CN104829554B - Phenothiazine compound and its preparation method and application - Google Patents
Phenothiazine compound and its preparation method and application Download PDFInfo
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- CN104829554B CN104829554B CN201510271507.5A CN201510271507A CN104829554B CN 104829554 B CN104829554 B CN 104829554B CN 201510271507 A CN201510271507 A CN 201510271507A CN 104829554 B CN104829554 B CN 104829554B
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- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 8
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- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 7
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 7
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The present invention relates to a kind of preparation methods of the phenothiazine compound with antitumaous effect and the compound, moreover, it relates to application and such compound anticancer drug as active ingredient of such compound in preparing anticancer drug.The present invention to phenthazine ternary chain of rings parent nucleus by being modified to obtain the compound with broad spectrum anticancer effect, and synthetic method is simple, yield is high；Such phenothiazine compounds has certain inhibiting effect for Breast cancer lines MCF 7 and human hepatoma cell strain Hep G2, and the new drug to meet clinical demand provides new approaches.
Description
Technical field
The invention belongs to anticancer drug fields, are related to a kind of phenothiazine compound with antitumaous effect and the compound
Preparation method, moreover, it relates to application of such compound in preparing anticancer drug, and contain such chemical combination
Anticancer drug of the object as active ingredient.
Background technology
Past, the cancer stem cell of various solid tumors and leukemia was also separated successively over more than 20 years.Cancer stem cell
(CSC：CancerStemCell) refer to sub-fraction cell subsets (about 0.1%-5%) in tumour cell, have and be similar to
The feature of stem cell has the characteristics that self-renewing, infinite multiplication and high oncogenicity, most of (G in a dormant state0),
With extremely strong drug resistance, traditional chemotherapy or radiotherapy cannot kill it, eventually lead to tumor recurrence and transfer.From 2009
The hoary hair research institute of Harvard University and the Massachusetts Institute of Technology killed with salinomycin the experiment made on the living of breast carcinoma stem cell
It rises, the research of small molecule anti-cancer disease stem cell drugs is developed rapidly.So far, have nearly 30 anticancer stem cells
Drug is pushed to clinical one, two, three phases.
Phenothiazines be widely used, a kind of more mature antipsychotic class drug, mainly act on maincenter
Dopamine receptor, have the effects that calm, town spits, antipsychotic and reduces body temperature.Recent studies indicate that phenothiazines
Drug has the function of inhibiting tumor stem cell.United States Patent (USP) US2013/0065887A1 discloses a kind of for treating acute bone
The dopamine-receptor antagonist of myelogenous leukemia, the antagonist are phenothiazines thioridazine or chlorine pyridazine, are had
Targeting is selected, leukemia stem cell can be targetedly damaged and other cells not encroached on.At phenothiazines
In the research for managing lymphoma cell, display is had been reported that, under clinical common dose, chlorpromazine and triperazine can promote lymph
The apoptosis of oncocyte and on normal lymphocytes without influence.Chinese patent application CN104114175 discloses dry for removing cancer
The medical composition of cell, the composition, which includes phenothiazines such as triperazine, can inhibit lung cancer stem cell.In the past
Research it has also been found that schizophreniac to suffer from cancer probability low compared with normal person, it is potential anti-swollen to also confirm that such compound has
Tumor effect.The above evidence shows that phenothiazine compound and its derivative have and inhibits tumor proliferation or inhibition Tumor Stem
The effect of cell.Thus industry worker is had become for the research of phenothiazine compound its broad spectrum anticancer effect to make great efforts specially to grind
One of direction, with wide spectrum, efficiently, where the novel phenothiazines of low toxicity are research hotspot, design and screen tool
There are this kind anti-cancer drugs of new chemical constitution, novel mechanism or new role target position to become urgent problem to be solved.
Invention content
The present inventor synthesizes by research and screening to phenothiazine compound structure-activity relationship with antitumaous effect
Phenothiazine compound, it is demonstrated experimentally that the compound is equal for MCF-7 cell strainHJ2mm and Human hepatoma cell line Hep-G2
There is certain inhibiting effect.
The technical proposal of the invention is realized in this way：A kind of phenothiazine compound, the compound structure such as general formula (I)
It is shown：
Wherein, A is piperazinyl, piperidyl, triazol radical, tetrazole base, pyrrole radicals, guanidine radicals, morpholinyl and its derivative
Group；R is C2-3Straight chain saturated alkyl；B can be independently Cl, methyl mercapto or trifluoromethyl.
Further, when B is methyl mercapto, A is piperazinyl, triazol radical, tetrazole base, pyrrole radicals, guanidine radicals, morpholinyl
And its derivatives group or piperidyl or N (CH3)2；When B is trifluoromethyl, A is morpholinyl, piperidyl, pyrrole radicals and its spreads out
Biological group or piperazinyl；When B be Cl when, A be piperidyl, triazol radical, tetrazole base, pyrrole radicals, guanidine radicals, morpholinyl and
Its derivatives group or piperazinyl.
The preparation method of above-mentioned phenothiazine compound is also claimed in the present invention, and presoma has the chemistry of general formula (II)
Substitution reaction occurs in organic solvent for structure, T1 groups and the ligand groups of the presoma；Wherein T1Selected from halogenopropane and
Its derivatives group, T2Selected from Cl, methyl mercapto or trifluoromethyl；
The ligand groups include：Piperidyl, piperazinyl, triazol radical, tetrazole base, pyrrole radicals, guanidine radicals, morpholinyl
And its derivatives group.
Another kind prepare above-mentioned phenothiazine compound method be：M is with the compound with general formula (III) organic molten
Substitution reaction occurs in agent；
Wherein, M is selected from the halothane and its derivative replaced by piperidyl or derivatives thereof group, and B can be independent
For Cl, methyl mercapto or trifluoromethyl.
Piperidyl, piperazinyl and its derivatives group of above method formula of (I) or (II) are by one or two continuous
Amino acid is connected by amidation or esterification.
Further, the organic solvent such as ether, alkane, aromatic hydrocarbon, amides, nitrile, amine, alcohols or ketone is molten
The mixture of one kind or above-mentioned solvent in agent, such as THF, toluene, DMF, acetonitrile, triethylamine, acetone or alcohol.
The present invention provides the new application of above-mentioned phenothiazine compound.
On the one hand, the phenothiazine compound is used to prepare the drug of anti-human breast cancer cell line mcf-7.
On the other hand, the phenothiazine compound is used to prepare the drug of anti-human liver cancer cell strain Hep-G2.
A kind of anticancer pharmaceutical composition, wherein the mixture conduct for containing any compound of above-mentioned phenothiazines or they has
Imitate ingredient and one or more pharmaceutically acceptable carriers.
Further, which can be made the pharmaceutically acceptable dosage form of any type, injection, spraying
Agent, inhalant or oral agents.
The part particular compound of the present invention is as shown in table 1.
1 compound list of table
The above-mentioned phenothiazine compound that the present invention synthesizes, synthetic method is simple, yield is high, by connecting to phenthazine ternary
Ring parent nucleus 10,2 modified, obtain have with desired broad spectrum anticancer effect, such phenothiazine compounds is for people
Breast cancer cell line mcf-7 and Human hepatoma cell line Hep-G2 have certain inhibiting effect, to meet the new drug of clinical demand
New approaches are provided.
Specific implementation mode
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.In following embodiments
The experimental method is unless otherwise specified conventional method；The reagent and biomaterial unless otherwise specified can be from
Commercial sources obtain.
Embodiment 1：Prepare 2-21-2
2-10：
It takes 2- trifluoromethyls phenthazine (2.00g, 7.4831mmol) to be placed in 500mL flasks, is added through anhydrous K2CO3It is dry
Dry THF (100mL), then in N260% NaH mineral oil (1.1973g, 29.9323mmol) and 1- are sequentially added under protection
Bromo- 3- chloropropanes (2.9601mL, 29.9323mmol) are refluxed overnight in 65 DEG C of bath temperatures.It is cooled to room temperature, then by reaction solution
It pours into mixture of ice and water, is extracted with ethyl acetate (300mL+100mL × 2), merge organic phase, with anhydrous MgSO4It is dry, mistake
Solid is filtered out, is then spin-dried for filtrate, adds ethyl acetate (50mL) dissolving, silica white (20g) is added into solution and revolves
Dry, dry method loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient elution, collects product, is spin-dried for, vacuum drying obtains
Product 2-10 (4.9444g, yield 69.8%).+c ESI Q1MS：[M+H+]344.00。
2-21-2：
Take 2-10 (250mg, 0.7272mmol) to be placed in 30mL straight tube bottles, then be added morpholine (95.0mg,
1.0908mmol), triethylamine (0.30mL, 2.1816mmol) and acetonitrile (10mL), are stirred overnight at 80 DEG C.It is cooled to room
Temperature is directly spin-dried for, and crude product is dissolved with methanol, filtering, silica white is added into filtrate, solid solution, dry method loading mistake is made
Silica gel column purification is collected product, is spin-dried for, is dried in vacuo to obtain product 2- with triethylamine, ethyl acetate and petroleum ether gradient elution
21-2 (108.5mg, yield 31.5%).1H-NMR(400MHz,CDCl3)δ7.23-7.10(m,4H),7.04(s,1H),7.00-
6.89 (m, 2H), 4.00 (t, J=6Hz, 2H), 3.76-3.62 (m, 4H), 2.61-2.39 (m, 6H), 2.08-1.92 (m, 2H)；
+c ESI Q1MS：[M+H+]395.09。
Embodiment 2：Prepare 2-21-6
In 30mL straight tube bottles, be added 2-10 (250mg, 0.7272mmol), prolinol (110.3mg, 1.0908mmol),
Triethylamine (0.5mL) and acetonitrile (10mL), are stirred overnight at 80 DEG C.It is cooled to room temperature, is directly spin-dried for, by crude product methanol
Dissolving, filtering, into filtrate, solid solution is made in addition silica white, and dry method loading crosses silica gel column purification, with triethylamine, acetic acid second
Ester and petroleum ether gradient elution collect product, are spin-dried for, are dried in vacuo to obtain product 2-21-6 (138.9mg, yield 38.9%).1H-
NMR(400MHz,CDCl3)δ7.25-7.13(m,4H),7.05(s,1H),7.01-6.89(m,2H),4.05-3.96(m,2H),
3.68-3.60(m,1H),3.51-3.42(m,1H),3.33-3.23(m,1H),3.14-3.03(m,1H),2.81-2.69(m,
1H),2.61-2.50(m,1H),2.35-2.24(m,1H),2.16-2.05(m,2H),1.85-1.72(m,3H),1.28-1.23
(m,2H)；+c ESI Q1MS：[M+H+]409.11。
Embodiment 3：Prepare 2-163,2-172
2-21-1：
It takes 2-10 (300mg, 0.8726mmol) to be placed in 30mL straight tube bottles, 1- tert-butoxycarbonyl-piperazines is then added
(243.8mg, 1.3089mmol), triethylamine (0.37ml, 2.6178mmol) and acetonitrile (10mL), reacted under the conditions of 80 DEG C
Night.It being cooled to room temperature, is directly evaporated, crude product is dissolved with methanol, silica white is then added into filtrate is made solid solution,
Dry method loading crosses silica gel column purification, is eluted with ethyl acetate, petroleum ether and triethylamine gradient, collects product, is spin-dried for, and is dried in vacuo
Obtain product 2-21-1 (63.4mg, yield 40.2%).1H-NMR(400MHz,CDCl3)δ7.24-7.10(m,5H),7.04(s,
1H),7.00-6.88(m,1H),4.08-3.95(m,2H),3.60-3.25(m,4H),2.70-2.25(m,6H),2.12-1.90
(m,2H),1.44(s,9H)；+c ESI Q1MS：[M+H+]494.20。
2-163：
In 100mL flasks, 2-21-1 (2.4458g, 4.9569mmol) is dissolved in CH2Cl2TFA is added in (50mL)
(4mL), is stirred overnight at room temperature.Concentration removes solvent and major part TFA, and crude product is dissolved with methanol, and NaHCO is then added3
Excessive TFA is neutralized, solid is filtered to remove, silica white is added into filtrate, solid solution is made, it is pure that dry method loading crosses silicagel column
Change, uses NH3·H2O, CH3OH and CH2Cl2Gradient elution, collect product, be spin-dried for, be dried in vacuo product 2-163 (2.4346g,
Yield 100%).1H-NMR(400MHz,CDCl3) δ=7.23-7.10 (m, 4H), 7.03 (s, 1H), 6.99-6.93 (t, J=
6Hz, 1H), 6.92-6.87 (d, J=8Hz, 1H), 3.99 (t, J=4Hz, 2H), 3.10-2.95 (m, 4H), 2.70-2.47 (m,
6H),1.95-1.86(m,2H).+c ESI Q1MS：[M+H+]394.25。
2-169：
2-163 (1.9146g, 4.8681mmol) is placed in 200mL flasks, Boc- glycine (Boc- is then added
Gly) (0.9381g, 5.3549mmol), HBTU (2.7404g, 7.3022mmol), HOBT (986.7mg, 7.3022mmol) and
DIEA (3.8159mL, 21.9065mmol) is added dropwise under the conditions of 0 DEG C, then moves to and is stirred overnight at room temperature by DMF (50mL).It will
Reaction solution is poured into saturation NaHCO3It in solution (500mL), is extracted with ethyl acetate (500mL), water phase is extracted with ethyl acetate again
Take (200mL × 3) split-phase；Merge organic phase, then with saturation NaHCO3Solution cleans (200mL × 2), then molten with saturation NaCl
Liquid cleans (200mL × 2)；The anhydrous MgSO of organic phase after split-phase4It is dry, it is filtered to remove solid, silica white is added into filtrate
Solid solution is made, dry method loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient elution, collects product, is spin-dried for, very
Empty dry product 2-169 (2.6138g, yield 97.54%).1H-NMR(400MHz,CDCl3)δ7.21-7.10(m,4H),
7.03 (s, 1H), 6.97-6.89 (m, 2H), 3.99 (t, J=4Hz, 2H), 3.93-3.88 (d, J=4Hz, 2H), 3.56-3.51
(m, 2H), 3.29-3.24 (m, 2H), 2.48 (t, J=6Hz, 2H), 2.40-2.33 (m, 4H), 1.95-1.88 (m, 2H), 1.44
(s,9H)
2-172：
2-169 (2.5949g, 4.7140mmol) is placed in 100mL flasks, CH is then added2Cl2(20mL) dissolves, then
TFA (5mL) is added to be stirred overnight.It is spin-dried for, by crude product CH3OH dissolves, and NaHCO is then added3Neutralize extra TFA；Filtering
Solid is removed, filtrate is spin-dried for, crude product uses CH again2Cl2Dissolving, wet method loading cross silica gel column purification, use NH3·H2O, first
Alcohol and dichloromethane carry out gradient elution, collect product, are spin-dried for, are dried in vacuo to obtain product 2-172 (1.3303g, yield
62.8%).1H-NMR(400MHz,CDCl3)δ7.22-7.11(m,4H),7.04(s,1H),6.98-6.89(m,2H),4.00
(t, J=6Hz, 2H), 3.56 (t, J=4Hz, 2H), 3.42 (s, 2H), 3.27 (t, J=4Hz, 2H), 2.49 (t, J=4Hz,
2H), 2.37 (t, J=4Hz, 4H), 1.97-1.89 (m, 2H), 1.25 (s, 2H)；+c ESI Q1MS：[M+H+]451.39。
Embodiment 4：Prepare 2-21-4,2-162
2-21-4：
With 2-10 (250mg, 0.7272mmol), piperidines -4- alcohol (110.3mg, 1.0908mmol), triethylamine (0.5mL)
With acetonitrile (10mL), it is stirred overnight at 80 DEG C.It is cooled to room temperature, is directly spin-dried for, crude product is dissolved with methanol, filter, it is past
Silica white is added in filtrate, solid solution is made, dry method loading crosses silica gel column purification, with triethylamine, ethyl acetate and petroleum ether ladder
Degree elution, collects product, is spin-dried for, is dried in vacuo to obtain product 2-21-4 (232.5mg, yield 65.1%).1H-NMR(400MHz,
CDCl3) δ 7.24-7.10 (m, 4H), 7.04 (s, 1H), 6.99-6.90 (m, 2H), 3.97 (t, J=6Hz, 2H), 3.79-3.66
(m,2H),2.82-2.72m,2H),2.60-2.50(m,2H),2.32-2.14(m,2H),1.98-1.86(m,2H),1.63-
1.50 (m, 2H), 1.14 (t, J=8Hz, 2H)；+c ESI Q1MS：[M+H+]409.13。
2-154：
2-21-4 (1.6316g, 3.9947mmol) is taken to be placed in 250mL flasks, addition Boc-Gly (839.7mg,
4.7936mmol), DMAP (48.8mg, 0.3995mmol) and CH2Cl2(200mL) is placed reaction liquid into and is stirred 30 points at 0 DEG C
Clock adds DCC (2.4727g, 11.9841mmol), then goes to and be stirred overnight at room temperature.It is filtered to remove solid impurity；Add
Enter methanol to dissolve crude product, silica white is added into solution, solid solution is made, dry method loading crosses silica gel column purification, uses acetic acid
Ethyl ester and petroleum ether gradient elution collect product, are spin-dried for, are dried in vacuo to obtain product 2-154 (3.2987g, yield 100%).1H-
NMR(400MHz,CDCl3)δ7.21-7.09(m,4H),7.04(s,1H),6.97-6.89(m,2H),4.86-4.77(m,1H),
3.96 (t, J=4Hz, 2H), 2.70-2.58 (m, 2H), 2.52-2.42 (m, 2H), 2.28-2.16 (m, 2H), 1.98-1.89
(m,4H),1.87-1.80(m,2H),1.77-1.70(m,4H),1.45(s,9H)；+c ESI Q1MS：[M+H+]551.42。
2-162：
It takes 2-154 (3.1691g, 5.6029mmol) to be placed in 100mL flasks, CH is added2Cl2(50mL) dissolves, and adds
TFA (2.15mL, 28.0143mmol), is stirred overnight at room temperature.It is spin-dried for removing CH2Cl2, crude product is dissolved with methanol, is stirred
Lower addition NaHCO3Extra TFA is neutralized, solid is filtered to remove, silica white is added into filtrate and is made solid solution, in dry method
Sample crosses silica gel column purification, uses NH3·H2O、CH3OH and CH2Cl2Gradient elution is carried out, product is collected, is spin-dried for, is dried in vacuo to obtain production
Product 2-162 (1.5027g, yield 57.7%).1H-NMR(400MHz,CDCl3)δ7.22-7.10(m,4H),7.04(s,1H),
6.98-6.90 (m, 2H), 4.84-4.75 (m, 1H), 3.96 (t, J=4Hz, 2H), 3.41 (s, 2H), 2.70-2.60 (m, 2H),
2.47 (t, J=6Hz, 2H), 2.25-2.16 (m, 2H), 1.97-1.89 (m, 2H), 1.89-1.81 (m, 2H), 1.68-1.57
(m,4H)；+c ESI Q1MS：[M+H+]466.38。
Embodiment 5：Prepare 4-215
7-78：
2- (piperidin-2-yl) ethane -1- alcohol (20.00g, 154.8947mmol) is placed in 500mL flasks, CH is added2Cl2
(300mL) dissolves, and triethylamine (45mL, 309.7894mmol) is then added, is added with stirring Boc2O(40.5669g,
185.8736mmol), it reacts 4 hours at room temperature.It is directly spin-dried for, by crude product CH3OH dissolves, and NaHCO is added3It is extra to neutralize
TFA, filtering, into filtrate be added silica white solid solution is made, dry method loading crosses silica gel column purification, with ethyl acetate and stone
Oily ether gradient elution, collects product, and concentration is dried in vacuo to obtain product 7-78 (36.2772g, yield 100%).ITMS+c ESI
[M+H+]230.18。
7-80：
It takes 7-78 (15.00g, 65.4094mmol) to be placed in 500mL flasks, is added through anhydrous K2CO3Dry THF
(150mL), triphenyl phosphorus (27.7142g, 105.6623mmol), at 0 DEG C stir under be added portionwise NBS (18.8058g,
105.6623mmol), it is transferred to and stirs 3 days at room temperature.It is directly spin-dried for, crude product CH2Cl2Dissolving, silica gel is added into solution
Solid solution is made in powder, and dry method loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient elution, collects product, concentrates,
It is dried in vacuo to obtain product 7-80 (12.0956g, yield 63.26%).1H-NMR(500MHz,CDCl3)δ4.44-4.35(m,1H),
4.09-3.94(m,1H),3.41-3.28(m,2H),2.80-2.66(m,1H),2.40-2.29(m,1H),1.98-1.84(m,
1H),1.76-1.61(m,3H),1.58-1.43(m,12H)。
4-197：
It takes triperazine (1.00g, 3.7415mmol) to be placed in 100mL three neck round bottom, is added through Anhydrous potassium carbonate
Dried THF (50mL), in N2NaH (359.2mg, 14.966mmol), the 7- of the lower mineral oil guard for being added 60% of protection
80 (1.0975g, 3.7415mmol), are refluxed overnight under 60 DEG C of heating conditions.After reaction, stop reaction, be cooled to room
Temperature pours into reaction solution in 200mL ice water, is extracted with ethyl acetate (200mL × 3), and it is dry with anhydrous magnesium sulfate to merge organic phase
Dry, filtering, into filtrate, solid solution is made in addition (3g) silica white, and dry method loading crosses silica gel column purification, silicagel column：2.5×
20cm makees solvent with petroleum ether and is homogenized wet method dress post, and dry method loading collects product with ethyl acetate and petroleum ether gradient elution,
It is spin-dried for, is dried in vacuo to obtain sterling 4-197 (1.40g, yield 78%).ITMS+c ESI[M+H+]479.12.4-215：
It takes 4-197 (1.30g, 2.7050mmol) to be placed in 100mL flasks, dichloromethane (50mL) is added, stirring is lower to be added
Enter TFA (2.0727ml, 27.0498mmol), is stirred overnight at room temperature.It is directly evaporated, crude product is dissolved with methanol, be added
NaHCO3Neutralize extra TFA；Filtering, into filtrate, solid solution is made in addition silica white, crosses silica gel column purification.Use NH3·
H2O, methanol and dichloromethane gradient elution, collect product, are spin-dried for, are dried in vacuo to obtain product 4-215 (539.2mg, yield
53%).1H-NMR(500MHz,CDCl3)δ7.26-7.14(m,4H),7.10-7.07(m,1H),7.01-6.92(m,2H),
4.08-3.94(m,3H),3.12-3.02(m,1H),2.73-2.59(m,2H),1.92-1.85(m,2H),1.84-1.76(m,
1H),1.72-1.64(m,2H),1.44-1.34(m,2H)；ITMS+c ESI：[M+H+]379.20。
Embodiment 6 prepares 2-30-3
2-133：
It takes 2- methyl mercaptos phenthazine (10.00g, 40.8163mmol) to be placed in 500mL flasks, is added through anhydrous K2CO3It is dry
Dry THF (250mL), in N2The NaH (6.5306g, 163.2653mmol) and 1- of the lower mineral oil guard for being added 60% of protection
Bromo- 3- chloropropanes (16.15mL, 163.2653mmol), are refluxed overnight at 65 DEG C.It is cooled to room temperature, reaction solution is poured into ice
In water, crude product is extracted with ethyl acetate (300mL+100mL × 2), merges the anhydrous MgSO of organic phase4It is dry, it is filtered to remove
Solid is spin-dried for, and ethyl acetate (50mL) is then added and dissolves set product, silica white (20g) is added into solution, solid is made
Solution.Dry method loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient elution, collects product, is spin-dried for, is dried in vacuo
Product 2-133 (13.798g, yield 100%).1H-NMR(400MHz,CDCl3) δ 7.20-7.14 (m, 2H), 7.07 (d, J=
8Hz, 1H), 6.97-6.88 (m, 2H), 6.87-6.81 (m, 2H), 4.08 (t, J=6Hz, 2H), 3.67 (t, J=6Hz, 2H),
2.47(s,3H),2.27-2.21(m,2H)；+c ESI Q1MS[M+H+]322.13。
2-30-3：
With 2-133 (300mg, 0.9320mmol), dimethylamine hydrochloride (114mg, 1.3980mmol), triethylamine
(0.39mL, 2.7961mmol) and acetonitrile (10mL), is stirred overnight at 80 DEG C.It is cooled to room temperature, is directly spin-dried for, by crude product
Dissolved with methanol, filter, into filtrate addition silica white solid solution is made, dry method loading crosses silica gel column purification, with triethylamine,
Ethyl acetate and petroleum ether gradient elution collect product, are spin-dried for, are dried in vacuo to obtain product 2-30-3 (83.2mg, yield
24.3%).1H-NMR(400MHz,CDCl3)δ7.18-7.10(m,2H),7.07-7.01(m,1H),6.94-6.86(m,2H),
6.84-6.78(m,3H),3.93-3.85(m,2H),2.46(s,3H),2.42-2.36(m,2H),2.22-2.19(s,6H),
1.98-1.90(m,2H)；+c ESI Q1MS:[M+H+]331.10,[M+NH3]347.08。
Embodiment 7 prepares 2-30-2
Take 2-133 (300mg, 0.9320mmol), morpholine (121.8mg, 1.3981mmol), triethylamine (0.39mL,
2.7961mmol) with acetonitrile (10mL), it is stirred overnight at 80 DEG C.It is cooled to room temperature, is directly spin-dried for, crude product methanol is molten
Solution, filtering, into filtrate, solid solution is made in addition silica white, and dry method loading crosses silica gel column purification, with triethylamine, ethyl acetate
With petroleum ether gradient elution, product is collected, is spin-dried for, is dried in vacuo to obtain product 2-30-2 (121mg, yield 33.5%).1H-NMR
(400MHz,CDCl3)δ7.18-7.09(m,2H),7.08-7.01(m,1H),6.95-6.86(m,2H),6.85-6.78(m,
2H), 3.94 (t, J=6Hz, 2H), 3.71-3.61 (m, 4H), 2.51-2.34 (m, 9H), 1.99-188 (m, 2H)；+c ESI
Q1MS:[M+H+]373.23。
Embodiment 8 prepares 2-30-4
With 2-133 (300mg, 0.9320mmol), piperidines -4- alcohol (141.4mg, 1.3979mmol), triethylamine
(0.39mL, 2.7961mmol) and acetonitrile (10mL), is stirred overnight at 80 DEG C.It is cooled to room temperature, is directly spin-dried for, by crude product
Dissolved with methanol, filter, into filtrate addition silica white solid solution is made, dry method loading crosses silica gel column purification, with triethylamine,
Ethyl acetate and petroleum ether gradient elution collect product, are spin-dried for, are dried in vacuo to obtain product 2-30-4 (126.1mg, yield
35.0%).+c ESI Q1MS:[M+H+]387.16。
Embodiment 9 prepares 2-30-5
It is placed in 30ml straight tube bottles with 2-133 (300mg, 0.9320mmol), addition 1- (2- ethoxys) pyrazine (182mg,
1.3980mmol), triethylamine (0.39mL, 2.7961mmol) and acetonitrile (10mL), are stirred overnight at 80 DEG C.Stop reaction,
It is cooled to room temperature, is spin-dried for, crude product is dissolved with methanol, silica white is added into filtrate, solid solution, dry method loading mistake is made
Silica gel column purification is collected product, is spin-dried for, is dried in vacuo to obtain product 2- with triethylamine, ethyl acetate and petroleum ether gradient elution
30-5 (106mg, yield 27.4%).+c ESI Q1MS:[M+H+]416.15。
Embodiment 10 prepares 2-30-6
2-133 (300mg, 0.9320mmol) is taken to be placed in 30mL straight tube bottles, addition prolinol (141.4mg,
1.3979mmol), triethylamine (0.39mL, 2.7961mmol) and acetonitrile (10mL), are stirred overnight at 80 DEG C.It is cooled to room
Temperature is spin-dried for, and crude product is dissolved with methanol, silica white is added into filtrate, solid solution is made, it is pure that dry method loading crosses silicagel column
Change, with triethylamine, ethyl acetate and petroleum ether gradient elution, collects product, be spin-dried for, be dried in vacuo to obtain product 2-30-6
(88.3mg, yield 24.5%).+c ESI Q1MS:[M+H+]387.16。
Embodiment 11 prepares 2-58
2-133 (0.3126g, 0.9712mmol) is taken, is placed in 30mL straight tube bottles, alcohol solvent (20mL), hydrochloric acid is added
NaOH (77.7mg, 1.9423mmol) is then dissolved in H by guanidine (185.5mg, 1.9423mmol)2Straight tube is added in O (1mL)
In bottle, it is stirred overnight under the conditions of 80 DEG C after sealing.Wet method loading crosses silica gel column purification, with ammonium hydroxide, methanol and dichloromethane ladder
Degree elution, collects product, is spin-dried for, is dried in vacuo to obtain product 2-58 (141mg, yield 38.1%).+c ESI Q1MS:[M+H+]
345.30。
Embodiment 12 prepares 2-60
2-133 (0.2964g, 0.9208mmol) is added in 30mL straight tube bottles, 1,2,4- triazoles are added
(0.1272g, 1.8417mmol), K2CO3(0.7636g, 5.5250mmol), KI (15.3g, 0.09208mmol) and acetone
(10mL) is stirred overnight after sealing under the conditions of 60 DEG C.Filtering, filtrate is spin-dried for, crude product is dissolved with dichloromethane, Xiang Rong
Silica white is added in liquid, solid solution is made, dry method loading crosses silica gel column purification, is eluted with methanol and dichloromethane gradient, collects
Product is spin-dried for, and is dried in vacuo to obtain product 2-60 (179.0mg, yield 54.8%).1H-NMR(400MHz,CDCl3)δ7.94(s,
1H),7.88(s,1H),7.24-7.10(m,3H),7.04-6.94(m,1H),6.90-6.78(m,2H),6.77-6.74(m,
1H),4.35-4.24(m,2H),3.85-3.74(m,2H),2.50-2.34(m,5H)；+c ESI Q1MS:[M+H+] 355.18,
[M+Na+]377.11。
Embodiment 13 prepares 2-138
2-133 (300mg, 0.9320mmol) is added in 100ml flasks, 5- methyl-1 H- tetrazoles are added
(156.6mg, 1.8640mmol), K2CO3(0.7729g, 5.5921mmol), KI (15.4mg, 0.09320mmol) and acetone
(15ml).It is stirred at reflux under the conditions of 60 DEG C overnight.It is cooled to room temperature, filters, it is molten that solid is made in addition silica white into filtrate
Liquid, dry method loading cross silica gel column purification, with ethyl acetate and petroleum ether gradient elution, collect product, are spin-dried for, and are dried in vacuo to obtain production
Product 2-138 (71.3mg, yield 20.7%).1H-NMR(400MHz,CDCl3) δ 7.20-7.11 (m, 2H), 7.09 (d, J=8Hz,
1H), 6.97-6.92 (m, 1H), 6.89-6.80 (m, 2H), 6,76-6.74 (m, 1H), 4.68 (t, J=6Hz, 2H), 3.98 (t,
J=6Hz, 2H), 2.52-2.44 (m, 8H).
Embodiment 14 prepares 2-139
2-133 (0.2964g, 0.9208mmol) is added in 100mL flasks, 1,2,3- of addition triazoles (0.11mL,
1.8640mmol), K2CO3(0.7729g, 5.5961mmol), KI (15.4mg, 0.09320mmol) and acetone (15mL).60
It is stirred at reflux under the conditions of DEG C overnight.It is cooled to room temperature, filters, silica white is added after filtrate is concentrated, solid solution, dry method is made
Loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient elution, collects product, is spin-dried for, is dried in vacuo to obtain product 2-139
(202.5mg, yield 61.3%).1H-NMR(400MHz,CDCl3)δ7.59-7.58(m,2H),7.21-7.02(m,3H),
7.00-6.68 (m, 4H), 4.59 (t, J=6Hz, 2H), 4.02-3.84 (m, 2H), 2.54-2.36 (m, 5H).
Embodiment 15 prepares 2-149
2-133 (300mg, 0.9320mmol) is added in 100mL flasks, addition 1H- tetrazoles (0.1306mg,
1.8640mmol), K2CO3(0.7729g, 5.5921mmol), KI (15.4mg, 0.09320mmol) and acetone (50mL).60
It is stirred overnight under the conditions of DEG C.It is cooled to room temperature, filters, silica white is added into filtrate, solid solution is made, dry method loading crosses silicon
Rubber column gel column purifies.With ethyl acetate and petroleum ether gradient elution, collect product, be spin-dried for, be dried in vacuo product 2-149 (44.1mg,
Yield 13.3%).+c ESI Q1MS:[M+H+]356.13,[M+Na+]378.11。
Embodiment 16 prepares 2-72
2-30-1：
It takes 2-12 (300mg, 0.9320mmol) to be placed in 30mL straight tube bottles, 1- tert-butoxycarbonyl-piperazines is then added
(260.4mg, 1.3980mmol), triethylamine (0.39mL, 2.7961mmol) and acetonitrile (10mL), after sealing under the conditions of 80 DEG C
It is stirred overnight.It is cooled to room temperature, is spin-dried for, crude product is dissolved with methanol, silica white is added into filtrate, solid solution is made, do
Method loading crosses silica gel column purification, with triethylamine, ethyl acetate and petroleum ether gradient elution, collects product, is spin-dried for, is dried in vacuo
Product 2-30-1 (75.1mg, yield 17.08%).+c ESI Q1MS:[M+H+]472.13,[M+NH3]488.11。
2-72：
It takes 2-30-1 (75.1mg, 0.1522mmol) to be placed in 100mL flasks, CH is added2Cl2(50mL) dissolves, and adds
TFA (4mL, 52.2014mmol), is stirred overnight at room temperature.It is spin-dried for, crude product is dissolved with methanol, NaHCO is then added3In
With extra TFA, filtering, into filtrate, solid solution is made in addition silica white, and dry method loading crosses silica gel column purification, uses NH3·
H2O、CH3OH and CH2Cl2Gradient elution collects product, is spin-dried for, is dried in vacuo to obtain product 2-72 (46.2mg, yield 84.5%).1H-NMR(400MHz,CDCl3) δ 7.18-7.10 (m, 2H), 7.05 (d, J=8Hz, 1H), 6.95-6.76 (m, 4H), 3.94 (t,
J=6Hz, 2H), 3.10-3.02 (m, 4H), 2.71-2.59 (m, 4H), 2.58-2.50 (m, 2H), 3.46 (s, 3H)；+c ESI
Q1MS[M+H+]373.23。
Embodiment 17 prepares 7-4
7-2：
Boc-Gly (0.8453g, 4.8251mmol) is taken to be placed in 500mL flasks, addition 2-30-4 (1.6955g,
4.3865mmol), HBTU (2.4693g, 6.5798mmol) and HOBT (0.8891g, 6.5798mmol)；It is dripped under the conditions of 0 DEG C
Add DIEA (3.4384mL, 19.7393mmol), goes to after 30 minutes and be stirred overnight at room temperature.Reaction solution is directly poured into saturation
NaHCO3It in solution (500mL), is extracted with ethyl acetate (500mL+200mL × 3+100mL), merges organic phase, first with saturation
NaHCO3Solution cleans (300mL × 2), then is cleaned (300mL × 2) with saturated salt solution；The anhydrous MgSO of organic phase4It is dry, mistake
Filter, into filtrate, solid solution is made in addition silica white, and dry method loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient
Elution collects product, is spin-dried for, is dried in vacuo to obtain product 7-2 (2.3893g, yield 100%).1H-NMR(400MHz,CDCl3)δ
7.20-7.10(m,2H),7.08-7.02(m,1H),6.96-6.86(m,2H),6.85-6.78(m,2H),4.88-4.81(m,
1H),3.96-3.91(m,2H),2.75-2.65(m,2H),2.60-2.50(m,2H),2.47(s,3H),2.40-2.25(m,
2H),2.02-1.84(m,4H),1.82-1.63(m,4H),1.45(s,9H)；+c ESI Q1MS:[M+H+]544.32。
7-4：
7-2 (2.3082g, 4.2453mmol) is placed in 200mL flasks, CH is added2Cl2(15mL), under magnetic agitation plus
Enter TFA (3.25mL, 42.4527mmol), is stirred overnight at room temperature.It is spin-dried for, by crude product CH3OH dissolves, and NaHCO is added3In
With extra TFA, filtering, into filtrate, solid solution is made in addition silica white, and dry method loading crosses silica gel column purification, uses NH3·
H2O、CH3OH and CH2Cl2Gradient elution collects product, is spin-dried for, is dried in vacuo to obtain product 7-4 (896.6mg, yield 47.7%).1H-NMR(400MHz,CDCl3)δ7.18-7.10(m,2H),7.08-7.02(m,1H),6.94-6.87(m,2H),6.85-6.78
(m, 2H), 4.85-4.77 (m, 1H), 3.92 (t, J=4Hz, 2H), 3.41 (s, 2H), 2.72-2.62 (m, 2H), 2.52-2.43
(m,5H),2.29-2.16(m,2H),2.00-1.83(m,4H),1.73-1.62(m,4H)。
Embodiment 18 prepares 7-86,7-92,7-147
7-82：
It takes 2- methyl mercaptos phenthazine (10.1029g, 41.2362mmol) to be placed in 500mL flasks, is added through anhydrous K2CO3
Dried THF (200mL), in N2The lower mineral oil guard for being successively added 60% of protection NaH (6.5978g,
164.9448mmol) and 7-80 (12.0956g, 41.2362mmol).It is refluxed overnight under the conditions of 60 DEG C.It is cooled to room temperature, it will
Reaction solution pours into mixture of ice and water, is extracted with ethyl acetate (500mL × 3), merges the anhydrous MgSO of organic phase4It is dry, mistake
Filter, into filtrate, solid solution is made in addition silica white, and dry method loading crosses silica gel column purification, with ethyl acetate and petroleum ether gradient
Elution, is spin-dried for, is dried in vacuo to obtain product 7-82 (19.1176g, yield 100%).1H-NMR(500MHz,CDCl3)δ7.18-
7.12(m,2H),7.08-7.03(m,1H),6.96-6.89(m,1H),6.88-6.80(m,2H),6.79-6.74(m,1H),
4.41 (s, 1H), 4.10-3.95 (m, 1H), 3.94-3.75 (m, 2H), 2.80 (t, J=15Hz, 1H), 2.46 (s, 3H),
2.28-2.14(m,1H),1.94-1.82(m,1H),1.61-1.53(m,3H),1.51-1.34(m,12H).7-86：
In 100mL flasks, 7-82 (19.00g, 41.5459mmol) is dissolved in dichloromethane (20mL), TFA is added
(15.92mL, 207.7297mmol), is stirred at room temperature overnight.It is spin-dried for, crude product is dissolved with methanol, is then added
NaHCO3Extra TFA is neutralized, is filtered, silica white is added into filtrate, solid solution is made, cross silica gel column purification.Use NH3·
H2O、CH3OH and CH2Cl2Gradient elution collects product, is spin-dried for, is dried in vacuo to obtain product 7-86 (19.0062g, yield
100%).1H-NMR(500MHz,CDCl3)δ7.20-7.13(m,2H),7.11-7.06(m,1H),6.98-6.92(m,1H),
6.88-6.82 (m, 2H), 6.80-6.77 (m, 1H), 3.96 (t, J=7.5Hz, 2H), 3.22-3.12 (m, 1H), 3.00-2.92
(m,1H),2.74-2.64(m,1H),2.46(s,3H),2.25-2.13(m,1H),2.02-1.90(m,1H),1.85-1.75
(m,1H),1.72-1.55(m,3H),1.54-1.33(m,2H)。
7-88：
Boc-Gly (10.2309g, 58.4025mmol) is taken to be placed in 500mL flasks, addition 7-86 (18.9118g,
53.0932mmol), HBTU (29.8880g, 79.6398mmol), HOBT (10.9609g, 79.7398mmol) and DMF
(200mL) DIEA (41.62mL, 238.9194mmol) is added dropwise under the conditions of 0 DEG C, goes to after 30 minutes and is stirred overnight at room temperature.
Reaction solution is directly poured into saturation NaHCO3In solution (500mL), (500mL+200mL × 3+100mL) is extracted with ethyl acetate,
Merge organic phase saturation NaHCO3Solution cleans (300mL × 2), then is cleaned (300mL × 2) with saturated common salt aqueous solution.Have
Machine is mutually with anhydrous MgSO4Dry, filtering, into filtrate, solid solution is made in addition silica white, crosses silica gel column purification.With acetic acid second
Ester and petroleum ether gradient elution collect product, are spin-dried for, are dried in vacuo to obtain product 7-88 (19.1364g, yield 70.2%).1H-
NMR(500MHz,CDCl3)δ7.22-7.02(m,3H),6.97-6.89(m,1H),6.88-6.80(m,2H),6.79-6.70
(m,1H),4.05-3.80(m,4H),3.75-3.65(m,1H),3.60-3.40(m,1H),3.14-3.05(m,1H),2.47
(s,3H),2.25-2.10(m,1H),1.95-1.85(m,1H),1.62-1.30(m,15H)。
7-92：
7-88 (19.0825g, 37.1703mmol) is placed in 200mL flasks, dichloromethane (20mL) is added and dissolves, so
TFA (14.24mL, 185.8516mmol) is added afterwards, is stirred overnight at room temperature.It is spin-dried for, crude product is dissolved with methanol, be added
NaHCO3Neutralize extra TFA.Filtering, into filtrate, solid solution is made in addition silica white, crosses silica gel column purification.Use NH3·
H2O, methanol and dichloromethane gradient elution, collect product, are spin-dried for, are dried in vacuo to obtain product 7-92 (13.6454g, yield
89.05%).1H-NMR(500MHz,CDCl3)δ7.24-7.10(m,2H),7.08-7.03(m,1H),7.00-6.77(m,3H),
6.76-6.70(m,1H),3.93-3.81(m,2H),3.65-3.47(m,2H),3.40-3.32(m,1H),3.26-3.19(m,
1H),3.13-3.04(m,1H),2.46(s,3H),2.25-2.05(m,2H),1.70-1.28(m,6H)。
7-145：
Boc-Gly (2.7978g, 15.9708mmol) is taken to be placed in 500ml flasks, addition 7-92 (6.00g,
14.5189mmol), HBTU (8.1732g, 21.7784mmol), HOBT (2.9427g, 21.7784mmol) and DMF (200mL)；
DIEA (11.38mL, 65.3351mmol) is added dropwise under the conditions of 0 DEG C, goes to after 30 minutes and is stirred overnight at room temperature.By reaction solution
Directly pour into saturation NaHCO3It in solution (500mL), is extracted with ethyl acetate (500mL+200mL × 3+100mL), merges organic
Mutually with saturation NaHCO3Solution cleans (200mL × 2), then is cleaned (200mL × 2) with saturated salt solution；Organic phase is with anhydrous
MgSO4Dry, filtering, into filtrate, solid solution is made in addition silica white, crosses silica gel column purification.With ethyl acetate and petroleum ether
Gradient elution collects product, is spin-dried for, is dried in vacuo to obtain product 7-145 (7.67g, yield 93%).1H-NMR(500MHz,
CDCl3)δ7.22-6.60(m,9H),5.03-4.93(m,1H),4.05-3.70(m,6H),2.45(s,3H),1.72-1.56
(m,6H),1.48(s,9H)。
7-147：
7-145 (7.57g, 13.2706mmol) is placed in 500mL flasks, dichloromethane (20mL) is added and dissolves, then
TFA (10.17mL, 132.7057mmol) is added, is stirred overnight at room temperature.It is spin-dried for, crude product is dissolved with methanol, is then added
NaHCO3Extra TFA is neutralized, is filtered, silica white is added into filtrate, solid solution is made, dry method loading crosses silica gel column purification,
Use NH3·H2O, methanol and dichloromethane gradient elution, collect product, are spin-dried for, and are dried in vacuo to obtain product 7-147 (5.3975g, production
Rate 86.48%).1H-NMR(500MHz,CDCl3)δ7.80-7.55(m,1H),7.22-7.09(m,2H),7.08-7.02(m,
1H),6.97-6.89(m,1H),6.87-6.79(m,2H),6.79-6.69(m,1H),5.03-4.94(m,1H),4.08-4.01
(m,1H),3.96-3.85(m,2H),3.84-3.65(m,1H),3.58-3.47(m,1H),3.40-3.29(m,2H),3.16-
3.06(m,1H),2.47(s,3H),2.27-2.08(m,1H),1.95-1.82(m,1H),1.62-1.13(m,6H)；ITMS+c
ESI[M+H+]571.19,[M+Na+]593.31。
Embodiment 19 prepares 6-78
6-71：
Under nitrogen protection, 2- chloro phenothiazines (5.00g, 21.3mmol) are added in 500ml flasks, are dissolved with THF, so
The NaH (4.2786g, 106.966mmol) of 60% mineral oil guard is added afterwards, releases a large amount of bubbles, the bromo- 3- of 1- are then added
Chloropropane (10.57mL, 106.966mmol).It is refluxed overnight in 65 DEG C of oil bath.Stop reaction, reaction solution is poured into ice water
It in mixture (500mL), is extracted with ethyl acetate (300mL × 3), merges organic phase and dried with anhydrous magnesium sulfate, filtered.Column layer
Analysis is collected product point, product 6-71 (6.6377g, yield is concentrated under reduced pressure to obtain with ethyl acetate and petroleum ether gradient elution
59.11%).+c ESI Q1 MS：[M+H+]310.10
6-78：
6-71 (500mg, 1.6117mmol) is added in cylinder bottle, piperidines -4- alcohol (244.5mg, 2.4175mmol) is used
CH3CN (15mL) dissolves, and is eventually adding triethylamine (0.67mL, 4.8346mmol), and reflux 72 is small in 80 DEG C of oil baths after sealing
When.It is spin-dried for, is then dissolved with methanol, NaHCO is added3It neutralizes, filtering.Column chromatography, with triethylamine, ethyl acetate and petroleum ether ladder
Degree elution, collects product point, is concentrated under reduced pressure, is dried in vacuo to obtain product 6-78 (541.6mg, yield 89.6%).1H-NMR
(400MHz,CDCl3) δ 7.18-7.09 (m, 2H), 7.01 (d, J=8Hz, 1H), 6.95-6.83 (m, 4H), 3.89 (t, J=
6Hz, 2H), 3.72-3.62 (m, 1H), 2.78-2.68 (m, 2H), 2.46 (t, J=6Hz, 2H), 2.20-2.06 (m, 2H),
1.98-1.83(m,4H),1.59-1.50(m,2H)。
Embodiment 20 prepares 6-80
6-71 (500mg, 1.6117mmol) and prolinol (244.5mg, 2.4175mmol) are added in cylinder bottle, uses
CH3CN (15mL) dissolves, and is eventually adding triethylamine (0.67mL, 4.8346mmol), and reflux 72 is small in 80 DEG C of oil baths after sealing
When.Stop reaction, be directly evaporated, then dissolved with methanol, NaHCO is added3It neutralizes, filters, concentration.Column chromatography, with acetic acid second
Ester and petroleum ether gradient elution, collect product point, and reduced pressure is dried in vacuo to obtain product 6-80 (307.1mg, yield 50.8%)
。1H-NMR(400MHz,CDCl3)δ7.20-7.12(m,2H),7.06-7.01(m,1H),6.97-6.92(m,1H),6.92-
6.87 (m, 2H), 6.86-6.83 (m, 1H), 3.92 (t, J=6Hz, 2H), 3.60-3.55 (m, 1H), 3.36-3.31 (m, 1H),
3.19-3.13(m,1H),2.97-2.89(m,1H),2.59-2.52(m,1H),2.40-2.32(m,1H),2.24-2.16(m,
1H),2.06-1.90(m,3H),1.87-1.81(m,1H),1.77-1.68(m,3H)。
Embodiment 21 prepares 6-86
6-71 (500mg, 1.6117mmol) is added in cylinder bottle, guanidine hydrochloride (168.4mg, 1.7728mmol) uses second
Alcohol/water (10mL) dissolves sodium hydroxide (70.9mg, 1.7728mmol), then flows back 72 hours in 80 DEG C of oil baths.Stop anti-
It answers, is directly evaporated.Column chromatography is eluted with ammonium hydroxide, methanol and dichloromethane gradient, collects product, and reduced pressure is dried in vacuo
Product 6-86 (513.9mg, yield 100%).1H-NMR(400MHz,CDCl3) δ 7.23-7.14 (m, 2H), 7.07 (d, J=
8Hz, 1H), 7.00-6.88 (m, 4H), 3.97 (t, J=6Hz, 2H), 3.28-3.19 (m, 2H), 2.10-2.02 (m, 2H).
Embodiment 22 prepares 6-87
The addition 6-71 (500mg, 1.6117mmol) in cylinder bottle, 1,2,4- triazoles (222.6mg,
3.2234mmol), it is dissolved with acetone (5mL), potassium carbonate (1.3365g, 9.6701mmol) and potassium iodide is then added
(18.7mg, 0.1612mmol) then flows back 72 hours in 80 DEG C of oil baths.Stop reaction, is directly evaporated.Column chromatography uses second
Product is collected in acetoacetic ester and petroleum ether gradient elution, is concentrated under reduced pressure, is dried in vacuo to obtain product 6-87 (552.6mg, yield
100%).1H-NMR(400MHz,CDCl3) δ 7.90 (s, 1H), 7.81 (s, 1H), 7.23-7.14 (m, 2H), 7.10 (d, J=
8Hz, 1H), 7.02-6.91 (m, 2H), 6.84-6.76 (m, 2H), 4.26 (t, J=6Hz, 2H), 3.78 (t, J=6Hz, 2H),
2.42-2.34(m,2H)。
Embodiment 23 prepares 6-88
6-71 (500mg, 1.6117mmol) and tetrazole (225.7mg, 3.2234mmol) are added in cylinder bottle, with third
Ketone (5mL) dissolves, and potassium carbonate (1.3365g, 9.6701mmol) and potassium iodide (18.7mg, 0.1612mmol) is then added, so
It flows back 72 hours in 80 DEG C of oil baths afterwards.Stop reaction, is directly evaporated.Column chromatography, petroleum ether and ethyl acetate gradient elution, are received
Collect product, is concentrated under reduced pressure, is dried in vacuo to obtain product 6-88 (554.2mg, yield 43.09%).1H-NMR(400MHz,CDCl3)δ
8.47 (s, 1H), 7.21-7.15 (m, 2H), 7.08 (d, J=8Hz, 1H), 7.01-6.91 (m, 2H), 6.85-6.78 (m, 2H),
4.77 (t, J=6Hz, 2H), 3.97 (t, J=6Hz, 2H), 2.55-2.47 (m, 2H).
Embodiment 24 prepares 6-89
The addition 6-71 (500mg, 1.6117mmol) in cylinder bottle, 5- methyl-1 H- tetrazoles (270.7mg,
3.2234mmol), it is dissolved with acetone (5mL), potassium carbonate (1.3365g, 9.6701mmol) and potassium iodide is then added
(18.7mg, 0.1612mmol) then flows back 72 hours in 80 DEG C of oil baths.Stop reaction, is directly evaporated.Column chromatography uses stone
Oily ether and ethyl acetate gradient elution, collect product, are concentrated under reduced pressure, are dried in vacuo to obtain product 6-89 (511.4mg, yield
88.67%).1H-NMR(400MHz,CDCl3) δ 7.20-7.14 (m, 2H), 7.07 (d, J=8Hz, 1H), 7.00-6.90 (m,
2H), 6.86-6.77 (m, 2H), 4.68 (t, J=6Hz, 2H), 3.95 (t, J=6Hz, 2H), 2.51-2.44 (m, 5H).:
Embodiment 25 prepares 6-109
6-81：
The addition 6-71 (500mg, 1.6117mmol) in cylinder bottle, 1- tert-butoxycarbonyl-piperazines (244.5mg,
2.4175mmol), use CH3CN (15mL) dissolves, and is eventually adding triethylamine (0.67mL, 4.8346mmol), rapid to seal, so
It flows back 72 hours in 80 DEG C of oil baths afterwards.Stop reaction, be directly evaporated, then dissolved with methanol, NaHCO is added3It neutralizes, mistake
Filter, concentration.Column chromatography collects product with ethyl acetate and petroleum ether gradient elution, is concentrated under reduced pressure, is dried in vacuo to obtain product 6-
81 (741.4mg, yield 100%) ITMS+ESI:[M+H+]460.19。
6-109：
In the flask of 50mL, 6-81 (877.7mg, 1.9079mmol) is added, dissolves (10mL) with dichloromethane, then
TFA (0.73mL, 9.5395mmol) is added, is stirred overnight at room temperature.Stop reaction being evaporated, is dissolved with methanol, be then added
Measure NaHCO3Extra TFA is neutralized, is filtered, silica white concentration is added into filtrate and is evaporated, dry method loading column chromatography.With ammonium hydroxide,
Methanol and dichloromethane gradient elution, collect product point, product 6-109 (558.3mg, yield 81%) are concentrated under reduced pressure to obtain.1H-
NMR(400MHz,CDCl3) δ 7.18-7.09 (m, 2H), 7.01 (d, J=8Hz, 1H), 6.95-6.83 (m, 4H), 3.91 (t, J
=6Hz, 2H), 2.95-2.88 (m, 4H), 2.51-2.42 (m, 6H), 1.97-1.88 (m, 2H).
Embodiment 26 prepares 4-219
4-195：
It takes 2- chloro phenothiazines (1.00g, 4.2786mmol) to be placed in 100mL three neck round bottom, is added through Carbon Dioxide
The dried THF of potassium (25mL), in N2The lower NaH (410.7mg, 17.1145mmol) that 60% mineral oil guard is added of protection and
4-170 (1.2550g, 4.2786mmol), is refluxed overnight under 60 DEG C of heating conditions.After reaction, stop reaction, be cooled to
Reaction solution is poured into ice water (200mL), is extracted with ethyl acetate (200mL × 3) by room temperature, merges organic phase anhydrous slufuric acid
Magnesium is dried, filtering, and silica white is added in filtrate, and solid solution, dry method loading column chromatography, with ethyl acetate and stone are made in drying
Oily ether gradient elution collects product, is evaporated to obtain sterling 4-195 (0.70g, yield 47%).ITMS+c ESI：[M+H+]
445.17.4-219：
It takes 4-195 (1.50g, 3.1444mmol) to be placed in 100mL flasks, dichloromethane (50mL) is added, is stirred in magnetic force
Lower addition TFA (2.41mL, 31.4436mmol) is mixed, at room temperature reaction overnight.Stopping reaction being evaporated, crude product is dissolved with methanol,
Excess NaHCO is added3TFA is neutralized, filtering is added dichloromethane and dissolves set product, wet method loading column chromatography.Use NH3·H2O、
Methanol and dichloromethane gradient elution, collect product, and concentration is dried to obtain product 4-219 (654.4mg, yield 60%).1H-
NMR(500MHz,CDCl3)δ7.20-7.165(m,2H),7.09-7.055(m,1H),7.00-6.95(m,1H),6.95-
6.915(dd,1H),6.91-6.87(d,1H),6.865-6.85(d,1H),4.00-3.94(t,2H),3.81-3.42(m,
2H),2.975-2.9425(s,1H),2.9025-2.8675(s,1H)2.26-2.12(m,1H),2.005-1.8975(m,1H),
1.768-1.665(m,2H),1.635-1.505(m,2H),1.495-1.40(m,2H)；ITMS+c ESI：[M+H+]345.22。
Biological test and result
This patent is directed to the cell of MCF-7 cell strainHJ2mm and Human hepatoma cell line Hep-G2 to synthesized compound
Toxicity has carried out detailed test.Culture medium used in MCF-7 and Hep-G2 cell strains is to contain 10%NCS, and 1% is dual anti-
DMEM-F12, inSolution.Cell is cultivated to its exponential phase of growth, cell suspension is counted using cell counting board, uses culture solution
Adjusting cell concentration is 20000/mL, then by cell suspension inoculation to 96 orifice plates, 100 μ L is inoculated with per hole, and reserve 4
Then culture plate is positioned over 5%CO by hole as blank control2, cultivate 24 hours in 37 DEG C of incubators and keep cell adherent.It takes out
Culture plate removes culture solution therein, then sequentially add each concentration (weigh each compound in the desired amount, then will be each
A compound first with 50 μ lDMSO dissolvings, is then diluted to 100 μm of ol/L, 50 μm of ol/L, 25 μm of ol/ successively with blank culture solution
L, 12.5 μm of ol/L, 6.25 μm of ol/L, 3.125 μm of ol/L, 1.5625 μm of ol/L) drug containing culture solution, blank control wells add
Enter blank culture solution, is put into incubator and continues culture 72 hours.By known anticancer drugs, doxorubicin, taxol respectively with this hair
The compound of bright preparation makees positive control, takes out culture plate, the MTT reagents (20 holes μ L/) of 5mg/mL are separately added into corresponding aperture,
Culture plate is relay into people 5%CO again2, continue culture 4 hours in 37 DEG C of incubators, culture plate is taken out, by the training in all holes
Nutrient solution removes, and DMSO (150 holes μ L/) is then added, measures the OD of cell at wavelength 490nm using enzyme-linked immunosorbent assay instrument
Value, then uses IC50Software for calculation calculates the IC of each compound50Value, as shown in table 2.According to the present invention, not expected hair
Existing, the compound that the present invention prepares gained will produce MCF-7 and Hep-G2 cell strains certain inhibiting effect.
2 phenothiazine compound IC of table50Value
Claims (3)
1. a kind of application of phenothiazine compound, which is characterized in that be used to prepare and meanwhile anti-human breast cancer cell line mcf-7 and
The drug of anti-human liver cancer cell strain Hep-G2, shown in the compound structure such as general formula (I)：
Wherein, R C2-3Straight chain saturated alkyl；B can be independently Cl, methyl mercapto or trifluoromethyl；When B is methyl mercapto, A
For triazol radical, tetrazole base, pyrrole radicals, guanidine radicals, morpholinyl；When B is trifluoromethyl, A is morpholinyl, pyrrole radicals；When B is
When Cl, A is triazol radical, tetrazole base, pyrrole radicals, guanidine radicals, morpholinyl.
2. a kind of anticancer pharmaceutical composition, which is characterized in that wherein contain phenothiazines shown in claim 1 formula of (I)
Compound is as active ingredient and one or more pharmaceutically acceptable carriers；The wherein anticancer pharmaceutical composition
Can simultaneously anti-human breast cancer cell line mcf-7 and anti-human liver cancer cell strain Hep-G2.
3. a kind of anticancer pharmaceutical composition as claimed in claim 2, which is characterized in that can be made into pharmaceutically acceptable injection
Agent, spray, inhalant or oral agents.
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