CN104513296B - A kind of cyclic peptide compounds and application thereof - Google Patents
A kind of cyclic peptide compounds and application thereof Download PDFInfo
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- CN104513296B CN104513296B CN201310455504.8A CN201310455504A CN104513296B CN 104513296 B CN104513296 B CN 104513296B CN 201310455504 A CN201310455504 A CN 201310455504A CN 104513296 B CN104513296 B CN 104513296B
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Abstract
The present invention relates to a kind of derivative of ciclosporin A, it is included with formula（I）The compound and its ester of structure, salt derivative, and their enantiomter or diastereoisomer and/or respective heterogeneous mixture：
Description
Technical field
The present invention relates to a kind of cyclic peptide compounds and application thereof.
Background technology
Ciclosporin A is the immunosuppressant drug that a kind of cyclic peptide compounds extract in the metabolin of the porous trichoderma of fungi
(Dreyfuss et al., 1976), it is made up of a kind of a kind of ten amino acid.The importance of ciclosporin A is that it can hinder
The only rejection during organ transplant, this is also one of important step of organ transplant.Ciclosporin A belongs to calcium neuroprotein
Inhibitor, its interference between T cell activity reduce immune system reactivity (Cantrell and Smith,
1984).Ciclosporin A can specifically suppress T lymphocytes, but not suppress suppressive lymphocyte T, promote its increasing on the contrary
Grow.It may also suppress the activity of bone-marrow-derived lymphocyte and optionally suppresses the proleulzin secreted by T lymphocytes and γ-interference
Element, it can also reduce the il-1 of monokaryon, macrophages secrete.Stop in its energy arresting cell cycle G0/G1 early stage phase
Lymphocyte, anti-rejection effect is played so as to suppress the generation of internal antigraft antibody.
Due to the above-mentioned effect of ciclosporin A, it can be applied to suppress the rejection effect after organ transplant, it can also be used to treat
Various autoimmune disease, such as：Activity and refractory rheumatoid arthritis, systemic loupus erythematosus merge High-grade Proteinuria
Lupus nephritis, psoriasis, arthritis, the uveitis of behcet disease, iridocyclitis, IBD, Reiter are comprehensive
Close disease.In addition with domestic and foreign literature report ciclosporin A and its substitutive derivative also have HIV-resistant activity, anti-rotavirus activity,
Antifungal activity, anti-inflammatory activity, nerval cell regenerative activity, reversing tumor multiple medicine patience activity, Antiparasitic Activity, treatment liver
Sick activity etc..
But ciclosporin A is synthesis of cyclic peptides, it can form restricted conformation, have stronger resistance to enzymolysis and anti-chemistry
Degradation capability, thus after its intake in body and blood more stable property, the metabolism time is longer, thus to kidney, liver etc.
Organ has side effect.Therefore find with ciclosporin A bioactivity and be easier human body metabolism substitute products always
It is the focus of this area.
In addition the Synthesis conversion of existing ciclosporin A and the like is low, yielding poorly is difficult to use in industrial production.
The content of the invention
We find a kind of compound similar with ciclosporin A, and it has good biological activity and hypotoxicity, easy generation
The advantages of thanking.Such compound can be obtained by organic chemical synthesis and Peptide systhesis, and this synthesis is more based on solution
Such a mode quickly and efficiently of peptide symthesis, therefore its yield high energy reaches industrial production rank.In addition the process purified
Also can help quickly to form these ciclosporin A analogs.
The present invention relates to a kind of derivative BSAZ-823 of ciclosporin A, including with formula（I）The compound of structure and its
Ester, salt derivative, and their enantiomter or diastereoisomer and/or respective heterogeneous mixture：
Wherein
X:It is selected from selected from the substitution of oxygen group elements, NH, C1-C12 alkylidene and one or polysubstituted derivative, its substituted radical
Commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, epoxide and/or epoxy radicals；
R1:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide, hydroxyl and their substitution or more
Substitutive derivative, its substituted radical are selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, oxygen
Base and/or epoxy radicals；
R2:Selected from H, halogen, C1-C12 alkyl, aromatic radical, cycloalkyl and their substitution or polysubstituted derivative
Thing, its substituted radical are selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, epoxide, epoxy
Base；
R3:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitution or more
Substitutive derivative, the substituted radical be selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical,
Epoxide, epoxy radicals, hydroxyl, monosaccharide groups, polysaccharide-based, heterocycle glycosyl, amino, carboxyl；
R4:Selected from H, halogen；
R5:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide and their substitution or multi-substituent
Group, the substituted radical are selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, epoxide, epoxy
Base, monosaccharide groups, polysaccharide-based, heterocycle glycosyl, amino, carboxyl；
R6:Selected from H, halogen；
R7:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide and their substitution or polysubstituted spread out
Biology, the substituted radical are selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, epoxide, ring
Epoxide, monosaccharide groups, polysaccharide-based, heterocycle glycosyl, amino, carboxyl；；
R8:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitution or more
Substitutive derivative, the substituted radical be selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical,
Epoxide, epoxy radicals, monosaccharide groups, polysaccharide-based, heterocycle glycosyl, amino, carboxyl；
R9:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide and their substitution or polysubstituted spread out
Biology, the substituted radical are selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, epoxide, ring
Epoxide, monosaccharide groups, polysaccharide-based, heterocycle glycosyl, amino, carboxyl；
R10:Selected from H, halogen；
R11:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide and their substitution or polysubstituted
Derivative, the substituted radical be selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical, epoxide,
Epoxy radicals, monosaccharide groups, polysaccharide-based, heterocycle glycosyl, amino, carboxyl；
R12:Selected from H, halogen；
R13:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitution or more
Substitutive derivative, the substituted radical be selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical,
Epoxide and/or epoxy radicals；
R14:Selected from H, C1-C12 alkyl, aromatic radical, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitution or more
Substitutive derivative, the substituted radical be selected from commutable halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, aromatic radical,
Epoxide and/or epoxy radicals；
Above-mentioned X, R1-R14 can be with identical or different.
Preferably
X：Alkylidene and its substitutive derivative have 1-6 carbon atoms；
R1:Alkyl, cycloalkyl, epoxy radicals, epoxide, hydroxyl and their substitutive derivative have 1-6 carbon atoms, aromatic radical
And its substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical, oxygen in its substituted radical
Base or epoxy radicals have 1-3 carbon atom；
R2:Alkyl, cycloalkyl, epoxy radicals, epoxide and their substitutive derivative have a 1-6 carbon atoms, aromatic radical and its
Substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical, epoxide or
Epoxy radicals has 1-3 carbon atom；
R3:Alkyl, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitutive derivative have 1-6 carbon atoms, aromatic radical
And its substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical, oxygen in its substituted radical
Base, hydroxyl or epoxy radicals have 1-3 carbon atom；
R4:Selected from H, halogen；
R5:Alkyl, cycloalkyl, epoxy radicals, epoxide and their substitutive derivative have a 1-6 carbon atoms, aromatic radical and its
Substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical, epoxide or
Epoxy radicals has 1-6 carbon atom；
R6:Selected from H, halogen；
R7:Alkyl, cycloalkyl, epoxy radicals, epoxide and their substitutive derivative have a 1-6 carbon atoms, aromatic radical and its
Substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical, epoxide or
Epoxy radicals has 1-6 carbon atom；
R8:Alkyl, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitutive derivative have 1-6 carbon atoms, aromatic radical
And its substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical, oxygen in its substituted radical
Base, acyl group or epoxy radicals have 1-6 carbon atom；
R9:Alkyl, cycloalkyl, epoxy radicals, epoxide and their substitutive derivative have a 1-6 carbon atoms, aromatic radical and its
Substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical, epoxide or
Epoxy radicals has 1-6 carbon atom；
R10:Selected from H, halogen；
R11:Alkyl, cycloalkyl, epoxy radicals, epoxide and their substitutive derivative have a 1-6 carbon atoms, aromatic radical and its
Substitutive derivative is selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical, epoxide or
Epoxy radicals has 1-6 carbon atom；
R12:Selected from H, halogen；
R13:Alkyl, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitutive derivative have 1-6 carbon atoms, fragrance
Base and its substitutive derivative are selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical,
Epoxide or epoxy radicals have 1-6 carbon atom；
R14:Alkyl, cycloalkyl, epoxy radicals, epoxide, acyl group and their substitutive derivative have 1-6 carbon atoms, fragrance
Base and its substitutive derivative are selected from five yuan or hexa-atomic aromatic radical；Aromatic radical is selected from five yuan or hexa-atomic aromatic radical in its substituted radical,
Epoxide or epoxy radicals have 1-6 carbon atom.
Most preferably
X：Selected from O, S, Se, CH2,CHF,CF2；
R1:Selected from methyl, CH2F,CHF2,CF3, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, benzyl,
CH2OH, cyclopropyl, Oxyranyle；
R2:Selected from F, Cl, Br, methyl, CH2F,CHF2,CF3, ethyl；
R3:Selected from methyl, CH2F,CHF2,CF3, formoxyl, ethyl, 2- hydroxyethyls, isopropyl, (HO) isopropyl, ring
Propyl group, Oxyranyle, isobutyl group, sec-butyl, benzyl, 2- (α-D- galactopyranoses) oxygen methyl, 2- (α-D- glucopyras
Sugar) oxygen methyl, 2- (α-D- pyrans altrose) oxygen methyl, 2- (α-D- pyrans allose) oxygen methyl, 2- (α-D- pyrans Gu sieve
Sugar) oxygen methyl, 2- (α-D- mannopyranoses) oxygen methyl, 2- (α-D- pyrans idose) oxygen methyl, 2- (α-D- pyrans tower sieve
Sugar) oxygen methyl, 2- (α-D- galactopyranoses) oxygen ethyl, 2- (α-D- glucopyranoses) oxygen ethyl, 2- (α-D- pyrans A Zhuo
Sugar) oxygen ethyl, 2- (α-D- pyrans allose) oxygen ethyl, 2- (α-D- pyrans gulose) oxygen ethyl, 2- (α-D- pyrans sweet dews
Sugar) oxygen ethyl, 2- (α-D- pyrans idose) oxygen ethyl, 2- (α-D- talopyranoses) oxygen ethyl, 2- [two (carboxymethyl) ammonia
Base] ethyl, 2- [two (methyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N- morpholinyls) second
Base, 2- [three (methyl) amino] ethyl Cl-, 2- [three (methyl) amino] ethyl H2PO3 -, 2- [three (methyl) amino] ethyl
HSO4 -, 2- [two (ethyl) amino] ethyl；
R4:Selected from F, Cl, Br；
R5:Selected from methyl, isopropyl, sec-butyl, isobutyl group, phenyl, benzyl, ring ethyl, 2- (α-D- galactopyranoses)
Ethyl, 2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- mannopyranoses) ethyl, 2-
(α-D- talopyranoses) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl,
2- (N- morpholinyls) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R6:Selected from F, Cl, Br;
R7:Selected from methyl, isopropyl, sec-butyl, normal-butyl, phenyl, benzyl, ring ethyl, 2- (α-D- galactopyranoses)
Ethyl, 2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- mannopyranoses) ethyl, 2-
(α-D- talopyranoses) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl,
2- (N- morpholinyls) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R8:Selected from methyl, CH2F, CHF2, CF3, formoxyl, ethyl, 2- hydroxyethyls, isopropyl, (HO) isopropyl, ring
Propyl group, Oxyranyle, isobutyl group, sec-butyl, benzyl, 2- (α-D- galactopyranoses) oxygen methyl, 2- (α-D- glucopyras
Sugar) oxygen methyl, 2- (α-D- pyrans altrose) oxygen methyl, 2- (α-D- pyrans allose) oxygen methyl, 2- (α-D- pyrans Gu sieve
Sugar) oxygen methyl, 2- (α-D- mannopyranoses) oxygen methyl, 2- (α-D- pyrans idose) oxygen methyl, 2- (α-D- pyrans tower sieve
Sugar) oxygen methyl, 2- (α-D- galactopyranoses) oxygen ethyl, 2- (α-D- glucopyranoses) oxygen ethyl, 2- (α-D- pyrans A Zhuo
Sugar) oxygen ethyl, 2- (α-D- pyrans allose) oxygen ethyl, 2- (α-D- pyrans gulose) oxygen ethyl, 2- (α-D- pyrans sweet dews
Sugar) oxygen ethyl, 2- (α-D- pyrans idose) oxygen ethyl, 2- (α-D- talopyranoses) oxygen ethyl, 2- [two (carboxymethyl) ammonia
Base] ethyl, 2- [two (methyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N- morpholinyls) second
Base, 2- [three (methyl) amino] ethyl Cl-, 2- [three (methyl) amino] ethyl H2PO3 -, 2- [three (methyl) amino] ethyl
HSO4 -, 2- [two (ethyl) amino] ethyl；
R9:Selected from methyl, isopropyl, sec-butyl, isobutyl group, propyl group, benzyl, ring ethyl, 2- (α-D- galactopyranoses)
Ethyl, 2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- mannopyranoses) ethyl, 2-
(α-D- talopyranoses) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl,
2- (N- morpholinyls) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R10:Selected from F, Cl, Br；
R11:Selected from methyl, CH2F, CHF2, CF3, ethyl, isopropyl, sec-butyl, isobutyl group, phenyl, benzyl, ring second
Base, 2- (α-D- galactopyranoses) ethyl, 2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-
D- mannopyranoses) ethyl, 2- (α-D- talopyranoses) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls)
Ethyl, 2- (N- piperazines) ethyl, 2- (N- morpholinyls) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R12:Selected from F, Cl, Br；
R13:Selected from methyl, CH2F,CHF2,CF3, formoxyl, ethyl, isopropyl, cyclopropyl, Oxyranyle, isobutyl
Base, sec-butyl；
R14:Selected from Me, CH2OH,CH2F,CHF2,CF3, formoxyl, ethyl, propyl group, isopropyl, cyclopropyl, oxirane
Base, butyl, isobutyl group, sec-butyl, benzyl.
Present invention additionally comprises a kind of ciclosporin A derivative, salt therein is physiologically acceptable salt, including inorganic acid,
The acid-addition salts of carboxylic acid and sulfonic acid.It is preferably selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, naphthalene two
Sulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, the salt of maleic acid and benzoic acid.
Present invention additionally comprises a kind of medicine, and it contains foregoing ciclosporin A derivative, and pharmaceutical auxiliaries or other treatments
Active component.Active treatment component can be cell factor, antiviral activity agent, immunomodulator, antibacterial activity agent etc..
Present invention additionally comprises a kind of method for preparing BSAZ-823, it is characterised in that comprises the following steps：
（1）Synthesize Bmt；
（2）Synthesize five yuan of amino acid fragment C；
（3）Utilize step（1）The obtained Bmt and hexa-atomic amino acid fragment F of other Material synthesis；
（4）Fragment C and fragment F are combined to form into cyclic peptide.
Step（1）Middle Bmt is obtained by following synthetic route：
Its synthetic route is specially：
In addition, Bmt can also be synthesized by following route：
In addition compound of the invention can also synthesize as follows：
（1）Synthesize five yuan of amino acid fragment C；
（2）Hexa-atomic amino acid fragment F is obtained using biological half synthesis method；
（3）Fragment C and fragment F are combined to form into cyclic peptide.
Fragment C is synthesized by following manner in the above method：
With combined in any order order synthesis of ternary amino acid fragment A, and binary amino acid fragment B, finally by fragment A and
Fragment B synthesis fragment C, the fragment A and fragment B are
Fragment F is synthesized by following manner：
Order synthesis binary amino acid fragment D in any combination, and quaternary amino acid fragment E, finally by fragment D and fragment
E synthesis fragment F, the fragment D and fragment E are
The specific reactions steps that fragment C and fragment F combines to form cyclic peptide are：
Fragment F C-terminal first couples to obtain ten unitary amino acid sequences with fragment C N-terminal, then by the N/ for the sequence
The solution protection of C-terminal and cyclization obtain cyclic peptide.
The present invention biological half synthesis method be：
The class cyclic peptide compounds extracted from fungus fermentation products, five yuan of peptide compounds containing MeBmt are obtained after hydrolysis
22, then by a step esterification, required fragment F is obtained, the compound 22 is：
The present invention includes a kind of method for preparing Bmt, it is characterised in that is obtained by following synthetic route：
Synthetic route is specially：
Present invention additionally comprises a kind of method for preparing Bmt, it is characterised in that is obtained by following synthetic route：
The invention further relates to purposes of the described ciclosporin A derivative in treating cancer medicine is prepared, the cancer bag
Include carcinoma in situ and ex situ cancer, including but not limited to stomach cancer, lung cancer, liver cancer, lymph cancer, breast cancer etc..
The invention further relates to described ciclosporin A derivative to prepare for preventing or treating the disease related to hepatopathy, resist
Rejection and autoimmune disease, HIV, parasitic infection, fungal infection, rotavirus infection medicine in use
On the way.And they are being prepared for the purposes in nerval cell regenerative activity or the medicine of reversing tumor multiple medicine patience activity.
The compound of the present invention can be with stereoisomer form（Enantiomter, diastereoisomer）In the presence of.Therefore,
The present invention includes described enantiomter or diastereoisomer and their respective mixtures.The stereoisomer is pure
Component can be separated in a known way from the mixture of enantiomter and/or diastereoisomer.
The physiologically nontoxic salt of the compounds of this invention is preferably as salt in the context of the present invention, however,
The present invention can also for example be used for separating or purifying the salt of the compounds of this invention comprising pharmaceutical applications are unsuitable for.
When the group of the compounds of this invention is substituted, then the group can be with unless otherwise stated, by a substitution or more
Substitution.In the context of the present invention, all groups repeatedly occurred all have implication independent mutually.All compounds all may be used
To be substituted by one or two identical or different substituent, can also be substituted by a substituent.
The compound of the present invention includes all tautomeric forms.
Compound 1-22 refers to numbered compound under structural formula respectively in the present invention.
In addition present invention additionally comprises the method that two kinds prepare BSAZ-823 compounds, one kind is de novo formation route, a kind of
For semi-synthetic route.
Advantages of the present invention：
There is a non-natural amino acid Bmt, in de novo formation route, prior art list in ciclosporin A derivative
Secondary synthesis Bmt transformation efficiencies are low, most tens grams of yield, but the synthetic method of the present invention has the production that high yield reaches 40%-80%
Rate so that a large amount of Bmt of single sintering feather weight are possibly realized.
The present invention rightly have selected the slit mode of cyclic peptide, the yield of either various fragments, or it is cyclic when production
Amount is all very high so that BSAZ-823 large-scale production is possibly realized.In addition the present invention also rightly have chosen coupling agent and enter one
Step improves yield.
The present invention obtains higher yield using suitable reaction coupling reagent.
Present invention discover that special site（The modification of the side chain and main chain of each amino acid）, promote the biological living of compound
Property and drug effect.
The present invention also develops a series of active derivative compounds, screens active drug molecule
Embodiment
【Embodiment A】Synthesize Bmt
1. synthesize compound 8（Structural formula is shown in reaction equation（I））
（1）Method one：
Such as following reaction equations（I）Shown, double alcoholic compounds 1 pass through and benzaldehyde, the stepwise reaction of tetra lithium aluminium hydride obtain
Compound 2, pass through again and modified with benzyl protection, and epoxidation reaction obtains epoxy intermediate compound 3, then it is anti-through lithium methide
It should react to obtain intermediate compound 4 with catalytic hydrogenating reduction, then through acetal protection and p-methyl benzenesulfonic acid base Protection Code and oxygen
Change reaction and obtain aldehyde product compound 5, transform into intermediate compound 6 under conditions of wittig reactions, it is passed through again
The oxidative deamination of the protection of solution acetal and Organic leadP guiding reacts to obtain aldehyde product compound 8.
（2）Method two
By 0 DEG C of the compound 20 containing 250ml diethyl ether lithium aluminium hydride reductions（Structural formula is seen below）Solution is adding 1M second
In ethereal solution.Then it is placed on cold soaking in the mixed solution of 15% sodium hydrate aqueous solution.The slurry obtained with anhydrous sodium sulfate drying
Liquid, then filter and condensed under 0 DEG C of vacuum condition, obtain edible vegetable oil and white crystal.Mix products are separated with the way of distillation, are obtained
To 9.2g edible vegetable oil compound 21.Then by TFAA (15.8ml, 112mmol), dissolving is realized clearly in dichloromethane (100ml)
The oxidation of oil 21, obtained mixture is cooled to -78 DEG C, dries (MgSO4), filters, volatilization, obtains compound 8.This step
Yield be 93-99%.
2. Bmt is synthesized by compound 8
Reference reaction formula（II）, n-BuLi diethyl ether solution or lithium hexane solution mix in a nitrogen environment, so
It is added to afterwards under the conditions of 10 DEG C in anhydrous THF (100ml) solution containing HMDS (HMDS).Cooling, then
The schiff bases being dissolved in minimum THF (40ML) are added, add compound 8.It is stirred under the conditions of -100 DEG C
After liquid 4 hours, it is allowed to heat up.Mixed liquor is quenched with saturated ammonium chloride solution, liquid phase is extracted with ether.Organic layer is dried
(MgSO4), it is concentrated under reduced pressure, then processing obtains curdy mixture.It is concentrated in vacuo, is quenched, extracts at room temperature, obtains edible vegetable oil
The compound 10 of state is Bmt.We can obtain up to 91% yield in this step.
【Embodiment B】Synthesize five yuan of amino acid fragment C
Fragment A is to be prepared by compound 10-12 through liquid phase reactor, and it can react preparation jointly by compound 10-12,
Preparation can be reacted successively with random order by compound 10-12.
Fragment B is to be prepared by compound 13,14 by liquid phase reactor.
Fragment A and fragment B has obtained five yuan of amino acid fragment C needed for cyclic peptide in liquid phase reactor.
Above-claimed cpd 10-14 corresponds respectively to a natural or alpha-non-natural amino acid.
Specifically, hydroxy acid compound 13 is dissolved in 100ml dry methylene chloride, then sequentially adds solid HATU
And DIEA, obtained clear solution are stirred at room temperature 10 minutes, add methylated amino-acid compound 14, the Huang that will be obtained
Color solution adds 150ml saturated nacl aqueous solution after being stirred at room temperature 45 minutes.Mixture is cooled to after 4 DEG C in vacuum
Filtration method separates, and then with 500ml deionized water rinsing, obtains white powder dipeptide fragment, yield more than 98%.By this two
Fragments of peptides is dissolved in 100ml dry methylene chloride, then sequentially adds solid HATU and DIEA, and obtained yellow solution exists
Methylated amino-acid compound 12 is added after stirring 10 minutes at room temperature, the yellow solution so obtained is stirred at room temperature 45
150ml saturated nacl aqueous solution is added after minute.Isolated by vacuum filtration after mixture is cooled into 4 DEG C, then with 500ml's
Deionized water rinsing, obtain white powder tripeptide fragment, yield 93%.Obtained mixture is stirred under 0 DEG C of environment, added
500ml cold diethyl ether continues to stir, and is then filtrated to get sediment, is rinsed with cold diethyl ether and dried under vacuum conditions, obtained
Substantial amounts of sour tripeptide fragment A.
Hydroxy acid compound 13 is dissolved in 100ml dry methylene chloride, then sequentially adds solid HATU and DIEA,
Obtained yellow solution is stirred at room temperature 10 minutes, adds methylated amino-acid compound 14, the yellow solution that will be obtained
150ml saturated nacl aqueous solution is added after being stirred at room temperature 45 minutes.Filtered after mixture is cooled into 4 DEG C in sintered glass
White depositions are separated by vacuum filtration process in device, then with 500ml deionized water rinsing, obtain white powder
Dipeptides 17.3g, yield 95%.The latter is handled 2 hours with 30% TFA dichlorides potassium solution, obtains diethanol amine piece after precipitation
Section B.Tripeptide fragment A is dissolved in 100ml dry methylene chloride, solid HATU and DIEA is then sequentially added, obtains
Yellow solution is stirred at room temperature 10 minutes, adds fragment B, and obtained yellow solution is stirred at room temperature, cooled down, very
Empty, separation, then with 500ml deionized water rinsing, the pure full guard five of 28.8g white powders is obtained after flash chromatography
Fragments of peptides C, yield more than 96%.
Fragment C can also react preparation successively with random order by compound 10-14.
【Embodiment C】Synthesize hexa-atomic amino acid fragment F
1st, de novo formation route
By compound 17, compound 18, compound 19 and Bmt prepared above（That is, compound 9）Mixing, at room temperature
Stirring adds 150ml saturated nacl aqueous solution after 200 minutes.Vacuum filter is by white precipitate after mixture is cooled into 4 DEG C
Thing is separated, and then with 500ml deionized water rinsing, the pure full guard four of white powder is obtained after flash chromatography
Fragments of peptides E, yield more than 90%.The latter is handled 5 minutes with 4M dry hydrogen chlorides, is then added cold diethyl ether and is precipitated, is obtained
Free diethanol amine fragment E, yield are larger.
The hydroxy acid fragment F of purifying is protected into reaction by solution, carboxy tert-butyl protection is removed, is dissolved in dry methylene chloride
In, HATU and DIEA reagent solution is then sequentially added, obtained yellow solution is stirred at room temperature, and adds fragment C, will
Obtained yellow solution adds saturated nacl aqueous solution after being stirred at room temperature 3 hours.White powder is obtained after flash chromatography
The linear ten unitary amino acid polypeptide of pure full guard, yield 88%.Obtained product need to pass through the THF of lithium hydroxide and water mixes
Solution processing is closed, saturated nacl aqueous solution is added afterwards, obtains white depositions, after being washed with cold diethyl ether, dries, then uses
20% piperidines/DMF solution removes fluorenylmethyloxycarbonyl（Fmoc）Blocking group.After solvent is drained, white solid continues to use
Cold diethyl ether is washed, and after drying, white powder is dissolved in dichloromethane, then adds HATU and DIEA, obtained yellow
The saturated nacl aqueous solution that solution adds after being stirred at room temperature 12 hours.Pure formula is obtained after flash chromatography（I）It is shown
Cyclic peptide, yield more than 84%.
In addition, fragment E can also react preparation successively with random order by compound 17-19,9.
2. semi-synthetic route
Culture and fermented fungal Cylindrotrichumoligospermum BONORDEN first, are carried from tunning
Class cyclic peptide compounds SDZ214-103 is taken, may be referred to EP0296123A2, THE JOURNAL of BIOLOGICACAL
CHEMISTRY Vol.266,No.24,Issue of August 25,pp.15567-15570,1991,Alfons Lawen
et.al（It is considered as in this true disclosure of two civilization and is all quoted）, then obtain containing in following formula by hydrolysis
MeBmt five yuan of peptide compounds 22, then by a step esterification, obtain required fragment F.The piece obtained by this method
Section F yields are high, greatly improve the yield of final goal compound.
【Embodiment D】Annulation
By the hydroxy acid fragment F of purifying by solving protection reaction, the protection of the hydroxy-acid group tert-butyl group is removed, is dissolved in dry dichloro
In methane, HATU and DIEA reagent solution are then sequentially added, obtained yellow solution is stirred at room temperature, and adds fragment
C, saturated nacl aqueous solution is added after obtained yellow solution is stirred at room temperature into 3 hours.White is obtained after flash chromatography
The linear ten unitary amino acid polypeptide of pure full guard of powdery, yield 88%.Obtained product need to pass through lithium hydroxide THF and
Water mixed solution processing, adds saturated nacl aqueous solution, obtains white depositions afterwards, after being washed with cold diethyl ether, dries, then
Fluorenylmethyloxycarbonyl is removed with 20% piperidines/DMF solution（Fmoc）Blocking group.After solvent is drained, white solid continues
Washed with cold diethyl ether, after drying, white powder is handled into white powder with DMF solution, evaporating completely under vacuum condition, with cold two
Ether washs white solid.White powder is dissolved in dichloromethane, then adds HATU and DIEA, obtained yellow is molten
The saturated nacl aqueous solution that liquid adds after being stirred at room temperature 12 hours.Pure formula is obtained after flash chromatography（I）Shown ring
Shape peptide, yield more than 84%.
It is hereby stated that hereinafter title " BSAZ823xxxx " is the title that compound is prepared in this embodiment.
【Embodiment 1】BSAZ8231001
, synthesis material：Fragment E, adds
It is as follows that structural formula of compound is prepared in embodiment A-D method：
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.99min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values ［ C64H114N10O13+Na]+:1253.8465, measured value 1253.8468
1H NMR(600MHz,CDCl3),δ=7.95(1H,d,J=9.8Hz),7.59(1H,d,J=7.2Hz),7.43(1H,
d,J=8.1Hz),7.22(1H,d,J=7.6Hz),5.67(1H,dd,J=4.1,10.5Hz),5.31(3H,m),5.01(1H,d,J
=10Hz),5.01(1H,t,J=7.3Hz),4.98(1H,dd,J=7.3,16.5Hz),4.93(1H,m),4.81(1H,ddd,J=
6.5,6.5,13.4Hz),4.72(1H,d,J=13.6Hz),4.52(1H,ddd,J=7.3,7.3,14.6Hz),3.78(2H,m),
3.53(3H,s),3.41(3H,s),3.28(3H,s),3.17(1H,d,J=13.6Hz),3.08(6H,brs),2.68(3H,s),
2.69(3H,s),2.32(2H,m),2.08(4H,m),1.99(1H,ddd,J=3.9,10.4,14.5Hz),1.78(1H,m),
1.71(1H,ddd,J=7.2,13.9,13.9Hz),1.59(7H,m),1.26(2H,m),1.35(3H,d,J=7.26Hz),1.28
(3H,d,J=6.5Hz), 1.25(3H,d,J=6.8Hz),1.07(3H,d,J=6.5Hz),1.03(3H,d,J=6.6Hz),1.03
(6H,d,J=6.7Hz),1.01(6H,d,J=6.7Hz),0.95(3H,d,J=6.7Hz),0.94(3H,d,J=6.7Hz),0.93
(3H,d,J=6.5Hz),0.88(3H,d,J=6.9Hz),0.87(3H,d,J=6.2Hz),0.87(6H,d,J=6.5Hz),0.86
(3H,d,J=7.3Hz),0.85(3H,d,J=6.6Hz),0.71(3H,d,J=6.1Hz)。
【Embodiment 2】BSAZ8231002
Following formula: compound is prepared with material similar to Example 1 and identical method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.65min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values ［ C65H116N10O13+Na]+:1267.8621, measured value 1267.8626.
【Embodiment 3】BSAZ8231003
Following formula: compound is prepared with material similar to Example 1 and identical method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.92min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values ［ C64H114N10O14+Na]+:1269.8414, measured value 1269.8418.
【Embodiment 4】BSAZ8231004
Synthesis material：Fragment E, adds
Prepared with embodiment A-D method, obtain the compound of following structural formula
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.49min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values ［ C70H124N10O19+Na]+:1431.8942, measured value 1431.8945.
【Embodiment 5】BSAZ8231006
Synthesis material：Fragment E, adds
Prepared with embodiment A-D methods describeds, obtain following formula: compound
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.29min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+H]+M/z calculated values ［ C69H125N11O13+H]+:1316.9537, measured value 1316.9534.
【Embodiment 6】BSAZ8231008
Synthesis material：Fragment E, adds
Prepared with embodiment A-D methods describeds, obtain following formula: compound
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.77min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again).
HRMS:[M+H]+M/z calculated values [C66H118N10O13+H]+:1259.8958, measured value 1259.8961.
【Embodiment 7】BSAZ8231011
Synthesis material：Fragment E, adds
Prepared with embodiment A-D methods describeds, obtain following formula: compound
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.07min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C70H123N11O17+Na]+:1412.8996, measured value 1412.8999.
【Embodiment 8】BSAZ8231013
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.99min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C70H118N10O13+Na]+:1329.8778, measured value 1329.8775.
【Embodiment 9】BSAZ8231016
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.72min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C76H128N10O19+Na]+:1507.9255, measured value 1507.9258.
【Embodiment 10】BSAZ8231019
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=4.21min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M]+M/z calculated values [C68H124N11O13]+:1302.9375, measured value 1302.9378.
【Embodiment 11】BSAZ8231020
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.85min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C70H118N10O13+Na]+:1329.8778, measured value 1329.8781.
【Embodiment 12】BSAZ8231022
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.72min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C71H120N10O13+Na]+:1343.8934, measured value 1343.8937.
【Embodiment 13】BSAZ8231029
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.51min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C64H111F3N10O13+Na]+:1307.8182, measured value 1307.8179.
【Embodiment 14】BSAZ8231030
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.35min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C62H107F3N10O13+Na]+:1279.7869, measured value 1279.7870.
【Embodiment 15】BSAZ8231031
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.45min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C65H114N10O13+Na]+:1265.8465, measured value 1265.8467.
【Embodiment 16】BSAZ8231032
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.15min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C66H116N10O13+Na]+:1279.8621, measured value 1279.8624.
【Embodiment 17】BSAZ8231033
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.07min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C66H116N10O13+Na]+:1279.8621, measured value 1279.8619.
【Embodiment 18】BSAZ8231034
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.51min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C65H116N10O12+Na]+:1251.8672, measured value 1251.8675.
【Embodiment 19】BSAZ8231035
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.18min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+H]+M/z calculated values [C65H114N10O14+H]+:1259.8594, measured value 1259.8592.
【Embodiment 20】BSAZ8231036
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.05min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C66H116N10O13+Na]+:1279.8621, measured value 1279.8624.
【Embodiment 21】BSAZ8232001
Synthesis material fragment E adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=5.95min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C64H114N10O12S+Na]+:1269.8236, measured value 1269.8238.
【Embodiment 22】BSAZ8232002
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=6.27min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C65H116N10O12S+Na]+:1283.8393, measured value 1283.8395.
【Embodiment 23】BSAZ8232004
Synthesis material, fragment E add
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=4.91min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C70H124N10O18S+Na]+:1447.8713, measured value 1447.8711.
【Embodiment 24】BSAZ8232006
Synthesis material, fragment E add
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=4.68min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C71H126N10O18S+Na]+:1461.8870, measured value 1461.8872.
【Embodiment 25】BSAZ8233002
Synthesis material：Fragment E, adds
Following formula: compound is prepared with embodiment A-D method
LC:Analysis level high performance liquid chromatography uses anti-phase C18 posts（YWG C18,250*4.0/10um）:tR=4.25min(λ
=214nm;A：The 0.1%TFA aqueous solution, B：0.1%TFA acetonitrile solution；Solution gradient program is set：Start 2 minutes 5%B,
Then B increases to 85% by 5% in 5 minutes, keeps within subsequent 2 minutes 85%, last 3 minutes pre-equilibrations 5% again)
HRMS:[M+Na]+M/z calculated values [C65H116N10O12Se+Na]+:1331.7837, measured value 1331.7839.
【Embodiment 26】
The anti-tumor activity test of MTT reducing process detection compounds
1. cell line and cell culture
Human breast carcinoma cell lines MCF-7, Human cervical cancer cell lines Hela, human prostate cancer cell line PC-3, human ovarian cancer
Cell line OVCAR-3, human leukemia cell line K562 and HL-60, human lung cancer cell line H322 and H1299, above-mentioned cell are purchased
From American Type culture center ATCC.Above-mentioned each cell is incubated in RPMI1640 complete mediums, is contained in the culture medium
The streptomysin of 10% calf serum, 100IU/ml penicillin and 100 μ g/ml.Every kind of cell routinely grows to the thin of logarithmic phase
Born of the same parents digest through 0.01% pancreatin, adjustment cell density to 2.0 × 105Individual/ml, it is inoculated in 90 μ l/well in 96 orifice plates,
37 DEG C contain 5%CO2Incubator in cultivate 24h.
2. experimental drug
Compound BSAZ8231001, BSAZ8231002, BSAZ8231003, BSAZ8231004, BSAZ8231006,
BSAZ8231008、BSAZ8231011、BSAZ8231013、BSAZ8231016、BSAZ8231019、BSAZ8231020、
BSAZ8231022、BSAZ8231029、BSAZ8231030、BSAZ8231031、BSAZ8231032、BSAZ8231033、
BSAZ8231034、BSAZ8231035、BSAZ8231036、BSAZ8232001、BSAZ8232002、BSAZ8232004、
BSAZ8232006 and BSAZ8233002 are prepared by above-described embodiment.
3. cell viability test experience
Every piece of 96 orifice plates set 9 groups, i.e. the 8 of positive controls and medicine concentration group.Positive control drug is taxol, is used
DMSO by taxol and each compound be configured to concentration for 10nM, 50nM, 100nM, 1000nM, 5000nM, 10000nM,
20000nM and 50000nM solution, the μ l of drug solution 10 of various concentrations are taken to be added in the hole of the corresponding group of 96 orifice plates respectively,
Positive controls add the taxol of 10 each concentration of μ l, and each concentration sets three holes, trained in 37 DEG C of incubators containing 5%CO2
Support.Human breast carcinoma cell lines MCF-7, Human cervical cancer cell lines Hela and human prostate cancer cell line PC-3 cultures 48h；People's ovary
Cancerous cell line OVCAR-3, human leukemia cell line K562 and HL-60 culture 72h；Human lung cancer cell line H322 and H1299 are cultivated
96h.Then 20 μ l 5mg/ml MTT is added per hole, continues in 37 DEG C of incubators containing 5%CO2 and cultivates 4h, removes culture
Liquid, 100 μ l DMSO solutions are added per hole.Light absorption value L1 is detected in wavelength 550nm using Spectra MAX340 ELIASAs, in
Reference wavelength 690nm detects light absorption value L2, and the difference of light absorption value is mapped to medicine various concentrations, calculates IC50 values, specific knot
Fruit is shown in Table.The inhibitory effect to different tumours is shown according to the visible BSAZ823 of the data each compound.
【Embodiment 27】The influence to cd4 t cell propagation of the compounds of this invention
1. cell line and cell culture
Human peripheral Streptococcus PBMC is derived from healthy volunteer's Peripheral blood, is separated and prepared with Ficoll liquid.
2. experimental drug
Ciclosporin A compound BSAZ823-1001, BSAZ823-1002, BSAZ823-1003, BSAZ823-1004,
BSAZ823-1006、BSAZ823-1008、BSAZ823-1011、BSAZ823-1016、BSAZ823-1019、BSAZ823-
1029、BSAZ823-1031、BSAZ823-1032、BSAZ823-1033、BSAZ823-1034、BSAZ823-1035、
BSAZ823-1036, BSAZ823-2001, BSAZ823-2002, BSAZ823-2004, BSAZ823-2006 and BSAZ823-
3002 are prepared by previous embodiment.
3. the Inhibition test of pair cd4 t cell propagation
107/mL suspensions are made with RPMI1640 complete mediums in human PBMC, add ConA make final concentration of 5 μ g/Ml point kinds in
96 well culture plates, per hole 0.1mL.Per hole dosing 0.1mL.It is placed in 37 DEG C of incubators containing 5%CO2 and cultivates 72h, 6h before termination
3H-TdR18.5kBq is added per hole.Cell is collected, c/min values are surveyed on β-scintillation counter, to breed percentage and logarithm
Concentration makees amount-result relation figure, tries to achieve IC50 values.
4. result
Result of the test shows that 21 kinds of compounds have inhibitory action to human PBMC, and IC50 is 3.9~88.3 μM.
Concrete numerical value is shown in Table：
Claims (12)
1. a kind of derivative of ciclosporin A, including compound and its salt derivative with formula (I) structure：
Wherein
X：Selected from oxygen group elements；
R1：Selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals, hydroxyl and they
One substitution or polysubstituted derivative, its substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or six
First aromatic radical and/or C2-C3 epoxy radicals；
R2：Selected from H, halogen, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl and they one substitution or
Polysubstituted derivative, its substituted radical are selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic fragrance
Base, C2-C3 epoxy radicals；
R3：Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical, C2-C3 epoxy radicals, hydroxyl, monosaccharide groups, amino, carboxyl；
R4:Selected from H, halogen；
R5:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted group, the substituted radical are selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic virtue
Perfume base, C2-C3 epoxy radicals, monosaccharide groups, amino, carboxyl；
R6:Selected from H, halogen；
R7:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical, C2-C3 epoxy radicals, monosaccharide groups, amino, carboxyl；；
R8:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical, C2-C3 epoxy radicals, monosaccharide groups, amino, carboxyl；
R9:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical, C2-C3 epoxy radicals, monosaccharide groups, amino, carboxyl；
R10:Selected from H, halogen；
R11:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical, C2-C3 epoxy radicals, monosaccharide groups, amino, carboxyl；
R12:Selected from H, halogen；
R13:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical and/or C2-C3 epoxy radicals；
R14:Taken selected from H, C1-C12 alkyl, five yuan or hexa-atomic aromatic radical, C1-C6 cycloalkyl, C2-C3 epoxy radicals and their one
Generation or polysubstituted derivative, the substituted radical be selected from halogen, C1-C6 alkyl, five yuan or hexa-member heterocycle, five yuan or hexa-atomic
Aromatic radical and/or C2-C3 epoxy radicals；
Above-mentioned X, R1-R14 can be with identical or different.
2. a kind of derivative of ciclosporin A, including compound and its salt derivative with formula (I) structure：
It is characterized in that：
X：Selected from O, S, Se；
R1:Selected from methyl, CH2F,CHF2,CF3, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, benzyl, CH2OH, ring
Propyl group, Oxyranyle；
R2:Selected from F, Cl, Br, methyl, CH2F,CHF2,CF3, ethyl；
R3:Selected from methyl, CH2F,CHF2,CF3, formoxyl, ethyl, 2- hydroxyethyls, isopropyl, (HO) isopropyl, cyclopropyl,
Oxyranyle, isobutyl group, sec-butyl, benzyl, 2- (α-D- galactopyranoses) oxygen methyl, 2- (α-D- glucopyranoses) oxygen first
Base, 2- (α-D- pyrans altrose) oxygen methyl, 2- (α-D- pyrans allose) oxygen methyl, 2- (α-D- pyrans gulose) oxygen first
Base, 2- (α-D- mannopyranoses) oxygen methyl, 2- (α-D- pyrans idose) oxygen methyl, 2- (α-D- talopyranoses) oxygen first
Base, 2- (α-D- galactopyranoses) oxygen ethyl, 2- (α-D- glucopyranoses) oxygen ethyl, 2- (α-D- pyrans altrose) oxygen second
Base, 2- (α-D- pyrans allose) oxygen ethyl, 2- (α-D- pyrans gulose) oxygen ethyl, 2- (α-D- mannopyranoses) oxygen second
Base, 2- (α-D- pyrans idose) oxygen ethyl, 2- (α-D- talopyranoses) oxygen ethyl, 2- [two (carboxymethyl) amino] ethyl,
2- [two (methyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N- morpholinyls) ethyl, 2- [three
(methyl) amino] ethyl Cl-, 2- [three (methyl) amino] ethyl H2PO3 -, 2- [three (methyl) amino] ethyl HSO4 -, 2- [two
(ethyl) amino] ethyl；
R4:Selected from F, Cl, Br；
R5:Selected from methyl, isopropyl, sec-butyl, isobutyl group, phenyl, benzyl, ring ethyl, 2- (α-D- galactopyranoses) ethyl,
2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- mannopyranoses) ethyl, 2- (α-D-
Talopyranose) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N-
Morpholinyl) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R6:Selected from F, Cl, Br；
R7:Selected from methyl, isopropyl, sec-butyl, normal-butyl, phenyl, benzyl, ring ethyl, 2- (α-D- galactopyranoses) ethyl,
2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- mannopyranoses) ethyl, 2- (α-D-
Talopyranose) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N-
Morpholinyl) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R8:Selected from methyl, CH2F, CHF2, CF3, formoxyl, ethyl, 2- hydroxyethyls, isopropyl, (HO) isopropyl, ring third
Base, Oxyranyle, isobutyl group, sec-butyl, benzyl, 2- (α-D- galactopyranoses) oxygen methyl, 2- (α-D- glucopyranoses)
Oxygen methyl, 2- (α-D- pyrans altrose) oxygen methyl, 2- (α-D- pyrans allose) oxygen methyl, 2- (α-D- pyrans gulose) oxygen
Methyl, 2- (α-D- mannopyranoses) oxygen methyl, 2- (α-D- pyrans idose) oxygen methyl, 2- (α-D- talopyranoses) oxygen first
Base, 2- (α-D- galactopyranoses) oxygen ethyl, 2- (α-D- glucopyranoses) oxygen ethyl, 2- (α-D- pyrans altrose) oxygen second
Base, 2- (α-D- pyrans allose) oxygen ethyl, 2- (α-D- pyrans gulose) oxygen ethyl, 2- (α-D- mannopyranoses) oxygen second
Base, 2- (α-D- pyrans idose) oxygen ethyl, 2- (α-D- talopyranoses) oxygen ethyl, 2- [two (carboxymethyl) amino] ethyl,
2- [two (methyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N- morpholinyls) ethyl, 2- [three
(methyl) amino] ethyl Cl-, 2- [three (methyl) amino] ethyl H2PO3 -, 2- [three (methyl) amino] ethyl HSO4 -, 2- [two
(ethyl) amino] ethyl；
R9:Selected from methyl, isopropyl, sec-butyl, isobutyl group, propyl group, benzyl, ring ethyl, 2- (α-D- galactopyranoses) ethyl,
2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- mannopyranoses) ethyl, 2- (α-D-
Talopyranose) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl, 2- (N- piperazines) ethyl, 2- (N-
Morpholinyl) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R10:Selected from F, Cl, Br；
R11:Selected from methyl, CH2F, CHF2, CF3, ethyl, isopropyl, sec-butyl, isobutyl group, phenyl, benzyl, ring ethyl, 2-
(α-D- galactopyranoses) ethyl, 2- (α-D- pyrans allose) ethyl, 2- (α-D- pyrans gulose) ethyl, 2- (α-D- pyrroles
Mutter mannose) ethyl, 2- (α-D- talopyranoses) ethyl, 2- [two (carboxymethyl) amino] ethyl, 2- (N- piperidyls) ethyl,
2- (N- piperazines) ethyl, 2- (N- morpholinyls) ethyl, 2- [three (methyl) amino] ethyl Cl-；
R12:Selected from F, Cl, Br；
R13:Selected from methyl, CH2F,CHF2,CF3, formoxyl, ethyl, isopropyl, cyclopropyl, Oxyranyle, isobutyl group is secondary
Butyl；
R14:Selected from Me, CH2OH,CH2F,CHF2,CF3, formoxyl, ethyl, propyl group, isopropyl, cyclopropyl, Oxyranyle, fourth
Base, isobutyl group, sec-butyl, benzyl.
3. the ciclosporin A derivative as described in one of claim 1-2, salt therein is pharmaceutically acceptable salt.
4. ciclosporin A derivative as claimed in claim 3, salt therein is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, first sulphur
Acid, ethyl sulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, rich horse
The salt of acid, maleic acid and benzoic acid.
5. a kind of medicine, it contains one of claim 1-4 ciclosporin A derivative, and pharmaceutical auxiliaries.
6. a kind of medicine, it contains one of claim 1-4 ciclosporin A derivative, and other therapeutic activity components.
7. purposes of the ciclosporin A derivative in treating cancer medicine is prepared as described in one of claim 1-4.
8. purposes of the ciclosporin A derivative as claimed in claim 7 in treating cancer medicine is prepared, it is characterised in that described
Cancer includes carcinoma in situ and ex situ cancer.
9. the ciclosporin A derivative as described in one of claim 1-4 is being prepared for preventing or treating the disease related to hepatopathy
Purposes in the medicine of disease.
10. the ciclosporin A derivative as described in one of claim 1-4 is being prepared for treating anti-rejection, autoimmunity
Purposes in the medicine of disease and/or anti-inflammatory.
11. the ciclosporin A derivative as described in one of claim 1-4 is being prepared for treating selected from HIV, rotavirus, posting
Infested, fungi causes the purposes in the medicine of disease.
12. the ciclosporin A derivative described in one of claim 1-4 is being prepared for nerve cell regeneration or reversing tumor multiple medicine
Purposes in the medicine of patience.
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| US7696166B2 (en) * | 2006-03-28 | 2010-04-13 | Albany Molecular Research, Inc. | Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders |
| CN102869367A (en) * | 2009-12-09 | 2013-01-09 | 西尼克斯公司 | Novel cyclic peptides |
| CN103153330A (en) * | 2010-08-12 | 2013-06-12 | 美国科技环球有限公司 | Novel cyclosporin derivatives for the treatment and prevention of a viral infection |
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| US9890198B2 (en) * | 2010-12-03 | 2018-02-13 | S&T Global Inc. | Cyclosporin derivatives and uses thereof |
| DE102011111991A1 (en) * | 2011-08-30 | 2013-02-28 | Lead Discovery Center Gmbh | New cyclosporin derivatives |
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| US7696166B2 (en) * | 2006-03-28 | 2010-04-13 | Albany Molecular Research, Inc. | Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders |
| CN102869367A (en) * | 2009-12-09 | 2013-01-09 | 西尼克斯公司 | Novel cyclic peptides |
| CN103153330A (en) * | 2010-08-12 | 2013-06-12 | 美国科技环球有限公司 | Novel cyclosporin derivatives for the treatment and prevention of a viral infection |
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| "环孢素A的药效学研究";杜美蓉等;《中国药学杂志》;20050131;第40卷(第1期);全文 * |
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