Wound repair promotor

文档序号：1776162 发布日期：2019-12-03 浏览：24次中文

阅读说明：本技术 创伤修复促进剂 (Wound repair promotor ) 是由吉冈龙藏田中阳子矢口学田中贵志于 2018-04-13 设计创作，主要内容包括：本发明提供一种具有组织创伤的修复促进效果的制剂。本发明的创伤修复促进剂包含选自下述式(1)所示的化合物、其盐和它们的水合物中的至少1种作为有效成分。下述式中,R1、R2相同或不同,表示氢原子或任选具有1个或2个以上的选自卤素原子、-COOR3、-CONR32、-COR3、-CN、-NO2、-NHCOR3、-OR3、-SR3、-OCOR3、-SO3R3和-SO2NR32中的基团作为取代基的烃基(上述R3相同或不同,表示氢原子或任选具有取代基的脂肪族烃基)。n表示1以上的整数。<Image he="214" wi="700" file="DDA0002235917460000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides a kind of preparation of repairing accelerant effect with tissue trauma.Wound repair promotor of the invention includes at least one kind of as effective component in following formula (1) compound represented, its salt and their hydrate.In following formula, R 1 、R 2 It is identical or different, indicate hydrogen atom or optionally with 1 or 2 or more selected from halogen atom ,-COOR 3 、‑CONR 3 2 、‑COR 3 、‑CN、‑NO 2 、‑NHCOR 3 、‑OR 3 、‑SR 3 、‑OCOR 3 、‑SO 3 R 3 With-SO 2 NR 3 2 In alkyl (above-mentioned R of the group as substituent group 3 It is identical or different, indicate hydrogen atom or optionally with the aliphatic alkyl of substituent group).N indicates 1 or more integer.)

1. a kind of wound repair promotor, it includes in following formula (1) compound represented, its salt and their hydrate It is at least one kind of be used as effective component,

In formula (1), R¹、R²It is identical or different, indicate hydrogen atom or optionally with 1 or 2 or more selected from halogen atom ,- COOR³、-CONR³ ₂、-COR³、-CN、-NO₂、-NHCOR³、-OR³、-SR³、-OCOR³、-SO₃R³With-SO₂NR³ ₂In group conduct The alkyl of substituent group, the R³It is identical or different, indicate hydrogen atom or optionally with substituent group aliphatic alkyl, n indicate 1 with On integer.

2. wound repair promotor according to claim 1 is the wound repair promotor of mucous membrane.

3. wound repair promotor according to claim 1 promotees for the wound repair comprising fibroblastic tissue Into agent.

4. wound repair promotor according to claim 1 is prevention or the therapeutic preparation of periodontosis.

5. wound repair promotor according to any one of claims 1 to 4, for comprising selected from shown in following formula (1) Compound, in its salt and their hydrate it is at least one kind of as the dentifrice of effective component, mouth cleaning agent, oral spray, Gargle, chewable tablets, mouth containing agent, drops, tablet agent, candy, chewing gum, smears, patch, nasal drop or eye drops,

6. wound repair promotor according to claim 1 is the wound repair promotor of eye mucous membranes.

Technical field

The present invention relates to the preparations of the repairing accelerant effect with tissue trauma.This application claims on April 17th, 2017 The priority of the Japanese Patent Application filed an application to Japan 2017-081239, its content is incorporated herein.

Background technique

How the surging huge project that has become state revenue and expenditure of medical expense is inhibited in the society of aging aggravation.And And as the means for solving the above subject, (preemptive medicine inhibits or postpones the doctor of disease incidence for prevention medical treatment Treat) more and more necessary increase.

For example, periodontosis is periodontium (tooth and support caused by the LPS for constituting the epicyte of periodontosis bacterium The tissue of tooth) various diseases general name, be to undergo gingivitis, periodontitis, absorption of alveolar bone until lose the disease of tooth, It not only makes troubles, but also is noted and diabetes, hepatitis, the artery sclerosis that myocardial infarction can be caused, chronic renal to dietetic life Disease, aspiration pneumonia are related.Therefore, prevent or treatment periodontosis is extremely important for preventing the generation of above-mentioned disease.

Prevention as periodontosis, it is known that remove the pathogen of periodontosis by cleaning facing, remove as its breeding ground Tartar, dental calculus mode be effective.But when causing living body functional to decline due to aging etc., only pass through facing Cleaning is difficult to prevent the morbidity of periodontosis.In addition, other than surgical operation, without the known method for restoring periodontium.

Patent document 1 describes: if used comprising inhibiting the composition of the active specific surfactant of LPS as clean Tooth agent can then inhibit periodontosis.But the periodontium already lost can not be repaired.

Wound refers to scratch, lacerated wound, incised wound, contusion, ulcer, bedsore, diabetic ulcer, burn, inflammation, meronecrosis Deng the state of the tissue surface defect as caused by certain factor.Wound repair be the immune or inflammatory reaction most changed in a organized way it One, it is roughly divided into (1) inflammatory phase, (2) granulation tissue forms the phase, (3) reconstruct this 3 processes of phase.In inflammatory phase, along with group It knits damage and causes local inflammation reaction, neutrophil cell, macrophage gradually move to wound site.Macrophages secrete Various inflammatory cytokines, chemotactic factor (CF), to further enhance inflammatory reaction.Then, the phase is formed in granulation tissue, passed through The proliferation of vascular endothelial cell and induction of vascular is newborn, and gradually infiltration arrive wound portion fibroblast proliferation, generate collagen Equal extracellular matrixs, to form granulation tissue and realize regeneration.In addition, the fibroblast in granulation tissue is divided into and contains There are more actin, the myofibroblast rich in convergent force.It is with the flesh into fibre in the Wound Contraction that the period is observed Phenomenon caused by based on dimension cell, is the process useful for efficiently reducing surface of a wound area.Also, it within the reconstruct phase, lures It leads and forms epithelial cell on the top of granulation tissue, normal configuration originally is reconstructed.

It is previous studies have shown that when carrying out wound repair, TGF-β is most important cell factor, when TGF-β and receptor In conjunction with when, signal transduction is carried out via Smad, it is (non-come finely regulating wound healing associated gene by TGF β/Smad signal Patent document 1).But " regulation " includes promoting and inhibiting the effect of both direction, actually simply promotes TGF-β/Smad Signal is not meant to wound repair reaction up-regulation.For example, the effect as Smad in wound healing, it is known that following aspects: By the defect of Smad3 show wound healing promotion, without TGF-β mediate signal transduction when promote wound repair it is (non- Patent document 2,3).And it is reported that, in the transgenic mice of overexpression TGF-β 1, wound healing is delay , show that TGF-β 1 has negative effect (non-patent literature 4) to wound healing.

PDLIM2 (PDZ and LIM domain albumen -2) is slaves to ubiquitin ligase in the core of LIM protein family, has PDZ and LIM domain.PDLIM2 is in core and as one of transcription factor needed for the Th1 cell differentiation in T cell STAT4 is combined, by its ubiquitination and decomposition, to terminate the signal transduction (non-patent literature 5) mediated by STAT4.In addition, specially It is described in sharp document 2 by inhibiting the expression of PDLIM2 and promotes the reparation of defect of skin.

In recent years it has defined, various Porcine HGFs play an important role in wound-healing process, create to skin Hurt the validity for the treatment of by expectation.Especially fibroblast growth factor (fibroblast growth factor:FGF) FGF2 (human alkaline fibroblast growth factor -2, also referred to as " bFGF ") in family has found that it is with remarkably promoting The effect of fibroblast proliferation and the protein for promoting angiogenesis effect.Therefore, using FGF2 as bedsore, skin ulcer etc. The therapeutic agent of intractable wound come using.

Summary of the invention

Subject to be solved by the invention

Therefore, the object of the present invention is to provide the preparations of the repairing accelerant effect with tissue trauma.

Another object of the present invention is to provide the preparations of the repairing accelerant effect with mucous membrane wound.

Another object of the present invention is to provide the repairing accelerant effects with the wound comprising fibroblastic tissue Preparation.

Another object of the present invention is to provide lose with periodontium of the prevention caused by periodontosis, have and repair The preparation for periodontium this effect lost due to periodontosis.

Solution for solving the problem

The inventors of the present invention have made intensive studies in order to solve the above problems, as a result, it has been found that, will be shown in following formula (1) Compound be used for have occurred inflammatory reaction fibroblast when,

[1] make with by raising neutrophil cell chemotaxis improve biological cell itself defense function this The generation of the IL-8 of one effect increases；

[2] increase the generation of solubility phase diagram histone, the matrix metalloproteinase for cleaning wound (MMP)；

[3] make with the epidermal growth factor (EGF) for stimulating fibroblastic proliferation, epithelium being promoted to form this effect Generation increase；

[4] make to be born with by the production for reducing the PDLIM2 that there is inhibition wound site to shrink this effect and remarkably promote The generation of the FGF2 of the effect of the effect and promotion angiogenesis of fibroblast proliferation increases.

And it was found that by said effect [1]~[4] combination, so that playing makes inflammation in early stage termination, promotes wound It repairs, shorten the effect for curing required time.The present invention is completed based on these opinions.

That is, the present invention provides a kind of wound repair promotor, it includes be selected from following formula (1) compound represented, its salt Effective component is used as at least one kind of in their hydrate.

[changing 1]

[in formula, R¹、R²It is identical or different, indicate hydrogen atom or optionally with 1 or 2 or more selected from halogen atom ,- COOR³、-CONR³ ₂、-COR³、-CN、-NO₂、-NHCOR³、-OR³、-SR³、-OCOR³、-SO₃R³With-SO₂NR³ ₂In group conduct Alkyl (the above-mentioned R of substituent group³It is identical or different, indicate hydrogen atom or optionally with the aliphatic alkyl of substituent group).N indicates 1 Above integer.]

The present invention additionally provides above-mentioned wound repair promotors, are the wound repair promotor of mucous membrane.

The present invention additionally provides above-mentioned wound repair promotors, promote for the wound repair comprising fibroblastic tissue Into agent.

The present invention additionally provides above-mentioned wound repair promotors, are prevention or the therapeutic preparation of periodontosis.

The present invention additionally provides above-mentioned wound repair promotor, for comprising selected from following formula (1) compound represented, its It is at least one kind of as the dentifrice of effective component, mouth cleaning agent, oral spray, gargle, chewing in salt and their hydrate Piece, mouth containing agent, drops, tablet agent, candy, chewing gum, smears, patch, nasal drop or eye drops.

[changing 2]

The effect of invention

Above-mentioned formula (1) compound represented does not have cytotoxicity, and safety is excellent.Also, above-mentioned (1) institute will contained When showing the preparation of compound for wound site, above-mentioned formula (1) compound represented and the inflammation for controlling wound site are anti- The cell factor (such as the anti-inflammatories such as TGF-β cell factor) by immunocompetent cell secretion answered is acted in phase, To disposably increase the generation of IL-8, MMP, FGF and EGF, and using the generation of compound inhibition PDLIM2, thus Increase the generation with the FGF2 for remarkably promoting fibroblastic cultivation effect and promoting angiogenesis effect, it is possible thereby to send out Wave the effect for making inflammation the time required to early stage termination, the reparation for promoting wound, shortening healing.

Therefore, wound site can be accelerated to cure using above-mentioned preparation, due to aging, disease and lead to organism function When can decline, the barrier function of organism can be improved, obtain preventing various as caused by the barrier function decline of organism The effect of disease.It should be noted that above-mentioned preparation is not limited to the mankind, same effect can also be played in animal.

For example, barrier function can be improved when above-mentioned preparation is used for oral mucosa, so as to inhibit the hair of periodontosis Disease can prevent the periodontium caused by periodontosis and lose.Even, can also be into addition, the periodontium already lost Row is repaired and makes its recovery.Therefore, prevention or therapeutic preparation of the above-mentioned preparation as periodontosis are extremely effective.

Detailed description of the invention

Fig. 1 is the figure for showing the safety evaluatio result of preparation obtained in embodiment.

Fig. 2 is the figure for showing the initial IL-8 generation facilitation effect of preparation obtained in embodiment.

Fig. 3 is the figure for showing the ongoing change using the IL-8 yield after preparation obtained in embodiment.

Fig. 4 is the figure for showing the ongoing change using the IL-8 gene expression amount after preparation obtained in embodiment.

Fig. 5 is the TGF-β shown using after one or both of preparation and TGF-β obtained in embodiment, double tune eggs The figure of white and MMP3 expression quantity.The longitudinal axis indicates that the expression quantity there will be no each gene under conditions of TGF-β and D-AP6 is set as Relative quantity when 1.

Fig. 6 be show it is rear or using one in Nalsgen and TGF-β using one or both of D-AP6 and TGF-β The figure of the expression quantity of MMP9, MMP13, HAS2 and PDLIM2 after person or both.The longitudinal axis indicate there will be no TGF-β, D-AP6 and The expression quantity of each gene under conditions of Nalsgen is set as relative quantity when 1.

Fig. 7 is the figure for showing the expression quantity using the FGF2 after one or both of Nalsgen and TGF-β.Longitudinal axis table Show the relative quantity when expression quantity there will be no the FGF2 under conditions of TGF-β and Nalsgen is set as 1.

Specific embodiment

In this specification, " wound " indicate scratch, lacerated wound, incised wound, contusion, ulcer, bedsore, diabetic ulcer, burn, The state of the tissue surface defect as caused by certain factor such as inflammation, meronecrosis.Above-mentioned tissue includes such as skin, mucous membrane. In addition, above-mentioned skin includes epidermis, corium and subcutaneous tissue.Above-mentioned mucous membrane includes epithelium (or mucous epithelium), proper mucous membrane And submucosa.

[wound repair promotor]

Wound repair promotor of the invention includes to be selected from following formula (1) compound represented, its salt and their hydration It is at least one kind of as effective component in object.It should be noted that following formula (1) compound represented has at least one asymmetric Atom.Therefore, there are at least two kinds of optical isomers for following formula (1) compound represented.Wound repair promotor of the invention In, as following formula (1) compound represented, can be used optical isomer (or mirror image isomer) equal amount of mixture (= Racemic modification), it also can be used and optical activity obtained from optical resolution carried out to the equal amount of mixture of above-mentioned optical isomer Body (or one of mirror image isomer).It should be noted that the optical resolution of racemic modification can using diastereoisomeric salt method, Customary way known in Split Method using chiral column etc..

[changing 3]

Above-mentioned R¹、R²In alkyl include aliphatic alkyl, alicyclic type hydrocarbon, aromatic hydrocarbyl and they via singly-bound key Group made of conjunction.

As aliphatic alkyl, preferably C_1-20(=carbon number 1~20) aliphatic alkyl, it can be mentioned, for example methyl, second The carbon numbers such as base, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, amyl, hexyl, decyl, dodecyl C_1-20It is (excellent It is selected as C_1-10, particularly preferably C_1-3) left and right alkyl；The C such as vinyl, allyl, 1- cyclobutenyl_2-20(preferably C_2-10, especially Preferably C_2-3) left and right alkenyl；The C such as acetenyl, propinyl_2-20(preferably C_2-10, particularly preferably C_2-3) left and right alkynyl Deng.

As alicyclic type hydrocarbon, preferably C_3-20Alicyclic type hydrocarbon, it can be mentioned, for example: cyclopropyl, cyclobutyl, cyclopenta, ring The C such as hexyl, cyclooctyl_3-20(preferably C_3-15, particularly preferably C_5-8) left and right naphthenic base；Cyclopentenyl, cyclohexenyl group etc. C_3-20(preferably C_3-15, particularly preferably C_5-8) left and right cycloalkenyl；Perhydronaphthalene -1- base, norborny, adamantyl, tricyclic [5.2.1.0^2,6] decane -8- base, Fourth Ring [4.4.0.1^2,5.1^7,10] the endocyclics alkyl such as dodecane -3- base etc..

As aromatic hydrocarbyl, preferably C_6-14(especially C_6-10) aromatic hydrocarbyl, it can be mentioned, for example phenyl, naphthalenes etc..

Group made of aliphatic alkyl is bonded with alicyclic type hydrocarbon includes cyclopentyl-methyl, cyclohexyl methyl, 2- hexamethylene The naphthenic base such as base ethyl substitution alkyl (such as C_3-20Naphthenic base replaces C_1-4Alkyl etc.) etc..In addition, aliphatic alkyl and aromatic series Group made of alkyl bonding includes aralkyl (such as C_7-18Aralkyl etc.), alkyl substituting aromatic base (such as replace have 1~4 The C of left and right_1-4The phenyl or naphthyl etc. of alkyl) etc..

As above-mentioned R³In aliphatic alkyl, can enumerate and above-mentioned R¹、R²In the same example of aliphatic alkyl.

As above-mentioned R³In the substituent group that optionally has of aliphatic alkyl, it can be mentioned, for example: halogen atom, oxo base, Hydroxyl, substituted oxygroup (such as C_1-4Alkoxy, C_6-10Aryloxy group, C_7-16Aralkoxy, C_1-4Acyloxy etc.), it is carboxyl, substituted Epoxide carbonyl (such as C_1-4Alkoxy carbonyl, C_6-10Aryloxycarbonyl, C_7-16Aromatic alkoxy carbonyl etc.), substituted or non-substituted ammonia Formoxyl (such as the C such as carbamyl, methylcarbamoyl_1-4Alkyl replaces the C such as carbamyl, phenylcarbamoyl_6-10Aryl Replace carbamyl), cyano, nitro, substituted or non-substituted amino (such as methylamino, dimethylamino, ethylamino, two The list such as ethylamino or two C_1-4Alkyl amino；The cyclic amino that 5~8 yuan of 1- pyrrolidinyl, piperidyl, morpholinyl etc.；Acetyl group The C such as amino, propanoylamino, benzoyl-amido_1-10Acyl amino；The sulphurs such as benzenesulfonylamino, p-toluenesulfonyl amino Acyl amino), sulfo group, hetero ring type group etc..In addition, above-mentioned hydroxyl, carboxyl can be by protections usual in organic synthesis field Base protection.

N indicates 1 or more integer, such as 1~10 integer.

As formula (1) compound represented, including following [I], [II].

OR in [I] formula (1)¹Base and OR²Base is the compound (compound (I)) of OH base

OR in [II] formula (1)¹Base and OR²At least one of base is the compound (compound of the group other than OH base (II))

As the n in compound (I), preferably 2~10 integer, particularly preferably 2~8 integer.

As the n in compound (II), preferably 1~8 integer, particularly preferably 2~6 integer.

As the OR in compound (II)¹Base and OR²The combination of base, the combination of preferably following [II-i]~[II-v].It is special In the case that not to be n in formula (1) be 1 or 2, the combination of preferably following [II-i]~[II-iv], the n in formula (1) is In the case where 3 or more integer, the combination of preferably following [II-v].

The combination of group shown in [II-i] following formula (i-1) and group shown in following formula (i-2)

[changing 4]

[in formula (i-1), R⁴It indicates the aromatic hydrocarbyl optionally with substituent group or optionally there is the hetero ring type base of substituent group Group]

[in formula (i-2), R⁵~R⁷It is identical or different, indicate selected from hydrogen atom, optionally with substituent group aliphatic alkyl, Optionally with aromatic hydrocarbyl, the halogen atom ,-COOR of substituent group⁸、-CONR⁸ ₂、-COR⁸、-OCOR⁸、-CF₃、-CN、-SR⁸、- SOR⁸、-SO₂R⁸、-SO₂NR⁸ ₂、-PO(OR⁸)₂With-NO₂In group.Above-mentioned R⁸Indicate hydrogen atom, alkyl or alkenyl.Selected from R⁵~ R⁷In two groups it is optionally mutually bonded, in the group shown in formula (i-2) with the carbon atom that is bonded on these groups together Form ring.]

As above-mentioned aliphatic alkyl, aromatic hydrocarbyl, can enumerate and above-mentioned R¹、R²In aliphatic alkyl, aromatic hydrocarbon The same example of base.

The heterocycle for constituting above-mentioned hetero ring type group includes aromatic series heterocycle and non-aromatic heterocycle.As this miscellaneous Ring, can enumerate and constitute the atom of ring includes the 3 of carbon atom and at least one kind of hetero atom (such as oxygen atom, sulphur atom, nitrogen-atoms etc.) ~10 member rings (preferably 4~6 member rings) and their fused rings.Specifically, can enumerate: comprising oxygen atom as heteroatomic Heterocycle (such as 3 member ring such as oxirane ring；4 member ring such as oxetane；Furan nucleus, tetrahydrofuran ring, oxazole ring, isoxazole 5 member rings such as ring, gamma-butyrolacton ring；6 member rings such as 4- oxo -4H- pyranoid ring, amylene oxide ring, morpholine ring；It is benzofuran ring, different The fused rings such as benzofuran ring, 4- oxo -4H- chromene ring, chroman ring, heterochromatic full ring；3- oxatricyclo [4.3.1.1^4,8] 11 Alkane -2- ketone ring, 3- oxatricyclo [4.2.1.0^4,8] bridged rings such as nonane -2- ketone ring), comprising sulphur atom as heteroatomic heterocycle (such as 5 member rings such as thiphene ring, thiazole ring, isothiazole ring, Thiadiazole；6 member rings such as 4- oxo -4H- thiapyran ring；Benzothiophene Fused rings such as ring etc.), comprising nitrogen-atoms as heteroatomic heterocycle (such as pyrrole ring, pyrrolidine ring, pyrazole ring, imidazole ring, three 5 member ring such as azoles ring；6 member rings such as isocyanide urea ring, pyridine ring, pyridazine ring, pyrimidine ring, pyridine ring, piperidine ring, piperazine ring；Indole ring, Fused rings such as indoline ring, quinoline ring, acridine ring, naphthyridines ring, quinazoline ring, purine ring etc.) etc..Hetero ring type group is from upper It states and removes group made of 1 hydrogen atom in the structural formula of heterocycle.

As above-mentioned R⁴~R⁷In the substituent group that optionally has of aliphatic alkyl, aromatic hydrocarbyl and hetero ring type group, can It enumerates and above-mentioned R³In the same example of substituent group that optionally has of aliphatic alkyl.

The combination of group shown in [II-ii] following formula (ii-1) and group shown in following formula (ii-2)

[changing 5]

[in formula (ii-1), R⁹Indicate hydrogen atom, the alkyl optionally with substituent group or the aryl optionally with substituent group, R¹⁰Indicate group shown in hydrogen atom or following formula (r10),

[changing 6]

(in formula, R¹¹Indicate hydrogen atom, methyl or ethyl.N1 indicates that 0~4 integer, n2 indicate 0 or 1, and n3 indicates 0~4 Integer.2 or more in n1~n3 can be identical.X¹Indicate amido bond or alkenylene, X²It indicates to be selected from-COOR³、- CONR³ ₂、-COR³、-CN、-NO₂、-NHCOR³、-OR³、-SR³、-OCOR³、-SO₃R³With-SO₂NR³ ₂In group (above-mentioned R³With it is upper State identical))]

[in formula (ii-2), Y¹It indicates to be selected from hydrogen atom, alkyl, alkenyl, alkoxy, alkenyloxy group, halogen atom ,-COOR⁸、- CONR⁸ ₂、-COR⁸、-OCOR⁸、-CF₃、-CN、-SR⁸、-SOR⁸、-SO₂R⁸、-SO₂NR⁸ ₂、-PO(OR⁸)₂With-NO₂In group.R⁸ It is same as described above.Y²It indicates selected from hydrogen atom, the alkyl optionally with substituent group, optionally with the alkenyl ,-COOR of substituent group³、- CONR³ ₂、-COR³、-CN、-NO₂、-NHCOR³、-OR³、-SR³、-OCOR³、-SO₃R³With-SO₂NR³ ₂In group (above-mentioned R³With it is upper It states identical).Y¹With Y²It is optionally mutually bonded and be formed together ring with the carbon atom of the composition phenyl ring in formula (ii-2).]

[II-iii] optionally has alkoxy of substituent group and is selected from group shown in following formula (iii-1)~(iii-4) In group combination

[changing 7]

(in formula, R¹²Indicate hydrogen atom, methyl or ethyl.Y¹、Y²It is same as described above.Y¹With Y²Optionally mutually bonded and and formula In the carbon atom of composition aromatic rings be formed together ring.)

[II-iv]OR¹Base and OR²Base is identical or different, the combination of group shown in following formula (iv-1)

[changing 8]

(in formula, Y¹、Y²It is same as described above.Y¹With Y²It is optionally mutually bonded and in formula composition phenyl ring carbon atom together with Form ring.)

[II-v] hydroxyl and aliphatic hydrocarbon oxygroup (the preferably C optionally with substituent group_1-6Alkoxy) combination

As the substituent group that abovementioned alkyl, alkenyl, aryl, alkoxy and aliphatic hydrocarbon oxygroup optionally have, can enumerate with Above-mentioned R³In the same example of substituent group that optionally has of aliphatic alkyl.

As the aliphatic alkyl for constituting above-mentioned aliphatic hydrocarbon oxygroup, can enumerate and above-mentioned R¹、R²In aliphatic alkyl it is same The example of sample.

As above compound (I), preferably following formula (I-1)~(I-5) compound represented (including optical isomer).

[changing 9]

As above compound (II), preferred following formula (II-1)~(II-2) compound represented (including optical siomerism Body).

[changing 10]

Formula (1) compound represented can be hydrate, in addition, formula (1) compound represented or its hydrate can also be with Forming salt.As formula (1) compound represented or the salt of its hydrate, it can be mentioned, for example: the alkali metal salts such as sodium salt, sylvite；Magnesium The alkali salts such as salt, calcium salt, barium salt；With the salt of ammonium；With trimethylamine, triethylamine, tri-n-butylamine, pyridine, quinoline, piperidines, imidazoles, It is picoline, dimethyl aminopyridine, n,N-Dimethylaniline, N- methyl piperidine, N-methylmorpholine, diethylamine, cyclohexylamine, general Shandong cacaine, dibenzyl amine, N- benyzl-ss-phenethylamine, 1- ephenamine (1-ephenamine), N, N '-dibenzyl-ethylenediamin, The salt of the nitrogenous organic bases such as N- methyl-D-glucosamine；With the salt of the basic amino acids such as lysine, arginine, ornithine；Transition gold Belong to salt；With the salt of the inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid；With the organic acids such as oxalic acid, acetic acid, p-methyl benzenesulfonic acid Salt etc..

In above-mentioned formula (1) compound represented, compound (I) can for example be manufactured by following processes [1]~[4]. In addition, compound (II) can for example be manufactured by following processes [1]~[10].

In following formula, n is same as described above.X indicates halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom), R, R ' It is identical or different, indicate the alkyl of carbon number 1~10.The protecting group of R " expression amino.DPR indicates the amino protected by protecting group Deprotection agent.It should be noted that the protecting group as amino, it can be mentioned, for example the alkyl of: carbon number 1~10, carbon number 7~18 Aralkyl, acyl group (R^aC (=O) base；R^aFor the alkyl of carbon number 1~10), alkoxy carbonyl (R^bOC (=O) base；R^bFor carbon number 1~ 10 alkyl), optionally benzyloxycarbonyl with substituent group, the phenylmethylene optionally with substituent group, optionally with substitution The diphenylmethylene etc. of base.In addition, it can be mentioned, for example halogen atoms, the alkoxy of carbon number 1~3, nitre as above-mentioned substituent group Base etc..

[changing 11]

[changing 12]

[changing 13]

The reaction of process [1] is that phosphite ester shown in formula (3) is obtained with saturated dihalide hydrocarbon reaction shown in formula (2) Reaction (the Michaelis-Arbuzov reaction of phosphono alkanoic acid shown in formula (4)；Michaelis-Arbuzov Reaction).For the usage amount of phosphite ester shown in above-mentioned formula (3) is relative to shown in formula (2) 1 mole of alkylene dihalide Such as 0.1~1.0 mole or so.

The reaction temperature of the reaction of process [1] is preferably such as 130~140 DEG C or so.Reaction time is such as 0.5~2 Hour or so.

The reaction of process [2] be formula (5) compound represented with by formula (4) institute obtained from the reacting of process [1] The phosphono alkanoic acid reaction shown is to obtain the reaction of formula (6) compound represented.The use of above-mentioned formula (5) compound represented Amount is such as 0.7~13 mole or so relative to 1 mole of phosphono alkanoic acid shown in formula (4).

From the viewpoint of being promoted the effect that reaction carries out, the reaction of process [2] is preferably carried out in the presence of a base.Make For above-mentioned alkali, it can be mentioned, for example: carbonates such as saleratus, sodium bicarbonate, potassium carbonate, sodium carbonate (especially alkali metal Carbonate)；The hydroxide of the alkali metal such as sodium hydroxide, potassium hydroxide；The hydrogen of the alkaline-earth metal such as calcium hydroxide, magnesium hydroxide Oxide；The phosphoric acid salts such as sodium dihydrogen phosphate, potassium dihydrogen phosphate (the especially phosphoric acid salt of alkali metal): sodium acetate, potassium acetate Equal metal carboxylates (the especially metal carboxylate of alkali metal)；The organic bases such as triethylamine, pyridine；The metals such as sodium methoxide, sodium ethoxide Alcohol salt (especially alkali alcoholate class)；Metal hydrides species such as sodium hydride etc..They can be used alone, can also To be used in combination of two or more.The usage amount of alkali is such as 0.9~1.1 relative to 1 mole of phosphono alkanoic acid shown in formula (4) Mole or so.

It is preferred that carrying out the reaction of process [2] in the presence of solvent.As above-mentioned solvent, it can be mentioned, for example: acetone, methyl ethyl ketone Equal ketones；The ethers such as tetrahydrofuran, dioxanes；The nitriles such as acetonitrile；The sulfoxide types such as dimethyl sulfoxide；The sulfones class such as sulfolane；Acetic acid The esters such as ethyl ester；The amides such as dimethylformamide；The alcohols such as methanol, ethyl alcohol, the tert-butyl alcohol；The hydrocarbon such as pentane, hexane, petroleum ether Class；Benzene,toluene,xylene etc. is aromatic hydrocarbon；The halogen-containing compound such as methylene chloride, chloroform, bromofom, chlorobenzene, bromobenzene；Carbon The linear carbonates such as dimethyl phthalate, diethyl carbonate, methyl ethyl carbonate；The cyclic carbonates such as ethylene carbonate, propylene carbonate Deng.They can be used alone, and can also be used in combination of two or more.

The reaction temperature of the reaction of process [2] is preferably such as 100~110 DEG C or so.Reaction time is such as 6~24 small When or so.

The reaction of process [3] is to formula (6) compound represented obtained from the reaction for passing through process [2] by protecting group The carboxyl (- COOR ') of protection, the amino (- NHR ") protected by protecting group and the phosphonic acid base (- P (=O) protected by protecting group (OR)₂) it is deprotected the reaction of the formula of obtaining (7) compound represented.The deprotection for the group protected by protecting group can be with It is carried out by making deprotection agent reaction.It (is indicated in above-mentioned formula with " DPR ") as above-mentioned deprotection agent, can be suitable for using strong Alkali (such as sodium hydroxide) or strong acid (such as hydrochloric acid).

The reaction temperature of the reaction of process [3] is preferably such as 90~100 DEG C or so.Reaction time is such as 20~24 small When or so.

The reaction of process [4] is to make with the compound for capturing this effect of deprotection agent and pass through reacting for process [3] Obtained from the reaction of formula (7) compound represented to obtaining the reaction of compound (I).As have capture deprotection agent this The compound of effect, such as when deprotection agent is hydrochloric acid, propylene oxide can be used.With capture this effect of deprotection agent The usage amount of compound relative to 1 mole of compound represented of formula (7) be such as 3.0~6.0 moles or so.

Process [5] is the process for importing protecting group to the carboxyl of compound (I), for example, can by make compound (I) with R^COH(R^CIndicate aryl or aralkyl optionally with substituent group, preferably benzyl, 4- nitrobenzyl) it reacts to import protection Base.The reaction preferably carries out in the presence of acid catalyst (such as hydrochloric acid etc.), under the temperature environment of near room temperature.When reaction Between be such as 12~24 hours or so.

Process [6] is the process for importing protecting group to the amino of compound (I), for example, can be by being dissolved in solvent Compound (I) in be added dropwise R " X, make its reaction to import protecting group.The reaction preferably depositing alkali (such as sodium bicarbonate etc.) In lower progress.

As above-mentioned solvent, such as water, halogenated hydrocarbon system solvent, saturation or unsaturated hydrocarbons series solvent, aromatic series can be used One or more of hydrocarbon system solvent, ether series solvent etc..

Temperature when dropwise addition is preferably room temperature hereinafter, near particularly preferably 0 DEG C.Reaction time is such as 0.5~2 hour Left and right.In addition, after completion of dropwise addition, preferably for example side is stirred such as 10~24 hours or so in the state that heat preservation is to 25~30 DEG C While making its curing.

Process [7] be replace the process of two hydroxyls of phosphate with halogen atom, for example, can by catalyst and React halogenating agent with by compound obtained from process [5], [6] to carry out.As above-mentioned catalyst, It can be used such as n,N-Dimethylformamide.In addition, as above-mentioned solvent, it is molten that halogenated hydrocarbon system solvent, ether system can be used One or more of agent etc..As above-mentioned halogenating agent, it can be mentioned, for example oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphinylidynes Chlorine etc..These can be used alone, and can also be used in combination of two or more.The reaction is preferably in the temperature of near room temperature It is lower to carry out 1 hour or so.

Process [8] is to make R¹OH reacts and will pass through the halogen atom for being bonded to phosphorus atoms obtained from process [7] In one be substituted by OR¹Process.The reaction preferably carries out in the presence of a base, and as alkali, it can be mentioned, for example triethylamines, three fourths Amine, diisopropylethylamine, N- methyl piperidine, N-methylmorpholine, diethylisopropylamide, N- methylimidazole, pyridine etc..In addition, should Reaction preferably carries out in the presence of solvent, as solvent, it is preferable to use dry methylene chloride.Reaction is preferably following to be carried out :- After 65 DEG C of stirrings 30 minutes or so nearby, it is slowly warming up to room temperature, 1~3 hour left side is then stirred in the state of keeping room temperature The right side carries out.

Process [9] is to make R²OH reacts and another in the halogen atom for being bonded to phosphorus atoms is substituted by OR²'s Process.Process [9] is in addition to using R²OH replaces R¹Other than OH, it can be carried out by method same as process [8].

Process [10] is the process being deprotected to the carboxyl and amino protected by protecting group, such as can pass through contact Hydrogen reduction method is defended the doctrine etc. using the remove-insurance of aluminium chloride to carry out.Above-mentioned contact hydrogen reduction method is to support palladium in activated carbon, sulphur Palladium series catalyst made of the carriers such as sour barium rouses in the presence of platinum group catalyst in by compound obtained from process [9] Enter the method for hydrogen.In addition, it is solvent (such as dry nitre joined alchlor that the above-mentioned remove-insurance using aluminium chloride, which is defended the doctrine, The high polar solvent such as methylmethane) in make the method to react by compound obtained from process [9] and anisole.

As the reaction atmosphere of each process, if do not inhibit reaction be not particularly limited, can be such as air atmosphere, Any one of nitrogen atmosphere, argon atmosphere etc..In addition, reaction can carry out under normal pressure, decompression or pressurization.Moreover, reaction It can also be carried out by method either in intermittent, semibatch, continous way etc..

After each process, obtained reaction product can be implemented for example to filter, be concentrated, distillation, extraction, crystallization, inhale Separation means that the separation means such as attached, recrystallization, column chromatography, these means are composed are purified.

The hydrate of formula (1) compound represented can be by by the compound obtained in aforementioned manners (I) or compound (II) it is manufactured for having used the crystallization treatment of water and water-soluble solvent.

As above-mentioned water-soluble solvent, preferably in room temperature (25 DEG C) Shi Yushui with miscible organic molten of arbitrary ratio Agent, solubility preferably in water are the organic solvent of 50% or more (preferably 80% or more, particularly preferably 95 or more).

As above-mentioned water-soluble solvent, it is preferable to use alcohol (such as lower alcohol of the carbon numbers such as methanol, ethyl alcohol 1~5).

The salt of formula (1) compound represented can make following substances and pass through compound obtained by the above method (I) or change It closes object (II) reaction and manufactures, the substance is for example: sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, hydroxide The alkali compounds such as barium；Ammonium；Trimethylamine, triethylamine, tri-n-butylamine, pyridine, quinoline, piperidines, imidazoles, picoline, dimethylamino Yl pyridines, n,N-Dimethylaniline, N- methyl piperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzyl amine, N- benyzl-ss-phenethylamine, 1- ephenamine, N, the nitrogenous organic bases such as N '-dibenzyl-ethylenediamin, N- methyl-D-glucosamine；Rely The basic amino acids such as propylhomoserin, arginine, ornithine；The inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid；It is oxalic acid, acetic acid, right Organic acids such as toluenesulfonic acid etc..

In wound repair promotor of the invention, as effective component, comprising being selected from above-mentioned formula (1) compound represented It is at least one kind of in (such as compound (I) and/or compound (II)), its salt and their hydrate, it is preferably selected from above-mentioned formula (I-1) at least one kind of (including light in~(I-5), (II-1)~(II-2) compound represented, its salt and their hydrate Learn isomers).

Above-mentioned formula (1) compound represented, its salt and their hydrate in wound repair promotor of the invention Content (containing two or more Shi Weiqi total amounts) can appropriate adjustment depending on the application.For example, promoting by wound repair of the invention Into agent for the prevention of periodontosis or when therapeutical uses, be such as 0.001~500 μ g/mL, preferably 0.005~300 μ g/mL, More preferably 0.01~200 μ g/mL, further preferably 0.01~100 μ g/mL, particularly preferably 0.01~10 μ g/mL, most Preferably 0.01~1.0 μ g/mL, especially preferably 0.01~0.5 μ g/mL.

In wound repair promotor of the invention, in addition to above-mentioned formula (1) compound represented, its salt and their hydrate In addition, other ingredients can also be contained.Other ingredients can appropriate adjustment depending on the application.For example, being repaired by wound of the invention When multiple promotor is used for prevention or the therapeutical uses of periodontosis, dentifrice, mouth cleaning agent, oral spray, oral cavity coating can be enumerated Agent (such as buccal cavity gel agent, oral cavity ointment), laryngeal is spraying, gargle, paste, ointment, laryngeal smears, chews The ingredient usually contained in piece, mouth containing agent, drops etc..

When wound repair promotor of the invention is used for wound portion, with do not use wound repair promotor of the invention When compare, can promote the generation of the TGF-β as one of anti-inflammatory cytokine.It should be noted that even if by of the invention Wound repair promotor is used for normal epithelium, will not increase the generation of TGF-β.Therefore, wound repair of the invention promotes Agent does not have cytotoxicity, and safety is excellent.

By wound repair promotor of the invention be used for wound portion (such as due to LPS stimulation etc. and to cause inflammation anti- The fibroblast answered) when, compared with when not using wound repair promotor of the invention, initial (such as 0.5~60 after use Hour, it is preferable to use 2~36 hours after latter 1~48 hour, particularly preferred use) when promote IL-8 generate, the then production of IL-8 It changes for the tendency of reduction.IL-8 yield is also the index for indicating degree of inflammation, and the reduction that IL-8 is generated indicates the journey of inflammation Degree is improved.It can thus be appreciated that: wound repair promotor of the invention has by promoting IL-8 generation to improve neutrophil(e) granule The chemotaxis of cell, thus the effect for curing inflammation in early stage termination, acceleration of wound.

In addition, even if by wound repair promotor of the invention be used for normal epithelium (or do not generate inflammatory reaction at Fibrocyte), the generation of IL-8 will not be increased.Therefore, wound repair promotor of the invention does not have cytotoxicity, safety Property is excellent.

When wound repair promotor of the invention is used for wound portion, with do not use wound repair promotor of the invention When compare, can promote solubility phase diagram histone, the MMP for cleaning wound (such as in MMP3, MMP9, MMP13 extremely Few a kind) generation.It should be noted that (or being not added with even if wound repair promotor of the invention is used for normal epithelium The fibroblast of TGF-β), the generation of MMP will not be increased.

In addition, when wound repair promotor of the invention is used for wound portion, and wound repair of the invention is not used It is compared when promotor, can promote the generation of FGF (specially FGF2), which, which has, promotes fibroblast and blood vessel endothelium thin The proliferation of born of the same parents, the effect for promoting granulation tissue to be formed.It should be noted that even if wound repair promotor of the invention is used for There is no the tissue of TGF-β or cells, will not increase the generation of FGF.Since the wound portion of organism is the life there are TGF-β Therefore reason state can promote the generation of FGF by the way that wound repair promotor of the invention is used for wound portion.

In addition, when wound repair promotor of the invention is used for wound portion, and wound repair of the invention is not used It is compared when promotor, can promote the generation of EGF (such as amphiregulin), which has the fibroblastic proliferation of stimulation and promote Into epitheliogenic effect.It should be noted that even if wound repair promotor of the invention is used for normal epithelium, also not It will increase the generation of EGF.

In addition, when wound repair promotor of the invention is used for wound portion, and wound repair of the invention is not used It is compared when promotor, the generation of PDLIM2 is inhibited.Also, by inhibiting the generation of PDLIM2 to induce the generation of FGF, thorn Swash fibroblastic proliferation.

Moreover, when wound repair promotor of the invention is used for wound portion, and wound repair of the invention is not used It is compared when promotor, promotes the generation of hyaluronic acid (such as at least one kind of in HAS1, HAS2, HAS3).It needs to illustrate It is that, even if wound repair promotor of the invention is used for normal epithelium, the generation of hyaluronic acid will not be increased.

When wound repair promotor of the invention is used for wound site, above-mentioned formula (1) compound represented be used for Control cell factor (such as the anti-inflammatories cell such as TGF-β by immunocompetent cell secretion of the inflammatory reaction of wound site The factor) it is acted in phase, to disposably increase the generation of IL-8, MMP, FGF, EGF and hyaluronic acid, inhibit The generation of PDLIM2, it is possible thereby to play the effect for making inflammation the time required to early stage termination, the reparation for promoting wound, shortening healing Fruit.

Wound repair promotor of the invention for example can with paste-like, gel, liquid, emulsion form, creams shape system Dosage form formula uses.Furthermore it is possible to enclose container and used with the dosage form of the preparation of aerosol form, spray form.

Wound repair promotor of the invention is as wound (such as scratch, lacerated wound, incised wound, contusion, ulcer, scald, cotton-padded mattress Sore, diabetic ulcer, burn, inflammation, meronecrosis etc.) restoration accelerator be useful, can be suitable for as skin, viscous Film [such as eye mucous membranes (cornea, corneal epithelium, conjunctiva etc.), schneiderian membrane, oral mucosa, gastric mucosa, intestinal mucosa, intrauterine Film, olfactory epithelium etc.] wound repair promotor come using.

Wound repair promotor of the invention can also be suitably as the wound repair comprising fibroblastic tissue Promotor come using.

The wound that wound repair promotor of the invention can be suitably used for skin (epidermis, corium and subcutaneous tissue) is repaired It is multiple, a part of epidermis and corium is not only injured also under the serious conditions of defect etc in wound, can also be played excellent Wound repair facilitation effect.That is, wound repair promotor of the invention can also suitably promote as the wound repair of corium Agent come using.

In wound (the preferably wound of corium) that wound repair promotor of the invention is used for skin, can prepare At the shapes such as smears (ointment, creams agent, lotion, gelling agent etc.), patch (adhesive plaster, adhesive tape agent etc.), nasal drop, eye drops Formula come using.It should be noted that they can use conventional method to prepare.

Especially when wound repair promotor of the invention is used for oral mucosa (such as periodontosis prevention or When therapeutical uses), toothpaste, liquid tooth paste, liquid toothpaste, wet tooth powder (tooth wet powder) etc. can be prepared into and cleaned the teeth Agent, mouth cleaning agent, oral spray, oral cavity smears (such as buccal cavity gel agent, oral cavity ointment), laryngeal be spraying, gargle, cream The forms such as agent, soft paste, laryngeal smears, chewable tablets, mouth containing agent, drops, tablet agent, candy, chewing gum and use.It needs Illustrate, they can conventionally be prepared.

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