CN104888189B - The new opplication of the phenyl valyl isoleucine analogues of 3 amino, 2 hydroxyl 4 - Google Patents
The new opplication of the phenyl valyl isoleucine analogues of 3 amino, 2 hydroxyl 4 Download PDFInfo
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- CN104888189B CN104888189B CN201510324171.4A CN201510324171A CN104888189B CN 104888189 B CN104888189 B CN 104888189B CN 201510324171 A CN201510324171 A CN 201510324171A CN 104888189 B CN104888189 B CN 104888189B
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Abstract
The invention provides a kind of phenyl valyl isoleucine analogues of 3 amino, 2 hydroxyl 4 for meeting logical formula (I) as active component prepare be used for prevent and treat inflammation disease and the pharmaceutical preparation of the infectious disease related to inflammation in application；Wherein, R1 be isopropyl or methyl-propyl, R2 be isopropyl, methyl-propyl or 2 methyl-propyls, R3 be carboxyl orWherein, R4It is selected from：H, the C1 C4 alkyl of straight or branched, the C1 C4 hydroxyalkyls of straight or branched, the C1 C4 mercaptoalkyls of straight or branched, the C1 C4 alkyl carboxyls of straight or branched and C1 C4 alkylamidoalkyls.Present invention also offers the pharmaceutical preparation for preventing and treating inflammation disease, active component and pharmaceutically acceptable carrier or excipient containing therapeutically effective amount, the active component is the phenyl valyl isoleucine analogues of 3 amino, 2 hydroxyl 4 for meeting logical formula (I), its optical isomer or its pharmaceutically acceptable salt.
Description
Technical field
It is similar more particularly to 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine the invention belongs to field of medicaments
Thing as active component prepare be used for prevent and treat inflammation disease and the pharmaceutical preparation of the infectious disease related to inflammation in
New opplication.
Background technology
Inflammation is a kind of very common and important basic pathology process, any to cause the factor of tissue damage,
Such as infection, non-infectious tissue damage (such as wound, operation) can cause the generation of inflammation, and these inflammation have many phases
As feature (Barton GM.A calculated response:control of inflammation by the
innate immune system.J.Clin.Invest.,2008,118:413-420).Using caused by bacterium infection inflammation as
Example, the endotoxin (bacteria lipopolysaccharide lipopolysaccharides, abbreviation LPS) of bacterial secretory be bacterium cause a disease it is main because
Element, can cause a series of inflammatory reactions of body.The inflammatory signals of LPS inductions are relevant with Toll-like receptor (TLRs) family etc..
When body is by bacterium infection, LPS acts on TLRs acceptors on cell membrane, is transmitted by intracellular signal, cascades gene expression
Change, LPS can stimulate internal cytokine profiles to synthesize and release inflammatory factor (such as NO, TNF-α, IL-6, IL-1 β
Deng), cause systemic inflammatory reaction, cause toxic shock, SIRS (SIRS) and multiple organ work(
The inflammation diseases such as energy distress syndrome (MODS) (Wang Xiaodong, endotoxin neutralizing protein and its effect in pyemia preventing and treating
[J], foreign medical science physiology, pathology science and clinical fascicle, 2001,21 (2)：144-146；Beautiful grain husk, Wang Xingpeng, block endotoxin
Signal transduction pathway treats pyemia or the progress [J] of septic shock, Chinese Journal of Emergency Medicine, 2003,12 (2)：
135-137；Wang Ying, Guo Chen, the treatment [J] of infectious shock, Chinese Applied Clinical Pediatrics magazine, 2007,22 (6)：403-
405；Zhang Xuemei, Xiong Huanzhang, the inflammatory reaction signal transduction pathway progress of LPS inductions, Chinese Veterinary Journal, 2010,46
(7)：45-47).Therefore, LPS can be considered the major virulent factor of bacterium, be played in the pathogenesis of bacterium infection very heavy
The effect wanted.Equally, in tissue damage, body can secrete large amount of cell factor to repair damage, but when overreact,
The inflammation diseases such as SIRS, MODS can be triggered.
Ubenimex (Ubenimex, also known as Bestatin) is common antitumour auxiliary drug, improving immunocompetence,
For (Umezawa, H., Aoyagi, T., Suda, H., Hamada, M.＆ such as anticancer chemotherapy, the auxiliary treatments of radiotherapy
Takeuchi,T.(1976).Bestatin,an inhibitor of aminopeptidase B,produced by
actinomycetes,(29).Pp.97-99；Muskardin,D.T.,Voelkel.N.F.& Fitzpatrick,F.A.
(1994).Modulation of pulmonary leukotriene formation and perfusion pressure
by bestatin,an inhibitor of leukotriene A4 hydrolase.(48).pp.131-137；
Hirayama,Y；Sakamaki,S；Takayanagi,N；Tsuji,Y；Sagawa,T；Chiba,H；Matsunaga,T；
Niitsu,Y.(2003).“Chemotherapy with ubenimex corresponding to patient age and
organ disorder for 18 cases of acute myelogeneous leukemia in elderly
patients—effects,complications and long-term survival”.Gan to
kagakuryoho.Cancer & chemotherapy 30(8):1113-8).The chemical structural formula of ubenimex is：
3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine is similar to ubenimex (Bestatin) structure
New derivatives, applicant of the present invention's first public change in the Chinese invention patent of Application No. 201110076554.6
Compound, its chemical structural formula is：
Compound 3- amino -2- hydroxyls are further disclosed in the Chinese invention patent of Application No. 201110076555.0
Base -4- phenyl-valyl-isoleucine is as the application of amastatin, and it is active better than ubenimex (Bestatin),
It can be used as oncotherapy or adjuvant therapy medicaments, with more preferable vivo immunization humidification, if strengthening T cell and lethal
NK cytoactives and function etc., but they to the effect in such as bacterial acute inflammation, there is not been reported.
The present inventor further grinds on the basis of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine
A series of its analogs have been studied carefully to the effect in such as bacterial acute inflammation.
The content of the invention
The present inventor further grinds on the basis of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine
Studied carefully its serial analogs to the effect in such as bacterial acute inflammation, research is found, its serial analogs for
Acute inflammation caused by LPS has obvious inhibitory action.Therefore, it is an object of the invention to provide 3- amino -2- hydroxyls -4-
The serial analogs of phenyl-valyl-isoleucine as active component prepare be used for prevent and treat inflammation disease and with
New opplication in the pharmaceutical preparation of the related infectious disease of inflammation.
To achieve the above object, the present invention uses following technical scheme：
The first aspect of the invention is to provide a kind of 3- amino -2- hydroxy-4-phenyl-valyls-for meeting logical formula (I)
Isoleucine analogues are being prepared for preventing and treating inflammation disease and the infectious disease related to inflammation as active component
Pharmaceutical preparation in application；
Wherein, R1 be isopropyl or methyl-propyl, R2 be isopropyl, methyl-propyl or 2- methyl-propyls, R3 be carboxyl or
Wherein, R4It is selected from：H, the C1-C4 alkyl of straight or branched, C1-C4 hydroxyalkyls, straight chain or the branch of straight or branched
The C1-C4 mercaptoalkyls of chain, the C1-C4 alkyl carboxyls of straight or branched and C1-C4 alkylamidoalkyls.
Further, the inflammation disease and the infectious disease related to inflammation include bacterium infection, uncomplicated wing
Guang inflammation, bronchitis, wound, Postoperative inflammatory reaction, unexpected injury, miocardial infarction, tuberculosis or sarcoidosis, pyemia, turn
Move property tumour, Active Rheumatoid Arthritis, the arthritis vertebralis of seronegativity, immune vasculitis, rheumatic polymyopathy,
Regional enteritis, inflammation of dvt formation etc..
The present invention have rated the antiphlogistic effects of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs,
Inventor's selection mouse monokaryon-macrophage system Raw264.7 is tested, and the inflammatory factor NO of detection LPS inductions is expressed and released
Put, found after detection, the inflammatory factor NO of LPS inductions burst size is greatly decreased.
The second aspect of the invention is to provide a kind of for preventing and treating inflammation disease and the infection related to inflammation
The pharmaceutical preparation of disease, active component and pharmaceutically acceptable carrier or excipient containing therapeutically effective amount, the activity
Composition is described 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine analog, its optical isomerism for meeting logical formula (I)
Body or its pharmaceutically acceptable salt.
Preferably, the formulation of the pharmaceutical preparation includes tablet, capsule, oral liquid, granule or injection (as freezed
Powder-injection).
Pharmaceutically acceptable salt pharmacologically pharmaceutically can all receive with it.Pharmacologically with its medicine
Acceptable salt can be alkali metal salt or alkali salt, particular certain cancers, sylvite, magnesium salts or calcium salt on.
The pharmaceutical preparation is related to enteral (such as oral, sublingual administration or rectally), parenteral or local
(such as transdermal medicine preparation) formulation.The organic or inorganic thing not reacted with active component can be used as carrier, Ru Shui, oil, benzene first
Alcohol, polyethylene glycol, glycerol triacetate or other fatty glycerides, gelatin, lecithin, cyclodextrin, lactobiose or starch etc.
Carbohydrate, magnesium stearate, talcum or cellulose.Oral medication preferred tablet, dragee, capsule, powder, syrup, concentrating agents or drop
Agent, the preferred suppository of rectally, parenteral preferred aqueous solutions or oil solution, or it is freeze-dried.Supensoid agent, breast can also be used
Agent or implant, local application can use patch or cream.The parenteral pharmaceutical preparation used includes the nothing of reactive compound
Bacterium is aqueous or without water injection, herein the solution isotonic preferably with cipient blood.
These pharmaceutical preparations can contain stabilizer, the additive of control pharmaceutically active compound release, antioxidant, buffering
Agent, bacteriostatic agent and the adjuvant for preparing isotonic solution.Aqueous and anhydrous sterile suspensions can containing suspension additive and
Thickener.Pharmaceutical preparation can be divided in single dose or multi-dose container such as sealant bottle, can also be used as freeze-dried system
Product are preserved, if desired, can be prepared when using with sterile liquid such as water or salting liquid.Aseptic powder can also be used in the same way
Agent, granule or tablet.
The pharmaceutical preparation can be used for prevention and treatment inflammation and inflammation related disease in humans and animals.
Brief description of the drawings
Figure 1A is what 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs were induced LPS
In Raw264.7 cells, the immunoblot results chart twice of iNOS protein expressions；
In the Raw264.7 cells that Figure 1B induces for LPS, the quantitative analysis chart of iNOS protein expressions；
Fig. 2 is the testing result chart that Griess methods detect NO burst sizes in culture supernatant.
Embodiment
The present invention is described in more detail below by specific embodiment, for a better understanding of the present invention,
But following embodiments are not intended to limit the scope of the invention.
First, examples of compounds
Present embodiments provide the serial analogs of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, meet as
Logical formula (I) down：
Wherein, R1 be isopropyl or methyl-propyl, R2 be isopropyl, methyl-propyl or 2- methyl-propyls, R3 be carboxyl or
Wherein, R4It is selected from：H, the C1-C4 alkyl of straight or branched, C1-C4 hydroxyalkyls, straight chain or the branch of straight or branched
The C1-C4 mercaptoalkyls of chain, the C1-C4 alkyl carboxyls of straight or branched and C1-C4 alkylamidoalkyls.
Meeting the examples of compounds of above-mentioned logical formula (I) includes：
2nd, Application Example
The concrete operations of detection method used in following Application Example are as follows：
1st, the acute inflammation model of LPS inductions is built：
By C57/BL mice groups, every group at least 5, weigh, respectively with physiological saline (negative control group) and 5mg/kg
LPS (inflammation group) carry out Intratracheal administration, given before lps injection after 12 hours, 10 minutes and after 12 hours compound 1~
6 intraperitoneal injection (except negative control group), 0,4, put to death after 24 hours, heart extracting blood rinses lung repeatedly with 1ml PBS,
Lung tissue is taken after collecting washing liquid, cell factor and inflammatory factor in histotomy, fluorescence quantitative PCR detection lung tissue is prepared
Expression.
2nd, quantitative fluorescent PCR (QPCR)：
Trizol cell lysis, extracting RNA, reverse transcription PCR obtains cDNA, and quantitative fluorescent PCR, inspection are carried out as template
Test the DNA transcriptional levels change of the inflammation-associated cytokine induced before and after medicine effect and inflammatory molecule etc..
3rd, Western blotting (Western Blot)：
Crack and collect cell, denaturation treatment, SDS electrophoresis 80V 2 hours, transferring film 80V 1 hour, 5% milk closing half
Hour, 4 DEG C are incubated primary antibody and stay overnight, and TBST buffer solutions (Tris-Buffered Saline and Tween 20) wash film 3 times, often
Temperature is incubated secondary antibody 1 hour, and TBST washes film 3 times, and an oxidation of induction before and after medicine effect is observed on Odyssey Far Infrared Observation instrument
Nitrogen synzyme iNOS protein expression levels change etc..
4th, Griess methods detection NO burst sizes：
NO easily forms NO in aqueous2 -, in acid condition, NO2 -Occur diazo reaction with diazol sulfanilamide (SN), it is raw
Into diazonium compound, further occur coupling reaction, its production concentration and NO with naphthylethenyl diamines2 -Concentration has linear pass
, there is maximum absorption band in system at 540-560nm.The burst size of NO in cell conditioned medium is can detect using this principle.
The antiphlogistic effects of Application Example, 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs：
The present embodiment by taking Raw264.7 mouse macrophages as an example, the inflammatories of 1~6 couple of LPS of comparative compound inductions because
The influence of sub- NO expression, including LPS stimulate 24 hours after in cell iNOS albumen expression (Figure 1A and Figure 1B) and cell culture
NO burst size (Fig. 2) in supernatant.
INOS protein expression level detection in the Raw264.7 cells induced as shown in FIG. 1A and 1B for LPS.Will
Raw264.7 cells are with 3.5 × 105The density in/hole is inoculated in 12 orifice plates, is trained with the 1640 culture medium containing 10% hyclone
Support overnight, compound 1~6 is incubated 30 minutes in advance with 0.2mg/ml concentration, control group is isometric nutrient solution (medium),
Induction 24 hours is stimulated with 0.1 μ g/ml LPS.Supernatant is collected, cell lysis carries out immunoblotting assay.Wherein, Tu1AWei
The immunoblot results twice of iNOS protein expressions, β-actin are control；Figure 1B is the quantitative analysis of iNOS protein expressions,
INOS and β-actin Reinhoit Zahl is calculated with Image J softwares, takes the result of three independent experiments to calculate average value standard
Error, the result of comparative compound 1~6 and LPS groups, carry out significant difference analysis, wherein * * P<0.01.
It is illustrated in figure 2 NO burst sizes in Griess methods detection culture supernatant.Cell culture and stimulate induction such as Figure 1A and
Described in Figure 1B, culture supernatant, kit detection wherein NO burst size are taken.The result of three independent experiments is taken to calculate average value mark
Quasi- error, comparative compound 1~6 and the result of LPS groups, carry out significant difference analysis, wherein * P<0.05, * * P<0.01.
Found out by Figure 1A, Figure 1B, Fig. 2 testing result, 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine series
The inflammatory factor of protein expression level and LPS inductions in the Raw264.7 cells that analog (compound 1~6) is induced LPS
NO burst size has 50% or so reduction.
Therefore, the invention provides 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs and its should
With that is, it is being prepared for preventing and treating inflammation disease and the medicine system of the infectious disease related to inflammation as active component
Application in agent.Thus, present invention also offers the pharmaceutical preparation for preventing and treating inflammation disease, therapeutically effective amount is contained
Active component and pharmaceutically acceptable carrier or excipient, the active component be 3- amino -2- hydroxy-4-phenyls-figured silk fabrics
Aminoacyl-isoleucine serial analogs, its optical isomer or its pharmaceutically acceptable salt.It is further preferred that it is preferred that
Ground, the formulation of the pharmaceutical preparation includes tablet, capsule, oral liquid, granule or injection (such as freeze drying powder injection).
The specific embodiment of the present invention is described in detail above, but it is intended only as example, and the present invention is not limited
It is formed on particular embodiments described above.To those skilled in the art, it is any to the equivalent modifications that carry out of the present invention and
Substitute also all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and
Modification, all should be contained within the scope of the invention.
Claims (1)
1. a kind of compound for meeting logical formula (I) answering in the pharmaceutical preparation for being used for suppressing NO releases is prepared as active component
With：
Wherein, R1 is isopropyl or methyl-propyl, and R2 is isopropyl, methyl-propyl or 2- methyl-propyls, and R3 is
Wherein, R4It is selected from：Isopropyl, methyl-propyl and 2- methyl-propyls.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198139A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Pharmaceutical composition with antineoplastic effect, and application method thereof |
| CN102198150A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Antitumor drug with double active components and application thereof |
| CN103588713A (en) * | 2013-06-07 | 2014-02-19 | 潍坊博创国际生物医药研究院 | Multi-target ubenimex prodrug derivative, as well as preparation method and application thereof |
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| CN102631664B (en) * | 2011-01-28 | 2014-10-01 | 上海来益生物药物研究开发中心有限责任公司 | Application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198139A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Pharmaceutical composition with antineoplastic effect, and application method thereof |
| CN102198150A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Antitumor drug with double active components and application thereof |
| CN103588713A (en) * | 2013-06-07 | 2014-02-19 | 潍坊博创国际生物医药研究院 | Multi-target ubenimex prodrug derivative, as well as preparation method and application thereof |
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