CN110256417A - A kind of kallikrein KLK7 mortifier, preparation method and purposes - Google Patents
A kind of kallikrein KLK7 mortifier, preparation method and purposes Download PDFInfo
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- CN110256417A CN110256417A CN201910604691.9A CN201910604691A CN110256417A CN 110256417 A CN110256417 A CN 110256417A CN 201910604691 A CN201910604691 A CN 201910604691A CN 110256417 A CN110256417 A CN 110256417A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to pharmaceutical technology field, it is as follows to be specifically related to a kind of kallikrein KLK7 mortifier, preparation method and purposes, structural formula:It include the structures such as anthraquinone, piperazine, phenyl in the compounds of this invention, for existing organic micromolecule compound class inhibitor, with certain difference and characteristic, the compounds of this invention has reached 28.955 μM to the IC50 value of KLK7, with good prospect, lay the foundation for further exploitation treatment atopic dermatitis drug.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is specifically related to a kind of kallikrein KLK7 mortifier, preparation method
And purposes.
Background technique
Kallikrein (Kallikrein, KLK) is a member of serine stretch protein enzyme family, a variety of KLK, especially KLK7
The great expression in human epidermal, to maintain the normal physiological activity of skin to play an important role.Studies have shown that idiocrasy skin
Inflammation (atopic dermatitis, AD) is as a kind of and hereditary inflammatory cutaneous class disease for having substantial connection, with KLK7 in epidermis
Active increase have close connection.Atopic dermatitis there is no the method for radical cure at present, and KLK7 is a kind of potential treatment
The drug targets of atopic dermatitis, therefore the inhibitor for researching and developing KLK7 will be helpful to facing for inflammatory dermatosis such as atopic dermatitis
Bed treatment provides new thinking.
Inhibit the activity of KLK7 to will be helpful to the speed of the control desquamation of skin with exogenous molecules, reduce the generation of inflammation,
To reach the dermopathic purposes such as treatment atopic dermatitis, but so far there is not yet related KLK7 inhibitor class drug is for clinic
The report for treating atopic dermatitis.Four classes can be substantially divided into for the research of KLK inhibitor in the world at present:
(1) protein-based macromolecular inhibitor.This kind of inhibitor is with the day of serpin SERPIN and KLK
Right inhibitor LETKI etc. is representative, and this kind of inhibitor usually has good inhibitory effect in vitro experiment, and (Kd is up to pM number
Magnitude) and idiocrasy, but since self-molecules present amount is excessive, bioavilability is very low.The protein attribute of their own simultaneously
Also cause its stability poor；
(2) peptide inhibitor.With bright too plain (leupeptin), sunflower trypsin inhibitor (sunflower
Trypsin inhibitor, SFTI), antipain (antipain) etc. be representative.This kind of inhibitor and protein-based inhibitor class
Seemingly, bioavilability is lower；
(3) universal inhibitor.This kind of inhibitor inhibits effect using small molecule compounds such as DFP, PSMF, CMK as representative
Fruit and idiocrasy are usually all not ideal enough, therefore this kind of inhibitor is frequently as the tool of research Serine protease molecule structure
Object is closed, for parsing the crystal structure of serine protease.
(4) idiocrasy organic micromolecule compound class inhibitor.Usually this kind of inhibitor relative molecular mass it is small (<
500000), there is good bioavilability and druggability, its own chemical property is also relatively stable.Become medicine with potential
The ability of object treatment related disease.Idiocrasy inhibitor in organic micromolecule compound class inhibitor, about targeting KLK7
Research and development only fragmentary report.As Novartis describes it in the patent (WO 2009/000878A1) disclosed in 2009
It was found that KLK7 micromolecular inhibitor.Novartis handles mouse skin (S-Sqame zero using different chemical reagent in the patent
RR, TPA, DNFB) simulation atopic dermatitis so that it is casted off a skin and is inflamed, to verify KLK7 inhibitor for mouse skin
Repair, anti-inflammatory and anti-allergic effects, facts proved that being effective.Then scientist Puzer study group, Brazil is from natural
Isocoumarin class inhibitor obtained in compound and we study in front in developed KLK7 reversible inhibitor,
Triazole covalent reversible inhibitor and the suicide substrate inhibitor of Coumarins.As KLK7 activity is abnormal in idiocrasy
Dermatitis occur in development process important function and its mechanism gradually illustrated, people have also turned one's attention to targeting in succession
The exploitation of KLK7 inhibitor is for treating atopic dermatitis.
CN106518868B- kallikrein 7 micromolecular inhibitor and preparation method thereof, purposes disclose a kind of organic
Micromolecular inhibitor, structural formula are as follows:
With certain inhibitory effect.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of kallikrein KLK7 mortifier, preparation method and purposes,
It can effectively inhibit KLK7, and special (answering) property is strong, can effectively treat atopic dermatitis.
The contents of the present invention include a kind of kallikrein KLK7 mortifier, and structural formula is as follows:
The present invention provides a kind of preparation method of kallikrein KLK7 mortifier, includes the following steps:
The preparation of compound 1 includes the following steps:
1- amino -2,4- dibromo-anthraquinone, copper carbonate, potassium acetate, the adjacent stupid formic acid of amino are mixed, reacted in 130-150 DEG C,
Then it is cooled to 75-85 DEG C, methanol is added；Filtering, is cleaned with methanol, dry；Thick solid is recrystallized from acetic acid, is changed
Close object 1.
The preparation of compound 2 includes the following steps:
Acetic acid weight is added in compound 1, and amyl nitrite is added, and stirs, and sodium azide is added to filtered by filtering
It in solution, dilutes, precipitates after reaction, filter, it is dry, in reflux in toluene, obtain compound 2.
The preparation of compound 3 includes the following steps:
Piperazine anhydrous, potassium iodide, toluene and ethyl alcohol are mixed, stirring, controls temperature at 18-12 DEG C, dropwise additionization thereto
Object 2 and ethyl alcohol are closed, drop finishes, and is warming up to 50 DEG C of heat preservations, and TLC tracking is reacted to terminating；Stirring cooling, filters, is added into filtrate
Ice water removes unreacted piperazine, is extracted with dichloroethanes, obtains compound 3.
The preparation of compound 4 includes the following steps:
Compound 3 and piperonal are mixed, adds anhydrous methanol stirring and dissolving, after being heated to reflux, be cooled to room temperature, obtains Huang
Color Schiff solution；At room temperature, reducing agent sodium borohydride is added portionwise；In enriching hydrochloric acid and extra reducing agent, after reaction
Generate white solid, filtering；Solution is extracted with chloroform, takes chloroform layer；Anhydrous sodium sulfate is added into chloroform layer to dry, filter,
Vacuum distillation, obtains compound 4.
The present invention also provides a kind of kallikrein KLK7 mortifier be used to prepare kallikrein KLK7 inhibitor or
Purposes in terms of person's atopic dermatitis drug.
The invention has the advantages that including the structures such as anthraquinone, piperazine, phenyl in the compounds of this invention, relative to existing
For some organic micromolecule compound class inhibitor, there is certain difference and characteristic, the compounds of this invention is to KLK7's
IC50 value has reached 28.955 μM, has good prospect, lays the foundation for further exploitation treatment atopic dermatitis drug.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the compound of the present invention.
Fig. 2 is suppression curve of the compounds of this invention to KLK7.
Specific embodiment
Embodiment 1
1,1- amino -2,4- dibromo-anthraquinone (0.13mol, 50g), copper carbonate (0.03mol, 4g), potassium acetate (0.46mol,
45g) and the adjacent stupid formic acid of amino (0.14mol, 19g) is reduced to 12H at 140 DEG C.Reaction is cooled to 80 DEG C, and methanol is added.
The solid of blue is filtered, and is cleaned, is air-dried with methanol.Thick solid is recrystallized from acetic acid, obtains blue solid
(46g, 81%).
2,1 (C of 0.1mol substance21H9O4N2Br it) is added in 500 milliliters of acetic acid, and 0.12 mole of amyl nitrite is added
It is stirred at room temperature, filters, the NaN of 0.12mol3It is added in filtered solution, mixture reacts 30 minutes, then with 1
Water dilution is risen, precipitating obtains substance 2 by filtering, drying and in the reflux in toluene 1.5-2h of 100-120mL again.
3, Piperazine anhydrous (36.7g, 0.43mol) is added into 250mL four-hole boiling flask, KI (38.4g, 0.23mol), toluene
(60g, 0.65mol) and ethyl alcohol (30g, 0.65mol) stirs and is cooled to 10 DEG C under ice bath, substance 2 is slowly added dropwise into flask
(C21H11O4N2Br) (43.5g, 0.10mol) and ethyl alcohol (30g, 0.65mol), 30min drop finish, and are warming up to 50 DEG C of heat preservations, TLC
(solvent petroleum ether: ethyl acetate=10: 1) tracking reaction is to terminating.Stirring cooling, filters, and 100mL ice is added into filtrate
Water removes unreacted piperazine, is extracted with the dichloroethanes of 40mL × 2.
4, synthetic method: add 3 (C of substance in the round-bottomed flask of 500ml25H20O4N4) 4.40mg (10mmol) and piperonal
(C8H6O3) 0.15mg (10mmol), add 150ml anhydrous methanol stirring and dissolving, after being heated to reflux 3h, is cooled to room temperature, obtains Huang
Color Schiff solution.At room temperature, reducing agent sodium borohydride 1.52g (40mmol), yellow Schiff are added portionwise in flask
Aqueous slkali slowly becomes colorless；With extra reducing agent in enriching HCl, a large amount of white solids are generated after reaction, are filtered；Solution is used
100ml chloroform extracts 3 times, takes chloroform layer；Anhydrous Na is added into chloroform layer2SO4It is dry, it is filtered after sufficiently dry 2h；Decompression
Distillation, obtains 4 (C of substance33H27O6N4))。
1H NMR (DMSO-d6,500MHz) δ 12.30 (s, 1H), 10.98 (s, 1H), 8.45 (d, J=8.0Hz, 1H),
8.18 (d, J=7.5Hz, 1H), 8.02 (d, J=7.5Hz, 1H), 7.86 (t, J=7.5Hz, 1H), 7.80 (d, J=7.5Hz,
1H), 7.74 (t, J=7.0,1H), 7.65 (t, J=7.5,1H), 7.34 (t, J=7.5,1H), 7.22 (s, 1H), 7.03-
7.01 (m, 2H), 6.56 (s, 1H), 6.08 (s, 2H), 4.61 (s, 2H), 4.28 (s, 2H), 3.67 (s, 6H) are as shown in Figure 1.
Experimental example 1
Multiple concentration gradients are arranged in the compounds of this invention, 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100 μM, 200 μM divide
It is not acted at 37 DEG C 15 minutes with KLK7, the fluorogenic substrate of KLK7 is then added, magnesium activity is surveyed after 15 minutes, is obtained such as table 1
With data shown in Fig. 2.
Inhibition concentration table of 1 the compounds of this invention of table to KLK7
It is seen from the above data that the compound of the present invention has the effect of inhibiting KLK7 well, IC50 value is lower,
It lays the foundation for exploitation treatment atopic dermatitis drug.
Claims (7)
1. a kind of kallikrein KLK7 mortifier, characterized in that structural formula is as follows:
2. a kind of preparation method of kallikrein KLK7 mortifier as described in claim 1, characterized in that including walking as follows
It is rapid:
3. the preparation method of kallikrein KLK7 mortifier as claimed in claim 2, characterized in that the preparation of compound 1
Include the following steps:
1- amino -2,4- dibromo-anthraquinone, copper carbonate, potassium acetate, the adjacent stupid formic acid of amino are mixed, reacted in 130-150 DEG C, then
It is cooled to 75-85 DEG C, methanol is added；Filtering, is cleaned with methanol, dry；Thick solid is recrystallized from acetic acid, obtains compound
1。
4. the preparation method of kallikrein KLK7 mortifier as claimed in claim 2, characterized in that the preparation of compound 2
Include the following steps:
Acetic acid weight is added in compound 1, and amyl nitrite is added, and stirs, and sodium azide is added to filtered solution by filtering
In, it dilutes, precipitates after reaction, filter, it is dry, in reflux in toluene, obtain compound 2.
5. the preparation method of kallikrein KLK7 mortifier as claimed in claim 2, characterized in that the preparation of compound 3
Include the following steps:
Piperazine anhydrous, potassium iodide, toluene and ethyl alcohol are mixed, stirring, controls temperature at 18-12 DEG C, compound 2 is added dropwise thereto
And ethyl alcohol, drop finish, and are warming up to 50 DEG C of heat preservations, TLC tracking is reacted to terminating；Stirring cooling, filters, and ice water is added into filtrate and goes
It except unreacted piperazine, is extracted with dichloroethanes, obtains compound 3.
6. the preparation method of kallikrein KLK7 mortifier as claimed in claim 2, characterized in that the preparation of compound 4
Include the following steps:
Compound 3 and piperonal are mixed, adds anhydrous methanol stirring and dissolving, after being heated to reflux, be cooled to room temperature, obtains yellow
Schiff solution；At room temperature, reducing agent sodium borohydride is added portionwise；With extra reducing agent in enriching hydrochloric acid, produced after reaction
Raw white solid, filtering；Solution is extracted with chloroform, takes chloroform layer；Anhydrous sodium sulfate is added into chloroform layer to dry, filter, subtracts
Pressure distillation, obtains compound 4.
7. a kind of kallikrein KLK7 mortifier as described in claim 1 is being used to prepare kallikrein KLK7 inhibitor
Or the purposes in terms of atopic dermatitis drug.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101687913A (en) * | 2007-06-28 | 2010-03-31 | 诺瓦提斯公司 | kallikrein 7 modulators |
| US20130338144A1 (en) * | 2011-03-03 | 2013-12-19 | Indiana University Research And Technology Corporation | uPAR-uPA INTERACTION INHIBITORS AND METHODS FOR TREATING CANCER |
| WO2017023994A1 (en) * | 2015-08-06 | 2017-02-09 | Yale University | Small molecule based antibody-recruiting compounds for cancer treatment |
| WO2017027465A1 (en) * | 2015-08-07 | 2017-02-16 | Purdue Pharma L.P. | Process of preparing tyrosine kinase inhibitor |
| CN106518880A (en) * | 2015-11-04 | 2017-03-22 | 衡阳师范学院 | Kallikrein 7 small-molecule inhibitor and preparation method and purpose thereof |
| US20170348266A1 (en) * | 2014-11-13 | 2017-12-07 | Buck Institute For Research On Aging | Inhibition of proline catabolism for the treatment of cancer and other therapeutic applications |
-
2019
- 2019-07-05 CN CN201910604691.9A patent/CN110256417A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101687913A (en) * | 2007-06-28 | 2010-03-31 | 诺瓦提斯公司 | kallikrein 7 modulators |
| US20130338144A1 (en) * | 2011-03-03 | 2013-12-19 | Indiana University Research And Technology Corporation | uPAR-uPA INTERACTION INHIBITORS AND METHODS FOR TREATING CANCER |
| US20170348266A1 (en) * | 2014-11-13 | 2017-12-07 | Buck Institute For Research On Aging | Inhibition of proline catabolism for the treatment of cancer and other therapeutic applications |
| WO2017023994A1 (en) * | 2015-08-06 | 2017-02-09 | Yale University | Small molecule based antibody-recruiting compounds for cancer treatment |
| WO2017027465A1 (en) * | 2015-08-07 | 2017-02-16 | Purdue Pharma L.P. | Process of preparing tyrosine kinase inhibitor |
| CN106518880A (en) * | 2015-11-04 | 2017-03-22 | 衡阳师范学院 | Kallikrein 7 small-molecule inhibitor and preparation method and purpose thereof |
| CN106518868A (en) * | 2015-11-04 | 2017-03-22 | 衡阳师范学院 | Kallikrein 7 small molecular inhibitor as well as preparation method and application thereof |
Non-Patent Citations (6)
| Title |
|---|
| FANG,等: "Design, synthesis, biochemical studies, cellular characterization, and structure-based computational studies of small molecules targeting the urokinase receptor", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| ROMEIRO,等: "Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| STEPANOV,等: "Chameleonic Reactivity of Vicinal Diazonium Salt of Acetylenyl-9,10-anthraquinones: Synthetic Application toward Two Heterocyclic Targets", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| 李林: "新型KLK7抑制剂的筛选及其在胰腺癌PANC-1细胞中的作用研究", 《中国优秀博硕士学位论文全文数据库(硕士)-医药卫生科技辑》 * |
| 王芳宇等: "激肽释放酶KLK7小分子抑制剂的筛选及活性初步研究", 《衡阳师范学院学报》 * |
| 谭潇等: "组织激肽释放酶KLK7是治疗特应性皮炎的潜在靶点", 《生命的化学》 * |
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