object, and it can be treated by the way that pharmaceutical composition of the invention is administered.
The term " treatment " that this document refers in the whole text has that well known to a person skilled in the art conventional senses, such as in order to support
The anti-, purpose that mitigates, reduce, alleviate, improve the case where disease or illness of sarcoma etc. manages or nurses individual.
The present invention, which leads to compound shown in formula (I), has good inhibition to human leukemia, liver cancer and lung cancer tumor cell strain
Activity, to the IC of A-549 human lung carcinoma cell50It is worth < 0.05 μ g/mL.Specifically, compound of the embodiment of the present invention is to A-549
The IC of human lung carcinoma cell50It is worth≤0.02 μ g/mL.Preferably, compound of the embodiment of the present invention 12,13,14,18,20,25-30
To the IC of A-549 human lung carcinoma cell50It is worth≤0.01 μ g/mL.
Also, the compounds of this invention also has lower cytotoxicity to normal cell.Specifically, chemical combination of the present invention
Object, such as the IC of embodiment compound 12-19,21,27,37,38,40,41,42 couple HELF-650It is worth < 0.4 μ g/mL.
Dosage and administration
It is real based on the known standard for being used to evaluate the compound for treating hyperproliferative disorders and angiogenesis illness
Room technology is tested, by standard toxicity test and by for determining the standard of the treatment to illness described above in mammal
Pharmacology test, and by being compared these results with the result for the known drug for being used to treat these illnesss, it can hold
It changes places and determines the effective dose of the compound of the present invention for treating each expectation indication.In controlling for one of these illnesss
The amount of the active constituent of medicine given in treatment can be according to following consider and great changes will take place: used particular compound and dosage
Unit, administration mode, the course for the treatment of, the property and degree at the age of subject and gender and condition being treated.For example, wait give
The total amount of the active constituent of medicine is typically about 0.001mg/kg- about 200mg/kg body weight/day, and preferably from about 0.01mg/kg- is about
20mg/kg body weight/day.Clinically useful dosage regimen can be once a day to three times be administered to every four weeks it is primary to
Medicine.The desired therapeutic modality of the compound of the present invention or its pharmaceutically acceptable salt or ester or composition and administration quantity can
It is determined by those skilled in the art using conventional therapeutic test.
Specific embodiment
Technical solution of the present invention is described in detail below by way of illustrative specific embodiment.But it should not be by these
Embodiment is construed to limiting the scope of the invention.All technologies realized based on above content of the present invention are encompassed by this
Invention is intended in the range of protection.
Unless otherwise indicated, raw materials and reagents used in embodiment are commercial materials.
The preparation of 1 compound 2 of embodiment
Weigh the methylene chloride that monomethyl ether 8 (2.08g, 3.31mmol) is dissolved in 40mL, be added DMP (2.813g,
It 6.62mmol) reacts at room temperature 5 hours, the Na of saturation2S2O3With the NaHCO of saturation3Solution quenching reaction.Anhydrous ether extraction, is closed
And organic phase, the washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, is spin-dried for, and column chromatographic purifying obtains compound 2,1.83g,
Yield 88.4%.1H NMR(300MHz,CDCl3) δ 9.54 (s, 1H), 7.44 (d, J=6.8Hz, 1H), 6.64 (d, J=
10.2Hz, 1H), 6.13 (t, J=8.0Hz, 1H), 5.57 (d, J=10.2Hz, 1H), 5.20 (t, J=5.9Hz, 1H), 5.08
(t, J=6.5Hz, 1H), 3.78 (s, 3H), 3.55-3.45 (m, 1H), 3.44-3.26 (m, 2H), 3.13 (dd, J=14.9,
9.8Hz, 1H), 2.88 (dd, J=14.8,6.5Hz, 1H), 2.55 (d, J=9.3Hz, 1H), 2.33 (dd, J=13.4,
4.3Hz,1H),2.12–1.97(m,2H),1.88–1.80(m,1H),1.78(s,3H),1.73(s,3H),1.66(s,6H),
1.63–1.58(m,1H),1.56(s,3H),1.51(s,3H),1.48(s,3H),1.42–1.37(m,1H),1.31(s,3H)
.ppm;13C NMR(101MHz,CDCl3)δ203.4,189.4,174.1,159.3159.1,155.4,140.6,137.3,
135.5,133.6,132.4,131.9,127.8,123.8,121.6,116.5,112.7,110.6,107.2,90.5,84.1,
83.8,80.9,62.1,49.0,46.8,41.9,30.0,29.0,27.4,26.7,25.7,25.7,25.7,22.8,22.0,
18.2,17.6,16.4.ppm;HRMS(EI)m/z calcd for C39H47O7627.3322,found for[M+H]+
627.3305.
The preparation of 2 compound 12 of embodiment
The hydrochloride (50.2mg, 0.723mmol) of azanol is dissolved in 5mL dehydrated alcohol, instill pyridine (0.194mL,
2.41mmol) when no solid, that is, hydrochloride of azanol is when being released complete, the ethyl alcohol of aldehyde 11 (370mg, 0.602mmol) is added
Solution, overnight, water quenching reaction, anhydrous ether extraction merges organic phase, and the washing of saturated common salt aqueous solution is anhydrous for room temperature reaction
Sodium sulphate is dry, is spin-dried for, column chromatographic purifying obtains compound 12,0.321g, yield 84.7%.1H NMR(400MHz,CDCl3)δ
13.00 (s, 1H), 7.90 (s, 1H), 7.64 (d, J=7.2Hz, 1H), 6.67 (d, J=10.1Hz, 1H), 5.56 (t, J=
7.7Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.13-5.02 (m, 2H), 3.41-3.29 (m, 2H), 3.30-3.20 (m,
1H), 3.08 (dd, J=5.3,2.2Hz, 1H), 2.96-2.86 (m, 1H), 2.58 (dd, J=14.8,5.8Hz, 1H), 2.35
(dd, J=14.2,4.1Hz, 1H), 2.28-2.21 (m, 1H), 2.18 (d, J=10.1Hz, 1H), 2.09-2.01 (m, 2H),
1.81(s,3H),1.79–1.76(m,1H),1.75(s,3H),1.74(s,3H),1.65(s,6H),1.61–1.57(m,1H),
1.56(s,3H),1.53(s,3H),1.43(s,3H),1.33–1.25(m,1H)ppm;13C NMR(101MHz,CDCl3)δ
179.8,161.2,158.1,157.6,148.0,142.1,131.8,131.7,131.6,131.0,129.1,124.5,
123.8,122.5,116.0,107.5,102.5,100.2,92.5,84.4,84.2,81.2,70.6,49.1,42.1,36.9,
32.2,30.2,28.5,27.8,25.7,25.7,25.0,22.7,21.9,19.2,18.2,17.6ppm;HRMS(EI)m/z
calcd for C38H46NO7628.3275,found for[M-H]+628.3285.
The preparation of 3 compound 13 of embodiment
With embodiment 2, difference is to replace compound 11 to react with compound 8, obtains compound 13, yield 93.1%.1H NMR(400MHz,CDCl3) δ 7.88 (s, 1H), 7.52 (d, J=7.1Hz, 1H), 6.67 (d, J=10.1Hz, 1H), 5.60
(t, J=7.4Hz, 1H), 5.53 (d, J=10.1Hz, 1H), 5.11 (s, 1H), 5.06 (t, J=6.9Hz, 1H), 3.84 (s,
3H), 3.45 (dd, J=14.6,7.6Hz, 1H), 3.39-3.31 (m, 1H), 3.23 (s, 1H), 2.87 (br, 1H), 2.58 (dd,
J=14.7,7.1Hz, 1H), 2.35-2.26 (m, 2H), 2.24-2.12 (m, 3H), 2.08-1.99 (m, 2H), 1.83-1.72
(m,10H),1.70–1.59(m,7H),1.55(s,3H),1.52(s,3H),1.43(s,3H),1.37–1.29(m,1H)ppm;13C NMR(101MHz,CDCl3)δ175.7,160.1,158.8,155.3,147.9,140.6,133.5,132.0,131.9,
131.3,129.2,127.3,123.8,122.1,116.7,112.6,109.9,107.4,92.5,84.5,84.0,80.5,
70.8,62.2,49.0,42.0,36.7,32.2,30.2,28.5,27.6,25.7,25.6,25.2,22.7,22.4,19.3,
18.2,17.6ppm;HRMS(EI)m/z calcd for C39H50NO7644.3578,found for[M+H]+644.3578.
The preparation of 4 compound 14 of embodiment
With embodiment 2, difference is to replace compound 11 to react with compound 2, obtains compound 14, yield 72.3%.1H NMR(400MHz,CDCl3) δ 7.64 (s, 1H), 7.58 (s, 1H), 7.38 (d, J=6.9Hz, 1H), 6.64 (d, J=
10.2Hz, 1H), 5.51 (d, J=10.2Hz, 1H), 5.28 (t, J=6.7Hz, 1H), 5.24-5.15 (m, 1H), 5.06 (t, J
=7.1Hz, 1H), 3.79 (s, 3H), 3.50-3.43 (m, 1H), 3.42-3.33 (m, 2H), 2.75 (dd, J=14.9,9.7Hz,
1H), 2.63 (dd, J=15.1,5.3Hz, 1H), 2.49 (d, J=9.3Hz, 1H), 2.31 (dd, J=13.4,4.5Hz, 1H),
2.09–1.98(m,2H),1.83–1.74(m,4H),1.71(s,3H),1.68(s,3H),1.65(s,3H),1.62–1.59(m,
1H),1.57(s,3H),1.55(s,3H),1.42(s,3H),1.38–1.35(m,1H),1.29(s,3H)ppm;13C NMR
(101MHz,CDCl3)δ203.8,174.3,159.5,159.0,155.4,147.2,135.7,133.0,132.3,131.9,
130.5,129.2,127.2,123.8,122.0,116.7,112.7,110.2,107.2,90.4,84.2,83.5,80.6,
62.1,49.1,46.8,42.1,30.0,29.1,27.7,27.7,25.8,25.7,25.7,22.7,22.1,19.0,18.3,
17.6ppm;HRMS(EI)m/z calcd for C39H48NO7642.3431,found for[M+H]+642.3430.
The preparation of 5 compound 15 of embodiment
NaH (25.36mg, 1.06mmol) is dissolved in 10mL DMF, under the conditions of ice-water bath will dissolved with substrate 12 (133mg,
DMF solution 0.211mmol) is added drop-wise in the former mixture, and ice-water bath reaction 30min is moved back to room temperature, is added dropwise to isopropyl
Bromine (0.1mL, 1.06mmol) then moves to 50 DEG C of oil bath and reacts 11 hours.Water quenching reaction, anhydrous ether extraction, is associated with
Machine phase, the washing of saturated common salt aqueous solution washing lotion, anhydrous sodium sulfate is dry, is spin-dried for, and column chromatographic purifying obtains compound 15,
0.62mg, yield 81.9%.1H NMR(400MHz,CDCl3) δ 13.01 (s, 1H), 7.82 (s, 1H), 7.63 (d, J=7.2Hz,
1H), 6.68 (d, J=10.1Hz, 1H), 5.53 (t, J=7.6Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.11-5.02
(m, 2H), 4.28 (dq, J=12.5,6.4Hz, 1H), 3.38-3.26 (m, 2H), 3.21 (s, 1H), 3.01 (s, 1H), 2.93-
2.87 (m, 1H), 2.56 (dd, J=14.3,5.9Hz, 1H), 2.33 (dd, J=14.2,4.2Hz, 1H), 2.17 (dd, J=
12.3,9.2Hz,2H),2.10–2.01(m,2H),1.84–1.71(m,10H),1.65(s,3H),1.65(s,3H),1.60
(dd, J=6.9,2.5Hz, 1H), 1.56 (s, 3H), 1.53 (s, 3H), 1.44 (s, 3H), 1.32-1.24 (m, 1H), 1.21 (d,
J=1.8Hz, 3H), 1.19 (d, J=1.8Hz, 3H) ppm;13C NMR(101MHz,CDCl3)δ179.9,161.2,158.2,
157.6,145.9,142.2,132.1,131.8,131.6,131.0,127.8,124.5,123.8,122.6,116.0,
107.5,102.6,100.0,92.6,84.4,84.1,81.1,75.4,70.7,49.0,42.0,36.9,32.2,30.3,
28.5,27.7,25.7,25.7,25.0,22.7,21.9,21.6,21.6,19.4,18.2,17.6ppm;HRMS(EI)m/z
calcd for C41H54NO8672.3900,found for[M+H]+672.3897.
The preparation of 6 compound 16 of embodiment
It weighs respectively substrate 12 (615mg, 0.98mmol), NaOH (78.2mg, 1.95mmol) and tetrabutylammonium bromide
(TBAB, 50.4mg, 0.156mmol) is then added 20mL THF and 4mL water, adds benzyl bromine (0.174mL, 1.47mmol)
In room temperature reaction 8 hours, water quenching reaction, anhydrous ether extraction merges organic phase, the washing of saturated common salt aqueous solution, anhydrous sulphur
Sour sodium is dry, is spin-dried for, column chromatographic purifying obtains compound 16,0.447g, yield 61.3%.1H NMR(400MHz,CDCl3)δ
13.00 (s, 1H), 7.90 (s, 1H), 7.62 (d, J=7.2Hz, 1H), 7.34-7.27 (m, 5H), 6.68 (d, J=10.1Hz,
1H), 5.56 (t, J=7.6Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.10-5.05 (m, 2H), 5.04 (s, 2H), 3.34
(dd, J=14.6,7.7Hz, 1H), 3.27 (dd, J=14.8,5.6Hz, 1H), 3.22-3.17 (m, 1H), 3.00 (d, J=
5.4Hz, 1H), 2.92-2.86 (m, 1H), 2.55 (dd, J=14.8,5.8Hz, 1H), 2.32 (dd, J=14.1,4.0Hz,
1H), 2.20-2.12 (m, 2H), 2.04 (dd, J=15.8,7.8Hz, 2H), 1.78 (s, 3H), 1.77 (s, 3H), 1.77-1.73
(m,1H),1.73(s,3H),1.64(s,3H),1.62(s,3H),1.60–1.57(m,1H),1.55(s,3H),1.52(s,
3H),1.42(s,3H),1.30–1.24(m,1H)ppm;13C NMR(101MHz,CDCl3)δ179.9,161.2,158.1,
157.7,147.0,142.2,137.4,131.8,131.7,131.6,131.0,128.8,128.4,128.4,127.9,
124.5,123.9,122.5,116.1,107.5,102.6,100.3,92.5,84.4,84.1,81.1,76.2,70.7,49.1,
42.0,36.9,32.3,30.2,28.5,27.7,25.7,25.7,25.0,22.7,21.9,19.3,18.2,17.6ppm;HRMS
(EI)m/z calcd for C45H53NO7Na 742.3720,found for[M+Na]+742.3720.
The preparation of 7 compound 17 of embodiment
With embodiment 6, difference is to replace compound 12 to react with compound 14, obtains compound 17, yield 21.2%.1H
NMR(400MHz,CDCl3) δ 7.64 (s, 1H), 7.38 (d, J=6.9Hz, 1H), 7.33-7.25 (m, 5H), 6.67 (d, J=
10.2Hz, 1H), 5.53 (d, J=10.2Hz, 1H), 5.30-5.20 (m, 2H), 5.05 (t, J=7.1Hz, 1H), 4.97-4.87
(m, 2H), 3.77 (s, 3H), 3.45 (dd, J=6.7,4.5Hz, 1H), 3.39-3.32 (m, 2H), 2.70 (dd, J=15.0,
9.1Hz, 1H), 2.59 (dd, J=15.2,6.4Hz, 1H), 2.49 (d, J=9.3Hz, 1H), 2.30 (dd, J=13.4,
4.6Hz,1H),2.08–1.98(m,2H),1.78–1.73(m,4H),1.71(s,3H),1.69–1.63(m,7H),1.60(s,
3H),1.54(s,3H),1.40(s,3H),1.37–1.32(m,1H),1.28(s,3H)ppm;13C NMR(101MHz,CDCl3)δ
203.7,174.3,159.5,158.9,155.3,146.2,137.7,135.7,133.1,132.2,131.9,130.8,
128.8,128.2,128.1,127.6,127.4,123.8,122.0,116.8,112.8,110.2,107.3,90.5,84.2,
83.5,80.5,75.9,62.1,49.1,46.8,41.9,30.0,29.0,27.6,27.5,25.7,25.7,25.7,22.6,
22.1,19.1,18.2,17.6ppm;HRMS(EI)m/z calcd for C46H54NO7732.3900,found for[M+H]+
732.3902.
The preparation of 8 compound 18 of embodiment
Substrate 12 (108mg, 0.172mmol) is dissolved in 5mL CH2Cl2, (13.8 μ L, 0.172mmol) pyridine is added, after
(12.1 μ L, 0.172mmol) chloroacetic chloride is added, reacts at room temperature 4 hours, water quenching reaction, anhydrous ether extraction merges organic
Phase, the washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, is spin-dried for, column chromatographic purifying obtains compound 18,71mg, yield
61.6%.1H NMR(400MHz,CDCl3) δ 12.99 (s, 1H), 8.12 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 6.67 (d,
J=10.1Hz, 1H), 5.85 (t, J=7.9Hz, 1H), 5.44 (d, J=10.1Hz, 1H), 5.06 (m, 2H), 3.35 (dd, J=
14.6,7.5Hz, 1H), 3.28 (d, J=5.5Hz, 1H), 3.23 (s, 1H), 2.96-2.90 (m, 1H), 2.59 (dd, J=
14.7,6.6Hz, 1H), 2.34 (dd, J=14.0,4.1Hz, 1H), 2.22-2.14 (m, 3H), 2.15 (s, 3H), 2.04 (dd, J
=16.0,7.7Hz, 2H), 1.87 (s, 3H), 1.83-1.72 (m, 7H), 1.65 (s, 6H), 1.62-1.58 (m, 1H), 1.55
(s,3H),1.53(s,3H),1.44(s,3H),1.31–1.23(m,1H)ppm;13C NMR(101MHz,CDCl3)δ179.8,
168.8,161.3,157.9,157.6,153.1,142.4,134.2,131.9,131.7,130.9,130.8,124.7,
123.8,122.4,115.8,107.4,102.7,100.2,92.5,84.3,84.2,81.3,70.9,49.1,42.0,36.9,
32.5,30.2,28.5,27.7,25.7,25.6,24.9,22.7,21.9,19.7,19.0,18.2,17.6ppm;HRMS(EI)
m/z calcd for C40H50NO8672.3536,found for[M+H]+672.3528.
The preparation of 9 compound 19 of embodiment
With embodiment 8, difference is to replace excess acetyl chloride with isobutyryl chloride, obtains compound 19, yield 78.0%.1H
NMR(400MHz,CDCl3) δ 12.99 (s, 1H), 8.16 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 6.67 (d, J=
10.1Hz, 1H), 5.87 (t, J=7.8Hz, 1H), 5.44 (d, J=10.1Hz, 1H), 5.06 (t, J=6.9Hz, 2H), 3.36
(dd, J=14.6,7.6Hz, 1H), 3.26 (dd, J=15.1,5.6Hz, 1H), 3.21 (d, J=5.4Hz, 1H), 2.98 (d, J
=5.5Hz, 1H), 2.95-2.89 (m, 1H), 2.69-2.59 (m, 2H), 2.34 (dd, J=14.2,4.2Hz, 1H), 2.23-
2.17 (m, 1H), 2.14 (dd, J=14.8,8.2Hz, 1H), 2.09-2.00 (m, 2H), 1.90 (s, 3H), 1.81-1.72 (m,
7H),1.68–1.61(m,7H),1.55(s,3H),1.53(s,3H),1.43(s,3H),1.34–1.26(m,1H),1.23(d,J
=6.8Hz, 3H), 1.23 (d, J=6.8Hz, 3H) ppm;13C NMR(101MHz,CDCl3)δ179.8,174.3,161.2,
158.0,157.6,153.5,142.5,134.0,131.8,131.6,131.0,130.8,124.6,123.8,122.4,
115.8,107.4,102.6,100.2,92.5,84.2,84.2,81.3,71.0,49.1,42.0,36.9,32.8,32.5,
30.1,28.5,27.7,25.7,25.6,24.9,22.7,21.9,21.9,19.0,19.0,18.9,18.2,17.6ppm;HRMS
(EI)m/z calcd for C42H54NO8700.3849,found for[M+H]+700.3837.
The preparation of 10 compound 20 of embodiment
With embodiment 8, difference is to replace excess acetyl chloride with phenyllacetyl chloride, obtains compound 20, yield 64.0%.1H
NMR(400MHz,CDCl3) δ 13.00 (s, 1H), 8.13 (s, 1H), 7.67 (t, J=9.4Hz, 1H), 7.34-7.26 (m, 5H),
6.67 (d, J=9.8Hz, 1H), 5.86 (s, 1H), 5.42 (t, J=10.7Hz, 1H), 5.06 (s, 2H), 3.72 (s, 2H),
3.36 (dd, J=14.6,7.6Hz, 1H), 3.27 (dd, J=15.1,5.6Hz, 1H), 3.20 (d, J=5.2Hz, 1H), 2.99
(d, J=5.5Hz, 1H), 2.95-2.89 (m, 1H), 2.60 (dd, J=14.3,7.2Hz, 1H), 2.33 (d, J=13.8Hz,
1H),2.21–2.11(m,2H),2.09–1.99(m,2H),1.87(s,3H),1.82–1.72(m,7H),1.68–1.60(m,
7H),1.56(s,3H),1.51(s,3H),1.43(s,3H),1.33–1.24(m,1H)ppm;13C NMR(101MHz,CDCl3)δ
179.8,169.0,161.3,158.0,157.7,153.6,142.6,134.4,133.3,131.8,131.7,130.9,
130.8,129.3,128.6,127.2,124.7,123.8,122.4,115.8,107.4,102.7,100.2,92.5,84.3,
84.2,81.3,71.0,49.1,42.0,39.9,36.9,32.5,30.2,28.5,27.7,25.7,25.7,24.9,22.7,
21.9,19.0,18.3,17.7ppm;HRMS(EI)m/z calcd for C46H54NO8748.3849,found for[M+H]+
748.3843.
The preparation of 11 compound 21 of embodiment
At room temperature, substrate 12 (200mg, 0.32mmol) is dissolved in 10mL methylene chloride by nitrogen protection, respectively
Be added EDCI (73.12mg, 0.38mmol), DMAP (3.88mg, 0.032mmol), be eventually adding parabromobenzoic acid (89.44mg,
0.44mmol), 5h is reacted at room temperature, anhydrous ether extraction merges organic phase, the washing of saturated common salt aqueous solution, and anhydrous sodium sulfate is done
It is dry, it is spin-dried for, column chromatographs to obtain compound 21,210mg, yield 86.1%.1H NMR(400MHz,CDCl3)δ13.00(s,1H),
8.30 (s, 1H), 7.94 (d, J=8.6Hz, 1H), 7.69 (d, J=7.2Hz, 1H), 7.61 (d, J=8.6Hz, 1H), 6.61
(d, J=10.2Hz, 1H), 5.94 (t, J=7.9Hz, 1H), 5.38 (d, J=10.2Hz, 1H), 5.23-4.95 (m, 1H),
3.37 (dd, J=14.7,7.8Hz, 1H), 3.30-3.21 (m, 2H), 3.00 (d, J=5.5Hz, 1H), 2.97-2.91 (m,
1H), 2.64 (dd, J=14.6,7.2Hz, 1H), 2.35 (dd, J=14.2,4.2Hz, 1H), 2.25-2.16 (m, 2H), 2.06-
1.97(m,2H),1.95(s,3H),1.81(s,3H),1.76–1.73(m,1H),1.71(s,3H),1.64(s,3H),1.62
(s,3H),1.58–1.56(m,1H),1.54(s,6H),1.36(s,3H),1.33–1.26(m,1H)ppm;13C NMR
(101MHz,CDCl3)δ179.8,163.1,161.3,157.9,157.6,154.3,142.6,134.8,131.8,131.8,
131.7,131.2,130.8,128.4,127.6,124.6,123.8,122.3,115.7,107.3,102.7,100.2,92.6,
84.3,84.2,81.3,71.2,49.1,42.0,36.9,32.6,30.1,28.5,27.7,25.7,25.7,24.8,22.7,
21.9,19.1,18.2,17.6.ppm;HRMS(EI)m/z calcd for C45H51BrNO8812.2798,found for[M+
H]+812.2783.
The preparation of 12 compound 22 of embodiment
With embodiment 11, difference is to replace parabromobenzoic acid to react with parafluorobenzoic acid, obtains compound 22, yield
72.0%.1H NMR(400MHz,CDCl3) δ 13.00 (s, 1H), 8.30 (s, 1H), 8.14-8.05 (m, 2H), 7.68 (d, J=
7.1Hz, 1H), 7.13 (t, J=8.5Hz, 2H), 6.61 (d, J=10.1Hz, 1H), 5.92 (t, J=7.7Hz, 1H), 5.38
(d, J=10.1Hz, 1H), 5.12-4.99 (m, 2H), 3.42-3.33 (m, 1H), 3.33-3.21 (m, 2H), 3.01 (br, 1H),
2.94 (br, 1H), 2.64 (dd, J=14.6,7.4Hz, 1H), 2.34 (d, J=13.5Hz, 1H), 2.22-2.16 (m, 2H),
2.08–1.98(m,2H),1.95(s,3H),1.81(s,3H),1.76–1.73(m,1H),1.72(s,3H),1.64(s,4H),
1.62(s,3H),1.54(s,6H),1.36(s,3H),1.33–1.28(m,1H)ppm;13C NMR(101MHz,CDCl3)δ
179.8,166.0,162.9,161.4,157.9,157.6,154.1,142.6,134.6,132.4,131.9,131.7,
130.9,130.8,125.0,124.6,123.7,122.3,115.8,115.7,107.4,102.7,100.2,92.6,84.3,
84.2,81.4,71.2,49.1,42.0,36.9,32.6,30.1,28.5,27.7,25.7,25.6,24.8,22.7,21.9,
19.1,18.2,17.6ppm;HRMS(EI)m/z calcd for C45H51FNO8752.3598,found for[M+H]+
752.3589.
The preparation of 13 compound 23 of embodiment
With embodiment 11, difference is to replace parabromobenzoic acid to react with paranitrobenzoic acid, obtains compound 23, yield
83.8%.1H NMR(400MHz,CDCl3) δ 13.01 (s, 1H), 8.34-8.30 (m, 3H), 8.26 (d, J=9.0Hz, 2H),
7.70 (d, J=7.2Hz, 1H), 6.59 (d, J=10.2Hz, 1H), 6.00 (t, J=8.0Hz, 1H), 5.38 (d, J=
10.2Hz, 1H), 5.09-5.00 (m, 2H), 3.37 (dd, J=14.7,7.8Hz, 1H), 3.30-3.20 (m, 2H), 3.00 (d, J
=5.6Hz, 1H), 2.97-2.91 (m, 1H), 2.64 (dd, J=14.6,7.9Hz, 1H), 2.35 (dd, J=14.2,4.0Hz,
1H),2.27–2.18(m,2H),2.05–1.97(m,2H),1.96(s,3H),1.82(s,3H),1.78–1.69(m,4H),
1.64(s,3H),1.63(s,3H),1.60–1.56(m,1H),1.55(s,3H),1.54(s,3H),1.37(s,3H),1.34–
1.29(m,1H)ppm;13C NMR(101MHz,CDCl3)δ179.8,162.0,161.4,157.9,157.6,154.8,150.7,
142.7,135.7,134.3,131.9,131.8,130.9,130.8,130.5,124.7,123.7,123.6,122.3,
115.7,107.3,102.7,100.2,92.6,84.4,84.2,81.4,71.4,49.1,42.0,36.9,32.7,30.1,
28.5,27.8,25.7,25.6,24.8,22.7,21.9,19.0,18.2,17.6.ppm;HRMS(EI)m/z calcd for
C45H51N2O10779.3543,found for[M+H]+779.3526.
The preparation of 14 compound 24 of embodiment
With embodiment 11, difference is to replace parabromobenzoic acid to react with m-trifluoromethylbenzoic acid, obtains compound 24,
Yield 82.5%.1H NMR(400MHz,CDCl3) δ 13.00 (s, 1H), 8.35 (s, 2H), 8.27 (d, J=7.5Hz, 1H),
7.85 (d, J=7.7Hz, 1H), 7.69 (d, J=7.1Hz, 1H), 7.62 (t, J=7.7Hz, 1H), 6.60 (d, J=10.1Hz,
1H), 5.96 (t, J=7.8Hz, 1H), 5.37 (d, J=10.1Hz, 1H), 5.10-4.99 (m, 2H), 3.37 (dd, J=14.7,
7.8Hz, 1H), 3.26 (d, J=10.7Hz, 2H), 3.02 (br, 1H), 2.94 (br, 1H), 2.66 (dd, J=15.0,7.7Hz,
1H), 2.35 (dd, J=14.2,4.0Hz, 1H), 2.28-2.18 (m, 2H), 2.06-1.96 (m, 2H), 1.95 (s, 3H), 1.82
(s,3H),1.77–1.70(m,1H),1.68(s,3H),1.64(s,3H),1.62–1.50(m,10H),1.35(s,3H),
1.31–1.26(m,1H)ppm;13C NMR(101MHz,CDCl3)δ179.8,162.6,161.3,157.9,157.6,154.6,
142.6,135.0,133.0,131.9,131.8,130.8,130.7,129.8,129.8,129.7,129.2,126.6,
126.6,124.7,123.7,122.3,115.7,107.4,102.7,100.2,92.6,84.4,84.2,81.4,71.3,
49.1,42.0,36.9,32.6,30.1,28.5,27.7,25.7,25.6,24.8,22.7,21.8,19.1,18.1,
17.6ppm;HRMS(EI)m/z calcd for C46H51F3NO8802.3567,found for[M+H]+802.3556.
The preparation of 14 compound 25 of embodiment
With embodiment 8, difference is to replace compound 12 to react with compound 13, obtains compound 25, yield 84.0%.1H
NMR(400MHz,CDCl3) δ 8.10 (s, 1H), 7.54 (d, J=7.1Hz, 1H), 6.66 (d, J=10.2Hz, 1H), 5.87 (t,
J=7.9Hz, 1H), 5.55 (d, J=10.2Hz, 1H), 5.09 (t, J=6.4Hz, 1H), 5.05 (t, J=7.1Hz, 1H),
3.85 (s, 3H), 3.44 (dd, J=14.5,7.8Hz, 1H), 3.33 (dd, J=14.5,5.3Hz, 1H), 3.20 (s, 1H),
2.90-2.85 (m, 1H), 2.59 (dd, J=14.6,7.3Hz, 1H), 2.34-2.26 (m, 2H), 2.22-2.16 (m, 2H),
2.15(s,3H),2.09–1.99(m,2H),1.87(s,3H),1.79(m,3H),1.78–1.71(m,4H),1.65(s,6H),
1.61–1.57(m,1H),1.55(s,3H),1.52(s,3H),1.44(s,3H),1.36–1.27(m,1H)ppm;13C NMR
(101MHz,CDCl3)δ175.6,168.7,160.0,158.9,155.3,153.3,140.8,134.6,133.3,132.0,
131.9,130.7,127.5,123.7,122.0,116.5,112.6,110.1,107.5,92.5,84.2,84.2,80.6,
71.1,62.3,49.0,41.9,36.7,32.5,30.1,28.5,27.6,25.7,25.6,25.2,22.6,22.4,19.6,
19.0,18.2,17.6ppm;HRMS(EI)m/z calcd for C41H52NO8686.3693,found for[M+H]+
686.3688.
The preparation of 15 compound 26 of embodiment
With embodiment 14, difference is to replace excess acetyl chloride with isobutyryl chloride, obtains compound 26, yield 86.7%.
Rf=0.3 (PE:AE=2:1);1H NMR(400MHz,CDCl3) δ 8.15 (s, 1H), 7.54 (d, J=7.1Hz, 1H), 6.66
(d, J=10.1Hz, 1H), 5.88 (t, J=7.7Hz, 1H), 5.54 (d, J=10.2Hz, 1H), 5.10 (t, J=6.4Hz,
1H), 5.05 (t, J=6.8Hz, 1H), 3.85 (s, 3H), 3.45 (dd, J=14.3,7.9Hz, 1H), 3.38-3.30 (m, 1H),
3.20(s,1H),2.93–2.82(m,1H),2.68–2.60(m,1H),2.36–2.26(m,2H),2.24–2.16(m,2H),
2.12 (dd, J=15.0,8.1Hz, 1H), 2.08-1.99 (m, 2H), 1.90 (s, 3H), 1.87-1.72 (m, 7H), 1.65 (s,
6H),1.62–1.58(m,1H),1.55(s,3H),1.52(s,3H),1.44(s,3H),1.37–1.31(m,1H),1.23(d,J
=6.8Hz, 6H) ppm;13C NMR(101MHz,CDCl3)δ175.6,174.3,160.0,158.8,155.2,153.6,
140.8,134.3,133.3,131.9,131.8,130.9,127.4,123.7,122.0,116.5,112.5,110.0,
107.5,92.5,84.2,84.1,80.6,71.1,62.2,49.0,41.9,36.7,32.8,32.5,30.1,28.5,27.6,
25.7,25.6,25.2,22.6,22.4,19.0,19.0,18.9,18.2,17.6ppm;HRMS(EI)m/z calcd for
C43H56NO8714.4006,found for[M+H]+714.4007.
The preparation of 16 compound 27 of embodiment
With embodiment 14, difference is to replace excess acetyl chloride with phenyllacetyl chloride, obtains compound 27, yield 58.2%.
Rf=0.20 (PE:AE=2:1);1H NMR(400MHz,CDCl3) δ 8.12 (s, 1H), 7.55 (d, J=7.0Hz, 1H), 7.37-
7.22 (m, 5H), 6.64 (d, J=10.2Hz, 1H), 5.88 (t, J=7.6Hz, 1H), 5.53 (d, J=10.1Hz, 1H),
5.15-5.03 (m, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 3.45 (dd, J=14.3,7.7Hz, 1H), 3.34 (d, J=
13.5Hz, 1H), 3.20 (s, 1H), 2.87 (br, 1H), 2.59 (dd, J=14.5,7.4Hz, 1H), 2.32 (d, J=11.9Hz,
1H), 2.19 (d, J=9.6Hz, 1H), 2.12 (dd, J=15.0,8.1Hz, 1H), 2.09-1.98 (m, 2H), 1.87 (s, 3H),
1.83–1.72(m,7H),1.70–1.60(m,7H),1.55(s,3H),1.51(s,3H),1.43(s,3H),1.37–1.26(m,
1H)ppm;13C NMR(101MHz,CDCl3)δ175.6,169.0,160.0,158.9,155.2,153.7,140.9,134.7,
133.3,133.2,132.0,131.9,130.7,129.3,128.6,127.5,127.2,123.7,122.0,116.5,
112.6,110.1,107.5,92.5,84.2,84.1,80.6,71.1,62.3,49.0,42.0,39.9,36.7,32.5,
30.1,28.5,27.6,25.7,25.7,25.1,22.6,22.4,19.0,18.3,17.6ppm;HRMS(EI)m/z calcd
for C47H56NO8762.4006,found for[M+H]+762.4003.
The preparation of 17 compound 28 of embodiment
With embodiment 8, difference is to replace compound 12 to react with compound 14, obtains compound 28, yield 49.2%.1H
NMR(300MHz,CDCl3) δ 7.87 (s, 1H), 7.41 (d, J=6.9Hz, 1H), 6.63 (d, J=10.1Hz, 1H), 5.60-
5.47 (m, 2H), 5.28 (t, J=6.2Hz, 1H), 5.03 (t, J=6.2Hz, 1H), 3.82 (s, 3H), 3.51-3.43 (m,
1H), 3.38 (d, J=6.6Hz, 2H), 2.75 (dd, J=14.7,9.7Hz, 1H), 2.64 (dd, J=15.3,7.2Hz, 1H),
2.51 (d, J=9.3Hz, 1H), 2.33 (dd, J=13.2,4.3Hz, 1H), 2.14-1.97 (m, 5H), 1.86-1.60 (m,
17H),1.53(s,3H),1.47(s,3H),1.44–1.37(m,1H),1.30(s,3H)ppm;13C NMR(101MHz,CDCl3)
δ203.4,174.1,168.6,159.2,158.9,155.3,152.3,135.5,134.4,133.3,132.4,132.0,
130.1,127.8,123.6,121.9,116.6,112.9,110.5,107.4,90.5,84.0,83.6,80.7,62.2,
49.0,46.8,41.7,30.0,29.1,27.9,27.2,25.8,25.7,25.6,22.5,22.1,19.7,18.8,18.3,
17.6ppm;HRMS(EI)m/z calcd for C41H50NO8684.3536,found for[M+H]+684.3531.
The preparation of 18 compound 29 of embodiment
With embodiment 17, difference is to replace excess acetyl chloride with isobutyryl chloride, obtains compound 29, yield 77.8%.1H NMR(400MHz,CDCl3) δ 7.92 (s, 1H), 7.41 (d, J=6.8Hz, 1H), 6.63 (d, J=10.1Hz, 1H), 5.64-
5.51 (m, 2H), 5.22 (t, J=6.6Hz, 1H), 5.04 (t, J=6.6Hz, 1H), 3.81 (s, 3H), 3.52-3.43 (m,
1H), 3.43-3.32 (m, 2H), 2.76-2.55 (m, 3H), 2.51 (d, J=9.3Hz, 1H), 2.32 (dd, J=13.2,
4.1Hz,1H),2.09–1.96(m,2H),1.80–1.60(m,17H),1.54(s,3H),1.47(s,3H),1.42–1.37(m,
1H),1.29(s,3H),1.21–1.15(m,6H)ppm;13C NMR(101MHz,CDCl3)δ203.5,174.2,159.3,
159.0,155.3,152.7,135.5,134.0,133.5,132.3,131.9,130.1,127.7,123.7,121.8,
116.6,112.9,110.5,107.4,90.5,83.9,83.6,80.6,62.2,49.0,46.8,41.8,32.6,30.0,
29.0,27.7,27.2,25.7,25.7,25.6,25.2,22.6,22.1,19.0,18.9,18.2,17.6ppm;HRMS(EI)
m/z calcd for C43H54NO8712.3849,found for[M+H]+712.3844.
The preparation of 19 compound 30 of embodiment
With embodiment 17, difference is to replace excess acetyl chloride with phenyllacetyl chloride, obtains compound 30, yield 61.5%.1H NMR(400MHz,CDCl3) δ 7.89 (s, 1H), 7.41 (d, J=6.8Hz, 1H), 7.35-7.24 (m, 5H), 6.61 (d, J=
10.2Hz, 1H), 5.62-5.50 (m, 2H), 5.25 (t, J=6.5Hz, 1H), 5.03 (t, J=6.5Hz, 1H), 3.81 (s,
3H), 3.66 (s, 2H), 3.46 (dd, J=11.1,5.8Hz, 1H), 3.42-3.33 (m, 2H), 2.71 (dd, J=14.9,
9.2Hz, 1H), 2.62 (dd, J=14.9,7.2Hz, 1H), 2.52 (d, J=9.2Hz, 1H), 2.32 (dd, J=13.3,
4.1Hz,1H),2.09–1.99(m,2H),1.80(s,3H),1.78–1.75(m,1H),1.72(s,6H),1.68(s,3H),
1.64(s,3H),1.62–1.58(m,1H),1.54(s,3H),1.47(s,3H),1.42–1.32(m,1H),1.29(s,3H)
ppm;13C NMR(101MHz,CDCl3)δ203.5,174.2,168.9,159.3,159.0,155.3,152.6,135.4,
134.5,133.6,133.3,132.3,131.9,129.9,129.3,128.6,127.8,127.2,123.7,121.8,
116.6,112.9,110.5,107.4,90.5,83.9,83.6,80.7,62.2,49.0,46.7,41.7,39.7,30.0,
29.0,27.8,27.3,25.7,25.7,25.7,22.5,22.1,18.8,18.3,17.6ppm;HRMS(EI)m/z calcd
for C47H54NO8760.3849,found for[M+H]+760.3840.
The preparation of 20 compound 31 of embodiment
With embodiment 8, difference is to replace excess acetyl chloride with chloro-carbonic acid -4- methoxyl group phenyl ester, obtains compound 31, produces
Rate 85.6%.1H NMR(400MHz,CDCl3) δ 12.99 (s, 1H), 8.22 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 7.12
(d, J=9.0Hz, 3H), 6.89 (d, J=9.1Hz, 2H), 6.68 (d, J=10.1Hz, 1H), 5.87 (t, J=7.8Hz, 1H),
5.43 (d, J=10.1Hz, 1H), 5.09 (d, J=6.4Hz, 1H), 5.06 (d, J=6.4Hz, 1H), 3.80 (s, 3H), 3.38
(dd, J=14.7,7.6Hz, 1H), 3.31 (dd, J=14.8,5.0Hz, 1H), 3.24 (d, J=5.3Hz, 1H), 3.01 (d, J
=5.5Hz, 1H), 2.93 (br, 1H), 2.63 (dd, J=14.5,6.9Hz, 1H), 2.34 (dd, J=14.2,4.0Hz, 1H),
2.21 (dd, J=12.4,7.9Hz, 2H), 2.04 (dd, J=14.5,8.8Hz, 2H), 1.89 (s, 3H), 1.81 (s, 3H),
1.78(s,3H),1.75–1.72(m,1H),1.66(s,3H),1.65(s,3H),1.64–1.61(m,1H),1.55(s,3H),
1.53(s,3H),1.43(s,3H),1.35–1.25(m,1H)ppm;13C NMR(101MHz,CDCl3)δ179.7,161.3,
157.9,157.6,157.4,153.9,152.4,144.5,142.5,134.8,131.9,131.8,130.9,130.5,
124.6,123.8,122.4,121.7,115.9,114.5,107.4,102.7,100.2,92.5,84.3,84.2,81.3,
70.8,55.6,49.1,42.0,36.9,32.5,30.2,28.5,27.7,25.7,25.7,24.9,22.7,21.9,18.9,
18.2,17.6ppm;HRMS(EI)m/z calcd for C46H53NO10780.3733,found for[M+H]+780.3726.
The preparation of 21 compound 32 of embodiment
With embodiment 8, difference is to obtain compound 32, yield with chloro-methyl-chloroformate replacement excess acetyl chloride
69.0%.1H NMR(400MHz,CDCl3) δ 12.97 (s, 1H), 8.16 (s, 1H), 7.66 (d, J=7.1Hz, 1H), 6.66 (d,
J=10.1Hz, 1H), 5.88 (t, J=7.4Hz, 1H), 5.80 (s, 2H), 5.43 (d, J=10.2Hz, 1H), 5.10-5.02
(m, 2H), 3.33 (dd, J=14.8,6.8Hz, 1H), 3.30-3.20m, 2H), 2.99 (d, J=5.6Hz, 1H), 2.93 (br,
1H), 2.60 (dd, J=14.9,7.0Hz, 1H), 2.33 (dd, J=13.8,3.8Hz, 1H), 2.23-2.16 (m, 2H), 2.04
(dd, J=15.1,8.3Hz, 2H), 1.87 (s, 3H), 1.84-1.80 (m, 1H), 1.79 (s, 3H), 1.76 (s, 3H), 1.64
(s,6H),1.63–1.60(m,1H),1.55(s,3H),1.52(s,3H),1.42(s,3H),1.33–1.26(m,1H)ppm;13C
NMR(101MHz,CDCl3)δ179.7,161.2,157.9,157.6,154.4,151.9,142.4,135.3,132.0,
131.8,130.8,130.3,124.7,123.8,122.3,115.8,107.4,102.7,100.1,92.4,84.4,84.2,
81.3,72.3,70.8,49.0,42.0,36.9,32.5,30.1,28.5,27.7,25.7,25.7,24.9,22.7,21.9,
18.8,18.2,17.6ppm;HRMS(EI)m/z calcd for C40H49ClNO9722.3083,found for[M+H]+
322.3103.
The preparation of 22 compound 33 of embodiment
With embodiment 8, difference is to obtain compound 33, yield with isobutyl chlorocarbonate replacement acyl chloride reaction
92.2%.1H NMR(400MHz,CDCl3) δ 12.98 (s, 1H), 8.14 (s, 1H), 7.65 (d, J=7.1Hz, 1H), 6.66 (d,
J=10.1Hz, 1H), 5.82 (t, J=7.7Hz, 1H), 5.42 (d, J=10.1Hz, 1H), 5.11-5.02 (m, 2H), 4.00
(d, J=5.7Hz, 2H), 3.35 (dd, J=14.8,7.6Hz, 1H), 3.27 (dd, J=14.5,5.6Hz, 1H), 3.21 (d, J
=5.1Hz, 1H), 2.99 (d, J=5.5Hz, 1H), 2.95-2.88 (m, 1H), 2.60 (dd, J=14.8,6.9Hz, 1H),
2.33 (dd, J=14.2,3.9Hz, 1H), 2.18 (d, J=10.3Hz, 2H), 2.07-2.02 (m, 2H), 1.98 (dd, J=
13.5,6.9Hz,1H),1.87(s,3H),1.79(s,3H),1.77–1.72(m,4H),1.66–1.61(m,7H),1.55(s,
3H), 1.52 (s, 3H), 1.42 (s, 3H), 1.33-1.22 (m, 1H), 0.96 (d, J=6.4Hz, 6H) ppm;13C NMR
(101MHz,CDCl3)δ179.7,161.2,157.9,157.6,153.8,153.1,142.4,134.2,131.8,131.8,
130.9,130.7,124.6,123.8,122.4,115.9,107.4,102.6,100.2,92.5,84.3,84.2,81.2,
74.5,70.8,49.0,42.0,36.9,32.5,30.2,28.5,27.8,27.7,25.7,25.7,24.9,22.7,21.9,
18.9,18.9,18.2,17.6ppm;HRMS(EI)m/z calcd for C43H56NO9730.3940,found for[M+H]+
730.3954.
The preparation of 23 compound 34 of embodiment
Substrate 12 (100mg, 0.159mmol) is dissolved in 5mL CH2Cl2, (44.6 μ L, 0.318mmol) triethylamine is added,
(50 μ L, 0.794mmol) ethyl isocyanate is added afterwards, reacts at room temperature 4 hours, water quenching reaction, anhydrous ether extraction merges
Organic phase, the washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, is spin-dried for, and column chromatographic purifying obtains compound 34,110.0mg,
Yield 98.8%.1H NMR(400MHz,CDCl3) δ 12.99 (s, 1H), 8.10 (s, 1H), 7.65 (d, J=7.2Hz, 1H),
6.65 (d, J=10.1Hz, 1H), 6.07 (t, J=5.5Hz, 1H), 5.77 (t, J=7.8Hz, 1H), 5.42 (d, J=
10.1Hz, 1H), 5.11-4.99 (m, 2H), 3.36 (dd, J=15.5,8.2Hz, 2H), 3.32-3.27 (m, 2H), 3.25 (s,
1H), 3.02 (d, J=5.6Hz, 1H), 2.95-2.89 (m, 1H), 2.58 (dd, J=14.7,6.5Hz, 1H), 2.33 (dd, J=
14.1,4.0Hz, 1H), 2.25 (dd, J=14.6,9.2Hz, 1H), 2.17 (d, J=10.0Hz, 1H), 2.07-1.98 (m,
2H), 1.79 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H), 1.76-1.70 (m, 1H), 1.64 (s, 6H), 1.58 (dd, J=
7.1,3.0Hz, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.43 (s, 3H), 1.33-1.25 (m, 1H), 1.18 (t, J=
7.2Hz,3H)ppm;13C NMR(101MHz,CDCl3)δ179.7,161.3,157.9,157.6,155.0,150.3,142.2,
134.1,132.0,131.8,130.9,130.5,124.7,123.8,122.2,115.8,107.5,102.6,100.1,92.4,
84.3,84.3,81.2,70.5,49.0,42.0,36.9,36.0,32.4,30.2,28.5,27.6,25.7,25.7,24.9,
22.6,21.9,19.0,18.3,17.6,15.1ppm;HRMS(EI)m/z calcd for C41H53N2O8701.3802,found
for[M+H]+701.3799.
The preparation of 24 compound 35 of embodiment
At room temperature, substrate GA (300mg, 0.48mmol) is dissolved in 10mL methylene chloride by nitrogen protection, respectively
It is added EDCI (109.91mg, 0.57mmol), DMAP (5.83mg, 0.048mmol) is eventually adding p-bromobenzaldehyde oxime
(133.06mg, 0.67mmol), reacts at room temperature 5h, and anhydrous ether extraction merges organic phase, the washing of saturated common salt aqueous solution, nothing
Aqueous sodium persulfate is dry, is spin-dried for, column chromatographic purifying obtains compound 35,312mg, yield 80.7%.1H NMR(400MHz,CDCl3)
δ 12.82 (s, 1H), 8.07 (s, 1H), 7.60-7.49 (m, 5H), 6.58 (d, J=10.1Hz, 1H), 6.17 (t, J=6.7Hz,
1H), 5.34 (d, J=10.1Hz, 1H), 5.09-4.98 (m, 2H), 3.47 (s, 1H), 3.31 (dd, J=14.3,8.1Hz,
1H), 3.17 (d, J=12.8Hz, 1H), 3.05-2.89 (m, 2H), 2.52 (d, J=9.2Hz, 1H), 2.31 (d, J=
13.1Hz,1H),2.06–1.95(m,2H),1.81(s,3H),1.77–1.67(m,7H),1.63(s,3H),1.63–1.56(m,
4H), 1.54 (s, 3H), 1.39 (d, J=12.5Hz, 1H), 1.32 (s, 3H), 1.29 (s, 3H) ppm;13C NMR(101MHz,
CDCl3)δ203.4,178.9,164.0,161.4,157.5,157.7,155.1,138.2,135.5,133.3,132.0,
131.8,131.6,129.8,129.3,126.0,126.0,124.6,123.7,122.2,116.0,107.7,102.5,
100.4,90.9,83.8,83.3,81.2,49.0,46.9,41.9,29.9,29.7,28.8,27.6,25.7,25.7,25.2,
22.7,21.7,20.6,18.1,17.6ppm;HRMS(EI)m/z calcd for C45H49BrNO8810.2641,found for
[M+H]+810.2606.
The preparation of 25 compound 36 of embodiment
With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with 3-bromobenzaldehyde oxime, obtains compound 36, produces
Rate 77.3%.1H NMR(400MHz,CDCl3)δ12.83(s,1H),8.07(s,1H),7.89(s,1H),7.64–7.52(m,
3H), 7.30 (t, J=7.8Hz, 1H), 6.60 (d, J=10.1Hz, 1H), 6.15 (t, J=6.7Hz, 1H), 5.35 (d, J=
10.1Hz, 1H), 5.09-4.98 (m, 2H), 3.48 (t, J=4.8Hz, 1H), 3.32 (dd, J=14.4,8.0Hz, 1H), 3.18
(d, J=12.4Hz, 1H), 3.04 (dd, J=16.4,7.2Hz, 1H), 2.94 (dd, J=16.6,6.6Hz, 1H), 2.53 (d, J
=9.2Hz, 1H), 2.37-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.82 (s, 3H), 1.77-1.67 (m, 7H), 1.67-
1.59(m,7H),1.54(s,3H),1.44–1.33(m,1H),1.32(s,3H),1.29(s,3H)ppm;13C NMR(101MHz,
CDCl3)δ203.4,178.9,164.0,161.4,157.5,154.7,138.2,135.4,134.3,133.3,132.4,
131.8,131.6,130.8,130.3,127.3,126.0,124.6,123.7,122.9,122.2,116.0,107.8,
102.6,100.4,90.9,83.8,83.4,81.2,49.0,46.9,41.9,29.9,29.7,28.8,27.5,25.7,25.7,
25.2,22.7,21.7,20.6,18.1,17.6ppm;HRMS(EI)m/z calcd for C45H49BrNO8810.2641,
found for[M+H]+810.2616.
The preparation of 26 compound 37 of embodiment
With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with to fluorobenzene first oxime, obtains compound 37, yield
76.5%.1H NMR(400MHz,CDCl3) δ 12.83 (s, 1H), 8.09 (s, 1H), 7.71 (dd, J=8.6,5.4Hz, 2H),
7.54 (d, J=6.9Hz, 1H), 7.10 (t, J=8.6Hz, 2H), 6.59 (d, J=10.1Hz, 1H), 6.17 (t, J=6.6Hz,
1H), 5.35 (d, J=10.4Hz, 1H), 5.08-4.99 (m, 2H), 3.48 (dd, J=6.5,4.7Hz, 1H), 3.31 (dd, J
=14.6,8.0Hz, 1H), 3.22-3.14 (m, 1H), 2.98 (qd, J=16.6,6.5Hz, 2H), 2.53 (d, J=9.3Hz,
1H), 2.32 (dd, J=13.5,4.7Hz, 1H), 2.05-1.95 (m, 2H), 1.82 (s, 3H), 1.77-1.72 (m, 1H), 1.71
(s,6H),1.64(s,3H),1.62(s,3H),1.59–1.54(m,1H),1.53(s,3H),1.40–1.35(m,1H),1.32
(s,3H),1.29(s,3H)ppm;13C NMR(101MHz,CDCl3)δ203.4,178.9,164.7,164.2,161.4,
157.5,155.0,138.0,135.4,133.3,131.8,131.6,130.6,126.7,126.6,126.1,124.6,
123.7,122.2,116.1,116.0,107.8,102.6,100.4,91.0,83.8,83.3,81.2,49.0,46.9,41.9,
29.9,29.6,28.8,27.6,25.7,25.6,25.2,22.7,21.7,20.6,18.1,17.6ppm;HRMS(EI)m/z
calcd for C45H49FNO8750.3442,found for[M+H]+750.3432.
The preparation of 27 compound 38 of embodiment
With embodiment 24, difference is that between, fluorobenzene first oxime replaces p-bromobenzaldehyde oxime to react, and obtains compound 38, yield
73.5%.1H NMR(400MHz,CDCl3) δ 12.83 (s, 1H), 8.10 (s, 1H), 7.54 (d, J=6.9Hz, 1H), 7.49-
7.43 (m, 2H), 7.38 (td, J=8.1,5.8Hz, 1H), 7.19-7.12 (m, 1H), 6.59 (d, J=10.1Hz, 1H), 6.15
(dd, J=7.2,6.0Hz, 1H), 5.34 (d, J=10.1Hz, 1H), 5.09-4.99 (m, 2H), 3.48 (dd, J=6.6,
4.7Hz, 1H), 3.31 (dd, J=14.6,8.1Hz, 1H), 3.18 (dd, J=14.5,4.9Hz, 1H), 3.03 (dd, J=
16.2,6.7Hz, 1H), 2.94 (dd, J=17.3,6.5Hz, 1H), 2.53 (d, J=9.3Hz, 1H), 2.32 (dd, J=13.5,
4.6Hz, 1H), 2.05-1.95 (m, 2H), 1.82 (d, J=0.9Hz, 3H), 1.77-1.72 (m, 1H), 1.70 (s, 6H), 1.63
(s,3H),1.63(s,3H),1.59–1.54(m,1H),1.53(s,3H),1.40–1.34(m,1H),1.32(s,3H),1.29
(s,3H)ppm;13C NMR(101MHz,CDCl3)δ203.4,178.9,162.8,161.5,157.6,157.5,155.1,
155.0,138.2,135.4,133.4,132.6,131.8,131.6,130.4,126.0,124.6,124.6,123.7,
122.2,118.5,116.0,114.7,107.8,102.6,100.4,90.9,83.8,83.4,81.2,49.0,46.9,41.9,
29.9,29.7,28.8,27.5,25.7,25.6,25.2,22.6,21.7,20.6,18.1,17.6ppm;HRMS(EI)m/z
calcd for C45H49FNO8750.3442,found for[M+H]+750.3422.
The preparation of 28 compound 39 of embodiment
With embodiment 24, difference is that between, chlorobenzene first oxime replaces p-bromobenzaldehyde oxime to react, and obtains compound 39, yield
45.1%.1H NMR(400MHz,CDCl3) δ 12.83 (s, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=13.2,
1H), 7.55 (d, J=12.4,1H), 7.43 (d, J=8.4Hz, 1H), 7.35 (t, J=7.8Hz, 1H), 6.60 (d, J=
10.1Hz, 1H), 6.15 (dd, J=7.2,6.0Hz, 1H), 5.35 (d, J=10.1Hz, 1H), 5.08-4.99 (m, 2H), 3.48
(dd, J=6.6,4.6Hz, 1H), 3.32 (dd, J=14.6,8.0Hz, 1H), 3.18 (dd, J=14.4,4.9Hz, 1H), 3.04
(dd, J=16.6,6.3Hz, 1H), 2.94 (dd, J=16.7,6.0Hz, 1H), 2.53 (d, J=9.3Hz, 1H), 2.32 (dd, J
=13.5,4.7Hz, 1H), 2.05-1.96 (m, 2H), 1.82 (d, J=0.8Hz, 3H), 1.78-1.72 (m, 1H), 1.71 (s,
3H), 1.71 (s, 3H), 1.64 (s, 6H), 1.59-1.55 (m, 1H), 1.54 (s, 3H), 1.39 (dd, J=13.4,9.5Hz,
1H),1.32(s,3H),1.30(s,3H)ppm;13C NMR(101MHz,CDCl3)δ203.4,178.9,164.0,161.4,
157.5,157.5,154.8,138.2,135.4,134.9,133.4,132.2,131.8,131.6,131.4,130.0,
128.0,126.8,126.0,124.6,123.7,122.2,116.0,107.8,102.6100.4,90.9,83.8,83.4,
81.2,49.0,46.9,41.9,29.9,29.7,28.8,27.5,25.7,25.7,25.2,22.7,21.7,20.6,18.1,
17.6ppm;HRMS(EI)m/z calcd for C45H49ClNO8766.3146,found for[M+H]+766.3131.
The preparation of 29 compound 40 of embodiment
With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with o-chlorobenzaldehyde oxime, obtains compound 40, produces
Rate 45.7%.1H NMR(400MHz,CDCl3) δ 12.81 (s, 1H), 8.62 (s, 1H), 8.08 (d, J=7.4Hz, 1H), 7.55
(d, J=6.9Hz, 1H), 7.42-7.35 (m, 2H), 7.33-7.27 (m, 1H), 6.57 (d, J=10.1Hz, 1H), 6.16 (t, J
=6.7Hz, 1H), 5.31 (d, J=10.1Hz, 1H), 5.09-4.98 (m, 2H), 3.51-3.45 (m, 1H), 3.33 (dd, J=
14.7,8.1Hz, 1H), 3.22-3.12 (m, 1H), 3.10-2.95 (m, 2H), 2.52 (d, J=9.3Hz, 1H), 2.32 (dd, J
=13.4,4.7Hz, 1H), 1.99 (dd, J=15.7,7.9Hz, 2H), 1.83 (s, 3H), 1.76-1.69 (m, 7H), 1.64 (s,
6H), 1.58-1.54 (m, 1H), 1.53 (s, 3H), 1.38 (dd, J=13.4,9.6Hz, 1H), 1.33 (s, 3H), 1.30 (s,
3H)ppm;13C NMR(101MHz,CDCl3)δ203.5,178.9,163.9,161.4,157.7,157.4,152.8,138.8,
135.2,134.9,133.4,132.4,131.8,131.5,129.8,128.6,128.4,127.1,125.9,124.4,
123.8,122.3,116.0,107.6,102.6,100.4,90.9,83.8,83.5,81.1,49.0,46.9,42.0,29.9,
29.5,28.8,27.6,25.7,25.7,25.2,22.6,21.7,20.5,18.1,17.6ppm;HRMS(EI)m/z calcd
for C45H49ClNO8766.3146,found for[M+H]+766.3133.
The preparation of 30 compound 41 of embodiment
With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with p-nitrophenyl first oxime, obtains compound 41, produces
Rate 40.4%.1H NMR(400MHz,CDCl3) δ 12.83 (s, 1H), 8.28 (d, J=8.8Hz, 2H), 8.19 (s, 1H), 7.90
(d, J=8.8Hz, 2H), 7.55 (d, J=6.9Hz, 1H), 6.57 (d, J=10.1Hz, 1H), 6.23 (dd, J=7.2,
5.9Hz, 1H), 5.35 (d, J=10.0Hz, 1H), 5.08-4.98 (m, 2H), 3.49 (dd, J=6.7,4.6Hz, 1H), 3.31
(dd, J=14.5,8.1Hz, 1H), 3.21-3.14 (m, 1H), 3.05-2.91 (m, 2H), 2.54 (d, J=9.3Hz, 1H),
2.33 (dd, J=13.5,4.7Hz, 1H), 2.05-1.95 (m, 2H), 1.83 (d, J=1.0Hz, 3H), 1.75 (dd, J=
12.1,4.6Hz,1H),1.71(s,6H),1.63(s,6H),1.57–1.54(m,1H),1.53(s,3H),1.40–1.35(dd,
J=13.4,9.6Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H) ppm;13C NMR(101MHz,CDCl3)δ203.4,179.0,
163.8,161.5,157.6,153.9,149.4,138.8,136.4,135.5,133.3,131.9,131.7,129.2,
125.7,124.7,124.0,123.6,122.1,115.9,107.8,102.6,100.4,91.0,83.9,83.3,81.2,
49.0,46.9,41.9,29.9,29.7,28.8,27.6,25.7,25.6,25.2,22.6,21.7,20.6,18.1,
17.6ppm;HRMS(EI)m/z calcd for C45H49N2O10777.3387,found for[M+H]+777.3360.
The preparation of 31 compound 42 of embodiment
With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with acetoxime, obtains compound 42, yield
38.4%.1H NMR(400MHz,CDCl3) δ 12.82 (s, 1H), 7.53 (d, J=6.9Hz, 1H), 6.64 (d, J=10.1Hz,
1H), 6.16 (t, J=6.3Hz, 1H), 5.42 (d, J=10.1Hz, 1H), 5.09-5.01 (m, 2H), 3.46 (dd, J=6.6,
4.6Hz, 1H), 3.32 (dd, J=14.7,8.0Hz, 1H), 3.21 (dd, J=14.6,5.1Hz, 1H), 3.04 (dd, J=
16.6,7.1Hz, 1H), 2.88 (ddd, J=17.0,6.1,1.4Hz, 1H), 2.52 (d, J=9.3Hz, 1H), 2.31 (dd, J=
13.4,4.6Hz, 1H), 2.07-1.98 (m, 5H), 1.83 (s, 3H), 1.81 (d, J=0.9Hz, 3H), 1.79-1.75 (m,
1H),1.73(s,3H),1.70(s,3H),1.65(s,3H),1.63(s,3H),1.61-1.56(m,1H),1.55(s,3H),
1.44 (s, 3H), 1.38 (dd, J=13.3,9.5Hz, 1H), 1.29 (s, 3H) ppm;13C NMR(101MHz,CDCl3)δ
203.6,178.9,164.2,163.6,161.5,157.6,157.5,137.8,135.3,133.3,131.8,131.5,
126.6,124.5,123.8,122.3,116.0,107.7,102.6,100.4,90.9,83.7,83.2,81.2,49.0,
47.0,42.0,30.0,29.7,28.8,27.8,25.7,25.7,25.3,22.7,22.1,21.7,20.5,18.1,17.6,
17.1;HRMS(EI)m/z calcd for C41H50NO8684.3536,found for[M+H]+684.3527.
The preparation of 32 compound 43 of embodiment
With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with isobutyl aldoxime, obtains compound 43, yield
36.5%.1H NMR(400MHz,CDCl3) δ 12.83 (s, 1H), 7.54 (d, J=6.9Hz, 1H), 7.34 (d, J=6.9Hz,
1H), 6.65 (d, J=10.1Hz, 1H), 6.24 (t, J=6.4Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.09-5.00
(m, 2H), 3.46 (dd, J=6.6,4.6Hz, 1H), 3.32 (dd, J=14.5,8.1Hz, 1H), 3.17 (dd, J=14.5,
4.7Hz, 1H), 2.99-2.82 (m, 2H), 2.65 (dq, J=13.7,6.9Hz, 1H), 2.53 (d, J=9.3Hz, 1H), 2.30
(dd, J=13.5,4.6Hz, 1H), 2.04 (dd, J=15.9,7.7Hz, 2H), 1.84-1.76 (m, 4H), 1.73 (s, 3H),
1.71 (s, 3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.60 (dd, J=7.0,3.0Hz, 1H), 1.55 (s, 3H), 1.44 (s,
3H), 1.38 (dd, J=13.3,9.6Hz, 1H), 1.29 (s, 3H), 1.13 (d, J=6.8Hz, 3H), 1.12 (d, J=6.8Hz,
3H)ppm;13C NMR(101MHz,CDCl3)δ203.5,178.9,164.7,164.1,161.4,157.6,157.5,137.3,
135.5,133.3,131.9,131.6,126.0,124.5,123.8,122.2,116.0,107.6,102.5,100.4,91.1,
83.8,83.2,81.2,49.0,46.9,42.0,29.4,29.6,29.5,28.8,27.9,25.7,25.7,25.2,22.8,
21.7,20.6,19.7,19.7,18.1,17.6ppm;HRMS(EI)m/z calcd for C42H52NO8698.3693,found
for[M+H]+698.3685.
BIOLOGICAL ACTIVITY EXAMPLES gambogicacid analog anti-tumor biological body outer screening test
1. material
1.1. sample and reagent:
Test specimen is dissolved with dimethyl sulfoxide (DMSO, final concentration 0.8%), is trained with containing 15% calf serum RPMI1640
Feeding basigamy is spare at 2mg/ml, and the used time is diluted to required concentration.
Cisplatin for injection (CDDP CISPLATIN FOR INJECTION), 10mg/ bottles, Qilu Pharmaceutical Co., Ltd. is raw
It produces.
RPMI1640 culture medium: GIBGO company, U.S. production.
Dimethyl sulfoxide (DMSO): Tianjin Fu Yu Fine Chemical Co., Ltd, lot number: in October, 2013 23B.
The production of MTT:Sigma company.
1.2. cell: A549 (human lung adenocarcinoma) is purchased from Cell Bank of Chinese Academy of Sciences.HELF-6 (human embryonic lung cell) cell,
Shandong Academy of Medical Sciences is given on basis.Using containing 15% calf serum RPMI1640 culture medium, set 37 DEG C, 5%CO2
Culture in incubator.
1.3. instrument:
Forma3111 water-jacket typ carbon dioxide incubator, the production of Forma company, the U.S..
Victor1420 multi-functional mark analyzer, the U.S..
96 orifice plates, it is Americanized.
2. method
2.1 cell culture and drug effect: take A549 (human lung adenocarcinoma) and HELF-6 (human embryonic lung cell) index raw respectively
After long-term cell is washed, with counting after the digestion of 0.25% pancreatin, adjustment cell concentration is 1 × 105/ ml, is inoculated in respectively
In 96 orifice plates, every hole 0.1ml sets 37 DEG C, 5%CO2Culture in incubator.Culture was loaded product after 24 hours.Act on A549 (people
Adenocarcinoma of lung) and 12 sample maximum dose level group drug concentrations of HELF-6 (human embryonic lung cell) cell be 100 μ g/ml, by 5 times according to
It is secondary to be diluted to 0.01 μ g/ml, totally 5 dosage groups.Each concentration sets 3 multiple holes, and sets Vehicle controls hole (DMSO, 0.8%), training
After supporting 48 hours, OD value is measured with MTT method, calculates cell inhibitory rate.This experiment is repeated twice.
The calculating of 2.2 cell inhibitory rates: after cell terminates culture, every hole is added 10 μ l 0.5%MTT and sets CO2Incubator
It is interior, liquid in hole of inclining is taken out after 4 hours, DMSO (hole 0.2ml/) is added, sufficiently vibrate, dissolve bluish violet formazan, Yu Duogong
OD value can be detected at labeled analysis instrument 570nm wavelength, using the mean value computation cell of 3 multiple holes OD value of various concentration test medicine
Inhibiting rate and IC50。
2.3. result judges:
According to new drug preclinical study guideline (Ministry of Health of the People's Republic of China bureau of drug administration 1993.7:139)
Plant extracts IC50≤ 30 μ g/ml think there is certain inhibiting effect;
Synthetic drug IC50≤ 10 μ g/ml think there is certain inhibiting effect.
Table 1: to the inhibiting rate % of growth of tumour cell
Claims (9)
1. being selected from following formula (III ')~(VII ') and formula (III ")~(VII ") compound represented or its being pharmaceutically acceptable
Salt:
Wherein, R1For H or C1-6Alkyl-;
R2Selected from O, S or OH, R2Between C-12Singly-bound or double bond are indicated, wherein working as R2When for O or S, with C-12 shape
At double bond, work as R2When for other groups in defined above, singly-bound is formed with C-12;
R3Selected from C1-6Alkyl-;
R5Selected from H, R is connected5C-4 and C-3 formed double bond;
R6、R7、R8、R9、R10It is independently from each other H ,-C (=O) Rb,-S (=O)2Rb, optionally by one or more RaReplace
C1-6Alkyl-, C6-14Aryl-;
RaIndependently selected from F, Cl, Br, I, OH, SH, CN ,=O, NRcRd、C1-6Alkyl-, C6-14Aryl-C1-6Alkyl oxy-,
C6-14Aryloxy-,-C (=O) Rb,-S (=O)2Rb;
RbSelected from optionally by one or more RaSubstituted following groups: C1-6Alkyl-, NRcRd、C6-14Aryl-;
RcAnd RdIt is independently selected from H or C1-6Alkyl-.
2. being selected from compound shown in following formula or its pharmaceutically acceptable salt:
3. the preparation method of compound as described in claim 1 or its pharmaceutically acceptable salt, including being selected from following one
Or the combination of multiple steps:
Step 1):
If desired, carrying out step 2):
Step 3):
Step 4):
Reaction the depositing in catalyst 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/or alkali
In lower progress;Or
Using identical method, by the compound (III ") in following compounds (e ") and (f ") preparation claim 1~
(VII "):
And step 5):
Optionally, by step 1)~4) resulting compound reacts with acid appropriate or alkali and prepares its pharmaceutically acceptable salt;
Wherein, R1~R3、R5To R10It is respectively provided with definition as described in claim 1;
R2aSelected from OH or SH;
R2bSelected from O or S;
X is selected from chlorine, bromine or iodine;
Z is selected from hydrogen, chlorine or bromine.
4. method as claimed in claim 3, the combination including being selected from following one or more steps:
Wherein, R1~R3And R5~R10The definition being each independently selected from claim 3.
5. pharmaceutical composition includes compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt.
6. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, which are used to prepare, treats or prevents disease
The purposes of pharmaceutical composition, wherein the disease is selected from neoplastic hematologic disorder, solid tumor and/or their transfer.
7. purposes as claimed in claim 6, wherein the disease is selected from leukaemia and myelodysplastic syndrome, pernicious leaching
Bar tumor, the head including brain tumor and brain metastes and tumor colli including non-fire power and small cell lung tumor exist
Interior breast tumor, gastroenteric tumor, endocrine tumors, tumor of breast and other gynecological tumors including kidney neoplasms, bladder tumor and
Patients with Urinary System Tumors, skin neoplasin and sarcoma, and/or their transfer including prostate tumor.
8. purposes as claimed in claim 6, wherein the disease is cancer.
9. purposes as claimed in claim 6, wherein the disease is lung cancer.
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