CN106333949B - Application and its synthetic method of the compound on the drug for inhibiting kallikrein KLK7 is prepared - Google Patents
Application and its synthetic method of the compound on the drug for inhibiting kallikrein KLK7 is prepared Download PDFInfo
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- CN106333949B CN106333949B CN201610608039.0A CN201610608039A CN106333949B CN 106333949 B CN106333949 B CN 106333949B CN 201610608039 A CN201610608039 A CN 201610608039A CN 106333949 B CN106333949 B CN 106333949B
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- 0 C*(C=*)=CC(C1)C1c(cc(CSc([n]1Cc(cc2)ccc2C(NCc2cnccc2)=O)nc2c1nccc2)cc1)c1F Chemical compound C*(C=*)=CC(C1)C1c(cc(CSc([n]1Cc(cc2)ccc2C(NCc2cnccc2)=O)nc2c1nccc2)cc1)c1F 0.000 description 1
- RZKJCEYLJICUDN-UHFFFAOYSA-N [O-][NH+](CCc1c[s]c(-c(cc2)ccc2Cl)n1)CCc1c(cccc2)c2ccc1 Chemical compound [O-][NH+](CCc1c[s]c(-c(cc2)ccc2Cl)n1)CCc1c(cccc2)c2ccc1 RZKJCEYLJICUDN-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to biomedical sector, more particularly, to application of the compound on the drug for inhibiting kallikrein KLK7 is prepared and synthetic method.Application of the compound on the drug for inhibiting kallikrein KLK7 is prepared, the structural formula of the compound are：The compound provided by the invention for inhibiting kallikrein KLK7 can effectively inhibit the activity of KLK7, and synthetic method is simple and practicable, and the pharmaceutical preparation for inhibiting KLK7 activity can be prepared by adding in appropriate auxiliary material and auxiliary agent.
Description
Technical field
The invention belongs to biomedical sectors, and the drug of inhibition kallikrein KLK7 is being prepared more particularly, to compound
On application and synthetic method.
Background technology
Atopic dermatitis (Atopic Dermatitis, AD) is a kind of chronic inflammatory skin of wide-scale distribution, feature
It is drying, flaky skin, inflammation, percutaneous permeability increase, the skin of patient AD is to common and harmless to normal person in environment
Factor also can be very sensitive so as to being susceptible to surface infection.In the hair of the atopic dermatitis of past 30 Nian Jian industrialized countries
Sick rate increases 2 to 3 times, it is estimated that the atopic dermatitis illness rate of children has reached 15-30%, and the atopic dermatitis of adult is suffered from
Sick rate has reached 2-10%.Due to the complexity of pathogenesis, few, but skin barrier function is solved to the pathogenesis of AD
Disorder has proven to be one of key factor in AD evolutions.The stabilization of skin barrier depends on the cutin shape of stratum granulosum
Into cell differentiation (i.e. furfur) is come off for horn cell and skin surface horn cell between balance, the furfur process bag of skin
It includes by the degradation of the KLKs desmosomes participated in, since desmosome is the Fibronectin of horn cell, the degradation of desmosome can then cause cutin
Cell detachment and cause the desquamation of skin.Evidence shows that the imbalance of local or temporary KLKs activity control, is AD patient skin screens
Barrier stablizes one of the main reason for missing.
KLKs (Kallikreins, kallikrein) is that have trypsase or the silk ammonia of chymotrypsin protein enzyme spcificity
Pepsin, encoding gene are positioned at 19q13.4, encode 15 secreting type serine protease KLK 1-KLK 15.
It proving, KLKs is present in the corneocyte of normal person, has now been found that, at least 8 kinds of KLK (KLK 5, KLK 6, KLK 7,
KLK 8, KLK 10, KLK 11, KLK 13 and KLK 14) it is present in the cuticula and sweat of people, wherein KLK7 accounts for total amount
40%.KLK7 may be a key enzyme of skin injury, and in patient AD it may to participate in a Systemic inflammation anti-
Should, it is the most prominent in the cuticula KLK7 rises of AD, this prompting KLK7 may be in the pathogenesis of AD it is vital, because
This, inhibit the activity of KLK7 seems mostly important for the treatment of AD.
LEKTI (Lympho-epithelial Kazal-type-related inhibitor, LEKTI) is by SPINK5
The member of the serpin family of gene code, LEKTI precursors include a signal peptide and be separated from each other 15
A serine protease inhibits domain (D1-D15), several protein fragments is hydrolyzed to by furin rapidly after expression, wherein wrapping
The LEKTI in the domain containing D6-D9 inhibition can inhibit the activity of the enzymes such as trypsase, chymotrypsin, KLK5 and KLK7.LEKTI's
Endogenous target includes at least KLK5, KLK7 and KLK14, they participate in the furfur process of skin jointly.In patient AD, LEKTI expression
The horizontal serious abnormal rise for reducing, resulting in KLK7 activity.Although LEKTI is the natural inhibitor of KLK7 in epidermis, make
To treat the externally applied drug of AD, keratoderma cannot be penetrated, and the characteristic of its macro-molecular protein also results in absorption and expands
The problem of scattered speed is excessively slow, degradation speed is too fast, thus act on very limited.Up to the present, there are no a kind of effective
KLK7 inhibitor is applied to clinic.
The content of the invention
Based on this, the present invention provides application and its synthesis of the compound on the drug for inhibiting kallikrein KLK7 is prepared
Method.
Technical solution of the present invention is：
Application of the compound on the drug for inhibiting kallikrein KLK7 is prepared, the structural formula of the compound are：
The method of the synthesis compound, the synthetic route are as follows：
Wherein：
The synthesis of substance 18：Substance 17, KOH, water, carbon disulfide are added to reaction bulb, are heated to flowing back, is reacted
2~8 it is small when, be cooled to 25 DEG C, substance 18, filtering, washing, drying is precipitated with 1~10wt% salt acid for adjusting pH value in filtering, filtrate
Obtain substance 18；
The synthesis of substance 20：Addition substance 18, substance 19, toluene and potassium carbonate into reaction bulb, back flow reaction,
Cold filtration washes solid with dichloromethane, and filtrate decompression concentrates, residue silica gel column chromatography, and hexane-ethylacetate elution obtains
Substance 20；
The synthesis of compound III：Substance 20,4- fluorine benzyl chloride, NaOH, acetonitrile are added in into reaction bulb, back flow reaction is cold
But, decompression steams solvent and obtains residue, and residue with Ethyl acetate extracts three times, and the volume of each ethyl acetate is residue
2~20 times, organic phase washing, then dried with anhydrous sodium sulfate, it filters, filtrate decompression steams solvent afforded crude material, and crude product is with acetonitrile
Recrystallize to obtain compound III.
Preferably, the substance 17, carbon disulfide, KOH, the molar ratio of water are 1:1.0~4.0:1.0~4.0:5~
30。
Preferably, the substance 18, substance 19, potassium carbonate, the molar ratio of toluene are 1.0:1.0~2.0:1.0~
2.0:5.0~30.0, back flow reaction, cooling, the hexane, ethyl acetate volume ratio 2:1.
Preferably, when the reflux time in the synthesis of the substance 20 is 4~12 small, 25 DEG C are cooled to.
Preferably, the substance 20,4- fluorine benzyl chloride, NaOH, the molar ratio of acetonitrile are 1.0:1.0~2.0:1.0~
2.0:10.0~100, when back flow reaction 4~8 is small.
The application of the compound or the method on the drug for inhibiting kallikrein KLK7 is prepared, it is described to prepare suppression
The drug of application on the drug of kallikrein KLK7 processed includes：
One or more of mixture.
Preferably, the drug for preparing the application on the drug for inhibiting kallikrein KLK7 includes：Compound I, change
The molar ratio for closing object II, compound III, compound IV and compound V is 1:1~4:1~5：1~3：1~2.
Advantage of the present invention：
1st, the compound provided by the invention for inhibiting kallikrein KLK7 can effectively inhibit the activity of KLK7, close
Simple and practicable into method, the pharmaceutical preparation for inhibiting KLK7 activity can be prepared by adding in appropriate auxiliary material and auxiliary agent.
2nd, being lacked using what synthetic method by-product of the present invention generated, impurity content is down to 0.05%~0.08%.
3rd, the compounds of this invention and the combination of other compounds, it is more efficient for the activity suppression of kallikrein KLK7.
4th, the serine protease mainly expressed in skin further includes KLK5, KLK14, Matriptase with
Elastase2.The compounds of this invention conjunction object is constant under 100 μM of concentration to above-mentioned serine protease to reveal inhibition work
Property, show that its KLK7 of formula has good specificity.
5th, the compounds of this invention is in pH8,150mM NaCl, and 72h is incubated in 37 DEG C of buffer solution, lives to the inhibition of KLK7
Property remain unchanged, show that the inhibition of the compounds of this invention is efficient, activity is strong, and its inhibition is stablized.
Description of the drawings
Fig. 1：The present invention implements the concentration of compound III and the relation curve of inhibiting rate.
Fig. 2：The H of the compounds of this invention III1Nuclear-magnetism figure.
Fig. 3：The C of the compounds of this invention III13Nuclear-magnetism figure.
Fig. 4：7 compound concentration of embodiment and inhibiting rate relation curve.
Specific embodiment
It is further illustrated the present invention with reference to embodiment, but the scope of protection of present invention is not limited to implement
The scope of example statement.
Embodiment 1
Application of the compound on the drug for inhibiting kallikrein KLK7 is prepared, the structural formula of the compound are：
Embodiment 2
The method of compound described in synthetic example 1, the synthetic route are as follows：
Wherein：
The synthesis of substance 18：Substance 17, KOH, water, carbon disulfide are added to reaction bulb, it is heated to flowing back, instead
Answer 2 it is small when, be cooled to 25 DEG C, substance 18 is precipitated with 1wt% salt acid for adjusting pH value in filtering, filtrate, filtering, washing, dry object
Matter 18；
The synthesis of substance 20：Addition substance 18, substance 19, toluene and potassium carbonate into reaction bulb, back flow reaction,
Cold filtration washes solid with dichloromethane, and filtrate decompression concentrates, residue silica gel column chromatography, and hexane-ethylacetate elution obtains
Substance 20.
The synthesis of compound III：Substance 20,4- fluorine benzyl chloride, NaOH, acetonitrile are added in into reaction bulb, back flow reaction is cold
But, decompression steams solvent and obtains residue, and residue with Ethyl acetate extracts three times, and the volume of each ethyl acetate is residue
2 times, organic phase washing, then dried with anhydrous sodium sulfate, it filters, filtrate decompression steams solvent afforded crude material, and crude product is tied again with acetonitrile
It is brilliant to obtain compound III.
The substance 17, carbon disulfide, KOH, the molar ratio of water are 1:1:1:5.
The substance 18, substance 19, potassium carbonate, the molar ratio of toluene are 1:1:1:5, back flow reaction cools down, described
Hexane-ethylacetate volume ratio is 2:1.
When reflux time is 4 small during the substance 20 synthesizes, 25 DEG C are cooled to.
The substance 20,4- fluorine benzyl chloride, NaOH, the molar ratio of acetonitrile are 1:1:1:10, when back flow reaction 4 is small.
Embodiment 3
The method of compound described in synthetic example 1, the synthetic route is described in embodiment 2：
The synthesis of substance 18：Substance 17, KOH, water, carbon disulfide are added to reaction bulb, it is heated to flowing back, instead
Answer 8 it is small when, be cooled to 25 DEG C, substance 18 is precipitated with 10wt% salt acid for adjusting pH value in filtering, filtrate, filtering, washing, dry object
Matter 18；
The synthesis of substance 20：Addition substance 18, substance 19, toluene and potassium carbonate into reaction bulb, back flow reaction,
Cold filtration washes solid with dichloromethane, and filtrate decompression concentrates, residue silica gel column chromatography, and hexane-ethylacetate elution obtains
Substance 20.
The synthesis of compound III：Substance 20,4- fluorine benzyl chloride, NaOH, acetonitrile are added in into reaction bulb, back flow reaction is cold
But, decompression steams solvent and obtains residue, and residue with Ethyl acetate extracts three times, and the volume of each ethyl acetate is residue
2~20 times, organic phase washing, then dried with anhydrous sodium sulfate, it filters, filtrate decompression steams solvent afforded crude material, and crude product is with acetonitrile
Recrystallize to obtain compound III.
The substance 17, carbon disulfide, KOH, the molar ratio of water are 1:4:4:30.
The substance 18, substance 19, potassium carbonate, the molar ratio of toluene are 1:2:2:30, back flow reaction, cooling, institute
Hexane-ethylacetate volume ratio is stated as 2:1.
When reflux time is 12 small during the substance 20 synthesizes, 25 DEG C are cooled to.
The substance 20,4- fluorine benzyl chloride, NaOH, the molar ratio of acetonitrile are 1:2:2:100, when back flow reaction 8 is small.
Embodiment 4
The method of compound described in synthetic example 1, the synthetic route is described in embodiment 2：
The synthesis of substance 18：Substance 17, KOH, water, carbon disulfide are added to reaction bulb, it is heated to flowing back, instead
Answer 6 it is small when, be cooled to 25 DEG C, substance 18 is precipitated with 8wt% salt acid for adjusting pH value in filtering, filtrate, filtering, washing, dry object
Matter 18；
The synthesis of substance 20：Addition substance 18, substance 19, toluene and potassium carbonate into reaction bulb, back flow reaction,
Cold filtration washes solid with dichloromethane, and filtrate decompression concentrates, residue silica gel column chromatography, and hexane-ethylacetate elution obtains
Substance 20.
The synthesis of compound III：Substance 20,4- fluorine benzyl chloride, NaOH, acetonitrile are added in into reaction bulb, back flow reaction is cold
But, decompression steams solvent and obtains residue, and residue with Ethyl acetate extracts three times, and the volume of each ethyl acetate is residue
15 times, organic phase washing, then dried with anhydrous sodium sulfate, it filters, filtrate decompression steams solvent afforded crude material, and crude product is tied again with acetonitrile
It is brilliant to obtain compound III.
The substance 17, carbon disulfide, KOH, the molar ratio of water are 1:3:3:20.
The substance 18, substance 19, potassium carbonate, the molar ratio of toluene are 1:1.5:1.5:20, back flow reaction is cold
But, the hexane-ethylacetate volume ratio is 2:1.
When reflux time is 10 small during the substance 20 synthesizes, 25 DEG C are cooled to.
The substance 20,4- fluorine benzyl chloride, NaOH, the molar ratio of acetonitrile are 1:1.5:1.5:50, when back flow reaction 6 is small.
Embodiment 5
1) compound III is dissolved in DMSO, is configured to the mother liquor of concentration 10mM；
2) compound III is added in KLK7 activity buffer liquids, is configured to 1.6 μM, 3.1 μM, 6.25 μM, 12.5 μM, 25 μ
M, 50 μM, 100 μM of solution, and acted on 15 minutes at 37 DEG C；
3) fluorogenic substrate MCa-R-P-K-P-V-E-Nval-W-R-K (Dnp)-NH is added in2, the work of survey KLK7 at 37 DEG C
Property 15 minutes, using fluorescence microplate reader detect fluorescent value, according to the size of fluorescent value calculate KLK7 activity.
Negative control group：DMSO is added in the activity buffer liquid of KLK7, other operating conditions are identical with experimental group.
The activity of the KLK7 obtained according to above-mentioned experimental group and negative control group calculates inhibiting rate of the compound III to KLK7,
The formula of inhibiting rate is calculated as %inhibition=(1-a/b) × 100%, result of calculation is as shown in table 1；Wherein, a is to be measured
The enzyme activity of sample, b are the enzyme activity of negative control.
Table 1 for compound III under various concentration to the inhibiting rate of KLK7 activity, the result drafting chemical combination according to table 1
The concentration of object III and the relational graph of inhibiting rate carry out curve fitting to obtain the concentration of compound III using KaleidaGraph softwares
With the relation curve of inhibiting rate, as shown in Figure 1.
With the increase of compound III concentration it can be seen from the result of table 1 and Fig. 1, to the inhibiting rate of KLK7 activity by
Cumulative height when the concentration of compound III is 50 μM, reaches 100% to the inhibiting rate of KLK7 activity.
Therefore, shown compound III has KLK7 excellent inhibition, which adds in suitable as active component
When auxiliary material and auxiliary agent can be prepared into inhibit KLK7 activity pharmaceutical preparation.
Compound III is under various concentration to the inhibiting rate of KLK7 activity
The preparation method letter of the compound provided by the invention for inhibiting kallikrein KLK7 it can be seen from foregoing description
It is single easy, it can effectively inhibit the activity of KLK7, the medicine for inhibiting KLK7 activity can be prepared by adding in appropriate auxiliary material and auxiliary agent
Object preparation.
Embodiment 6
The drug for preparing the application on the drug for inhibiting kallikrein KLK7 includes：
The compound I, compound II, compound III, the mass ratio of compound IV and compound V are 1:1~2:1~
2.5：2~3：1~2.
Embodiment 7
It is 1 in molar ratio in 6 composition of embodiment:1:1：1：After 1 mixing, tested according to the method for embodiment 5 different
To the inhibiting rate of KLK7 activity under concentration, 2 and Fig. 4 are the results are shown in Table
2 mixture of table is under various concentration to the inhibiting rate of KLK7 activity
By table 2 the results show that formula compound I, compound II, compound III, compound IV and compound V combination effects
It is more notable than effect is used alone, in the case of same additive amount, to KLK7 when the drug effect of mixture is than being used alone
Maximum inhibition higher.
Embodiment 8
The method for synthesizing compound I, the synthetic route are as follows：
Wherein：
The synthesis of substance three：Ethyl alcohol, substance one, the formalin of mass concentration 37%, hydrogen-oxygen are added in into reaction bulb
Change sodium and substance two, reaction, reaction finishes, and ethyl acetate extracts three times, and the dosage of each ethyl acetate is foregoing ethyl alcohol body
Long-pending 1~5 times merges organic phase, distills, and cools down, and filters, and washing, ethyl alcohol washes, dry substance three；
The synthesis of substance four：Substance three, aceticanhydride are added in into reaction bulb, controlled at -12 DEG C, mass concentration, which is added dropwise, is
90% fuming nitric aicd reaction, reaction finishes, rises to 25 DEG C, pour into ice water, and the volume of ice water is 5-10 times of reaction solution, mistake
Filter, is first washed, then washed with ice water with 1~5% sodium bicarbonate solution, dry substance four；
The synthesis of substance five：Addition ethyl alcohol, water, acetic acid, iron powder, ammonium chloride and substance four into reaction bulb, back flow reaction,
Ethyl alcohol is added, second of quality for adding in ethyl alcohol is 5 times of substance four, is filtered while hot, filtrate is cooled to 25 DEG C, pours into ice water
In, the volume of ice water is 10 times of filtrate, is filtered, washing, dry substance five；
The synthesis of substance seven：Substance five, substance six, dimethylformamide, potassium carbonate are added in into reaction bulb, reaction is cold
But to 25 DEG C, reaction solution is added in ice water, the quality of ice water is 10 times of reaction solution, is filtered, washing, dry substance
Seven.
The synthesis of substance eight：The mixture of substance seven and pyridine is added in into reaction bulb, then phosphorus oxychloride is added dropwise, heating is anti-
Should, reaction solution is cooled down, adds in chloroform, is stirred, cooling adds in cold water, separates organic phase, cold water washes chloroform layer as neutrality, dense
Contracting removes chloroform, dry substance eight.
The synthesis of compound I：Dimethylformamide, substance eight, potassium carbonate and substance nine are sequentially added in reaction bulb, added
Thermal response, cooling, reaction solution is poured into water, and is filtered, filter cake water wash, dry compound I.
The substance two, the formalin of mass concentration 37%, substance one, the mass ratio of sodium hydroxide and ethyl alcohol are 1:
1:1:1:When reacting 2 at 5,25 DEG C.
The substance three, aceticanhydride, the mass ratio of nitric acid are 1:0.5:0.5, when reaction 4 is small at -5 DEG C.
The substance four, ethyl alcohol, water, acetic acid, iron powder, ammonium chloride mass ratio are 1:2.5:2:0.05:1:0.02, reflux is anti-
Answer 2 it is small when.
The substance five, substance six, potassium carbonate, the molar ratio of dimethylformamide are 1:1:1:10, it is warming up to 80 DEG C instead
Answer 4 it is small when.
The substance seven, pyridine, the molar ratio of phosphorus oxychloride are 1:1:1.5, finish, be warming up to 100 DEG C reaction 3 it is small when,
Reaction solution is cooled to 50 DEG C, adds in chloroform, the volume of chloroform is 40 times of pyridine, when stirring 1 is small, is cooled to 0 DEG C, adds in 5
DEG C cold water, the volume of cold water is 0.6 times of chloroform, separates organic phase, and cold water washes chloroform layer as neutrality, and concentration removes chloroform,
Dry substance eight.
The substance eight, substance nine, potassium carbonate, the molar ratio of dimethylformamide are 1:2:2:20,50 DEG C are heated to, instead
1h is answered, cools down, reaction solution is poured into water, the volume of water is 10 times of reaction solution, is filtered, filter cake water wash is dry to change
Close object I.
Embodiment 9
The method for synthesizing compound II, the synthetic route are as follows：
Wherein：
The synthesis of substance 12：By substance ten, substance 11, POCl3It adds in the round-bottomed flask equipped with reflux condensing tube,
Round-bottomed flask is positioned over to be cleaned by ultrasonic in instrument and is reacted, decompression steams remaining POCl3, residue is poured into trash ice, trash ice
Quality is 20 times of residue, and precipitation is precipitated, and is filtered, and solid is washed with 1~5% NaOH solution, is washed to neutrality, obtains substance
12；
The synthesis of substance 13：Dichloromethane is added in reaction bulb and substance 12, salt ice bath are cooled to -15 DEG C, are protected from light,
Under nitrogen protection, the anhydrous methylene chloride solution of 20wt% Boron tribromides is added dropwise, after dripping, temperature reaction, reaction knot
Reaction solution is poured into ice water after beam, the quality of ice water is 5 times of reaction solution, separates organic phase, water is mutually extracted with ethyl acetate
Three times, the volume of each ethyl acetate is 0.5 times of water phase, merges organic phase, and organic phase is dried with sodium sulphate, steams solvent,
Obtain substance 13；
The synthesis of substance 14：Monoxone is mixed into obtain solution A with 5wt% sodium hydrate aqueous solutions, by substance 13 with
5wt% sodium hydrate aqueous solutions mix to obtain solution B, and solution A is added in reaction bulb, then solution B is added dropwise, and are added dropwise, and rise
Temperature reaction, cooling add 5wt% hydrochloric acid to be acidified to pH=1, filtering, washing, dry substance 14；
The synthesis of substance 15：Equipped with stirring rod, thermometer, reflux condensing tube, reflux condensing tube company in reaction bulb
Hydrogen chloride absorption device is connect, sequentially adds thionyl chloride and substance 14, stirs temperature reaction, depressurizes and steams low-boiling-point substance, in bottle
Residue is substance 15, is directly used in the next step without isolation；
The synthesis of compound II：Substance 15 made from step, adds triethylamine, dichloromethane on being added in reaction bulb
It with substance 16, is stirred to react, decompression steams solvent, cools down, and filters, and washing, acetone washes to obtain compound II.
The substance ten, substance 11, POCl3Mass ratio be 1:1:3, it is 50 DEG C to be cleaned by ultrasonic reaction temperature in instrument,
Power is 350W, ultrasonication 60 minutes.
The dichloromethane, substance 12,20wt% Boron tribromides dichloromethane solution mass ratio be 20:1:6, it rises
Temperature is to when reaction 2 is small at 25 DEG C, 25 DEG C.
The molar ratio of monoxone and sodium hydroxide is 1 in the solution A:1, substance 13 and hydroxide in the solution B
The molar ratio of sodium is 1:1, solution A is added in reaction bulb, then solution B is added dropwise, be added to substance 13 in reaction bulb with
Chloroacetic molar ratio is 1:1, be warming up to 60 DEG C reaction 1 it is small when, be cooled to 25 DEG C.
The molar ratio of the substance 14 and thionyl chloride is 1:1, stirring is warming up to 60 DEG C, when reaction 5 is small at 60 DEG C.
The substance 15, substance 16, the molar ratio 1 of triethylamine and dichloromethane:1:1:5, stir 2 at 0~25 DEG C
Hour.
Embodiment 10
The method for synthesizing compounds Ⅳ, the synthetic route are as follows：
Wherein：
The synthesis of substance 23：Substance 21, substance 22, glacial acetic acid are added to reaction bulb, are heated to back
It when stream reaction 4-~8 are small, cools down, filters, washing, dichloromethane is washed, and obtains substance 23；
The synthesis of substance 24：The mixture of substance 23 and pyridine is added in into reaction bulb, then trichlorine oxygen is added dropwise
Phosphorus finishes, temperature reaction, and reaction solution is cooled to 50 DEG C after reaction, adds in chloroform, is stirred to react, is cooled to 5 DEG C, adds
Enter cold water, separate organic phase, cold water washes chloroform layer as neutrality, and concentration removes chloroform, dry substance 24；
The synthesis of compounds Ⅳ：Substance 24, substance 25, toluene, potassium carbonate are added in into reaction bulb, reflux is anti-
Answer 4 it is small when, be cooled to 25 DEG C, filtering washes solid, filtrate decompression is concentrated to give crude product, and crude product is obtained with Gossypol recrystallized from chloroform with dichloromethane
Compounds Ⅳ.
The substance 21, substance 22, the molar ratio of glacial acetic acid are 1:1:1.5, when back flow reaction 4 is small, cooling
To 25 DEG C.
The substance 23, pyridine, the molar ratio of phosphorus oxychloride are 1:1:1.5, be warming up to 110 DEG C reaction 2 it is small when, will
Reaction solution is cooled to 50 DEG C, adds in chloroform, and the volume of the chloroform is 30 times of pyridine, be stirred to react 1 it is small when, be cooled to 0 DEG C,
5 DEG C of cold water is added in, the volume of cold water is 0.5 times of chloroform.
Embodiment 11
The technique for synthesizing compound V, the synthetic route are as follows：
Wherein：
The synthesis of substance 28：Substance 26 and substance 27 are added in dry round-bottomed flask, heating carries out
It being stirred to react, thin-layer chromatography tracking reaction to raw material disappears, and mixture is cooled to 25 DEG C, is poured into mixture of ice and water, filters,
Washing, chloroform are washed, and obtain substance 28；
The synthesis of substance 29:Ether, lithium aluminium hydride, stirring and dissolving, ice-water bath successively are added in reaction bulb and is cooled to 0
DEG C, substance 28 is slow added into, charging finishes, and is reacted under ice-water bath, reaction solution is poured into ice water, and standing allows sediment
Bottom is parked in, is filtered, chloroform filter wash slag, filtrate separates organic phase, and water is mutually extracted three times with chloroform, and organic phase merges, and decompression is dense
Contract to obtain substance 29.
The synthesis of compound V：Substance 29, triethylamine, dichloromethane and substance 30 are added in the reaction, and stirring is anti-
Should, concentration removes dichloromethane, then adds water, adds water quality for 10 times of concentrate, with chloroform extraction three times, extractant chloroform
Each dosage is 1 times of the volume of foregoing added water, and organic phase merges, and be concentrated under reduced pressure to obtain crude product, and crude product is obtained with Gossypol recrystallized from chloroform
Compound V.
The substance 26, the molar ratio of substance 27 are 1:1. rising to 80 DEG C is stirred reaction, the ice water
The quality of mixture is 5 times of substance 26.
The substance 28, lithium aluminium hydride, the mass ratio of ether are 1:0.5:15, charging rate is advisable with micro- reflux,
When reaction 1.5 is small under the ice-water bath, reaction solution is poured into ice water, the volume of ice water is 1 times of reaction solution, extractant chloroform
Each dosage is 1 times of water phase volume.
The substance 29, substance 30, the molar ratio of triethylamine and dichloromethane are 1:1:1:10,25 DEG C of stirrings
1.5 it is small when.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as the limitation for the present invention, this Shen
Please in embodiment and embodiment in feature in the case where there is no conflict, can mutually be combined.The protection model of the present invention
Enclosing should be with the technical solution of claim record, the equivalent substitution side of technical characteristic in the technical solution recorded including claim
Case is protection domain.Equivalent substitution i.e. within this range is improved, also within protection scope of the present invention.
Claims (2)
1. application of the compound on the drug for inhibiting kallikrein KLK7 is prepared, which is characterized in that the structure of the compound
Formula is：
2. application according to claim 1, which is characterized in that described to prepare on the drug for inhibiting kallikrein KLK7
The drug of application includes：Compound III and the mixture of compound V；Compound V structure formula is as follows：
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030078255A1 (en) * | 2001-03-23 | 2003-04-24 | Pinto Donald Joseph Phillip | 6-5, 6-6, or 6-7 Heterobicycles as factor xa inhibitors |
| WO2003047520A2 (en) * | 2001-12-04 | 2003-06-12 | Bristol-Myers Squibb Company | SUBSTITUTED AMINO METHYL FACTOR Xa INHIBITORS |
| CN103080104A (en) * | 2010-08-04 | 2013-05-01 | 诺瓦提斯公司 | N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein |
| WO2015171527A1 (en) * | 2014-05-05 | 2015-11-12 | Global Blood Therapeutics, Inc. | Pyrazolopyridine pyrazolopyrimidine and related compounds |
| CN105330665A (en) * | 2015-11-04 | 2016-02-17 | 衡阳师范学院 | Kallikrein KLK7 inhibiting compound and preparation method and application thereof |
-
2016
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030078255A1 (en) * | 2001-03-23 | 2003-04-24 | Pinto Donald Joseph Phillip | 6-5, 6-6, or 6-7 Heterobicycles as factor xa inhibitors |
| WO2003047520A2 (en) * | 2001-12-04 | 2003-06-12 | Bristol-Myers Squibb Company | SUBSTITUTED AMINO METHYL FACTOR Xa INHIBITORS |
| CN103080104A (en) * | 2010-08-04 | 2013-05-01 | 诺瓦提斯公司 | N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein |
| WO2015171527A1 (en) * | 2014-05-05 | 2015-11-12 | Global Blood Therapeutics, Inc. | Pyrazolopyridine pyrazolopyrimidine and related compounds |
| CN105330665A (en) * | 2015-11-04 | 2016-02-17 | 衡阳师范学院 | Kallikrein KLK7 inhibiting compound and preparation method and application thereof |
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