CN105330665B - A kind of compound, preparation method and purposes for suppressing kallikrein KLK7 - Google Patents
A kind of compound, preparation method and purposes for suppressing kallikrein KLK7 Download PDFInfo
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- CN105330665B CN105330665B CN201510744242.6A CN201510744242A CN105330665B CN 105330665 B CN105330665 B CN 105330665B CN 201510744242 A CN201510744242 A CN 201510744242A CN 105330665 B CN105330665 B CN 105330665B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of compound, preparation method and purposes for suppressing kallikrein KLK7, the preparation method of the compound comprises the following steps:With halogenopropane compound shown in nucleophilic substitution production III occurs for compound shown in Formula II;With halide reagent halogenation occurs for compound shown in formula III, and halogenated products occur hydrolysis and obtain compound shown in formula IV in the basic conditions;With hydrazine hydrate compound shown in condensation reaction production V occurs for compound shown in formula IV;Compound shown in nucleophilic substitution production VII occurs for compound shown in compound shown in Formula V and Formula IV;Compound shown in Formula VII is mixed with resolving agent and inorganic acid solution, stirred 1~2.0 hour at 60 100 DEG C, be cooled to room temperature, filtered, alkali is added to produce compound, preparation method and the purposes for suppressing kallikrein KLK7, i.e., compound shown in Formulas I into the solid filtered out.The compound that the present invention is provided substantially, can be used as the active component for preparing the active medicines of suppression KLK7 to KLK7 activity suppressions effect.
Description
Technical field
The present invention relates to biomedicine field, a kind of compound for suppressing kallikrein KLK7, preparation side are particularly related to
Method and purposes.
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 harmless to normal person to common 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 AD pathogenesis
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
It is the balance that horn cell and skin surface horn cell come off between (i.e. furfur), the furfur process bag of skin into cell differentiation
Include by the degraded of the KLKs desmosomes participated in, because desmosome is the Fibronectin of horn cell, the degraded 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
The one of the main reasons of the stable missing of barrier.
KLKs (Kallikreins, kallikrein) is with trypsase or the specific silk ammonia of chymotrypsin
Pepsin, its encoding gene is positioned at 19q13.4, encodes 15 secreting type serine protease KLK 1-KLK 15.
Prove, KLKs is present in the corneocyte of normal person, has now been found that, at least 8 kinds 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 is probably a key enzyme of skin injury, and in patient AD it may to participate in a Systemic inflammation anti-
Should, AD cuticula KLK7 rise the most protrude, this prompting KLK7 be probably in AD pathogenesis it is vital, because
This, the activity for suppressing KLK7 seems mostly important for AD treatment.
LEKTI (Lympho-epithelial Kazal-type-related inhibitor, lympho-epithelial tissue
Kazal type GAP-associated protein GAPs inhibitor) it is by the member of the serpin family of SPINK5 gene codes, LEKTI
Precursor includes a signal peptide and 15 serine stretch protein enzyme level domains (D1-D15) being spaced apart, rapidly by not woods after expression
Protease hydrolytic is several protein fragments, wherein can suppress trypsase, chymotrypsin protein comprising the D6-D9 LEKTI for suppressing domain
The activity of the enzymes such as enzyme, KLK5 and KLK7.LEKTI endogenous target at least includes KLK5, KLK7 and KLK14, and they participate in skin jointly
The furfur process of skin.In patient AD, LEKTI expressions are seriously reduced, and result in the abnormal rise of KLK7 activity.Although
LEKTI is the natural inhibitor of KLK7 in epidermis, but as treatment AD externally applied drug, it can not pass through keratoderma, and
The characteristic of its macro-molecular protein also results in the problem of absorption diffusion velocity is excessively slow, degradation speed is too fast, thus acts on very
It is limited.Up to the present, also it is applied to clinic without a kind of effective KLK7 inhibitor.
The content of the invention
In view of this, it is an object of the invention to propose a kind of compound, preparation method for suppressing kallikrein KLK7
And purposes, KLK7 activity can effectively be suppressed by suppressing kallikrein KLK7 compound, added appropriate auxiliary material and helped
Agent can be prepared into the pharmaceutical preparation for suppressing KLK7 activity.
A kind of suppression kallikrein KLK7 provided based on the above-mentioned purpose present invention compound, with knot shown in Formulas I
Structure:
The preparation method of compound shown in Formulas I comprises the following steps:
Step 1, compound shown in modus ponens II and halogenopropane are under the first solvent, the first catalyst and heated reflux condition
Compound shown in generation nucleophilic substitution production III;
Step 2, with halide reagent halogenation, formula III occur under solvent and temperature conditionss for compound shown in modus ponens III
The halogenated products of shown compound occur hydrolysis and obtain compound shown in formula IV in the basic conditions;
Step 3, with hydrazine hydrate condensation reaction generation occurs under ethanol and heated reflux condition for compound shown in modus ponens IV
Compound shown in Formula V;
Step 4, compound is in the second solvent, the second catalyst and is heated to reflux shown in compound shown in modus ponens V and Formula IV
Under the conditions of occur compound shown in nucleophilic substitution production VII;
Step 5, compound is mixed with resolving agent and inorganic acid solution shown in modus ponens VII, at 60-100 DEG C stir 1~
2.0 hours, room temperature is cooled to, is filtered, adds alkali to produce compound shown in Formulas I into the solid filtered out;
In some embodiments of the invention, compounds process for production thereof comprises the following steps shown in Formula IV:
(1) compound shown in modus ponens VIII and triphenylchloromethane are under the 3rd solvent, the 3rd catalyst and room temperature condition
Carry out amido protecting reaction and obtain compound shown in Formula IX, the organic base is triethylamine or pyridine;
(2) compound shown in modus ponens IX with to methyl benzyl chloride under the 4th solvent, the 4th catalyst and heated reflux condition
Compound shown in generation nucleophilic substitution production X;
(3) compound shown in modus ponens X be heated to reflux in 80% aqueous acetic acid after 1~3 hour add alkaline solution it is anti-
Should, obtain compound shown in Formula X I;
(4) compound shown in modus ponens XI is dissolved in the 5th solvent, the 5th catalyst, and chloracetyl chloride, room temperature bar is slowly added dropwise
Nitrogen acylation reaction occurs under part and obtains compound shown in Formula IV, 1~3 hour reaction time;
In other embodiments of the present invention, in the step 2, compound and diphenyl ether are heated to shown in modus ponens III
120~140 DEG C, chlorine is passed through under light illumination, is continued to be heated to 160~170 DEG C of generation halogenations, has been led to after chlorine and be cooled to
100~110 DEG C, add trbasic zinc phosphate and aqueous sodium carbonate issues raw hydrolysis in heated reflux condition and obtains chemical combination shown in formula IV
Thing;Compound shown in the formula III, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium hydroxide are 1.0:2.1~2.5:0.001~
0.003:1.4~1.8:0.3~0.8;
In other embodiments of the present invention, compound shown in the Formula II, n-propyl chloride, mole of the first catalyst
Than for 1.0:1.1~1.5:1.0~1.2;
Compound shown in the formula IV, the mol ratio of hydrazine hydrate are 1.0:1.5~2.0;
Compound shown in the Formula V, compound shown in Formula IV, the mol ratio of the second catalyst are 1.0:1.0~1.4:1.0
~2.0;
Compound shown in the Formula VII and the mol ratio of resolving agent are 1: 1.0~1.2.
Compound shown in the Formula VIII, triphenylchloromethane, the mol ratio of the 3rd catalyst are 1.0:1.1~1.5:
1.2~2.3;
Compound shown in the Formula IX, to methyl benzyl chloride, the mol ratio of the 4th catalyst is 1.0:1.1~1.5:1.0~
2.0;
Compound shown in the Formula X, the mol ratio of acetic acid are 1:8~11.0;
Compound shown in the Formula X I, chloracetyl chloride, the mol ratio of the 5th catalyst are 1:1.0~1.3:1.2~2.3.
In some embodiments of the invention, the resolving agent is dextrorotation dibenzoyl tartaric acid (D-DBTA), reaction temperature
Spend for 60~100 DEG C, the reaction time is 1~3 hour;The inorganic acid is hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid.
It is 60~140 DEG C, 1~4 hour reaction time that the nucleophilic substitution, which is heated to reflux temperature,;
The temperature that is heated to reflux of the condensation reaction is 78~100 DEG C, 6~12 hours reaction time;
The temperature of the amido protecting reaction is room temperature, 1~5 hour reaction time;
The temperature of the nitrogen acylation reaction is room temperature, 1~5 hour reaction time.
Alternatively, first solvent, the second solvent, the 3rd solvent, the 4th solvent and the 5th solvent are separately appointed
Meaning in toluene, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, chloroform, ether any one or one
More than kind;
First catalyst, the second catalyst, the 3rd catalyst, the 4th catalyst and the 5th catalyst are separately
Inorganic base or organic base are arbitrarily selected from, the inorganic base is potassium carbonate, sodium carbonate, sodium hydroxide, cesium carbonate or potassium hydroxide, institute
Organic base is stated for triethylamine or pyridine.
Application of the compound shown in Formulas I in the medicine for suppressing kallikrein KLK7 activity.
From the above it can be seen that the preparation method for suppressing kallikrein KLK7 that the present invention is provided is simple and easy to apply,
KLK7 activity can effectively be suppressed, the appropriate auxiliary material of addition and auxiliary agent can be prepared into the pharmaceutical preparation for suppressing KLK7 activity.
Brief description of the drawings
Fig. 1 is the relation curve of the concentration of compound and inhibiting rate shown in Formulas I of the embodiment of the present invention.
Fig. 2 is the nuclear-magnetism figure of compound shown in Formulas I of the embodiment of the present invention.
Embodiment
For the object, technical solutions and advantages of the present invention are more clearly understood, below in conjunction with specific embodiment, and reference
Accompanying drawing, the present invention is described in more detail.
The preparation method of compound shown in the Formulas I of embodiment 1
Step 1, it is 1.0 in molar ratio by compound shown in Formula II, n-propyl chloride, potassium carbonate and toluene:1.1:1.0:
10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3 hours, be concentrated under reduced pressure to obtain compound shown in formula III, column chromatography point
From purification.
Step 2, compound shown in formula III, diphenyl ether are added sequentially in reaction bulb, 120 DEG C are warming up to, in illumination
Under the conditions of be passed through chlorine, controlling reaction temperature has been led to after chlorine at 160 DEG C, is cooled to 100 DEG C, sequentially adds trbasic zinc phosphate, carbonic acid
Sodium solution, reacts 3 hours, is concentrated under reduced pressure to give crude compound shown in formula IV, column chromatography for separation purification.Shown in the formula III
Compound, diphenyl ether, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium carbonate are 1.0:10.0:2.2:0.001:1.4:0.3.
Step 3, it is 1.0 in molar ratio by compound shown in formula IV, hydrazine hydrate, ethanol:1.5:10 are added sequentially to reaction
In bottle, it is heated to reflux, reacts 10 hours, is concentrated under reduced pressure to give compound shown in Formula V, column chromatography for separation purification.
Step 4, it is 1.0 in molar ratio by compound, potassium carbonate, toluene shown in compound shown in Formula V, Formula IV:1.1:
1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3 hours, are concentrated under reduced pressure to give compound shown in Formula VII thick
Product, column chromatography for separation purification.
Step 5, it is compound shown in Formula VII and dextrorotation dibenzoyl tartaric acid (D-DBTA) is molten for 1: 1.0 in molar ratio
In dilute hydrochloric acid solution, stirred 3.0 hours at 60 DEG C, then be gradually cooling to room temperature, filtered out in crystal salt, plus alkali and crystallize
Salt, produces compound shown in Formulas I.
As shown in Fig. 21H NMR[(CD3)2SO, 500MHz], δ (ppm):7.14-8.78 (m, 9H, Ar-H), 4.80 (s,
2H, COCH 2N), 0.829 (t, 3H, NCH2CH2-CH 3), 2.28 (s, 3H, Ph-CH 3), 1.43-4.75 (m, 14H, RCH 2R, 1H,
C3 CH)。
The preparation method of compound shown in the Formulas I of embodiment 2
Step 1, it is 1.0 in molar ratio by compound shown in Formula II, 1- N-Propyl Bromides, sodium carbonate and toluene:1.1:1.0:
10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3 hours, be concentrated under reduced pressure to obtain compound shown in formula III, column chromatography point
From purification.
Step 2, compound shown in formula III, diphenyl ether are added sequentially in reaction bulb, 130 DEG C are warming up to, in illumination
Under the conditions of be passed through chlorine, controlling reaction temperature has been led to after chlorine at 170 DEG C, is cooled to 110 DEG C, sequentially adds trbasic zinc phosphate, carbonic acid
Sodium solution, is heated to reflux, and reacts 3 hours, is concentrated under reduced pressure to give crude compound shown in formula IV, column chromatography for separation purification.It is described
Compound shown in formula III, diphenyl ether, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium carbonate are 1.0:10.0:2.2:0.001:1.4:
0.3。
Step 3, it is 1.0 in molar ratio by compound shown in formula IV, hydrazine hydrate, ethanol:1.5:10 are added sequentially to reaction
In bottle, it is heated to reflux, reacts 6 hours, is concentrated under reduced pressure to give compound shown in Formula V, column chromatography for separation purification.
Step 4, it is 1.0 in molar ratio by compound, sodium carbonate, toluene shown in compound shown in Formula V, Formula IV:1.1:
1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3.5 hours, are concentrated under reduced pressure to give compound shown in Formula VII thick
Product, column chromatography for separation purification.
Step 5, it is compound shown in Formula VII and dextrorotation dibenzoyl tartaric acid (D-DBTA) is molten for 1: 1.0 in molar ratio
In dilute nitric acid solution, stirred 1 hour at 100 DEG C, then be gradually cooling to room temperature, filtered out in crystal salt, plus alkali and crystal salt,
Produce compound shown in Formulas I.
1H NMR[(CD3)2SO, 500MHz], δ (ppm):7.14-8.78 (m, 9H, Ar-H), 4.80 (s, 2H, COCH 2N),
0.829 (t, 3H, NCH2CH2-CH 3), 2.28 (s, 3H, Ph-CH 3), 1.43-4.75 (m, 14H, RCH 2R, 1H, C3 CH)。
The preparation method of compound shown in the Formulas I of embodiment 3
Step 1, it is 1.0 in molar ratio by compound shown in Formula II, iodopropane, cesium carbonate and DMF:
1.1:1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3~4 hours, be concentrated under reduced pressure to obtain chemical combination shown in formula III
Thing, column chromatography for separation purification.
Step 2, compound shown in formula III, diphenyl ether are added sequentially in reaction bulb, 130 DEG C are warming up to, in illumination
Under the conditions of be passed through chlorine, controlling reaction temperature has been led to after chlorine at 165 DEG C, is cooled to 105 DEG C, is sequentially added trbasic zinc phosphate and carbon
Acid sodium solution, is heated to reflux, and reacts 3 hours, is concentrated under reduced pressure to give crude compound shown in formula IV, column chromatography for separation purification.Institute
It is 1.0 to state compound shown in formula III, diphenyl ether, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium carbonate:10.0:2.2:0.001:
1.4:0.3.
Step 3, it is 1.0 in molar ratio by compound shown in formula IV, hydrazine hydrate, ethanol:1.5:10 are added sequentially to reaction
In bottle, it is heated to reflux, reacts 8 hours, is concentrated under reduced pressure to give compound shown in Formula V, column chromatography for separation purification.
Step 4, it is 1.0 in molar ratio by compound, sodium hydroxide, toluene shown in compound shown in Formula V, Formula IV:1.1:
1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 4 hours, are concentrated under reduced pressure to give compound shown in Formula VII thick
Product, column chromatography for separation purification.
Step 5, it is compound shown in Formula VII and dextrorotation dibenzoyl tartaric acid (D-DBTA) is molten for 1: 1.0 in molar ratio
In dilute sulfuric acid weak solution, stirred 2.0 hours at 90 DEG C, then be gradually cooling to room temperature, filtered out in crystal salt, plus alkali and crystallize
Salt, produces compound shown in Formulas I.
1H NMR[(CD3)2SO, 500MHz], δ (ppm):7.14-8.78 (m, 9H, Ar-H), 4.80 (s, 2H, COCH 2N),
0.829 (t, 3H, NCH2CH2-CH 3), 2.28 (s, 3H, Ph-CH 3), 1.43-4.75 (m, 14H, RCH 2R, 1H, C3 CH)。
The preparation method of compound shown in the Formulas I of embodiment 4
Step 1, it is 1.0 in molar ratio by compound shown in Formula II, N-Propyl Bromide, potassium hydroxide and acetonitrile:1.1:1.0:
10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3~4 hours, be concentrated under reduced pressure to obtain compound, column chromatography shown in formula III
Separating-purifying.
Step 2, compound shown in formula III, diphenyl ether are added sequentially in reaction bulb, 120 DEG C are warming up to, in illumination
Under the conditions of be passed through chlorine, controlling reaction temperature has been led to after chlorine at 160 DEG C, is cooled to 100 DEG C, is sequentially added trbasic zinc phosphate and carbon
Acid sodium solution, is heated to reflux, and reacts 3 hours, is concentrated under reduced pressure, column chromatography for separation purification, obtains compound shown in formula IV.The formula
Compound shown in III, diphenyl ether, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium hydroxide are 1.0:10.0:2.2:0.001:1.4:
0.3。
Step 3, it is 1.0 in molar ratio by compound shown in formula IV, hydrazine hydrate, ethanol:1.5:10 are added sequentially to reaction
In bottle, it is heated to reflux, reacts 11 hours, is concentrated under reduced pressure to give compound shown in Formula V, column chromatography for separation purification.
Step 4, it is 1.0 in molar ratio by compound, potassium hydroxide, tetrahydrofuran shown in compound shown in Formula V, Formula IV:
1.1:1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 4 hours, are concentrated under reduced pressure to give compound shown in Formula VII
Crude product, column chromatography for separation purification;
Step 5, it is compound shown in Formula VII and dextrorotation dibenzoyl tartaric acid (D-DBTA) is molten for 1: 1.0 in molar ratio
In inorganic acid weak solution, stirred 2.0 hours at 90 DEG C, then be gradually cooling to room temperature, filtered out in crystal salt, plus alkali and crystallize
Salt, produces compound shown in Formulas I.
1H NMR[(CD3)2SO, 500MHz], δ (ppm):7.14-8.78 (m, 9H, Ar-H), 4.80 (s, 2H, COCH 2N),
0.829 (t, 3H, NCH2CH2-CH 3), 2.28 (s, 3H, Ph-CH 3), 1.43-4.75 (m, 14H, RCH 2R, 1H, C3 CH)。
The preparation method of compound shown in the Formulas I of embodiment 5
Step 1, it is 1.0 in molar ratio by compound shown in Formula II, chloropropane, triethylamine and DMF:
1.1:1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3~4 hours, be concentrated under reduced pressure to obtain chemical combination shown in formula III
Thing, column chromatography for separation purification.
Step 2, compound shown in formula III, diphenyl ether are added sequentially in reaction bulb, 120 DEG C are warming up to, in illumination
Under the conditions of be passed through chlorine, controlling reaction temperature has been led to after chlorine at 160 DEG C, is cooled to 100 DEG C, is sequentially added trbasic zinc phosphate and carbon
Acid sodium solution, is heated to reflux, and reacts 3 hours, is concentrated under reduced pressure to give crude compound shown in formula IV, column chromatography for separation purification.Institute
It is 1.0 to state compound shown in formula III, diphenyl ether, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium hydroxide:10.0:2.2:0.001:
1.4:0.3.
Step 3, it is 1.0 in molar ratio by compound shown in formula IV, hydrazine hydrate, ethanol:1.5:10 are added sequentially to reaction
In bottle, it is heated to reflux, reacts 10 hours, is concentrated under reduced pressure to give compound shown in Formula V, column chromatography for separation purification.
Step 4, it is 1.0 in molar ratio by compound, cesium carbonate, toluene shown in compound shown in Formula V, Formula IV:1.1:
1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3-4 hours, are concentrated under reduced pressure to give compound shown in Formula VII thick
Product, column chromatography for separation purification;
Step 5, it is compound shown in Formula VII and dextrorotation dibenzoyl tartaric acid (D-DBTA) is molten for 1: 1.0 in molar ratio
In inorganic acid weak solution, stirred 3 hours at 70 DEG C, then be gradually cooling to room temperature, filtered out in crystal salt, plus alkali and crystallize
Salt, produces compound shown in Formulas I.
1H NMR[(CD3)2SO, 500MHz], δ (ppm):7.14-8.78 (m, 9H, Ar-H), 4.80 (s, 2H, COCH 2N),
0.829 (t, 3H, NCH2CH2-CH 3), 2.28 (s, 3H, Ph-CH 3), 1.43-4.75 (m, 14H, RCH 2R, 1H, C3 CH)。
The preparation method of compound shown in the Formulas I of embodiment 6
Step 1, it is 1.0 in molar ratio by compound shown in Formula II, N-Propyl Bromide, sodium carbonate and dioxane:1.1:1.0:
10.0 are added sequentially in reaction bulb, are heated to reflux, and react 4 hours, be concentrated under reduced pressure to obtain compound shown in formula III, column chromatography point
From purification.
Step 2, compound shown in formula III, diphenyl ether are added sequentially in reaction bulb, 120 DEG C are warming up to, in illumination
Under the conditions of be passed through chlorine, controlling reaction temperature has been led to after chlorine at 160 DEG C, is cooled to 100 DEG C, is sequentially added trbasic zinc phosphate and carbon
Acid sodium solution, is heated to reflux, and reacts 3 hours, is concentrated under reduced pressure to give crude compound shown in formula IV, column chromatography for separation purification.Institute
It is 1.0 to state compound shown in formula III, diphenyl ether, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium hydroxide:10.0:2.2:0.001:
1.4:0.3.
Step 3, it is 1.0 in molar ratio by compound shown in formula IV, hydrazine hydrate, ethanol:1.5:10 are added sequentially to reaction
In bottle, it is heated to reflux, reacts 12 hours, is concentrated under reduced pressure to give compound shown in Formula V, column chromatography for separation purification.
Step 4, it is 1.0 in molar ratio by compound, potassium carbonate, dioxane shown in compound shown in Formula V, Formula IV:
1.1:1.0:10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3-4 hours, are concentrated under reduced pressure to give chemical combination shown in Formula VII
Thing crude product, column chromatography for separation purification;
Step 5, it is compound shown in Formula VII and dextrorotation dibenzoyl tartaric acid (D-DBTA) is molten for 1: 1.0 in molar ratio
In dilute hydrochloric acid solution, stirred 1.5 hours at 75 DEG C, then be gradually cooling to room temperature, filtered out in crystal salt, plus alkali and crystallize
Salt, produces compound shown in Formulas I.
1H NMR[(CD3)2SO, 500MHz], δ (ppm):7.14-8.78 (m, 9H, Ar-H), 4.80 (s, 2H, COCH 2N),
0.829 (t, 3H, NCH2CH2-CH 3), 2.28 (s, 3H, Ph-CH 3), 1.43-4.75 (m, 14H, RCH 2R, 1H, C3 CH)。
The preparation method of compound shown in the Formula IV of embodiment 7
(1) it is 1.0 in molar ratio by compound shown in Formula VIII, triphenylchloromethane, chloroform, triethylamine:1.2:1.2:
10.0 are added sequentially in reaction bulb, are stirred at room temperature, and are concentrated under reduced pressure to give crude compound shown in Formula IX, and column chromatography for separation is carried
It is pure;
(2) by compound shown in Formula IX, to methyl benzyl chloride, cesium carbonate, dioxane are 1.0 in molar ratio:1.2:1.0:
10.0 are added sequentially in reaction bulb, are heated to reflux, and react 3 hours, are concentrated under reduced pressure to give compound shown in Formula X, column chromatography point
From purification;
(3) compound shown in Formula X, 80% aqueous acetic acid are added sequentially in reaction bulb, the compound VII, vinegar
The mol ratio of acid is 1.0:10.0, it is heated to reflux, reacts 1 hour, sodium hydroxide solution is added into reaction bulb, is separated by filtration
To compound shown in Formula X I, column chromatography for separation purification;
(4) compound shown in XI, ether, triethylamine are added sequentially in reaction bulb, then chloracetyl chloride is slowly added dropwise, institute
State compound shown in XI:Ether:Triethylamine:The mol ratio of chloracetyl chloride is 1:5:1.2:1.0, react at room temperature 2 hours, depressurize dense
Contracting obtains compound shown in Formula IV, column chromatography for separation purification.
The preparation method of compound shown in the Formula IV of embodiment 8
(1) it is 1.0 in molar ratio by compound shown in Formula VIII, triphenylchloromethane, chloroform, triethylamine:1.2:1.2:
10.0 are added sequentially in reaction bulb, are stirred at room temperature, and are concentrated under reduced pressure to give crude compound shown in Formula IX, and column chromatography for separation is carried
It is pure;
(2) by compound shown in Formula IX, to methyl benzyl chloride, potassium carbonate, toluene are 1.0 in molar ratio:1.2:1.0:10.0
It is added sequentially in reaction bulb, is heated to reflux, reacts 5 hours, be concentrated under reduced pressure to give compound shown in Formula X, column chromatography for separation is carried
It is pure;
(3) compound shown in Formula X, 80% aqueous acetic acid are added sequentially in reaction bulb, the compound VII, vinegar
The mol ratio of acid is 1.0:10.0, it is heated to reflux, reacts 3 hours, sodium hydroxide solution is added into reaction bulb, is separated by filtration
To compound shown in Formula X I, column chromatography for separation purification;
(4) compound shown in XI, ether, triethylamine are added sequentially in reaction bulb, then chloracetyl chloride is slowly added dropwise, institute
State compound shown in XI:Ether:Triethylamine:The mol ratio of chloracetyl chloride is 1:5:1.2:1.0, react at room temperature 3 hours, depressurize dense
Contracting obtains compound shown in Formula IV, column chromatography for separation purification.
The preparation method of compound shown in the Formula IV of embodiment 9
(1) it is 1.0 in molar ratio by compound shown in Formula VIII, triphenylchloromethane, chloroform, triethylamine:1.2:1.2:
10.0 are added sequentially in reaction bulb, are stirred at room temperature, and are concentrated under reduced pressure to give crude compound shown in Formula IX, and column chromatography for separation is carried
It is pure;
(2) by compound shown in Formula IX, to methyl benzyl chloride, potassium carbonate, toluene are 1.0 in molar ratio:1.2:1.0:10.0
It is added sequentially in reaction bulb, is heated to reflux, reacts 1 hour, be concentrated under reduced pressure to give compound shown in Formula X, column chromatography for separation is carried
It is pure;
(3) compound shown in Formula X, 80% aqueous acetic acid are added sequentially in reaction bulb, the compound VII, vinegar
The mol ratio of acid is 1.0:10.0, it is heated to reflux, reacts 2 hours, sodium hydroxide solution is added into reaction bulb, is separated by filtration
To compound shown in Formula X I, column chromatography for separation purification;
(4) compound shown in XI, ether, triethylamine are added sequentially in reaction bulb, then chloracetyl chloride is slowly added dropwise, institute
State compound shown in XI:Ether:Triethylamine:The mol ratio of chloracetyl chloride is 1:5:1.2:1.0, react at room temperature 3 hours, depressurize dense
Contracting obtains compound shown in Formula IV, column chromatography for separation purification.
Embodiment 10
Experimental group:
1) compound shown in Formulas I is dissolved in DMSO, is configured to 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100 μM, 200
μM solution;
2) compound shown in Formulas I is added in KLK7 activity buffer liquids, is 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 added2, KLK7 work is surveyed at 37 DEG C
Property 15 minutes, using fluorescence microplate reader detect fluorescent value, according to the magnitude estimation KLK7 of fluorescent value activity.
Negative control group:Do not add compound shown in Formulas I in KLK7 activity buffer liquid, other operating conditions with reality
Test group identical.
Suppression of the compound to KLK7 shown in the KLK7 obtained according to above-mentioned experimental group and negative control group active calculating formula I
Rate processed, the formula for calculating inhibiting rate is %inhibition=(1-a/b) × 100%, and result of calculation is as shown in table 1;Wherein, a
For the enzyme activity of testing sample, b is the enzyme activity of negative control.
Table 1 is inhibiting rate of the compound shown in Formulas I to KLK7 activity under various concentrations, and the result according to table 1 is painted
The graph of a relation of the concentration of compound and inhibiting rate shown in standard I, is carried out curve fitting using KaleidaGraph softwares and obtains Formulas I
The concentration of shown compound and the relation curve of inhibiting rate, as shown in Figure 1.
With the increase of compound concentration shown in Formulas I it can be seen from table 1 and Fig. 1 result, the suppression to KLK7 activity
Rate gradually increases, when the concentration of compound shown in Formulas I is 200 μM, and 100% is reached to the inhibiting rate of KLK7 activity.
Therefore, compound shown in Formulas I has excellent inhibition to KLK7, and the compound adds suitable as active component
When auxiliary material and auxiliary agent can be prepared into suppress KLK7 activity pharmaceutical preparation.
Inhibiting rate of the compound shown in the Formulas I of table 1 under various concentrations to KLK7 activity
The preparation method letter for the compound for suppressing kallikrein KLK7 that the present invention is provided it can be seen from foregoing description
It is single easy, it can effectively suppress KLK7 activity, the appropriate auxiliary material of addition and auxiliary agent can be prepared into the medicine for suppressing KLK7 activity
Thing preparation.
Those of ordinary skills in the art should understand that:The discussion of any of the above embodiment is exemplary only, not
It is intended to imply that the scope of the present disclosure (including claim) is limited to these examples;Under the thinking of the present invention, above example
Or can also not be combined between the technical characteristic in be the same as Example, step can be realized with random order, and be existed such as
Many other changes of upper described different aspect of the invention, for simplicity, they are provided not in details.Therefore, it is all
Within the spirit and principles in the present invention, any omission, modification, equivalent substitution, improvement for being made etc. should be included in the present invention's
Within protection domain.
Claims (9)
1. a kind of compound for suppressing kallikrein KLK7, it is characterised in that with structure shown in Formulas I:
2. the preparation method of compound described in a kind of claim 1, it is characterised in that comprise the following steps:
Step 1, compound shown in modus ponens II occurs with halogenopropane under the first solvent, the first catalyst and heated reflux condition
Compound shown in nucleophilic substitution production III;
Step 2, with halide reagent halogenation occurs under solvent and temperature conditionss for compound shown in modus ponens III, shown in formula III
The halogenated products of compound occur hydrolysis and obtain compound shown in formula IV in the basic conditions;
Step 3, with hydrazine hydrate condensation reaction production V institutes occur under ethanol and heated reflux condition for compound shown in modus ponens IV
Show compound;
Step 4, compound shown in compound shown in modus ponens V and Formula IV is in the second solvent, the second catalyst and heated reflux condition
Compound shown in lower generation nucleophilic substitution production VII;
Step 5, compound is mixed with resolving agent and inorganic acid solution shown in modus ponens VII, 1~2.0 is stirred at 60-100 DEG C small
When, room temperature is cooled to, is filtered, adds alkali to produce compound shown in Formulas I into the solid filtered out;
First solvent and the second solvent are separately arbitrarily selected from toluene, N,N-dimethylformamide, tetrahydrofuran, second
Any one or more than one in nitrile, dioxane, chloroform, ether;
First catalyst and the second catalyst are separately arbitrarily selected from inorganic base or organic base, and the inorganic base is carbon
Sour potassium, sodium carbonate, sodium hydroxide, cesium carbonate or potassium hydroxide, the organic base are triethylamine or pyridine;
3. preparation method according to claim 2, it is characterised in that compounds process for production thereof shown in the Formula IV include with
Lower step:
(1) compound shown in modus ponens VIII is carried out with triphenylchloromethane under the 3rd solvent, the 3rd catalyst and room temperature condition
Amido protecting reaction obtains compound shown in Formula IX;
(2) compound shown in modus ponens IX is with methyl benzyl chloride occurs under the 4th solvent, the 4th catalyst and heated reflux condition
Compound shown in nucleophilic substitution production X;
(3) compound shown in modus ponens X is heated to reflux adding alkaline solution reaction after 1~3 hour in 80% aqueous acetic acid, obtains
To compound shown in Formula X I;
(4) compound shown in modus ponens XI is dissolved in the 5th solvent, the 5th catalyst, and is slowly added dropwise under chloracetyl chloride, room temperature condition
Generation nitrogen acylation reaction obtains compound shown in Formula IV, 1~3 hour reaction time;
3rd solvent, the 4th solvent and the 5th solvent are separately arbitrarily selected from toluene, N,N-dimethylformamide, four
Any one or more than one in hydrogen furans, acetonitrile, dioxane, chloroform, ether;
3rd catalyst, the 4th catalyst and the 5th catalyst are separately arbitrarily selected from inorganic base or organic base, institute
Inorganic base is stated for potassium carbonate, sodium carbonate, sodium hydroxide, cesium carbonate or potassium hydroxide, the organic base is triethylamine or pyridine;
4. preparation method according to claim 2, it is characterised in that compound and diphenyl ether are heated to shown in modus ponens III
120~140 DEG C, chlorine is passed through under light illumination, is continued to be heated to 160~170 DEG C of generation halogenations, has been led to after chlorine and be cooled to
100~110 DEG C, add trbasic zinc phosphate and aqueous sodium carbonate issues raw hydrolysis in heated reflux condition and obtains chemical combination shown in formula IV
Thing;Compound shown in the formula III, chlorine, trbasic zinc phosphate, water, the mol ratio of sodium carbonate are 1.0:2.1~2.5:0.001~
0.003:1.4~1.8:0.3~0.8.
5. preparation method according to claim 2, it is characterised in that compound, halogenopropane, first shown in the Formula II
The mol ratio of catalyst is 1.0:1.1~1.5:1.0~1.2;
Compound shown in the formula IV, the mol ratio of hydrazine hydrate are 1.0:1.5~2.0;
Compound shown in the Formula V, compound shown in Formula IV, the mol ratio of the second catalyst are 1.0:1.0~1.4:1.0~
2.0;
Compound shown in the Formula VII and the mol ratio of resolving agent are 1: 1.0~1.2.
6. preparation method according to claim 3, it is characterised in that compound shown in the Formula VIII, triphenyl chloromethane
Alkane, the mol ratio of the 3rd catalyst are 1.0:1.1~1.5:1.2~2.3;
Compound shown in the Formula IX, to methyl benzyl chloride, the mol ratio of the 4th catalyst is 1.0:1.1~1.5:1.0~2.0;
Compound shown in the Formula X, the mol ratio of acetic acid are 1:8~11.0;
Compound shown in the Formula X I, chloracetyl chloride, the mol ratio of the 5th catalyst are 1:1.0~1.3:1.2~2.3.
7. preparation method according to claim 2, it is characterised in that the resolving agent is dextrorotation dibenzoyl tartaric acid,
Reaction temperature is 60~100 DEG C, and the reaction time is 1~3 hour;The inorganic acid is hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid.
8. preparation method according to claim 3, it is characterised in that it is 60 that the nucleophilic substitution, which is heated to reflux temperature,
~140 DEG C, 1~4 hour reaction time;
The temperature that is heated to reflux of the condensation reaction is 78~100 DEG C, 6~12 hours reaction time;
The temperature of the amido protecting reaction is room temperature, 1~5 hour reaction time;
The temperature of the nitrogen acylation reaction is room temperature, 1~5 hour reaction time.
9. the purposes of the compound for suppressing kallikrein KLK7 described in a kind of claim 1, it is characterised in that shown in Formulas I
Application of the compound in the medicine for suppressing kallikrein KLK7 activity is prepared.
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