CN106243058B - Application and its synthetic method of a kind of compound on the drug for inhibiting kallikrein KLK7 is prepared - Google Patents
Application and its synthetic method of a kind of compound on the drug for inhibiting kallikrein KLK7 is prepared Download PDFInfo
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- CN106243058B CN106243058B CN201610608087.XA CN201610608087A CN106243058B CN 106243058 B CN106243058 B CN 106243058B CN 201610608087 A CN201610608087 A CN 201610608087A CN 106243058 B CN106243058 B CN 106243058B
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- CIEQTKRJCRGZOK-UHFFFAOYSA-N CC(C)(C)c(cc(NCCCN1CCOCC1)[n]1nc2C)nc1c2C(CC1)=CC=C1F Chemical compound CC(C)(C)c(cc(NCCCN1CCOCC1)[n]1nc2C)nc1c2C(CC1)=CC=C1F CIEQTKRJCRGZOK-UHFFFAOYSA-N 0.000 description 1
- XITOUXFBGWEFED-UHFFFAOYSA-N CCC(C=C1)=CC(C)C1C(N)=O Chemical compound CCC(C=C1)=CC(C)C1C(N)=O XITOUXFBGWEFED-UHFFFAOYSA-N 0.000 description 1
- KWINJMHUPVOFOX-UHFFFAOYSA-N CCN(CCCNC(COc(cccc1)c1-c1nnc(C2=CC=CC(C)C2)[o]1)=O)Cc1ccccc1 Chemical compound CCN(CCCNC(COc(cccc1)c1-c1nnc(C2=CC=CC(C)C2)[o]1)=O)Cc1ccccc1 KWINJMHUPVOFOX-UHFFFAOYSA-N 0.000 description 1
- JRHCKECGYOWIIM-UHFFFAOYSA-N NC(SCc(cc1)ccc1F)=N Chemical compound NC(SCc(cc1)ccc1F)=N JRHCKECGYOWIIM-UHFFFAOYSA-N 0.000 description 1
- PIKVJEZBHXMFJC-UHFFFAOYSA-N O=C(Cc1c(cccc2)c2ccc1)NCCc1c[s]c(-c(cc2)ccc2Cl)n1 Chemical compound O=C(Cc1c(cccc2)c2ccc1)NCCc1c[s]c(-c(cc2)ccc2Cl)n1 PIKVJEZBHXMFJC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
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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
- A61K31/426—1,3-Thiazoles
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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
-
- 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
-
- 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
Abstract
The invention belongs to biomedical sectors, inhibit the application on the drug of kallikrein KLK7 and its synthetic method in preparation more particularly, to a kind of compound.A kind of application of 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, are preparing inhibition kallikrein KLK7's more particularly, to a kind of compound
Application and its synthetic method on drug.
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 be 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 packet 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 lead to 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-KLK15.Channel syndrome
Bright, KLKs is present in the corneocyte of normal person, has now been found that, at least 8 kinds of KLK (KLK5, KLK 6, KLK 7, KLK
8, KLK10, KLK 11, KLK13 and KLK14) it is present in the cuticula and sweat of people, wherein KLK7 accounts for the 40% of total amount.
KLK7 may be a key enzyme of skin injury, and it may participate in a systemic inflammatory responses in patient AD,
The cuticula KLK7 raisings of AD are the most prominent, this prompting KLK7 may be vital in the pathogenesis of AD, therefore, press down
The activity of KLK7 processed 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
Inhibit the LEKTI in domain that can inhibit the activity of the enzymes such as trypsase, chymotrypsin, KLK5 and KLK7 containing D6-D9.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 raising 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.
Invention content
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:
A kind of application of 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 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 20~50 times of residue, and precipitation is precipitated, and is filtered, and solid is washed with 1%~5% NaOH solution, is washed to neutrality,
Obtain 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 5-15 times of reaction solution, separates organic phase, water phase is extracted with ethyl acetate
It takes three times, the volume of each ethyl acetate is 0.5~5 times of water phase, merges organic phase, and organic phase is dried with sodium sulphate, steamed
Solvent obtains substance 13;
The synthesis of substance 14:Monoxone is mixed into obtain solution A with 5~20wt% sodium hydrate aqueous solutions, by substance ten
Three mix to obtain solution B with 5~20wt% sodium hydrate aqueous solutions, solution A are added in reaction bulb, then solution B is added dropwise, and are added dropwise
It finishes, temperature reaction, cools down, 5~20wt% hydrochloric acid is added to be acidified to pH=1~2, is filtered, washed, dries to obtain 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.
Preferably, the substance ten, substance 11, POCl3Mass ratio be 1.0:1.0~1.5:30~50, ultrasound is clear
It is 50~70 DEG C, power 350W to wash reaction temperature in instrument, ultrasonication 60~120 minutes.
Preferably, the dichloromethane, substance 12,20wt% Boron tribromides dichloromethane solution mass ratio be 20
~40:1:6~15,25 DEG C are warming up to, 25 DEG C are reacted 2~4 hours.
Preferably, the molar ratio of monoxone and sodium hydroxide is 1 in the solution A:1.0~2.0, object in the solution B
Matter 13 and the molar ratio of sodium hydroxide are 1:1.0~2.0, solution A is added in reaction bulb, then solution B is added dropwise, be added to
Substance 13 and chloroacetic molar ratio in reaction bulb are 1:1.0~2.0, temperature reaction, cooling.
Preferably, 60~90 DEG C are warming up to react 1~6 hour, is cooled to 25 DEG C.
Preferably, the molar ratio of the substance 14 and thionyl chloride is 1:1.0~4.0, stirring is warming up to 60~78 DEG C,
It is reacted 5~10 hours at 60~78 DEG C.
Preferably, the molar ratio 1.0 of the substance 15, substance 16, triethylamine and dichloromethane:1:0~2.0:1.0
~3.0:5.0~30, it is stirred 2 hours at 0~25 DEG C.
The application of the compound or the method on the drug for inhibiting kallikrein KLK7 is prepared, feature exist
In the drug for preparing the application on the drug for inhibiting kallikrein KLK7 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 of the inhibition kallikrein KLK7 of bright offer can effectively inhibit the activity of KLK7, synthesis side
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.
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 relation curve of concentration and inhibiting rate shown in formula compound of embodiment of the present invention II;
Fig. 2:The H of the compounds of this invention II1Nuclear-magnetism figure;
Fig. 3:The C of the compounds of this invention II13Nuclear-magnetism figure;
Fig. 4:The relation curve of 7 polymerisable compounds concentration of embodiment and inhibiting rate.
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 range 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 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 object
Matter 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 phase is 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, are filtered, washed, dry to obtain 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 reacting 2 hours 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, it is warming up to 60 DEG C and reacts 1 hour, 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, is reacted 5 hours at 60 DEG C.
The substance 15, substance 16, triethylamine and dichloromethane molar ratio 1:1:1:5, stir 2 at 0~25 DEG C
Hour.
Embodiment 3
The method of compound described in synthetic example 1, the synthetic route is described in embodiment 2:
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 50 times of residue, and precipitation is precipitated, and is filtered, and solid is washed with 5% NaOH solution, is washed to neutrality, obtains substance ten
Two;
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 15 times of reaction solution, separates organic phase, water phase is extracted with ethyl acetate
Three times, the volume of each ethyl acetate is 0.5~5 times of water phase, merges organic phase, and organic phase is dried with sodium sulphate, steamed molten
Agent obtains substance 13;
The synthesis of substance 14:Monoxone is mixed into obtain solution A with 20wt% sodium hydrate aqueous solutions, by substance 13 with
20wt% 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 20wt% hydrochloric acid to be acidified to pH=2, are filtered, washed, dry to obtain 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 1:1.5:50, it is 70 to be cleaned by ultrasonic reaction temperature in instrument
DEG C, power 350W, ultrasonication 120 minutes.
The dichloromethane, substance 12,20wt% Boron tribromides dichloromethane solution mass ratio be 40:1:15,
It is warming up at 25 DEG C, 25 DEG C and reacts 4 hours.
The molar ratio of monoxone and sodium hydroxide is 1 in the solution A:2, substance 13 and hydroxide in the solution B
The molar ratio of sodium is 1:2, 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 1:2, it is warming up to 90 DEG C and reacts 6 hours, be cooled to 25 DEG C.
The molar ratio of the substance 14 and thionyl chloride is 1:4, stirring is warming up to 78 DEG C, and it is small that 10 are reacted at 78 DEG C
When.
The substance 15, substance 16, triethylamine and dichloromethane molar ratio 1:2:3:30, it is small in 25 DEG C of stirrings 2
When.
Embodiment 4
The method of compound described in synthetic example 1, the synthetic route is described in embodiment 2:
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 30 times of residue, and precipitation is precipitated, and is filtered, and solid is washed with 3% NaOH solution, is washed to neutrality, obtains substance ten
Two;
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 10 times of reaction solution, separates organic phase, water phase is extracted with ethyl acetate
Three times, the volume of each ethyl acetate is 0.3 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 15wt% sodium hydrate aqueous solutions, by substance 13 with
15wt% 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 15wt% hydrochloric acid to be acidified to pH=1, are filtered, washed, dry to obtain 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 1:1.2:40, it is 60 to be cleaned by ultrasonic reaction temperature in instrument
DEG C, power 350W, ultrasonication 100 minutes.
The dichloromethane, substance 12,20wt% Boron tribromides dichloromethane solution mass ratio be 30:1:10,
It is warming up at 25 DEG C, 25 DEG C and reacts 3 hours.
The molar ratio of monoxone and sodium hydroxide is 1 in the solution A:1.5, substance 13 and hydrogen-oxygen in the solution B
The molar ratio for changing sodium is 1:1.5, solution A is added in reaction bulb, then solution B is added dropwise, the substance ten being added in reaction bulb
Three with chloroacetic molar ratio be 1:1.5, it is warming up to 80 DEG C and reacts 4 hours, be cooled to 25 DEG C.
The molar ratio of the substance 14 and thionyl chloride is 1:3, stirring is warming up to 70 DEG C, is reacted 8 hours at 70 DEG C.
The substance 15, substance 16, triethylamine and dichloromethane molar ratio 1:1:5:2:3, it is small in 20 DEG C of stirrings 2
When.
Embodiment 5
1) compound II is dissolved in DMSO, is configured to the mother liquor of concentration 10mM;
2) compound II is added in KLK7 activity buffer liquids, is configured to 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100 μM,
200 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 rates of the compound II to KLK7,
The formula for calculating inhibiting rate is %inhibition=(1-a/b) × 100%, and 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 II under various concentration to the inhibiting rate of KLK7 activity, the result drafting chemical combination according to table 1
The concentration of object II and the relational graph of inhibiting rate carry out curve fitting to obtain the concentration of compound II using KaleidaGraph softwares
With the relation curve of inhibiting rate, as shown in Figure 1.
With the increase of compound II concentration it can be seen from the result of table 1 and Fig. 1, to the inhibiting rate of KLK7 activity by
Cumulative height at a concentration of 200 μM of formula compound II, reaches 100% to the inhibiting rate of KLK7 activity.
Therefore, formula compound II has KLK7 excellent inhibition, and it is appropriate which adds in as active component
Auxiliary material and auxiliary agent can be prepared into inhibit KLK7 activity pharmaceutical preparation.
Compound II 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, compound IV and compound V mass ratio be 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 aforementioned 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, the quality of second of addition 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, sodium hydroxide and ethyl alcohol mass ratio be 1:
1:1:1:When reacting 2 at 5,25 DEG C.
The substance three, aceticanhydride, nitric acid mass ratio be 1:0.5:0.5, it is reacted 4 hours 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-
It answers 2 hours.
The substance five, substance six, potassium carbonate, dimethylformamide molar ratio be 1:1:1:10, it is warming up to 80 DEG C instead
It answers 4 hours.
The substance seven, pyridine, phosphorus oxychloride molar ratio be 1:1:1.5, it finishes, is warming up to 100 DEG C and reacts 3 hours,
Reaction solution is cooled to 50 DEG C, adds in chloroform, the volume of chloroform is 40 times of pyridine, stirs 1 hour, 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, dimethylformamide molar ratio be 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, so dry that change
Close object I.
Embodiment 9
The method for synthesizing compound III, 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
It answers 2 hours, is cooled to 25 DEG C, substance 18 is precipitated with 1wt% salt acid for adjusting pH value in filtering, filtrate, is filtered, washed, dries to obtain 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, water molar ratio be 1:1:1:5.
The substance 18, substance 19, potassium carbonate, toluene molar ratio be 1:1:1:5, back flow reaction cools down, described
Hexane-ethylacetate volume ratio is 2:1.
Reflux time is 4 hours during the substance 20 synthesizes, and is cooled to 25 DEG C.
The substance 20,4- fluorine benzyl chloride, NaOH, acetonitrile molar ratio be 1:1:1:10, back flow reaction 4 hours.
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
Stream reaction 4-~8 hour, cool down, filter, 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-
It answers 4 hours, is 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, glacial acetic acid molar ratio be 1:1:1.5, back flow reaction 4 hours, cooling
To 25 DEG C.
The substance 23, pyridine, phosphorus oxychloride molar ratio be 1:1:1.5, it is warming up to 110 DEG C and reacts 2 hours, it will
Reaction solution is cooled to 50 DEG C, adds in chloroform, and the volume of the chloroform is 30 times of pyridine, is stirred to react 1 hour, is 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 phase is 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 plus water, add that water quality is concentrate 10 times, and with chloroform extraction three times, extractant chloroform
Each dosage is 1 times of the volume of aforementioned added water, and organic phase merges, and crude product is concentrated under reduced pressure to obtain, crude product is obtained with Gossypol recrystallized from chloroform
Compound V.
The substance 26, substance 27 molar ratio be 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, ether mass ratio be 1:0.5:15, charging rate is advisable with micro- reflux,
It is reacted 1.5 hours 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, triethylamine and dichloromethane molar ratio be 1:1:1:10,25 DEG C of stirrings
1.5 hour.
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 absence of conflict, mutually can arbitrarily combine.The protection model of the present invention
The technical solution that should be recorded with claim is enclosed, the equivalent replacement side of technical characteristic in the technical solution recorded including claim
Case is protection domain.Equivalent replacement i.e. within this range is improved, also within protection scope of the present invention.
Claims (10)
1. application of a kind of compound on the drug for inhibiting kallikrein KLK7 is prepared, which is characterized in that the compound
Structural formula is:
2. the method for synthesis compound described in claim 1, which is characterized in that the synthetic route is 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, by circle
Bottom flask, which is positioned over to be cleaned by ultrasonic in instrument, to react, and decompression steams remaining POCl3, residue is poured into trash ice, trash ice quality
It is 20~50 times of residue, precipitation is precipitated, filter, solid is washed with 1%~5% NaOH solution, is washed to neutrality, obtains object
Matter 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, nitrogen
Under protection, the anhydrous methylene chloride solution of 20wt% Boron tribromides is added dropwise, after dripping, temperature reaction, after reaction
Reaction solution is poured into ice water, the quality of ice water is 5-15 times of reaction solution, separates organic phase, water phase is extracted with ethyl acetate three
Secondary, the volume of each ethyl acetate is 0.5~5 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 5~20wt% sodium hydrate aqueous solutions, by substance 13 and 5
~20wt% sodium hydrate aqueous solutions mix to obtain solution B, solution A are added in reaction bulb, then solution B is added dropwise, are added dropwise,
Temperature reaction, cooling, adds 5~20wt% hydrochloric acid to be acidified to pH=1~2, is filtered, washed, dries to obtain substance 14;
The synthesis of substance 15:Equipped with stirring rod, thermometer, reflux condensing tube, reflux condensing tube connection chlorine in reaction bulb
Change hydrogen absorption plant, sequentially add thionyl chloride and substance 14, stir temperature reaction, depressurize and steam low-boiling-point substance, it is remaining in bottle
Object 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 and object on being added in reaction bulb
Matter 16, is stirred to react, and decompression steams solvent, cools down, and filters, and washing, acetone washes to obtain compound II.
3. according to the method described in claim 2, it is characterized in that:In the synthesis of the substance 12,
The substance ten, substance 11, POCl3Mass ratio be 1.0:1.0~1.5:30~50, it is cleaned by ultrasonic in instrument and reacts temperature
It is 50~70 DEG C, power 350W to spend, ultrasonication 60~120 minutes.
4. according to the method described in claim 2, it is characterized in that:In the synthesis of the substance 13, the dichloromethane, object
Matter 12,20wt% Boron tribromides anhydrous methylene chloride solution mass ratio be 20~40:1:6~15, it is warming up to 25 DEG C, 25
DEG C reaction 2~4 hours.
5. according to the method described in claim 2, it is characterized in that:In the synthesis of the substance 14, chloroethene in the solution A
The molar ratio of acid and sodium hydroxide is 1:1.0~2.0, the molar ratio of substance 13 and sodium hydroxide is 1 in the solution B:1.0
~2.0, solution A is added in reaction bulb, then solution B is added dropwise, the substance 13 being added in reaction bulb rubs with chloroacetic
You are than being 1:1.0~2.0, temperature reaction, cooling.
6. according to the method described in claim 5, it is characterized in that:In the synthesis of the substance 14, it is warming up to 60~90 DEG C
Reaction 1~6 hour, is cooled to 25 DEG C.
7. according to the method described in claim 2, it is characterized in that:In the synthesis of the substance 15, the substance 14 with
The molar ratio of thionyl chloride is 1:1.0~4.0, stirring is warming up to 60~78 DEG C, is reacted 5~10 hours at 60~78 DEG C.
8. according to the method described in claim 2, it is characterized in that:In the synthesis of the compound II, the substance 15, object
The molar ratio 1.0 of matter 16, triethylamine and dichloromethane:1:0~2.0:1.0~3.0:5.0~30, it is small in 0~25 DEG C of stirring 2
When.
9. application of the compound described in claim 1 on the drug for inhibiting kallikrein KLK7 is prepared, which is characterized in that institute
State prepare the application on the drug for inhibiting kallikrein KLK7 drug include compound II or compound II and compound I,
The combination of one or more of compound III, compound IV, compound V, the compound I, compound II and its compound
III, compound IV, compound V structure formula are as follows:
One or more of mixture.
10. application according to claim 9, which is characterized in that described to prepare on the drug for inhibiting kallikrein KLK7
The drug of application include:Compound I, compound II, compound III, compound IV and compound V molar ratio be 1:1~
4:1~5:1~3:1~2.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6255453B1 (en) * | 1998-06-03 | 2001-07-03 | Cortech, Inc. | Peptoid and nonpeptoid containing alpha-keto oxadiazoles as serine protease inhibitors |
CN101687913A (en) * | 2007-06-28 | 2010-03-31 | 诺瓦提斯公司 | kallikrein 7 modulators |
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AU6645998A (en) * | 1996-12-23 | 1998-07-17 | Du Pont Pharmaceuticals Company | Oxygen or sulfur containing heteroaromatics as factor xa inhibitors |
-
2016
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6255453B1 (en) * | 1998-06-03 | 2001-07-03 | Cortech, Inc. | Peptoid and nonpeptoid containing alpha-keto oxadiazoles as serine protease inhibitors |
CN101687913A (en) * | 2007-06-28 | 2010-03-31 | 诺瓦提斯公司 | kallikrein 7 modulators |
Non-Patent Citations (3)
Title |
---|
"1,2,4-Triazole derivatives as transient inactivators of kallikreins involved in skin diseases";Xiao Tan et al.;《Bioorganic & Medicinal Chemistry Letters》;20130624;第23卷;第4547-4551页 * |
"组织激肽释放酶KLK7是治疗特应性皮炎的潜在靶点";谭潇 等;《生命的化学》;20151231;第35卷(第6期);第715-720页 * |
提供的化学产品目录;ChemDiv, Inc.;《数据库REGIDTRY(在线)》;20071026;CAS登记号:951473-68-0 * |
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