CN1756571A - Tissue reactive compounds and compositions and uses thereof - Google Patents

Tissue reactive compounds and compositions and uses thereof Download PDF

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Publication number
CN1756571A
CN1756571A CNA2003801100685A CN200380110068A CN1756571A CN 1756571 A CN1756571 A CN 1756571A CN A2003801100685 A CNA2003801100685 A CN A2003801100685A CN 200380110068 A CN200380110068 A CN 200380110068A CN 1756571 A CN1756571 A CN 1756571A
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compositions
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polymer
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戴维·M·格雷维特
A·陶卡克斯-麦克斯
P·M·特雷克斯
A·迈蒂
L·恩布里
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Angiotech International AG
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Abstract

A composition comprising a synthetic polymer, optionally in the presence of a drug, where the polymer comprises multiple activated groups. The multiple activated groups are reactive with functinality present on animal tissue, so that upon administration of the polymer to the tissue, the polymer binds to the tissue. Alternatively, the multiple activated groups are reactive with functionality present on a non-living surface, where the polymer binds to this surface to, e.g., increase the lubricity of the surface. When drug is present in the composition, the drug is then delivered to the site of polymer attachment.

Description

Tissue reactive compounds and compositions and application thereof
Background of invention
Invention field
The present invention relates generally to comprise the compositions of the synthetic polymer that carries a plurality of activatory groups and using these method for compositions in the medical application and in the device application.
Association area is described
The U.S. Patent number 5 that licensed to people such as Rhee on November 10th, 1992 and own together for the assignee of the present invention, 162, the 430 various derivants that disclose by collagen protein covalently being incorporated into synthetic hydrophobic polymer such as Polyethylene Glycol prepare collagen protein-synthetic polymer conjugate.
Licensed to people's such as Rhee U.S. Patent number 5 on June 28th, 1994,324,775 disclose various inserts (insert), and naturally occurring biocompatible polymer (such as polysaccharide) covalently combines with synthetic, non--immunogenic hydrophilic polyglycol polymer.
Licensed to people's such as Rhee U.S. Patent number 5 on June 12nd, 1994,328,955 disclose the various activatory form of Polyethylene Glycol and various keys, and described activatory form can be used to produce the collagen protein-synthetic polymer conjugate with a series of physics and chemical characteristic.
The U. S. application series number 08/403,358 that submit to March 14 nineteen ninety-five discloses use hydrophobicity cross-linking agent, or the mixture of hydrophilic and hydrophobicity cross-linking agent prepares crosslinked bio-material composition.Preferred hydrophobicity cross-linking agent comprises any hydrophobic polymer, and described hydrophobic polymer comprises, and maybe can comprise two or more succinimido group groups by chemically derived.
The U. S. application serial number 08/403 that submit to March 14 nineteen ninety-five, 360 disclose a kind of compositions that is used for the prevention of surgical surgical adhesions, described compositions comprises host material and anti--adhesion bonding agent, and wherein host material preferably includes collagen protein and bonding agent preferably comprises at least one tissue reactive functional group and at least one substrate reaction functional group.
The U. S. application series number 08/476 that submitted by people such as Rhee June 7 nineteen ninety-five, 825 disclose the compositions of bioadhesion, it comprises the crosslinked collagen protein of synthetic hydrophilic polymer that uses multifunctional activatable, and use these compositionss to influence the method for the adhesion between first surface and the second surface, wherein at least one preferably natural tissue surface in first surface and the second surface.
Japanese Unexamined Patent Publication No 07090241 discloses a kind of compositions, use it for the temporary transient adhesion of lens material and support, thereby material is fixed on the machinery, described compositions comprises the mixture of the Polyethylene Glycol of mean molecule quantity in the 1000-5000 scope, with mean molecule quantity 30,000-200, the poly-N-vinyl ketopyrrolidine in 000 scope.
West and Hubbell, Biomaterials (1995) 16:1153-1156, Polyethylene Glycol-common-polypropylene glycol the hydrogel that uses photopolymerisable Polyethylene Glycol-common-lactic acid diacrylate hydrogel and physical crosslinking is disclosed, poloxamer 407 (BASF AG, Mount Olive NJ) comes the prevention of surgical postoperative intestinal adhesion.
US 5,874,500, and US 6,051,648 and US 6,312,725 in-situ cross-linked or crosslinked polymer is disclosed.These publications have been introduced synthetic polymer, particularly based on the polymer of poly-(ethylene glycol) in the application that is used for producing crosslinked compositions.
The invention summary
In brief, the invention provides and the surface, intravital especially surface, such as tissue, but also with the compositions of the surface reaction of medical apparatus.By making synthetic polymer and surface reaction reach various favo(u)rable targets.Described compositions can maybe cannot comprise medicine.
For example, on the one hand, the invention provides a kind of compositions, described compositions comprises the synthetic polymer that a) carries a plurality of activatory groups, and b) aqueous buffer solution; Wherein said compositions is that pH is lower than 6 uniform solution.In related fields, the invention provides a kind of compositions, described compositions comprises the synthetic polymer that a) carries a plurality of activated groups; B) aqueous buffer solution; Wherein said compositions is that pH is higher than about 7.8 uniform solution.Preferred synthetic polymer with a plurality of activatory groups is described below.In the present invention's any aspect these, in various optional embodiments, it can further be set fourth as, and for example, described compositions does not comprise polymer any and the synthetic polymer reaction; And/or described compositions also comprises medicine; Described compositions also comprises hydrophobic drug, and described compositions also comprises hydrophilic medicament, and described compositions comprises that also hydrophobicity or hydrophilic medicament are connected with secondary carrier, for example, and the secondary carrier that exists with micelle, microsphere or nanometer spheroid; And/or synthetic polymer comprises alkylene oxide residue; And/or synthetic polymer comprises the thiol reactive group; And/or synthetic polymer comprises N-oxygen base succinimido group; And/or described synthetic polymer is one of 4-arm PEG polymer described herein; And/or described compositions is sterilized.These and other embodiment of this aspect of the present invention will be discussed in further detail below.
In related fields, the invention provides the preparation feedback method for compositions, described method comprises a) provides the synthetic polymer that carries a plurality of activatory groups; B) thus making synthetic polymer and pH be lower than 6 buffer combines and forms uniform solution; And c) pH that improves uniform solution is about 7.8 to being higher than, and makes synthetic polymer have reactivity thus.In addition, the invention provides the method that makes reactive synthetic polymer and tissue reaction.Aspect this, the invention provides and the method that adheres to in-vivo tissue in the synthesized polymer object, wherein said method are comprised the synthetic polymer that carries a plurality of activatory groups a) is provided; B) thus making synthetic polymer and pH be lower than 6 buffer combines and forms uniform solution; C) pH that improves uniform solution is about 7.8 to being higher than, and makes synthetic polymer have reactivity thus; With d) reactive synthetic polymer is contacted with in-vivo tissue.
The present invention also provides the method for apparatus for coating, comprising: the surface that a) multifunctional N-Hydroxysuccinimide base PEG derivant is applied to described device; And b) allows functional group reactions on described derivant and the apparatus surface.In certain embodiments, (for example use a kind of surface treatment method, plasma treatment method or surface treatment method, it comprise using carry and can apparatus surface be coated with the polymer of functional group's (for example, amino group) of multifunctional N-Hydroxysuccinimide base PEG derivatives reaction) functional surface groups that will install is incorporated into described device.The representative example of these polymer comprises chitosan and polymine.On the one hand, described multifunctional N-Hydroxysuccinimide base PEG derivant is poly-(ethylene glycol) succinimido glutarates of four senses.
Randomly, described synthetic polymer and medicine, for example, and the hydrophobic drug combination, wherein said medicine randomly links to each other with secondary carrier, and described secondary carrier is dispersed in the aqueous medium.At this paper this and other optional embodiments aspect these of the present invention is described in further detail.But, speaking briefly, some in these optional embodiments are, but are not limited to: the synthetic polymer that carries alkylene oxide residue; Carry the synthetic polymer of thiol reactive group; Carry the synthetic polymer of N-oxygen base succinimido group; Be elevated at the pH of uniform solution and be higher than before about 7.8, synthetic polymer is contacted with tissue; Be elevated to pH and be higher than after about 7.8, synthetic polymer is contacted with tissue in uniform solution.
Compositions of the present invention can be applied in the whole bag of tricks.For example, on the one hand, the invention provides a kind of method, described method comprises a) makes tissue contact with the synthetic polymer that carries a plurality of activatory groups in vivo, and wherein activatory group is a tissue-reactive; And b) thus make synthetic polymer and tissue reaction that synthetic polymer is covalently adhered to tissue.In related fields, the invention provides a kind of method, described method comprises a) makes lifeless surface contact with the polymer that carries a plurality of activatory groups, and wherein activatory group is a tissue-reactive; And b) thus make synthetic polymer and surface reaction that synthetic polymer is covalently adhered to tissue.When described compositions contacted with tissue, some typical tissues included, but are not limited to, and tend to the blood vessel and the tissue of restenosis.For example, alleviate in the adherent situation of tissue and secondary tissue at needs, it is favourable that synthetic polymer is made an addition to tissue.
When described compositions contacted with lifeless surface, this surface can be for example surface of conduit or contact lens of medical apparatus.In either side, in various optional embodiments, does not preferably react with any other synthetic polymer on surface (tissue or non--life); And/or described synthetic polymer not with the polymer mixed of any other and described polymer reaction; And/or described synthetic polymer not with the polymer mixed of any other and described surface reaction.This paper describes typical synthetic polymer in detail.But, in brief, in various optional embodiments of the present invention, can be characterized by described synthetic polymer and comprise alkylene oxide residue; And/or described synthetic polymer is 4-arm PEG as described herein; And/or described synthetic polymer carries a plurality of thiol-reactive groups and/or a plurality of hydroxyl-reactive group and/or a plurality of amine-reactive group.
In preferred aspects of the invention, provide composition useful for drug delivery and method, wherein these compositionss and method comprise the synthetic polymer that carries a plurality of activatory groups.Thereby, on the one hand, the invention provides a kind of compositions, described compositions comprises synthetic polymer and medicine, carries the polymer of a plurality of activatory groups.
Need drug delivery of the present invention aspect these in, the feature of described compositions can be one or more optional characteristics as the more abundant description of this paper.But in brief, some in those optional feature are including but not limited to: described synthetic polymer has ringlike core, for example, carries the ringlike core of the carbon ring group of 6-atom, or comprises inositol, the ringlike core of lactose residue or Sorbitol residue; Described synthetic polymer has the side chain core; Described synthetic polymer has the side chain core, and described side chain core is polyhydric chemical compound residue; Described synthetic polymer has the side chain core, and described side chain core is the glycerol residue; Described synthetic polymer has the side chain core, and described side chain core is the tetramethylolmethane residue; Described synthetic polymer has the side chain core, and described side chain core is two glycerol residues; Described synthetic polymer has the side chain core, and described side chain core is poly-(carboxylic acid) chemical compound residue; Described synthetic polymer has the side chain core, and described side chain core is the polyamino compound residue; Or described synthetic polymer has the side chain core that comprises polyamino acid.
In other optional embodiment: described synthetic polymer comprises polyalkylene oxide, and described synthetic polymer comprises ethylene oxide residue; Described synthetic polymer comprises propylene oxide residue.Synthetic polymer has a kind of molecular weight, it is characterized by, for example, about 100 to about 100,000 molecular weight; About 1,000 to about 20,000 molecular weight; About 1,000 to about 15,000 molecular weight; About 1,000 to about 10,000 molecular weight; About 1,000 to about 5,000 molecular weight; About 7,500 to about 20,000 molecular weight; About 7,500 to about 15,000 molecular weight; About 7,500 to about 20,000 molecular weight.These molecular weight can be number-average molecular weights.These molecular weight can be weight average molecular weight.
In other optional embodiment: described synthetic polymer has 2-12 activatory group; For example, have 2 activatory groups; Or have 3 activatory groups; Or have 4 activatory groups; Or have 6 activatory groups; Or have 9 activatory groups; Or have 12 activatory groups.Randomly, but be in the situation of tissue reactive at those synthetic polymers preferably, the activatory group of described synthetic polymer is a proteins react; With oh group reaction; With thiol group reaction; With amino group reaction.As for the chemical property of activatory group, in various optional embodiments, the feature of those groups can be: comprise the electrophilic site; It is carbonyl group; Comprise leaving group, wherein leaving group randomly is N-oxygen base butanimide group or N-oxygen base maleimide base group; Randomly, these activatory groups comprise the electrophilic site of contiguous leaving group; Described electrophilic site is a carbonyl group; Described leaving group is selected from N-oxygen base butanimide and N-oxygen base maleimide; Described electrophilic group is that carbonyl and leaving group are selected from N-oxygen base butanimide and N-oxygen base maleimide.
The synthetic polymer that carries a plurality of activatory groups can comprise following other parts discussed in detail.For example, described synthetic polymer can comprise formula (main polymer chain)-(Q-Y) n, wherein Q is a linking group, Y is activatory functional group, and n is the integer greater than 1.Randomly, main polymer chain comprises polyalkylene oxide; And/or Q is selected from by in the following group of forming :-G-(CH 2) n-, wherein G is selected from O, S, NH, S-CO-,-O-CO-and-O-CO-NH-(CH 2) nO 2C-CR 1H-is R wherein 1Be selected from hydrogen and alkyl; And O-R 2-CO-NH, wherein R 2Be selected from CH 2And CO-NH-CH 2CH 2, wherein randomly n is 2-12; Y comprises the electrophilic site of contiguous leaving group, wherein randomly, the electrophilic site be carbonyl group and randomly leaving group comprise (N-CO-CH 2) 2
As another example, described synthetic polymer can comprise formula (main polymer chain)-(Q-Y) n, wherein cahin extension agent randomly is positioned between (main polymer chain) and the Q or between Q and the Y.For example, the feature of described synthetic polymer can be formula (main polymer chain)-(D-Q-Y) n, wherein D is biodegradable group, and Q is a linking group, and Y is activatory functional group, and n is the integer greater than 1.Randomly, D comprises the chemical group that is selected from lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone and gathers ('alpha '-hydroxy acids), or D comprises the chemical group that is selected from poly-(aminoacid), poly-(acid anhydride), poly-(ortho esters).Randomly, Q is selected from by in the following group of forming :-G-(CH 2) n-, wherein G is selected from O, S, NH ,-O-CO-and-O-CO-NH-(CH 2) nO 2C-CR 1H-is R wherein 1Be selected from hydrogen and alkyl; And O-R 2-CO-NH, wherein R 2Be selected from CH 2And CO-NH-CH 2CH 2
On the one hand, the invention provides the compositions as top plain statement, described compositions comprises first and second polymer that carry a plurality of activatory groups, and wherein first and second polymer are inequality.For example, first and second polymer can comprise different activated groups; And/or first and second polymer have different number-average molecular weights; And/or first and second polymer have the activated group of different numbers.
The feature of carrying the synthetic composition of a plurality of activatory groups can be its physical attribute.In one aspect of the present invention, described synthetic polymer restrains in the concentration of water at least 1 gram polymer/99 in 25 ℃, is soluble in water; And on the other hand, described synthetic polymer restrains in the concentration of water at least 2 gram polymer/99 in 25 ℃, is soluble in water; And on the other hand, described synthetic polymer restrains in the concentration of water at least 3 gram polymer/99 in 25 ℃, is soluble in water; And on the other hand, described synthetic polymer restrains in the concentration of water at least 4 gram polymer/99 in 25 ℃, is soluble in water; And on the other hand, described synthetic polymer restrains in the concentration of water at least 5 gram polymer/99 in 25 ℃, is soluble in water.
In aspect the present invention includes these of medicine, this paper describes suitable medicine in detail.But, in brief, one optional aspect in, described medicine is that effectively described cytoactive is selected from by in the following group of forming on the cytoactive of one of inhibition or combination: cell division, emiocytosis, cell migration, cytoadherence, the generation of inflammatory activator and/or release, blood vessel generation and free radical form and/or discharge.For example, described medicine is an angiogenesis inhibitor; Or 5-lipoxygenase inhibitor or antagonist; Or chemokine receptor anagonists; Or cell cycle inhibitor or its analog or derivant (for example, microtubule stabilizer, such as paclitaxel, docetaxel, or Peloruside A; Taxane is such as paclitaxel or its analog or derivant; Antimetabolite, alkylating agent, or vinca alkaloids (for example, vinblastine, vincristine, vincristine sulfate, vindesine, vinorelbine or its analog or derivant); Camptothecine or its analog or derivant; Mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, Mitomycin-C, CDK-2 inhibitor and its analog or derivant); Or cyclin dependant kinases inhibitor or its analog or derivant; Or EGF (epidermal growth factor) inhibitors of kinases or its analog or derivant; Or elastase inhibitor or its analog or derivant; Or Xa factor inhibitor or its analog or derivant; Or farnesyl transferase inhibitor or its analog or derivant; Or fibrinogen antagonist or its analog or derivant; Or guanylate cyclase stimulant or its analog or derivant; Or heat shock protein 90 antagonist or its analog or derivant; Or HMGCoA reductase inhibitor or its analog or derivant; Or hydroorotic acid dehydrogenase (hydroorotate dehydrogenase) inhibitor or its analog or derivant; Or IKK2 inhibitor or its analog or derivant; Or IL-1, ICE or IRAK antagonist or its analog or derivant; Or IL-4 agonist or its analog or derivant; Or immunomodulator (for example, rapamycin, tacrolimus, everolimus, biolimus or its analog or derivant; Or inosine monophosphate dehydrogenase inhibitor or its analog or derivant; Or leukotreine inhibitor or its analog or derivant; Or MCP-1 antagonist or its analog or derivant; Or MMP inhibitor or its analog or derivant; NFkappa B inhibitor or its analog or derivant; Or NO antagonist or its analog or derivant; Or P38MAP inhibitors of kinases or its analog or derivant; Or phosphodiesterase inhibitor or its analog or derivant; Or TGF beta inhibitor or its analog or derivant; Or TXA2. antagonist or its analog or derivant; Or the TNFa antagonist, TACE or its analog or derivant; Or tyrosine kinase inhibitor or its analog or derivant; Or vitronectin inhibitor or its analog or derivant; Or fibroblast growth factor inhibitor or its analog or derivant; Or kinases inhibitor or its analog or derivant; Or pdgf receptor kinase inhibitor or its analog or derivant; Or endothelial growth factor receptor kinase inhibitor or its analog or derivant; Or RAR antagonists or its analog or derivant; Or platelet-derived growth factor receptor kinase inhibitor or its analog or derivant; Or fibrinogen antagonist or its analog or derivant; Or antifungal or its analog or derivant; Or diphosphate (bisphosphonate) or its analog or derivant; Or E.C. 3.1.1.32 inhibitor or its analog or derivant; Or histamine H 1/H2/H3 receptor antagonist or its analog or derivant; Or macrolide antibiotic or its analog or derivant; Or GPIIbIIIa receptor antagonist or its analog or derivant; Or endothelin-receptor antagonists or its analog or derivant; Or peroxisome proliferation activated receptors agonist or its analog or derivant; Or estrogen receptor reagent or its analog or derivant; Or somatostatin or its analog or derivant; Or JNK inhibitors of kinases or its analog or derivant; Or melanocortin analog or its derivant; Or raf inhibitors of kinases or its analog or derivant; Or lysyl hydroxylase inhibitor or its analog or derivant; Or IKK1/2 inhibitor or its analog or derivant; Or cytokine modulators; Or cytokine antagonist; Or described medicine is water-fast.
The back is additional concrete aspect of the present invention, and it only is exemplary: on the one hand, compositions of the present invention and method are used (that is, be included in the compositions or use in method) cell cycle inhibitor; On the one hand, compositions of the present invention and method are used paclitaxel; On the one hand, compositions of the present invention and method are used doxorubicin; On the one hand, compositions of the present invention and method are used mitoxantrone; On the one hand, compositions of the present invention and method are used podophyllotoxin (for example, etoposide); On the one hand, compositions of the present invention and method are used immunomodulator; On the one hand, compositions of the present invention and method are used rapamycin; On the one hand, compositions of the present invention and method are used everolimus; On the one hand, compositions of the present invention and method are used tacrolimus; On the one hand, compositions of the present invention and method are used biolimus; On the one hand, compositions of the present invention and method are used the heat shock protein 90 antagonist; On the one hand, compositions of the present invention and method are used geldanamycin; On the one hand, compositions of the present invention and method are used HMG CoA reductase inhibitor; On the one hand, compositions of the present invention and method are used simvastatin; On the one hand, compositions of the present invention and method are used the IMPDH inhibitor; On the one hand, compositions of the present invention and method are used Mycophenolic Acid; On the one hand, compositions of the present invention and method are used 1-α-25 dihydroxy vitamin d3; On the one hand, compositions of the present invention and method are used antifungal; On the one hand, compositions of the present invention and method are used sulconizole; On the one hand, compositions of the present invention and method are used the P38MAP inhibitors of kinases; On the one hand, compositions of the present invention and method are used SB220025.
In all fields, the feature of the present composition can be one or more following standards: described compositions exists with sterile form; Described polymer accounts for about 0.5-40% of described composition weight; Described compositions also comprises solvent, for example, and water; Described compositions also comprises buffer, for example keeps the buffer of the pH of compositions in the 4-10 scope, or keeps the buffer of described compositions pH in the 5-9 scope, or keep the buffer of described compositions pH in the 6-8 scope; Or keep described compositions pH and be lower than 6 buffer.Randomly, described buffer comprises phosphate.
In an optional embodiment, the present invention can maybe cannot comprise the compositions of medicine, can comprise protein.In all fields, these only are exemplary: described protein is collagen protein; Described albumen comprises the primary amino radical group.Compositions of the present invention also comprises polysaccharide, for example, and glysoaminoglycan, rather than comprise protein.
About the more details of the present composition and their production method, be described with detail more at this paper.In addition, as also describing with detail more at this paper, the present invention also provides the whole bag of tricks that influence the interior biological process of body.For example, on the one hand, the invention provides the method that influences biological process in the body, described method comprises the interior biological organization of body of a) selecting to carry X functional group; B) provide and comprise synthetic polymer and medicine, carry the compositions of the polymer of a plurality of activated group Y, wherein Y and X reaction; C) at i) X and Y reaction and ii) near the biological process the tissue by under the condition of drug influence the tissue of step a) is contacted with the compositions of step b).Randomly, with before the compositions of step b) contacts, biological organization has suffered surgery operating wound, thus tissue is placed under the risk that adhesion forms.The formation of adhesion is undesirable side-product in the abdominal surgery, or the formation of adhesion is undesirable side-product in the cardiac operation, or the formation of adhesion is undesirable side-product in the spinal surgery, or the formation of adhesion is undesirable side-product in the chirurgia nasalis operation, or the formation of adhesion is undesirable side-product in the throat surgical operation, or the formation of adhesion is undesirable side-product in the grafting of breast.
In influencing body in other optional embodiment of the method for biological process, biological organization has suffered surgery operating wound with before the compositions of step b) contacts, and described surgical operation is the surgical operation of tumor resection.Randomly, described surgical operation is the breast surgical operation; Described surgical operation is a lumpectomy; Described surgical operation is the brain surgical operation; Described surgical operation is the hepatectomy surgical operation; Described surgical operation is a colon tumor excision surgical operation; Or described surgical operation is the neurosurgery tumorectomy, and wherein the surgical operation of these types only is exemplary.
On the one hand, the invention provides the method that reduces the surgical operation adhesion, described method comprises multifunctional N-Hydroxysuccinimide base PEG derivant is applied on the tissue surface.Described multifunctional N-Hydroxysuccinimide base PEG derivant (for example, four functionalities gather (ethylene glycol) succinimido glutarate) can exist with the solution form, and wherein said solution has alkaline pH (for example, greater than 8 pH).On the one hand, described multifunctional N-Hydroxysuccinimide base PEG derivant is not mixed with any other tissue reactive compounds.On the other hand, described multifunctional N-Hydroxysuccinimide base PEG derivant will not mixed with the component of described derivatives reaction with any.On the one hand, provide the method that reduces the surgical operation adhesion, described method comprises that the tissue reactive compositions that will be made up of multifunctional N-Hydroxysuccinimide base PEG derivant basically is applied on the tissue surface.On the other hand, provide the method that reduces the surgical operation adhesion, described method comprises that the tissue reactive compositions that will be made up of multifunctional N-Hydroxysuccinimide base PEG derivant is applied on the tissue surface.
In various aspects of the present invention, the tissue that contacts with the synthetic polymer that carries a plurality of activatory groups is: the inner surface in physiology chamber; Blood vessel; Fallopian tube; Or any experience balloon catheter inserts the tissue of art.This paper describes and favourable these and other tissue that contacts of the present composition in more detail.
These and other aspects of the invention will be by coming more detailed introduction with reference to subsequently accompanying drawing and detailed description.Thereby will above describe and disclose the subject content that illustrates that it is quoted with each publication full content cited herein is incorporated herein by reference.
The accompanying drawing summary
Fig. 1. the activatory PEG succinimido of four senses glutarate (ester bond) is (SG-PEG).
Fig. 2. the activatory propoxyl group succinimido of four senses PEG (ehter bond) is (SP-PEG).
Fig. 3. the activatory ethyoxyl succinimido of four senses PEG (ehter bond) is (SE-PEG).
Fig. 4. the activatory methoxyl group succinimido of four senses PEG (ehter bond) is (SM-PEG).
Fig. 5. the activatory succinamide succinimido of four senses PEG (amido link) is (SSA-PEG).
Fig. 6. the activatory carbonic ester succinimido of four senses PEG (ehter bond) is (SC-PEG).
Fig. 7. the activatory propionic aldehyde PEG of four senses (A-PEG).
Fig. 8. the activatory glycidyl ether PEG of four senses (E-PEG).
Fig. 9. the activatory vinyl sulfone PEG of four senses (V-PEG).
Figure 10. the activatory isocyanates PEG of four senses (I-PEG).
Figure 11. the activatory maleimide PEG of four senses (Mal-PEG).
Figure 12 is that data are drawn, and it shows the influence of the concentration of 4-arm NHS PEG to effect (percentage ratio adhesion) in the rat caecum sidewall surgical operation adhesion model.
Figure 13 is that data are drawn, and it shows the influence of the concentration of 4-arm NHS PEG to effect (adhesion toughness) in the rat caecum sidewall surgical operation adhesion model.
Figure 14 is that data are drawn, and its display buffer liquid pH is to the influence of 4-arm NHS PEG effect (percentage ratio adhesion) in the rat caecum sidewall surgical operation adhesion model.
Figure 15 is that data are drawn, and its display buffer liquid pH is to the influence of 4-arm NHS PEG effect (adhesion toughness) in the rat caecum sidewall surgical operation adhesion model.
Figure 16 is a sketch map, and it shows the action site of biological pathway, there the cell cycle inhibitor inhibition cell cycle that can play a role.This pictorialization cell cycle inhibitor can show the position of effect in their bodies.
Figure 17 is a curve chart, and it shows that function as the concentration of mitoxantrone is to human fibroblasts inhibition of proliferation percentage ratio.
Figure 18 is a curve chart, and it shows the inhibition percentage ratio that the function as the concentration of mitoxantrone produces nitrogen oxide in the RAW264.7 cell.
Figure 19 is a curve chart, and it shows the inhibition percentage ratio of the TNF α of THP-1 cell being produced as the function of Bay11-7082 concentration.
Detailed Description Of The Invention
According to the present invention, the synthetic polymer that carries the group of a plurality of activation can be used in various medical applications and medical apparatus and use. More specifically, the invention provides and the synthetic polymer that carries a plurality of activated groups can be applied on the substrate, described substrate carries the functional group that can react with the activated group of synthetic polymer. Described substrate can be biological or synthetic source. The surface of biological origin comprises, but be not limited to, skin histology, musculature, the occular of vascular tissue tissue, the tissue of epidermal tissue, epithelial tissue, adventitial tissue, abdominal tissues, brain tissue, nose tissue, esophogeal tissue, lung tissue, spinal tissues, tendinous tissue and ligament tissue or any other kind of in mammal, finding. The surface in synthetic source includes, but not limited to the material for the production of medical apparatus, the material that is used for the coating medical apparatus, metal, plastics, pottery, glass etc.
The present invention recognize the functional group (electrophilic) of carrying one or more activation (below be expressed as " Y ") synthetic polymer will with comprise one or more can with functional group's (group of nucleophilic of the activation functional group reactions of synthetic polymer; The below represents with " X ") reaction, thus synthetic polymer covalently is combined with described surface, as follows:
Surface-Xm+ polymer-Yn→ polymer-Z-surface
M 〉=1 wherein, n 〉=1, and m+n 〉=2;
X＝-NH 2，-SH，-OH，-PH 2，-CO-NH-NH 2, etc., and can be identical or different;
Y＝-CO 2N(COCH 2) 2，-CO 2H，-CHO，-CHOCH 2，-N＝C＝O，
-SO 2-CH＝CH 2，-N(COCH 2) 2，-CO-O-CO-R，-S-S-(C 5H 4N), etc., and can be identical or different; And
Functional group's [electrophilic] of Z=activation (Y) with can with the corresponding functional group [nucleophilic] of the functional group reactions of activation (X) in conjunction with the functional group that produces.
As implied above, the present invention expects that also X can be identical or different with Y, namely, described polymer can have the functional group of two different activation, and described surface can have two or more can with the different functional groups of the activation functional group reactions of described polymer.
The main chain of each polymer preferably includes, alkylene oxide, especially, oxirane, expoxy propane, and the polymeric residues of their mixture. And the main chain of each polymer preferably includes poly-(alkylene oxide) part, for example, and oxirane, the polymerization of expoxy propane etc. or combined polymerization product.
The example of dual functional alkylene oxide can be expressed as:
Y-polymer-Y
Wherein Y as defined above, and term " polymer " " expression-(CH2CH 2O) n-or-(CH (CH3)CH 2O) n-or-(CH2CH 2O) m-(CH(CH 3)CH 2O) n-。
The example of polymer
Usually by linking group (below be expressed as " Q ") and main polymer chain coupling, wherein many is known or possible to the Y of functional group of required activation.
Polymer-(Q-Y)n
There are many methods can prepare various functionalized polymer, below some of them are listed in:
Q-wherein Total=
  -O-(CH 2) n-   -S-(CH 2) n-   -NH-(CH 2) n-   -O 2C-NH-(CH 2) n-   -O 2C-(CH 2) n   -O 2C-CR 1H-   -O-R 2-CO-NH- Polymer-O-(CH2) n-Y polymer-S-(CH2) n-Y polymer-NH-(CH2) n-Y polymer-O2C-NH-(CH 2) n-Y polymer-O2C-(CH 2) n-Y polymer-O2C-CRH-Y polymer-O-R-CO-NH-Y
N=1-12 in each case wherein;
R 1＝H，CH 3，C 2H 5Deng;
R 2＝CH 2，CO-NH-CH 2CH 2。
For example, work as Q=OCH2CH 2；Y＝-CO 2N(COCH 2) 2 And X=-NH2,-SH, or-during OH, the reaction that obtains and Z group are with as follows:
Can be with an additional group, the below is expressed as " D ", inserts between polymer and the linking group, thereby changes degradation model and the release that is attached to surperficial polymer.
Surface-X+ polymer-D-Q-Y → surface-Z-Q-D-polymer
Some useful biodegradable groups " D " comprise lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone, poly-('alpha '-hydroxy acids), poly-(aminoacid), poly-(acid anhydride), poly-(ortho esters), comprise polyester from one or more monomer residues, described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, glycolic (glycolic acid), 6-caprolactone, trimethylene carbonate, 1,4-dioxane-2-ketone, with 1, and 5-Dioxepane-2-ketone (1,5-dioxepan-2-one), peptide, carbohydrate and various two or tripeptides.
In another preferred embodiment, described chemical compound each all have 12 functional groups.By making activatory polymer of first four sense and the activatory polymer reaction of four senses form these chemical compounds, the functional group of each of wherein said two chemical compounds all is a reaction pair, to form the activatory polymer of " 12-arm " functionality.An example of " 12-arm " chemical compound like this is 12-sulfydryl-PEG, molecular weight 50,000, and it makes up oneself and four (outside) link coupled cores four of four-functional sulfydryl-PEG molecule-functional succinimide ester PEG.The molecular weight that depends on the activatory polymer initial substance of described four-sense, the size of these polymer is from surpassing 10,000 molecular weight to surpassing 100,000 molecular weight.
Use conventional synthesizing, can easily synthesize the polyfunctional poly compound of other type.But, should carefully prepare have consistent arm lengths the multi-arm product to avoid the steric hindrance of reactive group.Therefore, be suitable for activatory polymer of the present invention and can have many geometries and configuration.According to exemplary polymer of the present invention, and prepare them and use their method to be described in U.S. Patent number 5,874,500; 6,051,648; 6,166,130; 6,312,725; 6,323,278; With 6,458,889.
The chemical compound core
As mentioned above, each chemical compound has a plurality of activatory functional groups, succinimido group or maleimide reactive group.Think that the non--reactive remainder of chemical compound is its " core ".
Described polymer core can be synthetic polyamino acid, polysaccharide, or synthetic polymer.Preferred polymer core material is synthetic hydrophilic polymer.Suitable synthesis hydrophilic polymer comprises that particularly, polyalkylene oxide is such as poly(ethylene oxide) ((CH 2CH 2O) n), poly(propylene oxide) ((CH (CH 3) CH 2O) n) or polyethylene/polypropylene oxides mixture ((CH 2CH 2O) n-(CH (CH 3) CH 2O) n).A kind of particularly preferred synthesis hydrophilic polymer is Polyethylene Glycol (PEG), and its molecular weight (number average or weight average) is from about 100 to about 100,000 molecular weight, more preferably from about 1,000 to about 20,000 molecular weight.More preferably, when described polymer core is a Polyethylene Glycol, its molecular weight usually from about 7,500 to about 20,000 molecular weight.Most preferably, described Polyethylene Glycol has about 10,000 molecular weight.
Carrying a plurality of polyalkylene oxides that activate functional group can obtain from commercial channels, also can use known method easily to be prepared.For example, see Poly (ethylene Glycol) Chemistry:Biotechnical and Biomedical Applications, the 22nd chapter, J.MiltonHarris, ed., Plenum Press, NY (1992); The PEG Shop online catalogue; And Shearwater Polymers, Inc.Catalog, Polyethylene Glycol Derivatives, Huntsville, AL (2000-2001).
As described in more detail, can be with the compound administration of carrying a plurality of activable groups to tissue, described thereupon chemical compound and the reaction of structural reactive functional groups also form covalent conjunct agent.In a preferred embodiment, but the chemical compound that carries a plurality of activated groups only is to be added to structural tissue-reactive compounds, and described chemical compound does not combine with any other chemical compound, or with any other chemical compound reaction, that is, its only with tissue and/or with the related albumino reaction of tissue.Therefore, in a preferred embodiment, organize and carry the chemical compound reaction of a plurality of activable groups, and this tissue and this chemical compound do not react with any other chemicals.Carry these chemical compounds of a plurality of activated groups, with tissue reaction after, give the described Ideal Characteristics of organizing, and reduce in the situation of adhesion of described tissue and other tissue particularly useful at needs.
In one aspect of the method, in relating to the situation of restenosis, described chemical compound and tissue reaction.Restenosis refers to handling, the tremulous pulse of the same loci that has taken place such as angioplasty or metal stent operation again-narrow or block.The final result of restenosis is that the obstruction by material causes narrowing in the tremulous pulse, and it is flowing of occlude blood finally.But the chemical compound that carries a plurality of activated groups can be adhered to the tissue that relates to restenosis, thereby use it for the obstruction that alleviates undesirable material in the tissue site.
In yet another aspect, increase in the situation of lubricity described chemical compound and tissue reaction at needs.In other words, organize not in the situation of adhesion easily at the processed tissue of needs and other, described chemical compound is useful.In a related aspect, the surface reaction of described chemical compound and medical apparatus makes described device lubricity increase thus.In addition, one preferred aspect in, described surface (tissue surface or apparatus surface) but with the chemical compound reaction of carrying a plurality of activated groups, and should the surface and this chemical compound with any other chemicals reaction.
For the application in the compositions of prevention of surgical surgical adhesions, or the application in solving restenosis, or needs increase tissue or the lip-deep lubricity of medical apparatus Anywhere in use, preferred activatory polymer is as follows: the chemical compound that carries activatory functional group is four functional PEG, tetramethylolmethane gathers (ethylene glycol) ether four-butanimide glutarate (10,000 molecular weight).This " four-arm " PEGs forms by the ethoxylation of tetramethylolmethane, and wherein each of four chains all is about 2,500 molecular weight, subsequently with its derivatization, promptly all introduces functional group on four arms.Replace tetramethylolmethane, (ethylene glycol) chemical compound of similarly birdsing of the same feather flock together by two glycerol are polymeric also is preferred.
The little organic molecule of multifunctional activity can also be used in these application.These chemical compounds comprise two-sense, two-succinimido ester and two-maleimide based compound, and other well-known chemical compound that can obtain by commercial sources (Pierce Chemical Co., Rockford, IL).In addition, those skilled in the art can use the easily synthetic low-molecular-weight of conventional technique of organic chemistry many-functional response's property chemical compound.On this chemical compound is and four link coupled tetramethylolmethanes of 1,3-propanedicarboxylic acid that wherein each arm has N-hydroxyl-succinimido ester (NHS) medicated cap.Can be from inositol (radiation 6 arms), lactose (9 arm) or Sorbitol (straight chain 6-arm) synthesize similar compound.Described end-capping group can be dimaleoyl imino usually, vinyl sulfone etc., rather than NHS.
Reactive group and substrate key
In the present invention, most preferred key, Z, comprise sulfur, oxygen or the nitrogen-atoms on the surface compound and carry the activation functional group chemical compound on carbon or the covalent bond between the sulphur atom.Therefore, key can be an amido link, thio-acid ester bond, thioether bond, disulfide bond etc.The key of the wide range of types of in scientific literature, knowing the sulfydryl-reactive group of broad variety and when the reaction of they and mercapto groups, forming.For example, see Bodanszky, M., Principles of Peptide Synthesis, second edition, 21-37 page or leaf, Springer-Verlog, Berlin (1993); And Lundbland, R.L., Chemical Reagents forProtein Modification, second edition, chapter 6, CRC Press, Boca Raton, Fla. (1991).
Use for great majority, preferably form the thio-acid ester bond or react the activatory functional group that forms amide with amine groups with the mercapto groups reaction.These chemical compounds are described in Fig. 1 and are comprised, particularly, following chemical compound, numeral in the bracket is corresponding to the structure that shows among Fig. 1: blended anhydride, such as PEG-glutaryl-acetyl group-anhydride (1), PEG-glutaryl-isovaleryl-anhydride (2), PEG-glutaryl-pivaloyl-anhydride (3) and at Bodanszky, the related compound that occurs in 23 pages; The ester derivant of phosphorus is such as structure (4) and (5); The ester derivant of p-nitrophenol (6), the ester derivant (7) of p-nitro thiophenol, the ester derivant of Pentafluorophenol (8), the ester derivant of structure (9) and as at Bodanszky, the related activity ester that occurs in 31-32 page or leaf and the table 2; The ester of the hydroxylamine that replaces, such as those (10) of N-hydroxyl-phthalimide, N-hydroxyl-butanimide (11), those of N-hydroxyl-glutarimide (12), and at Bodanszky; The dependency structure that occurs in the table 3; The ester of 1-hydroxyl-benzotriazole (13), 3-hydroxyl-3,4-dihydro-benzo three azines (benzotriazine)-4-ketone (14) and 3-hydroxyl-3,4-dihydro-chinazoline-4-ketone; The derivant of carbonylic imidazole; And isocyanates.With these chemical compounds, can also use the formation of adjuvant promotion key, such as using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide to promote the coupling of carboxylic group (that is, 1,3-propanedicarboxylic acid and succinic acid) and mercapto groups.
Except the sulfydryl reactive compounds that forms the thio-acid ester bond, can use various other chemical compounds that form other type bonds.For example, the chemical compound and the mercapto groups formation imino group-thio-acid ester bond that comprise methyl imidate derivant.Perhaps, can use sulfydryl reactive group and mercapto groups to form disulfide bond, such as the ortho position pyridyl disulfide, 3-nitro-2-pyridene sulfenyl, 2-nitro-5-sulfo-cyanobenzoic acid, 5,5 '-dithio-two (2-nitrobenzoic acid), the derivant of thiosulfuric acid methyl ester and 2,4-dinitrophenyl cysteinyl disulphide.In these situations, can be with adjuvant, the two-tert-butyl ester such as hydrogen peroxide or azo-2-carboxylic acid is used to promote the formation of disulfide bond.
In addition, another kind of sulfydryl reactive group and mercapto groups form thioether bond.These groups comprise, particularly, and iodoacetamide; N-ethyl maleimide and other maleimide comprise the glucosan maleimide, list-bromo-bimane and related compound; vinyl sulfone; epoxide, the derivant of O-methyl-isourea, piperazine; aziridine; and 4-(amino-sulfonyl-) 7-fluoro-2,1,3-Ben Bing oxadiazole.
Cahin extension agent
Functional group directly can be linked to each other with the chemical compound core, perhaps they be linked to each other indirectly by cahin extension agent.These cahin extension agents are known in the art.See, for example, PCT WO97/22371, " linking group " of its description is suitable for being used as cahin extension agent in the present composition.Cahin extension agent is useful avoiding on relevant with the formation of the intermolecular Direct Bonding sometimes steric hindrance problem.Perhaps, can use cahin extension agent that the activatory chemical compound of some many-senses is joined together to form bigger molecule.In a particularly preferred scheme, can also use cahin extension agent behind the gel formation of using and producing, to change the degraded character of described compositions.For example, cahin extension agent can be participated in activatory polymer, hinder hydrolysis, or the site of enzymatic degradation is provided to promote hydrolysis.Cahin extension agent can also activate or suppress the activity of amine reactivity or sulfydryl reactive group.For example, because steric hindrance, near the big group of expection activation functional group reduces combination rate.The electron withdraw group of the reactive carbonyl of the contiguous glutaryl of expection-N-hydroxy-succinamide base makes this carbonyl carbon and surface amino groups or sulfydryl gametophyte even has more reactivity.
Cahin extension agent can provide degradation site, that is, and and hydrolyzable site.The example of hydrolyzable cahin extension agent comprises, particularly, and 'alpha '-hydroxy acids such as lactic acid and glycolic (glycolic acid); Gather (lactone) such as caprolactone, valerolactone, γ butyl lactone and p-diethyleno dioxide ketone; Poly-(aminoacid); Poly-(anhydride) such as glutarate and succinate; Poly-(ortho esters); Poly-(orthocarbonic ester) is such as trimethylene carbonate; With poly-(phosphate ester).The non-degradable cahin extension agent comprises, particularly, and butanimide, propanoic acid and carboxymethyl ester.See that for example PCT WO 99/07417.The example of cahin extension agent that can enzymatic degradation comprises the leucine-glycine-proline-alanine that can degrade with collagenase; With the glycine-proline-lysine that can use the plasmin enzymatic degradation.
Synthetic polymer
In order to prepare the present composition, two or more activatory functional groups are carried at first necessary providing, such as first synthetic polymer of butanimide group or dimaleoyl imino group.When being used for this paper, term " polymer " " refer in particular to poly-alkyl (polypolyalkyl), polyamino acid and polysaccharide.In addition, for device, graft, the outside or Orally administered, described polymer can be polyacrylic acid or carbopol.
When being used for this paper, term " synthetic polymer " refers to not be naturally occurring but passes through the polymer that chemistry produces.Like this, natural protein such as collagen protein and the natural polysaccharide that exists of existing foreclosed especially such as hyaluronic acid.Synthetic collagen protein and synthetic hyaluronic acid and derivant thereof are included.The synthetic polymer that carries electrophilic group is also referred to as at this paper " multifunctional activatory synthetic polymer ".Term " multifunctional activatory " (or, simply, " activatory ") refers to have or have through chemical modification the synthetic polymer of two or more electrophilic groups, and described electrophilic group can form covalent bond with the nucleophilic group reaction.The type of multifunctional activatory synthetic polymer comprises that difunctionality is activatory, the polymer of the activatory and limb ray of four senses.
Be used in multifunctional activatory synthetic polymer of the present invention and must comprise at least two, more preferably, at least three functional groups.
Carry the synthetic polymer of a plurality of activatory functional groups
The synthetic polymer that will carry a plurality of activatory functional groups at this paper is also referred to as " activatory polymer ".For use in the present invention, activatory multifunctional synthetic polymer must carry at least two, more preferably, at least three, activation functional group and most preferably, at least four activatory functional groups.
Use preferred activatory polymer in the present composition is the polymer that carries two or more succinimido groups, and described succinimido group can form covalent bond with electrophilic group on other molecule.The succinimido group with carry primary amino radical (NH 2) material of group, such as tissue surface, poly-(lysine), the polymer of aminofunctional or collagen protein have highly reactive.The succinimido group with carry thiol (SH) material of group, such as many-thiol PEG, tissue surface, the polymer that thiol is functionalized or carry that the synthetic polypeptide of a plurality of cysteine residues is less to have a reactivity.
When being used for this paper, term " carries two or more succinimido groups " and is intended to contains the polymer that carries two or more succinimido groups that can obtain by commercial sources, and must pass through chemically derived those of two or more succinimido groups of comprising.When being used for this paper, term " succinimido group " is intended to contain other such variant of sulfosuccinimide base group and " generally " succinimido group.The existence of the sodium sulfite part on the sulfosuccinimide base group provides the increase of described polymer dissolution.
Hydrophilic polymer
The preferred hydrophilic polymer and, especially, various Polyethylene Glycol use in the present composition.When being used for this paper, term " PEG " refers to have repetitive structure (OCH 2CH 2) nPolymer.
Fig. 1 to 11 shows that some are concrete, the structure of the PEG of four sense activated form.Described in figure, the succinimido group is to be expressed as-N (COCH 2) 2Five-atom ring structure.
Fig. 1 shows the activatory PEG succinimido of four senses glutarate, is called the structure of SG-PEG at this paper.The another kind of activated form of PEG is called PEG succinyl phosphorons amino propyl acid ester (SE-PEG).Fig. 2 shows the structural formula of the activatory SE-PEG of four senses.In the universal architecture formula of described chemical compound, subscript 3 quilts " m " replace.In Fig. 4 embodiments shown, m=3 promptly has three to repeat CH on each side of PEG 2Group.
The structure of Fig. 2 produces a kind of conjugate, and described conjugate comprises less " ether " key that suffers hydrolysis.The structure of the conjugate that ester bond wherein is provided that this and Fig. 1 show is distinct.Under physiological condition, ester bond suffers hydrolysis.
In addition, the another kind of official of Polyethylene Glycol can activatory form be shown among Fig. 3.
Fig. 4 provides the another kind of official's energy that is similar to Fig. 2 and Fig. 3 chemical compound activatory PEG.
The another kind of official of PEG can activated form be called PEG succinimido succinamide (being presented at the SSA-PEG among Fig. 5).In being shown in the structure of Fig. 5, m=2; But, can also be with related compound, wherein m=1 or m=3-10 use in the present composition.
Structure among Fig. 5 produces the conjugate of a kind of comprising of " amide " key, described " amide " key, and ehter bond as described previously lessly is subjected to hydrolysis and therefore more stable than ester bond.
When m=0, provide the another kind of activated form of PEG in addition.This chemical compound is called PEG succinimdyl carbonate (SC-PEG).Fig. 6 shows the structural formula of the activatory SC-PEG of four senses.
As above discuss, the preferred activated polyethylene glycol derivant of using is in the present invention carried the succinimido group as reactive group.But different activated groups can be attached to the site along the length of PEG molecule.For example, PEG can derive the formation official can activatory PEG propionic aldehyde (A-PEG), and Fig. 7 shows its four sense activated form.The key that Fig. 5 is shown is called-(CH 2) m-NH-key, wherein m=1-10.
In addition, the another kind of form of activated polyglycol is the activatory PEG glycidyl ether of sense (E-PEG), and wherein its activatory compound exhibits of four senses is in Fig. 8.
Another activated derivatives of Polyethylene Glycol is the activatory PEG-vinyl sulfone of sense (V-PEG), and it is shown among Fig. 9.The another kind of activated derivatives of Polyethylene Glycol is the activatory PEG-isocyanates of sense (I-PEG), and it is shown among Figure 10, and another kind of activated polyglycol is the activatory vinyl sulfone PEG of sense, and it is shown among Figure 11.
The multifunctional activated polyglycol of preferably using in the present composition is to carry the Polyethylene Glycol of succinimido group, such as SG-PEG and SE-PEG (being shown among Fig. 1-4), preferably exists with trifunctional or four sense activated form.
The activated form of many above-described Polyethylene Glycol now can be from SunBio PEG-SHOP, Anyang City, South Korea, Shearwater Polymers, Huntsville, AL, and UnionCarbide, South Charleston, WV obtains by commercial sources.
Hydrophobic polymer
Hydrophobic polymer can also be used to prepare compositions of the present invention.Preferably the hydrophobic polymer that uses in the present invention carries, thereby or can be derived and be carried, two or more electrophilic groups, such as the succinimido group, most preferably, two, three, or four electrophilic groups.As when being used in this paper, term " hydrophobic polymer " refers to comprise the oxygen of relative small scale or the polymer of nitrogen-atoms.
The hydrophobic polymer that has carried two or more succinimido groups comprises, but be not limited to, suberic acid two succinimido esters (DSS), suberic acid two (sulfosuccinimide base) ester (BS3), dithio two (propanoic acid succinimido ester) (DSP), two (2-succinimido oxygen ketonic oxygen) ethyl sulfone (BSOCOES) and 3,3 '-dithio two (propanoic acid sulfosuccinimide base ester) (DTSPP) and their analog and derivant.Above-cited polymer from Pierce (Rockford, IL), respectively at Catalogue#s.21555,21579,22585,21554 and obtain by commercial sources for 21577 times.
The preferred hydrophobic polymer that uses in the present invention has the carbochain no longer than about 14 carbon usually.Polymer with the carbochain of being longer than 14 carbon basically has the dissolubility of non-constant usually in aqueous solution, and like this, when with the aqueous solution of the synthetic polymer that carries a plurality of nucleophilic groups, has the very long response time.
Thereby make polymer-derived carry functional group
Some polymer such as polyacid, is carried two or more functional groups thereby can derive, such as the succinimido group.The polyacid of Shi Yonging includes, but not limited to the tricarboxylic acids based on trimethylolpropane in the present invention, based on the tetrabasic carboxylic acid of two (trimethylolpropanes), and 1,5-pentanedicarboxylic acid., suberic acid, and hexadecandioic acid (hexadecane diacid) (thapsic acid).Many these polyacid can (Wilmington obtains by commercial sources in DE) from the DuPont chemical company.
According to conventional method, polyacid can be by at N, and N '-dicyclohexylcarbodiimide (DCC) is when existing, with the N-hydroxy-succinamide (NHS) of suitable mole thus reaction by chemically derived two or more succinimido groups that carry.
Make and in all sorts of ways, polyhydric alcohol such as trimethylolpropane and two (trimethylolpropane) can be changed into carboxylic acid form, when existing, DCC produces trifunctional and the activatory polymer of four senses respectively then by further it being derived with the reaction of NHS, as described in U. S. application series number 08/403,358.By adding the succinimido group, with polyacid such as 1,5-pentanedicarboxylic acid. (HOOC-(CH 2) 5-COOH), suberic acid (HOOC-(CH 2) 6-COOH), and thapsic acid (HOOC-(CH 2) 14-COOH) derive to produce the activatory polymer of two senses.
Can be with polyamines such as ethylenediamine (H 2N-CH 2CH 2-NH 2), tetra-methylenedimine (H 2N-(CH 2) 4-NH 2), five methylene diamine (1,5 pentanediamine) (H 2N-(CH 2) 5-NH 2), hexamethylene diamine (H 2N-(CH 2) 6-NH 2), two (2-hydroxyethyl) amine (HN-(CH 2CH 2OH) 2), two (2) amino-ethyls) amine (HN-(CH 2CH 2NH 2) 2) and three (2-amino-ethyl) amine (N-(CH 2CH 2NH 2) 3) chemically derived be polyacid, then when DCC exists, by polyacid can being derived to carrying two or more succinimido groups, as described in U. S. application series number 08/403,358 with the N-hydroxy-succinamide reaction of suitable mole.Many these polyamines are commercially available from DuPont ChemicalCompany.
Preparation of compositions
Usually, the concentration that is used to prepare the activated polymer of the present composition will depend on several factors and change, and these factors comprise that the type of specific synthetic polymer of use and molecular weight and ideal final use use.
Usually, we have found that when using many-succinimido PEG that preferably it uses on the concentration of about percent 40 scopes in about percent 0.5 of final composition weight as synthetic polymer.For example, the final composition with 1g (1000mg) gross weight will comprise many succinimidos PEG of about 5 to about 400mg.
Also have the potentiality of reacting because carry a plurality of polymer that activate functional group with water, usually activated polymer is prepared with dried forms, packing and storage are to prevent owing to reacting with water, these activatory functional group loss of activity, this reaction typically occur in these activated groups are exposed to contact with aqueous medium.Prepare asepticly, the method for the synthesis hydrophilic polymer that carries a plurality of electrophilics (electrophylic) group of dried forms sees U. S. application series number 08/497,573, and submit to June 30 nineteen ninety-five.For example, can be with dry synthetic polymer compression molding flakiness or film, and then use γ, or the e x radiation x carries out sterilization treatment with it.Exsiccant film or the sheet that obtains can be cut into the size that needs or be cut into the littler granule of size.
Other component is participated in described activatory synthetic polymer
Naturally occurring protein such as the derivant of collagen protein and various naturally occurring polysaccharide, additionally can be participated in the compositions of the present invention such as glysoaminoglycan.When these other components also carry with synthetic polymer on the functional group of functional group reactions the time, the formation that they will cause crosslinked synthetic polymer-naturally occurring polymeric matrix in the mixing and/or the existence in the cross-linking process of first and second synthetic polymers.Especially, when these naturally occurring polymer (protein or polysaccharide) also carry nucleophilic group such as primary amino radical group, electrophilic group on second synthetic polymer will with the primary amino radical group of these components, and first the nucleophilic group reaction on the synthetic polymer, thereby cause these other components to become the part of polymeric matrix.
Usually, glysoaminoglycan must pass through deacetylation, desulfidation, thereby or both carry out chemically derived carry can with the primary amino radical group of electrophilic group on synthetic polymer molecule reaction.Can be comprised following by deutero-glysoaminoglycan according to one or both of preceding method: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate, and heparin.The derivatization that glysoaminoglycan is carried out by deacetylation and/or desulfidation and glysoaminoglycan derivant that obtains and synthesis hydrophilic polymer covalently bind in common transfer, describe in detail in the U.S. Patent Application Serial of submitting on November 3rd, 1993 of having authorized 08/146,843.
Similarly, the electrophilic group on second synthetic polymer will with primary amino radical group on some natural lysine residue that exists on the albumen or the thiol radical reaction on the cysteine residues.Be rich in the protein of lysine, have reactive especially to electrophilic group on the synthetic polymer such as the derivant of collagen protein and it.When being used for this paper, term " collagen protein " is intended to contain any kind, from the collagen protein in any source, it comprises, but be not limited to, the collagen protein that extracting or reorganization produce from tissue, collagen protein analog, collagen derivative, the collagen protein of modifying and the collagen protein of degeneration are such as gelatin.The covalent bond of collagen protein and synthesis hydrophilic polymer is described in detail in common transfer, licenses on November 10th, 1992 in people's such as Rhee the U.S. Patent number 5,162,430.
Normally, the collagen protein in any source can be used in compositions of the present invention; For example, can such as extracting and collagen purification albumen in corium cattle or pig and the people's Placenta Hominis, maybe can adopt recombinant technique or other method to produce collagen protein from people or other mammal source.From the purification of Corii Bovis seu Bubali, in essence the collagen protein in non--antigenic solution be prepared as known in the art.The U.S. Patent number 5,428,022 that licenses to people such as Palefsky June 27 nineteen ninety-five discloses extracting and the proteic method of collagen purification from people's Placenta Hominis.The U.S. patent application serial numbers 08/183,648 that is filed on January 18th, 1994 discloses transgenic animal, comprises producing the proteic method of recombinant human collagen in the milk of transgenic cow.When being used for this paper, term " collagen protein " or " collagen substance " refer to various forms of collagen protein, comprise handling or other those of modified.
Though usually preferred I type can be used the collagen protein that includes but not limited to any kind of I, II, III, IV type or their any combination in the present composition.Can use the collagen protein that comprises atelopeptide or end peptide; But, when using from allogenic collagen protein, during such as bovine collagen albumen, usually preferred atelopeptide collagen protein, because hold the collagen protein of peptide to compare with comprising, its immunogenicity minimizing.
Though can use previous crosslinked collagen protein, in the present composition, the preferred use before not by method such as heating, radiation, or chemical cross-linking agent carries out crosslinked collagen protein.Can be by commercial sources from Inamed Aesthetics (Santa Barbara, CA) obtain trade (brand) name and be respectively ZYDERM I Collagen and ZYDERM II Collagen, collagen concentration is the noncrosslinking atelopeptide fibril collagen protein of 35mg/ml and 65mg/ml.Can obtain trade mark ZYPLAST Collagen by name from Inamed Aesthetics by commercial sources, collagen concentration is the atelopeptide fibril collagen protein of the glutaraldehyde cross-linking of 35mg/ml.
Make collagen protein used in this invention usually with the concentration between about 20mg/ml and about 120mg/ml; Preferably the concentration between about 30mg/ml and about 90mg/ml is present in the waterborne suspension.
Though preferred complete collagen protein can also use degeneration in the present composition, often be called the collagen protein of gelatin.Gelatin can have the degradable speed additional advantage faster than collagen protein.
Because the viscosity denseness of non-fibril collagen protein, the non-fibril collagen protein of preferred usually use tends to used as bioadhesive polymer in the present composition.Term " non-fibril collagen protein " refers to any through that modify or not modified collagen substance, and it exists with non-fibril form basically at pH7, and is indicated as the optical transparency of the waterborne suspension by collagen protein.
Can in the present composition, use the collagen protein that has existed with non-fibril form.When being used for this paper, term " non-fibril collagen protein " tends to contain the non-fibril collagen protein type that exists with native form, thereby and through chemical modification or the collagen protein that exists with non-fibril form about neutral pH.Non-fibril (or little fibril) the collagen protein type that exists with native form comprises IV, VI and VII type.
The collagen protein through chemical modification that exists with non-fibril form in neutral pH comprises the collagen protein and the methylated collagen protein of succinylation; the method for preparing them is described in U.S. Patent number 4; 164; 559; on August 14th, 1979 licensed to people such as Miyata, hereby it was incorporated herein by reference in full.As disclosed in U. S. application series number 08/476,825, because the inherent viscosity of methylated collagen albumen is especially preferably used it in the compositions of bioadhesion.
The collagen protein of use in the crosslinked polymer composition of the present invention can work the fibril form that starts from, and makes it become non-protofibre by adding one or more fiber distintegrants then.Described fiber distintegrant must exist so that collagen protein becomes non-protofibre in fact when the pH7, as mentioned above with q.s.Make fiber distintegrant used in this invention include, but not limited to the alcohol of various biocompatibility, aminoacid, inorganic salt, and carbohydrate, wherein the alcohol of biocompatibility is particularly preferred.The alcohol of preferred biocompatibility comprises glycerol and propylene glycol.Be used in when of the present invention, the alcohol of non-biocompatible, such as ethanol, methanol and isopropyl alcohol are not preferred, because they have potential adverse effect to the patient's body that absorbs them.Preferred amino acids comprises arginine.Preferred inorganic salt comprises sodium chloride and potassium chloride.Though carbohydrate such as the various sugar that comprise sucrose, can be used in the practice of the present invention, because they can have cellulotoxic effect in vivo, to their preferred fiber distintegrant not as other type.
Because the fibril collagen protein is opaque and is not so good as the viscosity of non-fibril collagen protein, so its less being optimized in the bioadhesive composition.But, as disclosed in U. S. application series number 08/476,825, if do not need optical transparency, preferably fibril collagen protein, or the mixture of non-fibril collagen protein and fibril collagen protein is used in the adhesive composition, expects that described compositions has long-term persistency in vivo.
For the compositions that is intended to be used in the tissue increase, preferred fibril collagen protein, because those of this and the non-fibril collagen protein preparation of use compare, it tends to form has the bigger crosslinked gel of more long-term persistent intensity in vivo.
Usually, collagen protein is added on first synthetic polymer, then the collagen protein and first synthetic polymer are thoroughly mixed to obtain the compositions of homogeneous.Then second synthetic polymer is added and mix with the mixture of collagen protein/first synthetic polymer, wherein its will with primary amino radical group on first synthetic polymer and the primary amino radical group covalent bond on thiol group and the collagen protein, thereby formed the crosslinked network of homogeneous.With with the similar fashion of above-described collagen protein, can take off glysoaminoglycan derivant acetyl and/or desulfurization and participate in the described compositions various.
For the use in tissue adhesion as discussing below, such as albumin, the promotion cell adhesion also is ideal in the described crosslinked polymer composition thereby fibrin or fibrinogen participate in protein.
In addition, introduce hydrocolloid (hydrocolloids) and can promote tissue adhesion and/or swellability such as carboxymethyl cellulose.
Using of synthetic polymer compositions
Can use compositions of the present invention with many different modes.
In one embodiment, activatory polymer can be applied to the surface that needs with solid.Preferred solid exists with powder type.By described powder is sprayed, brushes or spray on the surface, can be to the surface with activatory polymer applications.Then, be in the situation of tissue on the surface, the activated polymer of pressed powder form is with slow hydration.Then, it will allow activatory functional group and suitable surface functional group reaction.For the activatory group of succinimido, expect that this reaction will be relatively slow, because the fluidic pH of expection absorption is in about 7.2-7.4 scope.
In another embodiment, when second solid chemical compound exists, can be with activatory polymer applications to described surface.Second chemical compound will produce alkaline environment (for example, pH＞about 7.5) after fluid-absorbent and dissolving.This second solid chemical compound can be before using activatory polymer, simultaneously or use afterwards.When this activatory polymer comprises the succinimido group, the generation of alkaline environment will increase the response speed on the surface that activatory polymer is applied to it.
In another embodiment, the activatory powder of described solid can be dissolved in can the biological solution of accepting in.In preferred embodiments, this solution is that pH is lower than about 6.5 aqueous buffer solution.The buffer capacity of this aqueous solution can and change according to the pH requirement of specifically using.By this solution is brushed, dripped or sprays organizationally, this solution can be administered to required surface then.
In another embodiment, can be before at the polymer solution (being prepared as mentioned above) of administration of activated, simultaneously or use the second biological acceptable solution afterwards.In preferred embodiments, can to accept solution be a kind of pH to second biology greater than about 7.6 aqueous buffer solution.
In another embodiment, activatory polymer can be with solid form (as mentioned above) with before using the activatory polymer of solid form, and while or the second biological acceptable solution of using are afterwards used together.In preferred embodiments, can to accept solution be pH to second biology greater than about 7.6 aqueous buffer solution.
In another embodiment, the present composition can also comprise a kind of viscosity improver.In preferred embodiments, this viscosity improver will increase the solution viscosity of described compositions.The example of viscosity improver includes, but not limited to hyaluronic acid, and polyalkylene oxide is (for example, from BASFCorporation, Mount Olive, the PLURONIC F127 of NJ), glycerol, carboxymethyl cellulose, sodium alginate, chitosan, glucosan, dextran sulfate and collagen protein.Can carry out chemical modification to prevent they and described activatory polymer reaction to these viscosity improvers.Other viscosity improver known in the art can also be incorporated in the compositions of the present invention.
As mentioned above,, described surface is immersed in the compositions or by described compositions is sprayed on the surface, can directly be used compositions of the present invention by brushing on the surface.U. S. application numbers 6,152,943,6,15,201 and 6,328,229 and US publication 2002/0082636 are described and can be used to use the different device of the present composition, and are incorporated by reference hereby
Activatory synthetic polymer is used to transmit the purposes of bioactivator
Polymer composition of the present invention can also be used for the location of various medicines and other bioactivator and transmit.When being used for this paper, term " bioactivator " or " activating agent " refer to bring into play in vivo the organic molecule of biological action.In brief, in one aspect in, the invention provides compositions and the method for handling the surgical operation adhesion.In yet another aspect, the invention provides compositions and the method that alleviates restenosis.In another fermentation, the invention provides the compositions and the method that suppress fibroid degeneration.In one aspect of the method, the invention provides the compositions and the method that increase surface lubrication, wherein in one embodiment, this surface is a tissue, and in another embodiment, this surface is the surface of medical apparatus.
One aspect of the present invention comprises with the development of surgical operation adhesion and/or restenosis and/or keeps relevant cell and/or the pharmacology of non--cell processes changes and/or to the inhibition of the one or more processes relevant with fibroid degeneration.Therefore, the medicament in the scope of the invention includes but not limited to suppress those of process of or combination, and described process is such as cell division, emiocytosis, cell migration, cytoadherence, cytokine (for example, TNF α, IL-1, IL-6), (or other inflammation activator, for example chemotactic factor (for example, MCP-1 or IL-8) generation and/or release, immunomodulating, blood vessel hyperplasia, and/or free radical forms and/or release.
Those that provide based on (animal) model such as embodiment 8-13 in the external and body can easily be determined suitable inhibition fibroid degeneration, adhesion or narrow reagent.Identify many inhibition fibroid degenerations, adhesion or narrow treatment chemical compound, be used for of the present invention comprising:
1. angiogenesis inhibitor
In one embodiment; pharmaceutically active compound is angiogenesis inhibitor (2-ME (NSC-659853) for example; PI-88 (D-mannose; O-6-O-phosphono-α-D-mannopyranose base-(1-3)-O-α-D-mannopyranose base-(1-3)-O-α-D-mannopyranose base-(1-3)-O-α-D-mannopyranose base-(1-2)-hydrogen sulfate [CAS]); Thalidomide (1H-iso-indoles-1; 3 (2H)-diketone; 2-(2; 6-dioxo-3-piperidyl)-[CAS]); CDC-394; CC-5079, and ENMD-0995 (S-3-amino-phthalidoglutarimide), AVE-8062A; Vatalanib; SH-268, halofuginone hydrobromide)), or its analog or derivant.
2.5-Zhi Yanghuameiyizhiji ﹠amp; Antagonist
In another embodiment; pharmaceutically active compound be 5-lipoxygenase inhibitor or antagonist (for example; licofelone (ML3000)); 2-uredo thiophene/2 aminothiophenes; 15-deoxidation-prostaglandin J2; Wy-50295 (2-naphthalene acetic acid); Alpha-Methyl-6-(2-quinolyl methoxyl group)-; (S)-[CAS]); ONO-LP-269 (2; 11; 14-20 carbon triolefin amide; N-(4-hydroxyl-2-(1H-tetrazolium-5-yl)-8-quinolyl)-; (E; Z; Z)-[CAS]); licofelone (1H-pyrrolizine-5-acetic acid; 6-(4-chlorphenyl)-2; 3-dihydro-2; 2-dimethyl-7-phenyl-[CAS]); CMI-568 (urea; N-butyl-N-hydroxy-n '-(((tetrahydrochysene-5-(3 for 3-(mesyl)-2-propoxyl group-5-for 4-; 4; the 5-2,4,5-trimethoxyphenyl)-and the 2-furyl) phenoxy group) butyl)-; trans-[CAS]); IP-751 ((3R; 4R)-(δ 6)-THC-DMH-11-acid); PF-5901 (benzyl alcohol; α-amyl group-3-(2-quinolyl methoxyl group)-[CAS]); LY-293111 (benzoic acid; 2-(3-(3-[(5-ethyl-4 '-fluoro-2-hydroxyl [1; 1 '-diphenyl]-the 4-yl) oxygen] propoxyl group)-2-propyl group phenoxy group)-[CAS]); RG-5901-A (benzyl alcohol; α-amyl group-3-(2-quinolyl methoxyl group)-; hydrochloric acid [CAS]); rilopirox (2 (1H)-pyridones; 6-((4-(4-chlorophenoxy) phenoxy group) methyl)-1-hydroxy-4-methyl-[CAS]); L-674636 (acetic acid; ((4-(4-chlorphenyl)-1-(4-(2-quinolyl methoxyl group) phenyl) butyl) sulfo-)-AS)); 7-((3-(4-methoxyl group-tetrahydrochysene-2H-pyrans-4-yl) phenyl) methoxyl group)-4-phenyl naphtho-[2; 3-c] furan-1 (3H)-ketone; MK-886 (1H-indole-2-propanoic acid; 1-((4-chlorphenyl) methyl)-3-[(1; the 1-dimethyl ethyl) sulfo-]-α; alpha-alpha-dimethyl-5-(1-Methylethyl)-[CAS]); quiflapon (1H-indole-2-propanoic acid; 1-((4-chlorphenyl) methyl)-3-((1; the 1-dimethyl ethyl) sulfo-)-α; alpha-alpha-dimethyl-5-(2-quinolyl methoxyl group)-[CAS]); quiflapon (1H-indole-2-propanoic acid; 1-((4-chlorphenyl) methyl)-3-((1, the 1-dimethyl ethyl) sulfo-)-α, alpha-alpha-dimethyl-5-(2-quinolyl methoxyl group)-[CAS]); docebenone (2; 5-cyclohexadiene-1,4-diketone, 2-(12-hydroxyl-5; 10-12 carbon diynyls)-3; 5,6-trimethyl-[CAS]), zileuton (urea; N-(the 1-benzo (b] thiophene-2-base ethyl)-N-hydroxyl-[CAS]), or its analog or derivant.
3. chemokine receptor anagonists CCR (1,3 ， ﹠amp; 5)
In another embodiment, pharmaceutically active compound be chemokine receptor anagonists (for example, AMD-3100 (Anormed), ONO-4128 (1,4,9-thriazaspiro (5.5) hendecane-2,5-diketone, 1-butyl-3-(cyclohexyl methyl)-9-((2,3-dihydro-1,4-Ben Bing dioxine-6-yl) methyl-[CAS]), L-381, CT-112 (L-arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminate acyl-L-valyl-L-arginyl-L-prolyl-[CAS]), AS-900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB-380732, vMIP II, SB-265610, DPC-168, TAK-779 (N, N-dimethyl-N-(4-(2-(4-aminomethyl phenyl)-6,7-dihydro-5H-benzocyclohepta alkene-8-base amide groups] tetrahydrochysene-2H-pyrans-4-ammonium chloride], TAK-220, KRH-1120), or its analog or derivant.
4. cell cycle inhibitor
In another embodiment, pharmaceutically active compound is cell cycle inhibitor and analog or derivant.In relevant embodiment, cell-cycle inhibitor is taxanes (for example, paclitaxel, or its analog or derivant), antimetabolite, alkanisation reagent, or vinca alkaloids.In another embodiment, cell cycle inhibitor is a camptothecine, or its analog or derivant.Other suitable compound comprises mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, paclitaxel, Peloruside A-a microtubule stabilizer, mitomycin and CDK-2 inhibitor.
When being used for this paper " Cell cycle inhibitor" refer to postpone or damage somatoblast and advance by any protein, peptide, chemicals or other molecule of the cell cycle and the ability of duplicating.Can use extensive various method to determine that chemical compound suppresses the ability of cell cycle, described method comprises the univariate analysis and the multi parameter analysis of cell DNA content (seeing embodiment)The antibacterial cycle inhibitor can be in any step in the biological pathway that Figure 16 shows, and other the inhibition cell cycle that may step plays a role in other biological approach.In addition, should be appreciated that, when often mentioning single cell cycle reagent, it in fact should be understood to include two or more cell cycle reagent, reason is can be in compositions described herein, use more than one cell cycle reagent (for example, can select two cell cycle inhibitors, it acts on the different step of Figure 16 demonstration) in method and/or the device.
Contain carrier or do not contain carrier (for example, polymer or ointment or carrier) and can use extensively various cell cycle to suppress reagent, with treatment or prevention of surgical surgical adhesions.The representative instance of these reagent comprises taxanes (for example, paclitaxel (below in more detail discuss) and many Xi Tasai) (people such as Schiff, Nature 277:665-667,1979; Long and Fairchid, Cancer Research54:4355-4361,1994; Ringel and Horwitz, J.Nat ' l cancer Inst.83 (4): 288-291,1991; People such as Pazdur, Cancer Treat.Rev.19 (40): 351-386,1993), etanidazole, nimorazole (B.A.Chabner and D.L.Longo.Cancer Chemotherapy andBiotherapy-Principles and Practice.Lippincott-Raven Publishers, New York, 1996, the 554th page), perfluorochemical with hyperbaric oxygen, blood transfusion (transfusion), erythropoietin, BW12C, nicotiamide, hydralazine, BSO, WR-2721, ludR, DUdR, etanidazole, WR-2721, BSO, mono-substituted keto-aldehyde chemical compound (L.G.Egyud.Keto-aldehyde-amineaddition products and method of making same. U.S. Patent number 4,066,650, on January 3rd, 1978), nitre imidazoles (K.C.Agrawal and M.Sakaguchi.Nitroimidazoleradiosensitizers for Hypoxic tumor cells and compositions thereof. U.S. Patent number 4, on July 31st, 462,992,1984), 5-replaces-4-nitre imidazoles (people such as Adams, Int.J.Radiat.Biol.Relat.Stud.Phys.Chem.Med.40 (2): 153-61,1981), SR-2508 (people such as Brown, Int.J.Radiat.Oncol., Biol.Phys.7 (6): 695-703,1981), 2H-isoindoledione (J.A.Myers, 2H-lsoindolediones, their synthesis and use asradiosensitizers. patent No. No.4,494,547, on January 22nd, 1985), chirality (((2-bromoethyl)-amino) methyl)-nitro-1H-imidazoles-1-ethanol (people such as V.G.Beylin, Process for preparingchiral (((2-bromoethyl)-amino) methyl)-nitro-1H-imidazole-1-ethanol andrelated compounds. U.S. Patent number 5,543, on August 6th, 527,1996; U.S. Patent number 4,797,397; On January 10th, 1989; U.S. Patent number 5,342, on August 30th, 959,1994), the nitroaniline derivant (W.A.Denny, etc.Nitroaniline derivatives and their use asanti-tumor agents. U.S. Patent number 5,571,845, on November 5th, 1996), DNA-affinic hypoxia-selective cytotoxin (M.V.Papadopoulou-Rosenzweig.DNA-affinic hypoxiaselective cytotoxins. U.S. Patent number 5,602,142, on February 11st, 1997), halogenated DNA part (R.F.Martin, Halogenated DNA ligand radiosensitizers for cancer therapy. U.S. Patent number 5,641,764, on June 24th, 1997), 1,2,4 benzotriazine oxides (.1 such as W.W.Lee, 2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. U.S. Patent number 5,616, on April 1st, 584,1997; U.S. Patent number 5,624, on April 29th, 925,1997; Process for Preparing 1,2,4 Benzotriazine oxides. U.S. Patent numbers 5,175,287, on December 29th, 1992), nitrogen oxide (people such as J.B.Mitchell, Use of Nitric oxidereleasing compounds as hypoxic cell radiation sensitizers. U.S. Patent number 5,650,442, on July 22nd, 1997), 2-nitre imdazole derivatives (.2-Nitroimidazolederivatives useful as radiosensitizers for hypoxic tumor cells. U.S. Patent number 4,797 such as M.J.Sut, on January 10th, 397,1989; T.Suzuki.2-Nitroimidazole derivative, production thereof, 5,270,330,1993 years Decembers of and radiosensitizer containing the same as active ingredient. U.S. Patent number 14 days; .2-Nitroimidazolederivative such as T.Suzuki, production thereof, 5,270,330,1993 years Decembers of and radiosensitizer containing the same asactive ingredient. U.S. Patent number 14 days; T.Suzuki.2-Nitroinidazole derivative, production thereof and radiosensitizer containingthe same as active ingredient; Patent No. EP 0 513 351B1, on January 24th, 1991), fluorine-containing nitro-pyrrole derivant (T.Kagiya.Fluorine-containing nitroazole derivativesand radiosensitizer comprising the same. U.S. Patent number 4,927,941, May 22 nineteen ninety), copper (M.J.Abrams.Copper Radiosensitizers.U.S.Patent No.5,100,885, on May 31st, 1992), the cancer therapy of associated form (D.H.Picker etc., Combinationmodality cancer therapy. U.S. Patent number 4,681, on July 21st, 091,1987).5-CldC or (d) H 4U or 5-halo-2 '-halo-2 '-deoxidation-cytidine or-uridine derivatives (S.B.Greer.Method and Materials for sensitizing neoplastic tissue to radiation. U.S. Patent number 4,894,364 January 16 nineteen ninety), platinum complex (K.A.Skov.PlatinumComplexes with one radiosensitizing ligand. U.S. Patent number 4, on May 1st, 921,963.1990; K.A.Skov.Platinum Complexes with one radiosensitizing ligand. patent No. EP 0 287 317 A3), fluorine-containing nitro-pyrrole (T.Kagiya, Fluorine-containingnitroazole derivatives and radiosensitizer comprising the same. U.S. Patent number 4,927,941.1990 on May 22), Benzoylamide (W.W.Lee.Substituted BenzamideRadiosensitizers. U.S. Patent number 5,032,617, on July 16th, 1991), autobiotic (L.G.Egyud.Autobiotics and their use in eliminating nonself cells in vivo. U.S. Patent number 5,147,652.1992 on JIUYUE 15), Benzoylamide and nicotiamide (.Benzamide and Nictoinamide Radiosensitizers. U.S. Patent number 5 such as W.W.Lee, 215,738, on June 1st, 1993), acridine-intercalator (M.Papadopoulou-Rosenzweig.AcridineIntercalator based hypoxia selective cytotoxins. U.S. Patent number 5,294,715, on March 15th, 1994), fluorine-containing nitroimidazole (.Fluorine containingnitroimidazole compounds. U.S. Patent number 5 such as T.Kagiya, 304,654, on April 19th, 1994), hydroxylated texaphyrins (people Hydroxylated texaphrins. U.S. Patent number 5 such as J.L.Sessler, 457,183, October 10 nineteen ninety-five), the derivant of hydroxylated compounds (.Heterocyclic compound derivative such as T.Suzuki, production thereof and radiosensitizer andantiviral agent containing said derivative as active ingredient. publication number 011106775A (Japan), on October 22nd, 1987; .Heterocycliccompound derivative such as T.Suzuki, production thereof and radiosensitizer, antiviral agentand anti cancer agent containing said derivative as active ingredient. publication number 01139596A (Japan), on November 25th, 1987; .Heterocycliccompound derivative such as S.Sakaguchi, its production and radiosensitizer containing saidderivative as active ingredient; Publication number 63170375A (Japan), on January 7th, 1987), fluorine-containing 3-nitro-1,2,4-triazole (.Novel fluorine-containing3-nitro-1 such as T.Kagitani, 2,4-triazole and radiosensitizer containing same compound. publication number 02076861A (Japan), on March 31st, 1988), 5-sulfo-terazole derivatives or its salt (.Radiosensitizer for Hypoxic cell. publication number 61010511 A (Japan) such as E.Kano, on June 26th, 1984), nitrothiazole (.Radiation-sensitizing agent. publication number 61167616A (Japan) such as T.Kagitani on January 22nd, 1985), imdazole derivatives (.Imidazolederivative. publication number 6203767 A (Japan) such as S.Inayma on August 1st, 1985; Publication number 62030768 A (Japan) on August 1st, 1985; Publication number 62030777 A (Japan) on August 1st, 1985), 4-nitro-1,2,3-triazole (.Radiosensitizer. publication number 62039525 A (Japan) such as T.Kagitani, on August 15th, 1985), 3-nitro-1,2,4-triazole (.Radiosensitizer. publication number 62138427A (Japan) such as T.Kagitani, on December 12nd, 1985), system cancer effect regulator (H.Amagase.Carcinostatic action regulator. publication number 63099017 A (Japan), on November 21st, 1986), 4,5-dinitro imdazole derivatives (S.Inayama.4,5-Dinitroimidazole derivative. publication number 63310873 A (Japan) on June 9th, 1987), nitro-triazole chemical compound (T.Kagitanil.Nitrotriazole Compound. publication number 07149737 A (Japan) on June 22nd, 1993), cisplatin, doxorubin, misonidazole, mitomycin, tiripazamine, nitroso ureas, the neck purine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide (I.F.Tannock.Review Article:Treatment ofCancer with Radiation and Drugs.Journal of Clinical Oncology14 (12): 3156-3174,1996), camptothecine (.Local delivery ofchemotherapy and concurrent external beam radiotherapy prolongs survival inmetastatic brain tumor models.Cancer Research 56 (22): 5217-5223 such as Ewend M.G., 1996) and paclitaxel (Taxol:a novel radiation sensitizer.InternationalJournal of Radiation Oncology and Biological Physics 22 (3): 613-617 such as Tishler R.B., 1992).
Many above-mentioned cell cycle inhibitors also have extensively multiple analog and derivant, and it includes, but are not limited to cisplatin, cyclophosphamide, misonidazole, tiripazamine, nitroso ureas, mercaptopurine, methotrexate, fluorouracil, epirubicin, doxorubicin, vindesine and etoposide.
In a preferred embodiment of the invention, cell cycle inhibitor is a paclitaxel, and is a kind of by forming the chemical compound that anomomitotic spindle destroys mitosis (M-phase) in conjunction with tubulin, or its analog or derivant.In brief, paclitaxel is a kind of height diterpene-kind compound (Wani etc. derivatively, J.Am.Chem.Soc.93:2325,1971), it is from mountain mahogany (Taxusbrevifolia) (Pacific yew (Pacific Yew)) and Taxomyces Andreanae results and exsiccant leaves and the endogenetic fungus acquisition (Stierle etc. of Pacific yew, Science 60:214-216,1993)." paclitaxel " (it is construed as at this paper and comprises preparation, prodrug, analog and derivant are such as for example TAXOL (Bristol-Myers Squibb company, New York, NY), TAXOTERE (Aventis Pharmaceuticals, France), docetaxel, the 10-deacetylate analog of paclitaxel and 3 ' N-of paclitaxel take off benzoyl-3 ' uncle N--butoxy carbonyl analog) technology that can use those skilled in the art to be familiar with easily is prepared and (sees, for example, Schiff etc., Nature 277:665-667,1979; Long and Fairchild, Cancer Research 54:4355-4361,1994; Ringel and Horwitz, J.Natl.Cancer Inst.83 (4): 288-291,1991; Pazdur etc., Cancer Treat.Rev.19 (4): 351-386,1993; WO 94/07882; WO94/07881; WO 94/07880; WO 94/07876; WO 93/23555; WO 93/10076; WO 94/00156; WO 93/24476; EP 590267; WO 94/20089; U.S. Patent number 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850; 5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984; 5,248,796; 5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 5,440,056; 4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184; Tetrahedron Letters 35 (52): 9709-9712,1994; J.Med.Chem.35:4230-4237,1992; J.Med.Chem.34:992-998,1991; J.NaturalProd.57 (10): 1404-1410,1994; J.Natural Prod.57 (11): 1580-1583,1994; J.Am.Chem.Soc.110:6558-6560,1988), or from many commercial source acquisitions, described commercial source for example comprises, Sigma Chemical Co., St.Louis, Missouri (T7402-is from mountain mahogany (Taxus brevifolia)).
The representative instance of paclitaxel derivant or analog comprises 7-deoxidation-docetaxel (docetaxol), 7,8-cyclopropataxanes, the 2-azetidones that N-replaces, 6,7-epoxy paclitaxel, 6, the paclitaxel that 7-modifies, 10-removes the acetoxyl group paclitaxel, 10-deacetylate paclitaxel (from 10-deacetylate Baccatine III), the phosphonato of paclitaxel and carbonic acid ester derivative, paclitaxel 2 ', 7-two (1,2-benzene dicarboxylic acid sodium, 10-removes acetoxyl group-11,12-dihydro paclitaxel-10,12 (18)-diene derivatives, 10-removes the acetoxyl group paclitaxel, Protaxol (2 '-and/or the 7-O-ester derivant), (2 '-and/or the 7-O-carbonic acid ester derivative), the asymmetric synthesis of paclitaxel lateral chain, fluorine paclitaxel, 9-deoxidation taxanes, (13-acetyl group-9-deoxy baccatine III III, 9-deoxy taxol, 7-deoxidation-9-deoxy taxol, 10-removes acetoxyl group-7-deoxidation-9-deoxy taxol, the derivant of hydrogeneous or Acetyl Groups and hydroxyl and uncle-butoxy carbonyl amino, sulfonated 2 '-acryloyl paclitaxel and sulfonated 2 '-O-acyl acid taxol derivant, succinyl paclitaxel, 2 '-gamma-amino bytyry paclitaxel formic acid esters, 2 '-acetyl group paclitaxel, 7-acetyl group paclitaxel, 7-glycine carbamate paclitaxel, 2 '-OH-7-PEG (5000) carbamate paclitaxel, 2 '-benzoyl and 2 ', 7-dibenzoyl paclitaxel derivant, other prodrug (2 '-acetyl group paclitaxel; 2 ', 7-diacetyl paclitaxel; 2 ' succinyl paclitaxel; 2 '-(β-alanyl)-paclitaxel); 2 ' gamma-amino bytyry paclitaxel formic acid esters, the ethylene glycol derivative of 2 '-succinyl paclitaxel; 2 ' glutaryl paclitaxel; 2 '-(N, N-dimethyl glycyl) paclitaxel; 2 '-2 (N, N-dimethylamino) propiono) paclitaxel; 2 ' ortho position carboxylbenzoyl paclitaxel; 2 ' aliphatic carboxylic acid derivates of paclitaxel, prodrug { 2 ' (N, N-diethylamino propiono) paclitaxel, 2 ' (N, N-dimethyl glycyl) paclitaxel, 7 (N, N-dimethyl glycyl) paclitaxel, 2 ', 7-two (N, N-dimethyl glycyl) paclitaxel, 7 (N, N-diethylamino propiono) paclitaxel, 2 ', 7-two (N, N-diethylamino propiono) paclitaxel, 2 '-(L-glycyl) paclitaxel, 7-(L-glycyl) paclitaxel, 2 ', 7-two (L-glycyl) paclitaxel, 2 '-(L-alanyl) paclitaxel, 7-(L-alanyl) paclitaxel, 2 ', 7-two (L-alanyl) paclitaxel, 2-' (L-leucyl) paclitaxel, 7-(L-leucyl) paclitaxel, 2 ', 7-two (L-leucyl) paclitaxel, 2 '-(L-isoleucyl-) paclitaxel, 7-(L-isoleucyl-) paclitaxel, 2 ', 7-two (L-isoleucyl-) paclitaxel, 2 ' (L-valyl) paclitaxel, 7-(L-valyl) paclitaxel, 2 ', 7-two (L-valyl) paclitaxel, 2 ' (L-phenylalanyl) paclitaxel, 7-(L-phenylalanyl) paclitaxel, 2 ', 7-two (L-phenylalanyl) paclitaxel, 2 ' (L-prolyl) paclitaxel, 7-(L-prolyl) paclitaxel, 2 ', 7-two (L-prolyl) paclitaxel, 2 ' (L-lysyl) paclitaxel, 7-(L-lysyl) paclitaxel, 2 ', 7-two (L-lysyl) paclitaxel, 2 ' (L-glutamy) paclitaxel, 7-(L-glutamy) paclitaxel, 2 ', 7-two (L-glutamy) paclitaxel, 2 ' (L-arginyl) paclitaxel, 7-(L-arginyl) paclitaxel, 2 ', 7-two (L-arginyl) paclitaxel }, paclitaxel analogs with phenylisoserine side chain of modification, taxotere, (N-removes benzoyl-N-uncle-(butoxy carbonyl)-10-deacetylate paclitaxel, and taxanes (for example, Baccatine III, cephalomannine, 10-deacetylate Baccatine III, brevifoliol, yunantaxusin and taxusin); With other 10-deacetyltaxol and derivant, comprise that 14-beta-hydroxy-10 removes the acetyl Baccatine III, go benzoyl-2-acyl taxol derivant, the benzoate paclitaxel derivant, phosphonato and carbonic ester paclitaxel derivant, sulfonated 2 '-acryloyl paclitaxel; Sulfonated 2 '-O-acyl acid taxol derivant; the paclitaxel derivant of 18-position-replacement; chlorating paclitaxel analogs; C4 methoxy-ether paclitaxel derivant; the sulfenamide Taxane derivative; the paclitaxel analogs of bromination; the Girard Taxane derivative; the nitrobenzophenone paclitaxel; the paclitaxel derivant of the replacement of 10-deacetylateization; 14-beta-hydroxy-10 deacetylate Baccatine III Taxane derivative; the C7 Taxane derivative; the C10 Taxane derivative; 2-removes benzoyl-2-acyl group Taxane derivative; 2-go benzoyl and-2-acyl taxol derivant; carry the taxane and the Baccatine III analog of new C2 and C4 functional group; n-acyl taxol analog; 10-deacetylate Baccatine III and derived from 10-deacetylate paclitaxel A; the 10-deacetylate Baccatine III of 10-deacetylate paclitaxel B and 10-deacetylate paclitaxel and 7-protection-10-deacetylate baccatin III derivative; the benzoate derivatives of paclitaxel; 2-aroyl-4-acyl taxol analog; the ortho esters paclitaxel analogs, 2-aroyl-4-acyl taxol analog and 1-deoxy taxol and 1-deoxy taxol analogs.
On the one hand, described cell cycle inhibitor is the taxane that has as shown in the formula (C1):
Figure A20038011006800601
Wherein the part that Lycoperdon polymorphum Vitt is outstanding is can be substituted, and Tu Chu part is not the taxane core.Wish to exist side chain (among the figure " A " of labelling) so that chemical compound has good activity as cell cycle inhibitor.Examples for compounds with this structure comprises paclitaxel (Merck index entry 7117); docetaxel (taxotere, Merck index entry 3458) and 3 '-go phenyl-3 '-(4-nitrobenzophenone)-N-to remove benzoyl-N-(uncle-butoxy carbonyl)-10-deacetylate paclitaxel.
On the one hand, suitable taxanes such as paclitaxel and its analog and derivant are disclosed in the patent No. 5,440,056, and it has structure (C2):
Figure A20038011006800602
Wherein X can be oxygen (paclitaxel), hydrogen (9-deoxidation derivative), sulfo-acyl group (thioacyl) or dihydroxy precursor; R 1Be selected from the alkanoyl of paclitaxel or taxotere side chain or formula (C3).
Figure A20038011006800603
R wherein 7Be selected from hydrogen, alkyl, phenyl, alkoxyl, amino, phenoxy group (replacement or unsubstituted); R 8Be selected from hydrogen, alkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, phenyl (replacement or unsubstituted), α or betanaphthyl; And R 9Be selected from hydrogen, alkanoyl, the alkanoyl of replacement and aminoalkanoyl radical; Wherein substituent group refers to hydroxyl, sulfydryl, allalkoxyl, carboxyl, halogen, thio alkoxy, N, the N-dimethylamino, alkyl amino, dialkyl amido, nitro and-OSO 3H, and/or can refer to comprise the group of these replacements; R 2Be selected from hydrogen or oxygen containing group, such as hydroxyl, alkoxyl (alkoyl), alkanoyloxy, amino alkanoyloxy and peptidyl alkanoyloxy; R 3Be selected from hydrogen or oxygen containing group, such as hydroxyl, alkoxyl, alkanoyloxy, amino alkanoyloxy and peptidyl alkanoyloxy and can be to comprise the group of silicyl or the group of sulfur-bearing; R 4Be selected from acyl group, alkyl, alkanoyl, aminoalkanoyl radical, peptide alkanoyl and aroyl; R 5Be selected from acyl group, alkyl, alkanoyl, aminoalkanoyl radical, peptidyl alkanoyl and aroyl; R 6Be selected from hydrogen or oxygen containing group, such as H, hydroxyl, alkoxyl, alkanoyloxy, amino alkanoyloxy and peptidyl alkanoyloxy.
On the one hand, be disclosed in pct international patent application number WO 93/10076 as the paclitaxel analogs and the derivant of cell cycle inhibitor in the present invention.As disclosed in this publication, described analog or derivant should, shown in (formula 4), have at C 13The side chain that the place is connected with taxane nuclear, thus give the taxane anti-tumor activity.
WO 93/10076 discloses taxane and has endorsed to be substituted in any position except that existing methyl group.Described replacement for example can comprise, hydrogen, alkanoyloxy, alkenoyl oxygen base, aroyl oxygen base.In addition, oxo group can be connected and be labeled as 2,4, on 9,10 the carbon.Equally, the oxetanes ring can be connected on 5 in carbon 4 and the carbon.Equally, oxirane can be connected and be labeled as on 4 the carbon.
On the one hand, U.S. Patent number 5,440,056 discloses the useful in the present invention cell cycle inhibitor based on this taxane, its open 9-deoxidation taxanes.These are the chemical compounds that lack oxo group on 9 the carbon that are labeled as that show in the above in the taxane structure of (formula C4).The ring of described taxane can be used H being labeled as on 1,7 and 10 the carbon (independently), OH, and O-R, or O-CO-R replaces, and wherein R is alkyl or aminoalkyl.Equally, it can be labeled as on 2 and 4 the carbon (independently) with aroyl (aryol), alkanoyl, and aminoalkanoyl radical or alkyl group replace.The side chain of formula (C3) can be at R 7And R 8(independently) use phenyl ring, the phenyl ring of replacement, linear paraffin/alkene and comprise H, the group of O or N replaces.R 9Can replace with alkanoyl group H or replacement or unsubstituted.
It has been generally acknowledged that taxane, particularly paclitaxel is by serving as anti-microtubule agent, more specifically brings into play function as cell cycle inhibitor as stabilizing agent.Shown that these chemical compounds are that effectively described disease comprises non-small cell (NSC) pulmonary carcinoma in the treatment of proliferative disorders; Small cell lung cancer; Breast carcinoma; Carcinoma of prostate; Cervical cancer; Carcinoma of endometrium; Head and neck cancer.
On the other hand, cell cycle inhibitor is a vinca alkaloids.Vinca alkaloids has following universal architecture.They are indole-indoline dimers.
As at U.S. Patent number 4,841, disclosed in 045 and 5,030,620, R 1Can be formoxyl or methyl or H alternatively.R 1Can also be alkyl (for example, the CH that alkyl group or aldehyde replace 2CHO).R 2CH typically 3Or NH 2Group.But its ester that can alternatively replace or be connected with indoline nuclear with lower alkyl esters can be NH with R wherein 2C (O)-R, amino-acid ester or peptide ester replace.R 3C (O) CH typically 3, CH 3Or H.Alternatively, protein fragments can connect such as maleoyl aminoacid by difunctional.Can also be to R 3Replace the Arrcostab that can further be replaced to form.R 4Can be-CH 2-or singly-bound.R 5And R 6Can be H, OH or low alkyl group, typically-CH 2CH 3Perhaps R 6And R 7Can form the oxetanes ring together.R 7Alternatively H.Replacement in addition comprises that wherein methyl is replaced with unsaturated ring can be by adding side group such as alkyl, thiazolinyl, alkynyl, halogen, ester group, amide groups or amino by the molecule of derivatization thus by other alkyl.
Exemplary vinca alkaloids is the vinblastine with following array structure, vincristine, and vincristine sulfate, vindesine and vinorelbine:
R 1 R 2 R 3 R 4 R 5
Vinblastine: CH 3CH 3C (O) CH 3OH CH 2
Vincristine: CH 2O CH 3C (O) CH 3OH CH 2
Vindesine: CH 3NH 2H OH CH 2
Vinorelbine: CH 3CH 3CH 3The H singly-bound
Analog typically requires pendant groups (shadow region) to have activity.Think that these chemical compounds normally by as anti--microtubule agent, more specifically suppress polymerization and play a role as cell cycle inhibitor.Shown that these chemical compounds are that effectively described disease comprises NSC pulmonary carcinoma in the treatment proliferative disease; Small cell lung cancer; Breast carcinoma; Carcinoma of prostate; The brain cancer; Head and neck cancer; Retinoblastoma; Bladder cancer and carcinoma of penis; And soft tissue sarcoma.
On the other hand, cell cycle inhibitor is a camptothecine, or its analog or derivant.Camptothecine has following formula:
Figure A20038011006800632
In this structure, X is O typically, but can be other group, for example, and the NH in the 21-lactam derivatives.R 1H or OH can be other groups still typically, for example, and the C of terminal hydroxylization 1-3Alkane.R 2H or comprise amino group typically such as (CH 3) 2NHCH 2, but can be for example NO of other group 2, NH 2, halogen (as for example at U.S. Patent number 5,552,156 in open) or comprise the short alkane of these groups.R 3H or short alkyl are such as C typically 2H 5R 4H can be other group still typically, for example has R 1Methylene dioxy base.
Exemplary Comptothecin compounds comprises hycamtin, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactams-20 (S)-camptothecine, 10,11-methylene dioxy base camptothecine, SN-38,9-nitrocamptothecin, 10-hydroxycamptothecine.Exemplary compound has following structure:
R 1 R 2 R 3
Camptothecine: H H H
Hycamtin: OH (CH 3) 2NHCH 2H
SN-38： OH H C 2H 5
X: for most of analog are O, are NH for the 21-lactam analogs
Camptothecine has 5 rings that show herein.For the activity and the minimum toxicity of maximum, the ring that is labeled as E must be complete (lactone rather than carboxylate form).These chemical compounds are effectively as cell cycle inhibitor, and wherein they play topoisomerase I inhibitor and/or dna cleavage agent.Shown that they are effectively in proliferative disease treatment, described disease comprises, for example, and NSC pulmonary carcinoma; Small cell lung cancer and cervical cancer.
On the other hand, cell cycle inhibitor is a podophyllotoxin, or its derivant or analog.Such exemplary chemical compound is etoposide or the teniposide with following structure:
Think that these chemical compounds are by bringing into play the effect of cell cycle inhibitor as topoisomerase II inhibitor and/or dna cleavage reagent.Shown they as anti-hypertrophy reagent for example, small cell lung cancer is effective in the carcinoma of prostate and the brain cancer and the retinoblastoma.
In another embodiment, cell cycle inhibitor is an anthracycline.Anthracycline has following universal architecture, and wherein the R group can be multiple organic group:
Figure A20038011006800651
According to U.S. Patent number 5,594,158, the suitable R group is: R 1Be CH 3Or CH 2OH; R 2Be daunosamine or H; R 3And R 4Be OH independently, NO 2, NH 2, F, Cl, Br, I, CN, the group that H or these derive; R 5-7All be H or R 5And R 6Be H, R 7And R 8Be alkyl or halogen, otherwise or: R 7And R 8Be H, R 5And R 6Be alkyl or halogen.
According to U.S. Patent number 5,843,903, R 2It can be conjugated peptide.According to U.S. Patent number 4,215,062 and 4,296,105, R 5It can be the alkyl group that OH or ether connect.R 1Group that can also be by non-C (O) is such as have C (O) coupling part such as-CH at its end 2CH (CH 2-X) C (O)-R 1Alkyl or ramose alkyl group, wherein X is H or alkyl group (see, for example, U.S. Patent number 4,215,062).R 2The group that can alternatively be connected by functional group=N-NHC (O)-Y, wherein Y is the group such as the phenyl ring of phenyl or replacement.R alternatively 3Can be following structure:
Figure A20038011006800652
R wherein 9Be in plane of a loop or outer OH, or second sugar moieties is such as R 3R 10Can be H or form secondary amine such as aromatic group that described aromatic group is 5 yuan or 6 yuan of heterocycles (seeing U.S. Patent number 5,843,903) that carry the saturated or fractional saturation of at least one ring nitrogen with a group.Alternatively, R 10Can be derived from aminoacid, it has structure-C (O) CH (NHR 11) (R 12), R wherein 11Be H, or and R 12Form C 3-4The alkylidene of atomic number.R 12Can be H, alkyl, aminoalkyl, amino, hydroxyl, sulfydryl, phenyl, benzyl or methyl mercapto (seeing U.S. Patent number 4,296,105).
Exemplary anthracycline is a doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin.Suitable compound can have following structure:
Figure A20038011006800661
R 1， R 2， R 3，
Doxorubicin: OCH 3CH 2OH OH is outside plane of a loop
Epirubicin: OCH 3CH 2OH OH is in plane of a loop
(4 ' epimer of doxorubicin)
Daunorubicin: OCH 3CH 3OH is outside plane of a loop
Idarubicin: H CH 3OH is outside plane of a loop
Pirarubicin OCH 3OH A
Zorubicin OCH 3=N-NHC (O) C 6H 5B
Carubicin OH CH 3B
Other suitable anthracycline is the antramycin with following structure, mitoxantrone, menogaril, nogalamycin, Aclacnomycin A, Olivomycin A, chromomycin A 3And plicamycin:
R 1 R 2 R 3 R 4
Olivomycin A COCH (CH 3) 2CH 3COCH 3H
Chromomycin A 3COCH 3CH 3COCH 3CH 3
Plicamycin H H H CH 3
Think that these chemical compounds are by bringing into play effect as cell cycle inhibitor as topoisomerase enzyme inhibitor and/or by the dna cleavage agent.Shown that they are that effectively described proliferative disease comprises small cell lung cancer in the treatment proliferative disease; Breast carcinoma; Carcinoma of endometrium; Head and neck cancer; Retinoblastoma; Hepatocarcinoma; Cancer of biliary duct; Islet-cell carcinoma; And bladder cancer; And soft tissue sarcoma.
On the other hand, cell cycle inhibitor is a platinum compounds.Usually, suitable platinum complexes can be Pt (II) or Pt (IV), and has this basic structure:
Wherein X and Y be the anion leaving group such as sulfate radical, phosphate radical, carboxylate radical, and halogen; R 1And R 2Be alkyl, amine, aminoalkyl, any one can further be replaced, and is inertia or bridged group basically.Concerning Pt (II) complex, Z 1And Z 2Do not exist.Concerning Pt (1V), Z 1And Z 2Can be anionic group such as halogen, hydroxyl, carboxylate radical, ester, sulfate radical or phosphate radical.See, for example, U.S. Patent number 4,588,831 and 4,250,189.
Suitable platinum complexes can comprise a plurality of pt atoms.See, for example, U.S. Patent number 5,409,915 and 5,380,897.For example such pair platinum and three platinum complexes:
Exemplary platinum compounds is the cisplatin with following structure, carboplatin, and oxaliplatin and rice platinum:
Figure A20038011006800682
The cisplatin carboplatin
Oxaliplatin rice platinum
Think that these chemical compounds pass through in conjunction with DNA, that is, and by bring into play effect as the alkylating agent of DNA as cell cycle inhibitor.Shown that these chemical compounds are effectively in the cell hyperplastic disease in treatment, described disease comprises, for example, and NSC pulmonary carcinoma; Small cell lung cancer; Breast carcinoma; Cervical cancer; The brain cancer; Head and neck cancer; The esophageal carcinoma; The retinoblastoma cancer; Hepatocarcinoma; Cancer of biliary duct; Bladder cancer; Carcinoma of penis; With carcinoma vulvae and soft tissue sarcoma.
In another aspect, cell cycle inhibitor is a nitroso ureas.Nitroso ureas has following universal architecture (C5), wherein shows the typical R group below.
The R group:
Figure A20038011006800692
Carmustine Ranimustine lomustine
Figure A20038011006800693
Figure A20038011006800694
Fotemustine nimustine chlorozotocin streptozocin
Other suitable R group comprises cycloalkane, alkane, the group that halogen replaces, sugar, aryl and heteroaryl groups, phosphono and sulfonyl group.As at U.S. Patent number 4,367, disclosed in 239, R can suitably be CH 2-C (X) is (Z) (Y), and wherein X and Y can be the identical or different members in the following groups: phenyl, or by group such as halogen, low alkyl group (C 1-4), trifluoromethyl, cyano group, phenyl, cyclohexyl, lower alkoxy (C 1-4) phenyl or the cyclohexyl groups that replace.Z has following structure :-alkylidene-N-R 1R 2, R wherein 1And R 2Can be the identical or different member in the following group: low alkyl group (C 1-4) and benzyl, or R 1And R 2Can form 5 or 6 yuan of saturated heterocycles together such as pyrrolidine, piperidines, morpholine, thiomorpholine, N-low alkyl group piperazine, wherein heterocycle can be replaced arbitrarily by low-grade alkyl group.
As U.S. Patent number 6,096,923 is disclosed, and the R and the R ' of formula (C5) can be identical or different, and wherein each can be replacement or the unsubstituted hydrocarbon with 1-10 carbon.Replacement can comprise alkyl, halogen, ester, amide, carboxylic acid, ether, thioether and alcohol groups.As U.S. Patent Publication No. 4; 472; disclosed in 379, the R of formula (C5) can be amido link and pyranose structure (for example, methyl 2 '-(N-(N-(2-chloroethyl)-N-nitroso-group-carbamoyl]-glycyl] amino-2 '-deoxidation-α-D-pyranglucoside).As U.S. Patent number 4,150,146 is disclosed, the R in the formula (C5) can be 2-6 carbon alkyl group and can be by ester, sulfonyl or oh group replace.It can also be by carboxylic acid or CONH 2Group replaces.
Exemplary nitroso ureas is the BCNU (carmustine) with following structure, Semustine (semustine), and CCNU (lomustine), Ranimustine, nimustine, chlorozotocin, fotemustine, streptozocin and streptozocin:
Think that these nitroso-urea compounds pass through in conjunction with DNA, that is, and by bring into play function as the DNA alkylating agent as cell cycle inhibitor.Shown that these cell cycle inhibitors are in treatment cell hyperplastic disease such as, islet-cell carcinoma for example; Small cell lung cancer; Be effective in the melanoma and the brain cancer.
On the other hand, cell cycle inhibitor is a nitroimidazole, and wherein exemplary nitroimidazole is the metronidazole with following structure, benznidazole, and etanidazole and misonidazole:
Figure A20038011006800711
R 1 R 2 R 3
Metronidazole OH CH 3NO 2
Benznidazole C (O) NHCH 2-benzyl NO 2H
Etanidazole CONHCH 2CH 2OH NO 2H
Suitable nitroimidazole compound exists, for example, U.S. Patent number 4,371, open in 540 and 4,462,992.
On the other hand, cell cycle inhibitor is an antifol, such as methotrexate or its derivant or analog, comprises edatrexate, trimetrexate, and thunder is for Qu Sai, piritrexim, 9,10-dimethylpteroylglutamic acid, Tomudex and Pteropterin.The methotrexate analog has following universal architecture:
The identity of R group can be selected from organic group, particularly at U.S. Patent number 5,166, and those groups that propose in 149 and 5,382,582.For example, R 1Can be N, R 2Can be N or C (CH 3), R 3And R ' 3Can be H or alkyl, for example, CH 3, R 4Can be singly-bound or NR, wherein R be H or alkyl group.R 5,6,8Can be H, OCH 3, or alternatively, they can be halogen or hydrogen group.R 7Be the side chain of following universal architecture:
Wherein for methotrexate n=1, for Pteropterin, n=3.Carboxylic group in the side chain can be esterification or form salt such as Zn 2+Salt.R 9And R 10Can be NH 2Or can replace by alkyl.
Exemplary folic acid antagonist immunomodulator compounds has following structure:
Figure A20038011006800721
R 0 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8
Methotrexate NH 2N N H N (CH 3) H H A (n=1) H
Edatrexate NH 2N N H N (CH 2CH 3) H H A (n=1) H
Trimetrexate NH 2N C (CH 3) H NH H OCH 3OCH 3OCH 3
Pteropterin NH 2N N H N (CH 3) H H A (n=3) H
9,10-dimethylpteroylglutamic acid OH N N CH 3N (CH 3) H H A (n=1) H
Piritrexim NH 2N C (CH 3) H singly-bound OCH 3H H OCH 3H
Figure A20038011006800722
Tomudex
Think that these chemical compounds are by bringing into play the function as cell cycle inhibitor as the antimetabolite of folic acid.Shown that they comprise at the treatment cell hyperplastic disease, for example, soft tissue sarcoma, small cell lung cancer, breast carcinoma, the brain cancer, head and neck cancer, bladder cancer is effective in the carcinoma of penis.
On the other hand, cell cycle inhibitor is a cytidine analog, such as cytosine arabinoside or its derivant or analog, it comprises enocitabine, FMdC ((E (2 '-deoxidation-2 '-(fluorine methylene) cytidine), gemcitabine, 5-azacitidine, ancitabine and 6-azauridine.Exemplary chemical compound has following structure:
Figure A20038011006800731
R 1 R 2 R 3 R 4
Cytosine arabinoside H OH H CH
Enocitabine C (O) (CH 2) 20CH 3OH H CH
Gemcitabine H F F CH
Azacitidine H H OH N
FMdC H CH 2F H CH
Ancitabine 6-azauridine
Think that these chemical compounds are by bringing into play the function as cell cycle inhibitor as the antimetabolite of pyrimidine.Shown that these chemical compounds comprise at the treatment cell hyperplastic disease, cancer of pancreas for example, breast carcinoma, cervical cancer is effective in NSC pulmonary carcinoma and the cancer of biliary duct.
On the other hand, cell cycle inhibitor is a pyrimidine analogue.On the one hand, pyrimidine analogue has following structure:
Wherein 2 ', 3 ' and 5 ' on the sugar ring (is respectively R 2, R 3And R 4) can be H, hydroxyl, phosphoryl (see, for example, U.S. Patent number 4,086,417) or ester (see, for example, U.S. Patent number 3,894,000).Ester can be an alkyl, cycloalkyl, aryl or heterocycle/aryl type.Can be at R 2Or R 2' locate 2 ' carbon is carried out hydroxylating, another group is H.Alternatively, for example can use halogen, fluorine or difluoro cytidine such as gemcitabine replaces 2 ' carbon.Alternatively, sugar can be by another heterocyclic group such as furyl or alkane, amide such as C (O) NH (CH of alkyl ether or connection alkane 2) 5CH 3Replace.2 ° of aliphatic acyl radical (R that amine can be connected with amide 1) (see, for example, U.S. Patent number 3,991,045) or urethane (see, for example, U.S. Patent number 3,894,000) key replaces.Can also further replace to form quaternary ammonium salt it.R on pyrimidine ring 5Can be N or CR, wherein R be H, comprises the group of halogen or alkyl (see, for example, U.S. Patent number 4,086,417).R 6And R 7Can form oxo group or R together 6=-NH-R 1And R 7=H.R 8Be H or R 7And R 8Form two keys or R together 8Can be X, wherein X be
Concrete pyrimidine analogue is disclosed in U.S. Patent number 3,894,000 (see, for example, 2 '-O-cetyl-ara-cytidine, 3 '-O-benzoyl-ara-cytidine and more than other example of 10); U.S. Patent number 3,991,045 (sees that for example, N4-acyl group-1-β-D-arabinofuranosyl adenin cytosine and carboxyl groups derivant many as that wherein list are such as palmityl.
On the other hand, cell cycle inhibitor is the fluoro-pyrimidine analogue, such as 5-fluorouracil, or its analog or derivant, comprise carmofur, doxifluridine, emitefur, ftorafur and floxuridine.Exemplary chemical compound has following structure:
Figure A20038011006800742
R 1 R 2
5-fluorouracil H H
Carmofur C (O) NH (CH 2) 5CH 3H
Doxifluridine A 1H
Floxuridine A 2H
Emitefur CH 2OCH 2CH 3B
Ftorafur C H
Figure A20038011006800751
Other suitable fluoropyrimidine analogue comprises 5-FudR (5-fluoro-BrdU) or its analog or derivant, comprise 5-iododeoxyuridine (5-ludR), 5-bromouracil deoxyribose (5-BudR), fluorouridine triphosphate (5-FUTP) and fluorodeoxyuridine one phosphoric acid (5-dFUMP).Exemplary chemical compound has following structure:
Figure A20038011006800752
5-fluoro-2 '-BrdU: R=F
5-bromo-2 '-BrdU: R=Br
5-iodo-2 '-BrdU: R=I
Think that these chemical compounds are by bringing into play the function as cell cycle inhibitor as the antimetabolite of pyrimidine.
On the other hand, cell cycle inhibitor is a purine analogue.Purine analogue has following structure:
Figure A20038011006800761
X carbon typically wherein, R 1Be H, halogen, the phenyl of amine or replacement; R 2Be H, the primary, secondary amine or tertiary amine, the group of sulfur-bearing, typically-and SH, alkane, cycloalkanes, heterocycle or sugar; R 3Be H, sugar (typically furanose or pyranose structure), the sugar of replacement or ring or heterocycle alkane or aromatic yl group.Such chemical compound sees, for example, and U.S. Patent number 5,602,140.
In the situation of pentostatin, X-R2 is-CH 2CH (OH)-.In this case, second carbon atom being inserted ring goes up between the nitrogen-atoms of X and vicinity.The two keys of this X-N become singly-bound.
U.S. Patent number 5,446,139 have described the suitable purine analogue of the type of following formula demonstration:
Figure A20038011006800762
Wherein under following condition, N represents nitrogen, V, and W, X, Z can be carbon or nitrogen.Ring A can have 0-3 nitrogen-atoms in its structure.If have two nitrogen in ring A, one must be on the W position.If an existence is only arranged, it must be on the Q position.V and Q can not be nitrogen simultaneously.Z and Q can not be nitrogen simultaneously.If Z is a nitrogen, R 3Do not exist.And, R 1-3Be one of the following: H independently, halogen, C 1-7Alkyl, C 1-7Thiazolinyl, hydroxyl, sulfydryl, C 1-7Alkylthio, C 1-7Alkoxyl, C 2-7Alkene oxygen base, aryloxy group, nitro comprises the group of primary amine, secondary amine or tertiary amine.R 5-8Be H or wherein can comprise one of the following: OH independently on two positions, halogen, cyano group, azido, the amino of replacement, R at the most 5And R 7Can form two keys together.Y is H, C 1-7Alkyl-carbonyl or one, two or triguaiacyl phosphate.
Exemplary suitable purine analogue comprises Ismipur, Thiguanosine, ITG, cladribine, fludarabine, tubercidin, puromycin, Pentoxyfilline; Wherein these chemical compounds can be by any phosphorylation.
Exemplary chemical compound has following structure:
R 1K 2R 3Ismipur H SH HThioguanosine NH 2SH B 1ITG NH 2A H cladribine Cl NH 2B 2Fludarabine F NH 2B 3Puromycin H N (CH 3) 2B 4Tubercidin H NH 2B 1
Figure A20038011006800773
Pentoxyfilline
Think that these chemical compounds are by bringing into play the function of cell cycle inhibitor as the antimetabolite of purine.
On the other hand, cell cycle inhibitor is a chlormethine.Can be with many known suitable chlormethine in the present invention as cell cycle inhibitor.Also suitable chlormethine is called cyclophosphamide.
Preferred chlormethine has following general structure:
Wherein A is
Figure A20038011006800775
Or-CH 3Or other alkane, or halogenated alkane, typically CH 2CH (CH 3) Cl, or polycyclic group is such as B, or phenyl such as the C that replaces or heterocyclic group are such as D.
Figure A20038011006800781
The chlormethine that is fit to is disclosed in U.S. Patent number 3,808,297, and wherein A is:
Figure A20038011006800782
R 1-2Be H or CH 2CH 2Cl; R 3Be that H or oxygen containing group are such as hydroperoxy; And R 4Can be alkyl, aryl, heterocyclic radical.
The part of ring needs not be complete.See that for example, U.S. Patent number 5,472,956,4,908,356,4,841,085 wherein is described below structure type:
Figure A20038011006800783
R wherein 1Be H or CH 2CH 2Cl, and R 2-6Be various substituted radicals.
Exemplary chlormethine comprises methyl chloride ethamine and its analog or derivant, comprises methyl chloride amine oxides hydrochloride, novoembichin and mannomustine (halogenated sugar).Exemplary chemical compound has following structure:
Figure A20038011006800791
R
Methyl chloride ethamine CH 3Methyl chloride amine oxides HCl
Novoembichin CH 2CH (CH 3) Cl
Described chlormethine can be a cyclophosphamide, ifosfamide, and perfosfamide, or Torofosfamide, wherein these chemical compounds have following structure:
Figure A20038011006800792
R 1 R 2 R 3
Cyclophosphamide H CH 2CH 2Cl H
Ifosfamide CH 2CH 2Cl H H
Perfosfamide CH 2CH 2Cl H OOH
Torofosfamide CH 2CH 2Cl CH 2CH 2Cl H
Chlormethine can be estramustine or its analog or derivant, comprises phenesterin, prednimustine and estramustine PO 4Therefore, the cell cycle inhibitor of these suitable chlormethine types of the present invention has following structure:
Figure A20038011006800793
R
Estramustine OH
Phenesterin C (CH 3) (CH 2) 3CH (CH 3) 2
Figure A20038011006800801
Prednimustine
Described chlormethine can be chlorambucil or its analog or derivant, comprises melphalan and Chlormaphazine.Therefore the suitable chlormethine type cell cycle inhibitor of the present invention has following structure:
Figure A20038011006800802
R 1 R 2 R 3
Chlorambucil CH 2COOH H H
Melphalan COOH NH 2H
Chlormaphazine H forms phenyl ring together
Chlormethine can be a NSC-34462, and it has following structure:
Figure A20038011006800803
Think that chlormethine is by bringing into play the function as cell cycle as the alkylating agent of DNA.
Cell cycle inhibitor of the present invention can be a hydroxyurea.Hydroxyurea has following formula:
Figure A20038011006800811
Suitable hydroxyurea is disclosed in, for example, and U.S. Patent number 6,080,874, wherein R 1Be:
And R 2Alkyl group with 1-4 carbon, R 3Be H, acyl group, methyl, one of ethyl and their mixture are such as methyl ether.
Other suitable hydroxyurea is disclosed in, for example, U.S. Patent number 5,665, in 768, R wherein 1Be the cycloolefin group, for example N-(3-(5-(4-fluorophenyl sulfur)-furyl]-2-cyclopentenes-1-yl] the N-hydroxyurea.R 2Be H or alkyl group and R with 1-4 carbon 3Be H; X is H or cation.
Other suitable hydroxyurea is disclosed in U.S. Patent number 4,299, in 778, and R wherein 1The phenyl group that is replaced by one or more fluorine atoms; R 2It is the cyclopropyl group; And R 3With X be H.
Other suitable hydroxyurea is disclosed in, for example, U.S. Patent number 5,066, in 658, R wherein 2And R 3Form together with contiguous nitrogen
Wherein m is 1 or 2, and n is that 0-2 and Y are alkyl groups.
On the one hand, described hydroxyurea has following structure:
Figure A20038011006800814
Hydroxyurea
Think that hydroxyurea synthesizes the function of bringing into play as cell cycle inhibitor by being used to suppress DNA.
On the other hand, described cell cycle inhibitor is bleomycin (Belomycin), such as bleomycin A 2, it has following structure
Figure A20038011006800821
The R=terminal amine
Widely collect mycin
Bleomycin A 2: R=(CH 3) 2S +(CH 2) 3NH-
Think that bleomycin brings into play its function as cell cycle inhibitor by crack DNA.Shown they treatment hyperplasia sexually transmitted disease (STD) such as, for example be effective in the carcinoma of penis.
In yet another aspect, described cell cycle inhibitor is a mitomycin, such as ametycin, or its analog or derivant, such as methylmitomycin.Suitable chemical compound has following structure:
Figure A20038011006800822
Ametycin H
Methylmitomycin C H 3
(N-methylmitomycin C)
Think that these chemical compounds are by bringing into play the function as cell cycle inhibitor as the DNA alkylating agent.
On the other hand, cell cycle inhibitor be alkylsulfonate (ester) such as busulfan, or its analog or derivant, such as treosulfan, an improsulfan, piposulfan, and pipobroman.Exemplary chemical compound has following structure:
Figure A20038011006800831
R
The busulfan singly-bound
An improsulfan-CH 2-NH-CH 2-
Piposulfan
Figure A20038011006800833
Pipobroman
Think that these chemical compounds are by bringing into play the function as cell cycle inhibitor as the DNA alkylating agent.
On the other hand, cell cycle inhibitor is a Benzoylamide.In one aspect of the method, cell cycle inhibitor is a nicotiamide.These chemical compounds have following basic structure:
Wherein, X is O or S; A is common to be NH 2Or it can be OH or alkoxy base; B is N or C-P 4, R wherein 4Be that H or the hydroxylating alkane that connects ether are such as OCH 2CH 2OH, this alkane can be straight chain or side chain and can comprise one or more oh groups.Alternatively, B can be N-R 5, in this case, comprise that the two keys on the ring of B are singly-bounds.R 5Can be H and alkyl or aryl group (see, for example, U.S. Patent number 4,258,052); R 2Be H, OR 6, SR 6Or NHR 6, R wherein 6It is an alkyl group; And R 3Be H, low alkyl group, the low alkyl group that connects ether such as-O-Me or-O-ethyl (see, for example, U.S. Patent number 5,215,738).
Suitable benzamide compounds has following structure:
Figure A20038011006800841
Benzoylamide
X=O or S
Y=H, OR, CH 3, acetoxyl group
Z＝H，OR，SR，NHR
The R=alkyl group
Wherein additional compounds is disclosed in U.S. Patent number 5,215,738 (enumerating some 32 kinds of chemical compounds).
Suitable nicotiamide chemical compound has following structure:
Figure A20038011006800842
Nicotiamide
X=O or S
Z＝H，OR，SR，NHR
The R=alkyl group
Wherein additional compounds is disclosed in U.S. Patent number 5,215,738 (enumerate some 58 kinds of chemical compounds, for example, 5-OH nicotiamide, 5-aminonicotinamide, 5-(2,3-dihydroxy propoxyl group) nicotiamide), and chemical compound has following structure:
Nicotiamide
X=O or S (only describing O)
A=OH, NH 2Or alkoxyl
B＝O
R=alkyl or aryl group
With U.S. Patent number 4,258,052 (enumerate some 46 kinds of chemical compounds, for example, 1-methyl-6-ketone-1,6-dihydro nicotinic acid).
On the one hand, cell cycle inhibitor is the tetrazine chemical compound, such as the temozolomide, or its analog or derivant, comprise dacarbazine.Suitable chemical compound has following structure:
Figure A20038011006800852
Temozolomide's dacarbazine
Another kind of suitable tetrazine chemical compound is a procarbazine, comprises HCI and HBr salt, and it has following structure:
Figure A20038011006800853
Procarbazine
On the other hand, cell cycle inhibitor is an actinomycin D, or other member of this family, comprises actinomycin D, actinomycin C 1, actinomycin C 2, actinomycin C 3And D actinomycin D F 1Suitable chemical compound has following structure:
R 1 K 2 K 3
Actinomycin D (C 1) D-Val D-Val singly-bound
Actinomycin C 2D-Val D-alloisoleucine O
Actinomycin C 3D-alloisoleucine D-alloisoleucine O
In one aspect of the method, cell cycle inhibitor is the ethylene imine chemical compound, such as benzodepa, or its analog or derivant, comprise meturedepa, uredepa, and carboquone.Suitable chemical compound has following structure:
Figure A20038011006800862
Figure A20038011006800863
R 1 R 2
Benzodepa phenyl H
Meturedepa CH 3CH 3Carboquone
Uredepa CH 3H
On the other hand, cell cycle inhibitor is halogenated sugar, such as mitolactol, or its analog or derivant, comprise mitobronitol and mannomustine.Suitable chemical compound has following structure:
Mitolactol mitobronitol mannomustine
On the other hand, described cell cycle inhibitor is a diazonium compound, such as azaserine, or its analog or derivant, comprise 6-diazonium-5-oxo-L-nor-leucine and 5-diazouracil (also being pyrimidine analogue).Suitable chemical compound has following structure:
Figure A20038011006800872
R 1 R 2
Azaserine O singly-bound
6-diazonium-5-oxo-L-nor-leucine singly-bound CH 2
According to the present invention can be pazelliptine as other chemical compound of cell cycle inhibitor; Wortmannin; Metoclopramide; RSU; Buthionine sulfoxime; Rhizoma Curcumae Longae; Curcumin; AG337, a kind of thymidylate synthase inhibitor; Levamisole; Lentinan, a kind of polysaccharide; Razoxane, a kind of EDTA analog; Indomethacin; Chlorpromazine; α and interferon-; MnBOPP; Gadolinium texaphrin; 4-amino-1,8-naphthylenediamine (naphthalimide); The staurosporine derivatives of CGP; And SR-2508.
Therefore, on the one hand, described cell cycle inhibitor is the DNA alkylating agent.On the other hand, described cell cycle inhibitor is anti--microtubule reagent.On the other hand, described cell cycle inhibitor is a topoisomerase enzyme inhibitor.On the other hand, described cell cycle inhibitor is the dna cleavage agent.On the other hand, described cell cycle inhibitor is a kind of antimetabolite.On the other hand, described cell cycle inhibitor is by suppressing adenosine deaminase performance function (for example, as purine analogue).On the other hand, described cell cycle inhibitor is synthetic and/or as nucleotide interconversion inhibitor performance function (for example, as purine analogue such as purinethol) by suppressing purine ring.On the other hand, described cell cycle inhibitor is by suppressing dihydrofolate reduction and/or bringing into play function (for example, methotrexate) as breast adenosine monophosphate blocking-up thing.On the other hand, described cell cycle inhibitor is brought into play function (for example, bleomycin) by causing DNA damage.On the other hand, described cell cycle inhibitor is by bringing into play function (for example doxorubicin) as DNA intercalating agent and/or the synthetic inhibitory action of RNA.On the other hand, described cell cycle inhibitor synthesizes and brings into play function (for example, N-phosphono acetyl group-L-aspartate (ester)) by suppressing pyrimidine.On the other hand, described cell cycle inhibitor is brought into play function (for example, hydroxyurea) by suppressing ribonucleotide.On the other hand, described cell cycle inhibitor is brought into play function (for example, 5-fluorouracil) by suppressing thymidine 5'-monophosphate.On the other hand, described cell cycle inhibitor synthesizes and brings into play function (for example, cytosine arabinoside) by suppressing DNA.On the other hand, described cell cycle inhibitor is brought into play function (for example, platinum compounds) by the formation that causes dna adduct.On the other hand, described cell cycle inhibitor synthesizes by Profilin matter and brings into play function (for example, altheine enzyme).On the other hand, described cell cycle inhibitor is brought into play function (for example, taxanes) by suppressing the microtubule function.On the other hand, the one or more steps of described cell cycle inhibitor in the biological pathway that Figure 16 shows work.
Useful in the present invention other cell cycle inhibitor, and to the discussion of their mechanism of action, can see Hardman J.G., Limbird L.E.Molinoff R.B., Ruddon R.W., Gilman A.G. edits, Chemotherapy of Neoplastic Diseases in Goodman andGilman ' s The Pharmacological Basis of Therapeutics the 9th edition, McGraw-HillHealth Professions Division, New York, 1996, the 1225-1287 pages or leaves.Also see U.S. Patent number 3,387,001; 3,808,297; 3,894,000; 3,991,045; 4,012,390; 4,057,548; 4,086,417; 4,144,237; 4,150,146; 4,210,584; 4,215,062; 4,250,89; 4,258,052; 4,259,242; 4,296,105; 4,299,778; 4,367,239; 4,374,414; 4,375,432; 4,472,379; 4,588,831; 4,639,456; 4,767,855; 4,828,831; 4,841,045; 4,841,085; 4,908,356; 4,923,876; 5,030,620; 5,034,320; 5,047,528; 5,066,658; 5,166,149; 5,190,929; 5,215,738; 5,292,731; 5,380,897; 5,382,582; 5,409,915; 5,440,056; 5,446,139; 5,472,956; 5,527,905; 5,552,156; 5,594,158; 5,602,140; 5,665,768; 5,843,903; 6,080,874; 6,096,923; And RE030561 (as implied above, that all these full contents are incorporated herein by reference).
Can also be with many polypeptide, protein and peptide, and these proteinic nucleic acid of encoding are used as cell cycle inhibitor in treatment.This can realize (Walther﹠amp by the transmission by the gene delivery vector of appropriate carriers or Codocyte cycle inhibitor; Stein, Drugs 60 (2): 249-71, in August, 2000; Kim etc., Archives of Pharmacal Res.24 (1): 1-15, February calendar year 2001; With Anwer etc., Critical Reviews in Therapeutic Drug Carrier Systems 17 (4): 377-424,2000.The proteic gene of coding and regulating cell cycle comprises gene (US5,889,169 of INK4 family; US 6,033, and 847), ARF-p19 (US 5,723,313), p21 WAF1/CIP1And p27 KIP1(WO 95/13375; WO 98/35022), p27 KIP1(WO97/38091), p57 KIP2(US6,025,480), ATM/ATR (WO 99/04266), Gadd 45 (US 5,858,679), Myt1 (US5,744,349), (US 6,100 for Wee1 (WO 99/49061) smad 3 and smad 4,032), 14-3-3 σ (WO 9931240), GSK3 β (Stambolic, V. and Woodgett, J.R., Biochem Journal303:701-704,1994), HDAC-1 (Furukawa, Y etc., Cytogenet.Cell Genet.73:130-133,1996; Taunton, J. etc., Science 272:408-411,1996), PTEN (WO99/02704), p53 (U.S. 5,532,220), p33 ING1(U.S. 5.986.078), retinoblastoma (EPO 390530), and NF-1 (WO 9200387).
Can use extensively that various gene delivery vector transmits and expresses albumen as herein described, (for example, U.S. Patent number 5,591 for example to comprise viral vector such as retrovirus vector, 624,5,716,832,5,817,491,5,856,185,5,888,502,6,013,517 and 6,133,029; And the subclass of retrovirus vector such as lentivirus carrier (for example, PCT publication number WO00/66759, WO 00/00600, and WO 99/24465, and WO 98/51810, WO 99/51754, and WO 99/31251, WO 99/30742 and WO 99/15641)), based on the viral system of alphavirus (for example, U.S. Patent number 5,789,245,5,814,482,5,843,723 and 6,015,686), based on system (for example, U.S. Patent number 6,221,646 of adeno-associated virus, 6,180,613,6,165,781,6,156,303,6,153,436,6,093,570,6,040,183,5,989,540,5,856,152 and 5,587,308) with based on system (for example, U.S. Patent number 6,210,939,6 of adenovirus, 210,922,6,203,975,6,194,191,6,140,087,6,113,913,6,080,569,6,063,622,6,040,174,6,033,908,6,033,885,6,020,191,6,020,172,5,994,128 and 5,994,106), based on system (for example, U.S. Patent number 5,928,913,5 herpesvirus or ' amplicon ', 501,979,5,830,727,5,661,033,4,996,152 and 5,965,441) and based on the system of " naked DNA " (for example, U.S. Patent number 5,580,859 and 5,910,488) (as implied above, that all the elements all are incorporated herein by reference).
In one aspect of the invention, ribozyme or antisense sequences (and the gene therapy vector that can transmit these sequences) can be used as cell cycle inhibitor.A representative example of these inhibitor is disclosed in PCT publication number WO 00/32765 (with it, as implied above, all be incorporated herein by reference).
5. the kinases inhibitor of cyclin dependant
In another embodiment, pharmaceutically active compound is kinases inhibitor (for example, the R-roscovitine of cyclin dependant, CYC-101, CYC-103, CYC-400, MX-7065, alvocidib (4H-1-.alpha.-5:6-benzopyran-4-ketone, 2-(2-chlorphenyl)-5,7-dihydroxy-8-(3-hydroxyl-1-methyl-4-piperidyl)-, cis-(-)-[CAS]), SU-9516, AG-12275, PD-0166285, CGP-79807, fascaplysin, GW-8510 (benzsulfamide, 4-(((Z)-(and 6,7-dihydro-7-oxo-8H-pyrroles [2,3-g] benzothiazole-8-thiazolinyl) methyl] amino)-N-(3-hydroxyl-2, the 2-dimethyl propyl)-[CAS]), GW-491619, indirubin 3 ' monoxime, or its analog or derivant GW8510).
(6.EGF epidermal growth factor) receptor kinase inhibitor
In another embodiment, pharmaceutically active compound is EGF (epidermal growth factor) inhibitors of kinases (for example, erlotinib (4-quinazoline amine, N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy)-, monohydrochloride [CAS]), Viatris, erbstatin (erbstatin), BIBX-1382, or its analog or derivant gefitinib (4-quinazoline amine, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-(4-morpholinyl) propoxyl group) [CAS])).
7. elastase inhibitor
In another embodiment; pharmaceutically active compound be elastase inhibitor (for example; ONO-6818; sivelestat sodium hydroxide (glycine; (((((4-(2 for 2-for N-; 2-dimethyl-1-oxopropoxy) benzoyl amino sulfonyl phenyl))))-[CAS]); erdosteine (acetic acid; ((2-oxo-2-[(tetrahydrochysene-2-oxo-3-thienyl) amino] ethyl) sulfo-)-[CAS]); MDL-100948A; MDL-104238 (N-(4-(4-morpholinyl carbonyl) benzoyl)-L-valyl-N '-(3; 3; 4; 4; 4-five fluoro-1-(1-Methylethyl)-2-oxo butyl)-L-2-azetamide); MDL-27324 (L-prolineamide (Prolinamide); N-((5-(dimethylamino)-1-naphthyl) sulfonyl)-L-alanyl-L-alanyl-N-[3; 3; 3-three fluoro-1-(1-Methylethyl)-2-oxopropyl]-; (S)-[CAS]); SR-26831 (thieno [3; 2-c] pyridine; 5-((2-chlorphenyl) methyl)-2-(2; 2-dimethyl-1-oxopropoxy)-4; 5; 6; 7-tetrahydrochysene-5-hydroxyl-[CAS]); Win-68794; Win-63110; SSR-69071 (2-(9 (2-piperidino ethyoxyl)-4-oxo-4H-pyridos (1; 2-a) pyrimidine-2-yloxy methyl)-4-(1-Methylethyl)-6-methoxyl group-1; 2-benzisothiazole-3 (2H)-ketone-1; the 1-dioxide); (N (α)-(1-adamantyl sulfonyl) N (ε)-succinyl group-L-lysyl-L-prolyl-L-figured silk fabrics ammonium aldehyde (valinal)); Ro-31-3537 (N α-(1-diamantane (obsolete) sulfonyl) N-(4-carboxylbenzoyl)-L-lysyl-alanyl-L-figured silk fabrics ammonium aldehyde); R-665; FCE-28204; ((6R; 7R)-2-(benzyloxy)-7-methoxyl group-3-methyl-4-pivaloyl-3-cephalosporin (cephem) 1; the 1-dioxide); 1; 2-benzisothiazole-3 (2H)-ketone; 2-(2; the 4-dinitrophenyl)-; 1; 1-dioxide [CAS]; L-658758 (L-proline; 1-((3-((acetoxyl group) methyl)-7-methoxyl group-8-oxo-5-sulfo--1-azabicyclo [4.2.0] oct-2-ene-2-yl) carbonyl)-; S; the S-dioxide; (6R-cis)-[CAS]); L-659286 (nafoxidine; 1-((7-methoxyl group-8-oxo-3-(((1; 2; 5; 6-tetrahydrochysene-2-methyl-5; 6-dioxo-1; 2,4-triazine-3-yl) sulfo-) methyl)-5-sulfo-(thia)-1-azabicyclo [4.2.0] oct-2-ene-2-yl) carbonyl)-, S; the S-dioxide; (6R-cis)-[CAS]), and L-680833 (phenylacetic acid, 4-((3; 3-diethyl-1-(((1-(4-aminomethyl phenyl) butyl) amino) carbonyl)-4-oxo-2-azetidinyl) oxygen)-, (S-(R *, S *)]-[CAS])), or its analog or derivant.
8.Xa factor inhibitors
In another embodiment, pharmaceutically active compound be the Xa factor inhibitor (for example, CY-222, fondaparinux sodium (α-D-glycopyranoside, methyl O-2-deoxidation-6-O-sulfo group-2-(sulfo group amino)-α-D-glycopyranosyl-(1-4)-O-β-D-glucopyranuronosyl-(1-4)-O-2-deoxidation-3,6-two-O-sulfo group-2-(sulfo group amino)-α-D-glycopyranosyl-(1-4)-O-2-O-sulfo group-α-L-idopyranuronosyl-(1-4)-2-deoxidation-2-(sulfo group amino)-, 6-(disulfate) [CAS]), or its analog or derivant danaparoid sodium).
9. farnesyl transferase inhibitor
In another embodiment; pharmaceutically active compound be farnesyl transferase inhibitor (for example; dichloro benzoprim (2; (4-(3 for 4-diaminourea-5-; 4-dichloro benzyl amino)-the 3-nitrobenzophenone)-the 6-ethyl-pyrimidine); B-581; B-956 (N-(8 (R)-amino-2 (S)-benzyl-5 (S)-isopropyls-9-sulfane base-3 (Z); 6 (E)-nonadiene acyl groups (nonadienoyl))-the L-methionine); OSI-754; perillyl alcohol (1-cyclohexene-1-methanol; 4-(1-methyl ethylene)-[CAS]; RPR-114334; lonafarnib (1-piperidines carboxylic acid amides, 4-(2-(4-((11R)-3,10-two bromos-8-chloro-6; 11-dihydro-5H-benzo (5; 6) ring heptan (1,2-b) pyridine-11-yl)-piperidino also)-the 2-oxoethyl)-[CAS]), Sch-48755; Sch-226374; (7,8-two chloro-5H-dibenzo (b, e) (1; 4) diaza-11-yl)-the pyridin-3-yl methyl amine; J-104126, L-639749, L-731734 (pentane amide; 2-((2-((2-amino-3-sulfydryl propyl group) amino)-3-methyl amyl) amino)-3-methyl-N-(tetrahydrochysene-2-oxo-3-furyl)-, (3S-(3R *(2R *(2R *(S *), 3S *), 3R *)))-[CAS]), L-744832 (butanoic acid, 2-((2-((2-((2-amino-3-sulfydryl propyl group) amino)-3-methyl amyl) oxygen base)-1-oxo-3-phenyl propyl) amino)-4-(methyl sulphonyl)-, 1-Methylethyl ester, (2S-(1 (R *(R *)), 2R *(S *), 3R *))-[CAS]); L-745631 (1-piperazine propanethiol; beta-amino-2-(2-methoxy ethyl)-4-(1-naphthyl carbonyl)-; ((β R; 2S)-[CAS]); N-acetyl group-N-naphthyl methyl-2 (S)-((1-(4-cyano group benzyl)-1H-imidazoles-5-yl) acetyl group] amino-3 (S)-dimethylpentylamines, (2 α)-2-hydroxyl-24,25-dihydroxylanost-8-alkene-3-ketone; BMS-316810; UCF-1-C (2,4-decadinene amide, N-(5-hydroxyl-5-(7-((2-hydroxyl-5-oxo-1-cyclopentenes-1-yl) amino-oxo-1; 3; 5-heptantriene base)-and 2-oxo-7-oxabicyclo (4.1.0) heptan-3-alkene-3-yl) 2,4, the 6-trimethyl; (1S-(1 α; 3 (2E, 4E, 6S *), 5 α, 5 (1E, 3E, 5E), 6 α))-[CAS], UCF-116-B, or its analog or derivant.
10. fibrinogen antagonist
In another embodiment; pharmaceutically active compound is fibrinogen antagonist (for example, 2 (S)-((p-tosyl) amino)-3-(((5,6; 7; 8-tetrahydrochysene-4-oxo-5-(2-(piperidin-4-yl) ethyl-4H-pyrazolo (pyrazolo)-(1,5-a) (1,4] diaza-2-yl] carbonyl]-amino] propanoic acid; streptokinase (kinases (activation-enzyme); strepto--[CAS]), urokinase (kinases (activation-enzyme), urine-[CAS]); the former activator of dimension lyase; pamiteplase, Monteplase, heberkinase; anistreplase; alteplase, preceding-urokinase, picotamide (1; 3-benzene dicarboxamide; 4-methoxyl group-N, N '-two (3-pyridylmethyl)-[CAS]), or its analog or derivant.
11. guanylate cyclase stimulus object
In another embodiment, pharmaceutically active compound be the guanylate cyclase stimulus object (for example, isosorbide-5-mononitrate (ester) (the D-sorbitol, 1,4:3, the two dehydrations of 6--, 5-nitrate (ester) [CAS], or its analog or derivant.
12. heat shock protein 90 antagonist
In another embodiment, described pharmaceutically active compound is heat shock protein 90 antagonist (for example a, geldanamycin; NSC-33050 (17-allyl amino geldanamycin mycin), rifabutin (rifamycin XIV, 1 ', 4-two dehydrogenations-1-deoxidation-1,4-dihydro-5 '-(2-methyl-propyl)-1-oxo-[CAS]), 17AAG), or its analog or derivant.
13.HMGCoA reductase inhibitor
In another embodiment, described pharmaceutically active compound is HMGCoA reductase inhibitor (for example, BCP-671, BB-476, fluvastatin (6-heptenoic acid, 7-(3-(4-fluorophenyl)-1-(1-Methylethyl)-1H-indole-2-yl)-3, the 5-dihydroxy-, a sodium salt, (R *, S *-(E))-(±)-[CAS]), dalvastatin (2H-pyran-2-one, 6-2-(2-(2-(4-fluoro-3-aminomethyl phenyl)-4,4,6,6-tetramethyl-1-cyclohexene-1-yl) tetrahydrochysene vinyl))-the 4-hydroxyl-, (4 α, 6 β (E))-(+/-)-[CAS]), glenvastatin (2H-pyran-2-one, 6-(2-(4-(4-fluorophenyl)-2-(1-Methylethyl)-6-phenyl-3-pyridine radicals) vinyl) tetrahydrochysene-4-hydroxyl-, (4R-(4 α, 6 β (E)))-[CAS]), S-2468, N-(1-oxo dodecyl)-4 α, 10-dimethyl-8-azepine-trans-naphthalane-3 β-alcohol, Atorvastatin calcium (1H-pyrroles-1-enanthic acid, 2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-((phenyl amino) carbonyl)-, calcium salt (R-(R *, R *))-[CAS]), CP-83101 (6, the 8-nonadienoic acid, 3,5-dihydroxy-9, the 9-diphenyl-, methyl ester, (R *, S *-(E))-(+/-)-[CAS]), pravastatin (1-naphthalene enanthic acid, 1,2,6,7,8,8a-six hydrogen-β, δ, 6-trihydroxy-2-methyl-8-(2-methyl isophthalic acid-oxo butoxy)-, a sodium salt, (1S-(1 α (β S *, δ S *), 2 α, 6 α, 8 β (R *), 8a α))-[CAS]), U-20685, and Pitavastatin (the 6-heptenoic acid, 7-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl)-3,5 dihydroxy-, calcium salt (2: 1), (S-(R *, S *-(E)))-[CAS]), N-((1-methyl-propyl) carbonyl)-8-[2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl]-mistake hydrogen-isoquinolin, dihydro lovastatin (butanoic acid, the 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl ester (1 α (R *), 3 α, 4 α, 7 β, 8 β (2S *, 4S *), 8 α β))-[CAS]), HBS-107, the dihydro lovastatin (butanoic acid, the 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthyl ester (1 α (R *), 3 α, 4 α, 7 β, 8 β (2S *, 4S *), 8a β))-[CAS]), L-669262 (butanoic acid, 2, the 2-dimethyl-, 1,2,6,7,8,8a-six hydrogen-3,7-dimethyl-6-oxo-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthalene thiazolinyl (1S-[1 α, 7 β, 8 β (2S *, 4S *), 8 α β])-[CAS]), simvastatin (butanoic acid, 2, the 2-dimethyl-, 1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthalene alkenyl esters, (1S-(1 α, 3 α, 7 β, 8 β (2S *, 4S *), 8 α β))-[CAS]), rosuvastatin calcium (6-heptenoic acid, 7-(4-(4-fluorophenyl)-6-(1-Methylethyl)-2-(methyl (methyl sulphonyl) amino)-5-pyrimidine radicals)-3,5-dihydroxy-calcium salt (2: 1) (S-(R *, S *-(E))) [CAS]), meglutol (2-hydroxy-2-methyl-1,3-propane dicarboxylic acid), lovastatin (butanoic acid, the 2-methyl-, 1,2,3,7,8,8a-six hydrogen-3,7-dimethyl-8-(2-(tetrahydrochysene-4-hydroxyl-6-oxo-2H-pyrans-2-yl) ethyl)-1-naphthalene alkenyl esters, (1S-(1. α. (R *), 3 α, 7 β, 8 β (2S *, 4S *), 8 α β]]-[CAS])), or its analog or derivant.
14. hydroorotic acid dehydrogenase inhibitor
In another embodiment, described pharmaceutically active compound be the hydroorotic acid dehydrogenase inhibitor (for example, leflunomide (4-isoxazole carboxylic acid amides (carboxamide), 5-methyl-N-4-(trifluoromethyl) phenyl]-[CAS]), laflunimus (2-acrylamide (Propenamide), 2-cyano group-3-cyclopropyl-3-hydroxy-n-(3-methyl-4 (trifluoromethyl) phenyl)-, (Z)-[CAS])), or its analog or derivant.
15.IKK2 inhibitor
In another embodiment, described pharmaceutically active compound be the IKK2 inhibitor (for example, MLN-120B, SPC-839), or its analog or derivant.
16.IL-1, ICE and IRAK antagonist
In another embodiment; described pharmaceutically active compound is IL-1; ICE ((aryl) acyloxy methyl ketone) and the IRAK antagonist (for example; VX-765 (Vertex Pharmaceuticals CambridgeInc.; MA); VX-740 (Vertex Pharmaceuticals Inc.); E-5090 (2-propanoic acid; 3-(5-ethyl-4-hydroxyl-3-methoxyl group-1-naphthalene thiazolinyl)-2-methyl-; (Z)-[CAS]); CH-164; CH-172; CH-490; AMG-719; iguratimod (N-(3-(formoxyl amino)-4-oxo-6-phenoxy group-4H-chromene (chromen)-7-yl) Methanesulfomide); AV94-88; (the 6H-pyridazine is (Pyridazino) (1 also for pralnacasan; 2-a) (1; 2) diaza-1-carboxylic acid amides; N-((2R; 3S)-and 2-ethyoxyl tetrahydrochysene-5-oxo-3-furyl) octahydro-9-((1-isoquinolyl carbonyl) amino)-6; the 10-dioxo-; (1S; 9S)-[CAS]); (2S-cis)-5-(benzyloxycarbonyl amino-1; 2; 4; 5; 6; 7-six hydrogen-4-(oxo azepine also (3; 2; 1-hi) indole-2-carbonyl)-amino)-the 4-ketobutyric acid; AVE-9488; Esonarimod (benzenebutanoic acid; α-((acetyl group sulfo-) methyl)-4-methyl-γ-oxo-[CAS]); Taisho Pharmaceutical Co.; Ltd.; Japan); pralnacasan (6H-pyridazine also (1; 2-a) (1; 2) diaza-1-carboxylic acid amides; N-((2R; 3S)-and 2-ethyoxyl tetrahydrochysene-5-oxo-3-furyl) octahydro-9-((1-isoquinolyl carbonyl) amino)-6; the 10-dioxo-; (1S; 9S)-[CAS], tranexamic acid (cyclohexane-carboxylic acid, 4-(amino methyl)-; trans-[CAS]); Win-72052, romazarit (Ro-31-3948) (propanoic acid, 2-((2-(4-chlorphenyl)-4-methyl-5-oxazolyl) methoxyl group)-2-methyl-[CAS]); PD-163594; SDZ-224-015 (L-aminopropanamide N-((phenyl methoxyl group) carbonyl)-L-valyl-N-((1S)-3-((2,6-dichloro-benzoyl base) oxygen base)-1-(2-ethyoxyl-2-oxoethyl)-2-oxopropyl)-[CAS]), L-709049 (L-aminopropanamide; N-acetyl group-L-tyrosyl-L-valyl-N-(2-carboxyl-1-formyl ethyl)-; (S)-[CAS]), TA-383 (1H-imidazoles), 2-(4-chlorphenyl)-4; 5-dihydro-4; the 5-diphenyl-, monohydrochloride, cis-[CAS]); EI-1507-1 (6a; 12a-epoxy benzene (a) anthracene)-1,12 (2H, 7H)-diketone; 3; 4-dihydro-3,7-dihydroxy-8-methoxyl group-3-methyl-[CAS]), ethyl 4-(3; the 4-Dimethoxyphenyl)-6; 7-dimethoxy-2-(1,2,4-triazol-1-yl methyl) quinoline-3-carboxylation's (ester); EI-1941-1
TJ-114, Antril (Synergen) (interleukin 1 receptor antagonist (x is reductive for people's isoform), N2-L-methionyl-[CAS])), or its analog or derivant.
17.IL-4 agonist
In another embodiment, pharmaceutically active compound is that (for example, (L-glutamic acid has the polymer of L-alanine, L-lysine and L-tyrosine to glatiramiracetate to the IL-4 agonist, or its analog or derivant acetas (salt) [CAS])).
18. immunomodulator
In another embodiment; pharmaceutically active compound is immunomodulator (Biolimus for example; leflunomide (1eflunamide); ABT-578; methylamino sulfonic acid 3-(2-methoxyl group phenoxy group)-2-(((methylamino) sulfonyl) oxygen base) propyl diester; sirolimus; CCI-779 (rapamycin 42-(3-hydroxyl-2-(hydroxymethyl)-2 Methylpropionic acid ester) [CAS]); LF-15-0195; NPCl5669 (L-leucine, N-(((2,7-dimethyl-9H-fluorenes-9-yl) methoxyl group) carbonyl)-[CAS]); NPC-15670 (L-leucine; N-(((4,5-dimethyl-9H-fluorenes-9-yl) methoxyl group) carbonyl)-[CAS]), NPC-16570 (4-(2-(fluorenes-9-yl) ethyoxyl-carbonyl) amino benzoic Acid); sufosfamide (ethanol; 2-((3-(2-chloroethyl) tetrahydrochysene-2H-1,3,2-oxazaphosphorin-2-yl) amino)-; mesylate (ester); P-oxide [CAS], tresperimus (2-(N-[4-(3-amino propyl amino) butyl] carbamoyl oxygen base)-N-(6-guanidine radicals hexyl) acetamide), 4-[2-fluorenes-9-yl] and ethoxy carbonyl amino)-benzo-hydroxamic acid; laquinimod; PBI-1411, azathioprine (6-((1-methyl-4-nitro-1H-imidazoles-5-yl) sulfo-)-1H-purine), PBI0032; beclometasone; MDL-28842 (9H-purine-6-amine, 9-(5-deoxidation-5-fluoro-beta-D-Soviet Union-pent-4-enofuranosyl)-, (Z)-[CAS]); FK-788; AVE-1726, ZK-90695, ZK-90695; Ro-54864; didemnin-B, lllinois (DidemninA, N-(1-(2-hydroxyl-1-oxopropyl)-L-prolyl); (S)-[CAS]); SDZ-62-826 (Ethanaminium, 2-((hydroxyl [[1-[(oxygen base in eight last of the ten Heavenly stems) carbonyl]-the 3-piperidyl] methoxyl group] phosphinyl) oxygen oneself)-N, N; the N-trimethyl-; inner salt [CAS]), argyrin B ((4S, 7S; 13R; 22R)-and 13-ethyl-4-(1H-indol-3-yl methyl)-7-(4-methoxyl group-1H-indol-3-yl methyl) 18,22-dimethyl-16-methyl-alkene-24-sulfo-(thia)-3,6; 9; 12,15,18; 21; 26-eight azabicyclos [21.2.1]-26-1 (25), 23 (26)-diolefins-2,5; 8; 11,14,17; 20-heptanone [CAS]); everolimus (rapamycin, 42-O-(2-hydroxyethyl)-[CAS]), SAR-943; L-687795; 6-((4-chlorphenyl sulfinyl)-2,3-dihydro-2-(4-methoxyl group-phenyl)-5-methyl-3-oxo-4-pyridazine nitrile, 91Y78 (1H-imidazoles (4; 5-c) pyridine-4-amine; 1-β-D-ribofuranosyl-[CAS]), auranofin (gold, (1-sulfo--β-D-Glucopyranose. 2; 3; 4,6-tetrem acid group closes-S) (triethyl phosphine)-[CAS]), the 27-O-demethyl rapamycin; tipredane (Androsta-1; 4-diene-3-ketone, 17-(ethylmercapto group)-9-fluoro-11-hydroxyl-17-(methyl mercapto)-, (11 β; 17 α)-[CAS]); AI-402, and LY-178002 (the 4-thiazolidone, 5-((3; 5-two (1; the 1-dimethyl ethyl)-and the 4-hydroxy phenyl) methylene)-[CAS]), SM-8849 (abadol, 4-(1-(2-fluorine [1; 1 ' diphenyl]-the 4-yl) ethyl)-N-methyl-[CAS]); piceatannol, resveratrol (resveratrol), triamcinolone acetonide (pregna-1; 4-diene-3; the 20-diketone, 9-fluoro-11,21-dihydroxy-16; 17-[(1-methyl ethylidene) two (oxygen)]-; (11 β, 16 α)-[CAS], ciclosporin (ciclosporin A-[CAS]); tacrolimus (15; 19-epoxy-3H-pyrido (2,1-c) (1,4) oxoazacyclotricosine-1; 7; 20,21 (4H, 23H)-tetraketone; 5; 6,8,11; 12; 13,14,15; 16; 17,18,19; 24; 25,26,26a-16 hydrogen-5; 19-dihydroxy-3-(2-(4-hydroxyl-3-methoxyl group cyclohexyl)-1-methyl ethylene)-14; the 16-dimethoxy-4 ', 10,12; 18-tetramethyl-8-(2-acrylic)-, (3S-(3R *(E (1S *, 3S *, 4S *)), 4S *, 5R *, 8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, 19S *, 26aR *))-[CAS]); gusperimus (2-heptamide; 7-((amino imino methyl) amino)-N-(2-((4-((3-aminopropyl) amino) butyl) amino)-1-hydroxyl-2-oxoethyl)-; (+/-)-[CAS]); tixocortol cuts down ester (Pregn-4-alkene-3; the 20-diketone; 21-((2; 2-dimethyl-1-oxopropyl) sulfo-)-11; the 17-dihydroxy-; (11 β)-[CAS]; (1-92LFA-3 (antigen) (people) has the fusion rotein of immunoglobulin G 1 (people's hinge-CH2-CH3 γ 1-chain) to alefacept; dimer); halobetasol propionate (pregna-1; 4-diene-3; the 20-diketone; 21-chloro-6; 9-two fluoro-11-hydroxyl-16-methyl-17s-(1-oxopropoxy)-; (6 α; 11 β; 16 β)-[CAS]); iloprost trometamol (valeric acid; 5-(six hydrogen-5-hydroxyl-4-(3-hydroxy-4-methyl-1-octene-6-alkynyl)-2 (1H)-pentalenylidene yls)-[CAS]); Beraprost (1H-cyclopenta (b) benzofuran-5-butanoic acid); 2; 3; 3a, 8b-tetrahydrochysene-2-hydroxyl-1-(3-hydroxy-4-methyl-1-octene-6-base alkynyl)-[CAS]), rimexolone (Androsta-1; 4-diene-3-ketone; 11-hydroxyl-16,17-dimethyl-17-(1-oxopropyl)-, (11 β; 16 α; 17 β)-[CAS] dexamethasone (Pregna-1,4-diene-3); the 20-diketone; 9-fluoro-11,17,21-trihydroxy-16-methyl-; (11 β; 16 α)-[CAS]), sulindac (cis-5-fluoro-2-methyl isophthalic acid-((p-methyl sulfinyl) benzal) indeno-3-acetic acid), proglumetacin (1H-indole-3-acetic acid; 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-; 2-(4-(3-((4-(benzoyl-amido)-5-(dipropyl amino)-1,5-dioxo amyl group) oxygen base) propyl group)-1-piperazinyl) ethyl ester, (+/-)-[CAS]); alclometasone diproionate (Pregna-1; 4-diene-3,20-diketone, 7-chloro-11-hydroxyl-16-methyl-17; 21-two (1-oxopropoxy)-; (7 α, 11 β, 16 α)-[CAS]); pimecrolimus (15; 19-epoxy-3H-pyrido (2,1-c) (1,4) oxaazacyclotricosine-1; 7; 20,21 (4H, 23H)-tetraketone; 3-(2-(4-chloro-3-methoxyl group cyclohexyl)-1-methyl ethylene)-8-ethyl-5; 6,8,11; 12; 13,14,15; 16; 17,18,19; 24; 25,26,26a-16 hydrogen-5; 19-dihydroxy-14; the 16-dimethoxy-4 ', 10,12; the 18-tetramethyl-, (3S-(3R *(E (1S *, 3S *, 4R *)), 4S *, 5R *, 8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, 19S *, 26aR *))-[CAS]); hydrocortisone-17-butyrate (salt) (Pregn-4-alkene-3; the 20-diketone; 11; 21-dihydroxy-17-(1-oxo butoxy)-; (11 β)-[CAS]); mitoxantrone (9; the 10-amerantrone; 1; 4-dihydroxy-5; 8-two ((2-((22-hydroxyethyl) amino) ethyl) amino)-[CAS]); mizoribine (1H-imidazoles-4-carboxylic acid amides; 5-hydroxyl-1-β-D-ribofuranosyl-[CAS]); prednicarbate (Pregna-1; 4-diene-3; the 20-diketone; 17-((ethoxy carbonyl) oxygen base)-11-hydroxyl-21-(1-oxopropoxy)-; (11 β)-[CAS]); lobenzarit (benzoic acid; 2-((2-carboxyl phenyl) amino)-4-chloro-[CAS]); glucametacin (D-glucose; 2-(((1-(4-chlorobenzene formacyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl group) amino)-2-deoxidation-[CAS]); fluocortolone monohydrate ((6 α)-fluoro-16 α-methylpregna-1; 4-diene 11 β; 21-glycol-3; the 20-diketone); but chlorine butyl ester (Pregna-1; 4-diene-21-acid; 6-fluoro-11-hydroxyl-16-methyl-3, the 20-dioxo-, butyl ester; (6 α; 11 β, 16 α)-[CAS]), difluprednate (Pregna-1; 4-diene-3; the 20-diketone, 21-(acetoxyl group)-6,9-two fluoro-11-hydroxyl-17-(1-oxo butoxy)-; (6 α; 11 β)-[CAS] diflorasone diacetate (Pregna-1,4-diene-3); the 20-diketone; 17, the 21-diacetoxy)-6,9-two fluoro-11-hydroxyl-16-methyl-; (6 α; 11 β, 16 β)-[CAS]), valeric acid dexamethasone (Pregna-1; 4-diene-3; the 20-diketone, 9-fluoro-11,21-dihydroxy-16-methyl-17-((1-oxo amyl group) oxygen base)-; (11 β; 16 α)-[CAS]), methylprednisolone, propanoic acid deprodone (Pregna-1; 4-diene-3; the 20-diketone, 11-hydroxyl-17-(1-oxopropoxy)-, (11. β .)-[CAS]); bucillamine (L-cysteine; N-(2-sulfydryl-2-methyl isophthalic acid-oxopropyl)-[CAS]), amcinonide (phenylacetic acid, 2-amino-3-benzoyl-; one sodium salt; monohydrate [CAS]), acemetacin (the 1H-indole-3-acetic acid, 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-; or its analog or derivant carboxymethyl ester [CAS])).In addition, the analog of rapamycin comprises tacrolimus and its derivant (for example, EP0184162B1 and U.S. Patent number 6,258,823) everolimus and its derivant (for example, U.S. Patent number 5,665,772).The other representative example of the analog of sirolimus and derivant comprises ABT-578, and other can see following PCT publication number: WO9710502, WO9641807, WO9635423, WO9603430, WO9600282, WO9516691, WO9515328, WO9507468, WO9504738, WO9504060, WO9425022, WO9421644, WO9418207, WO9410843, WO9409010, WO9404540, WO9402485, WO9402137, WO9402136, WO9325533, WO9318043, WO9313663, WO9311130, WO9310122, WO9304680, WO9214737, and WO9205179.Representational United States Patent (USP) comprises U.S. Patent number 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; With 5,091,389.
Sirolimus is provided below, everolimus, the structure of sirolimus:
Title The coding title Company Structure
Everolimus SAR-943 Novartis As follows
Sirolimus Rapamune rapamycin AY-22989 NSC-226080 Wyeth As follows
Tacrolimus FK506 Fujusawa As follows
Figure A20038011006800991
Everolimus
Figure A20038011006800992
Tacrolimus
Figure A20038011006800993
Sirolimus
19. inosine monophosphate dehydrogenase inhibitor
In another embodiment, pharmaceutically active compound be inosine monophosphate dehydrogenase inhibitor (for example, Mycophenolic Acid morpholine ethyl ester (4-hexenoic acid, 6-(1,3-dihydro-4-hydroxyl-6-methoxyl group-7-methyl-3-oxo-5-isobenzofuran-base)-4-methyl-, 2-(4-morpholinyl) ethyl ester, (E)-[CAS]), ribavirin (1H-1,2,4-triazole-3-carboxylic acid amides, 1-β-D-ribofuranosyl-[CAS]), tiazofurine (4-thiazole carboxylic acid amides, 2-β-D-ribofuranosyl-[CAS]), viramidine, amino thiadiazoles, thiophenfurin, the thiophene furan is held up woods), or its analog or derivant.Other representative example is included in U.S. Patent number 5,536,747; 5,807,876; 5,932,600; 6,054,472,6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518291; 6,541496; 6,596,747; 6,617,323; With 6,624,184, US publication 2002/0040022A1,2002/0052513A1,2002/0055483A1,2002/0068346A1,2002/0111378A1,2002/0111495A1,2002/0123520A1,2002/0143176A1,2002/0147160A1,2002/0161038A1,2002/0173491A1,2002/0183315A1,2002/0193612A1,2003/0027845A1,2003/0068302A1,2003/0105073A1,2003/0130254A1,2003/0143197A1,2003/0144300A1,2003/0166201A1,2003/0181497A1,2003/0186974A1,2003/0186989A1 and 2003/0195202A1 and PCT publication number WO00/24725A1, WO 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO0056331A1, WO 00/73288A1, WO 01/00622A1, WO01/66706A1, WO01/79246A2, WO01/81340A2, WO 01/85952A2, WO 02/16382A1, WO02/18369A2, WO 02/51814A1, WO 02/57287A2, WO 02/57425A2, WO02/60875A1, WO 02/60896A1, WO 02/60898A1, WO 02/68058A2, WO03/20298A1, WO 03/37349A1, WO 03/39548A1, WO 03/45901A2, WO03/47512A2, WO 03/53958A1, WO 03/55447A2, WO 03/59269A2, WO03/63573A2, WO03/87071A1, WO 90/01545A1, WO97/40028A1, WO97/41211A1 is among WO 98/40381A1 and the WO 99/55663A1.
20. leukotriene inhibitors
In another embodiment; pharmaceutically active compound be leukotriene inhibitors (for example; DTI-0026; CNO-4057 (benzenpropanoic acid; 2-(4-carboxyl butoxy)-6-((6-(4-methoxyphenyl)-5-hexenyl) oxygen base)-; (E)-[CAS]); ONO-LB-448; pirodomast 1; 8-1; 5-benzodiazine-2 (1H)-ketone; 4-hydroxyl-1-phenyl-3-(1-pyrrolidinyl)-[CAS]; Sch-40120 (benzo (b) [1; 8]) 1; 5-benzodiazine-5 (7H)-ketone; 10-(3-chlorphenyl)-6; 8; 9; 10-tetrahydrochysene-[CAS]); L-656224 (4-benzofuran alcohol; 7-chloro-2-((4-methoxyphenyl) methyl)-3-methyl-5-propyl group-[CAS]); MAFP (methylarachidonyl fluorophosphonate); ontazolast (2-benzoxazole amine; N-(2-cyclohexyl-1-(2-pyridine radicals) ethyl)-5-methyl-; (S)-[CAS]); amelubant (carbamic acid; ((4-((3-((4-(1-(4-hydroxy phenyl)-1-Methylethyl) phenoxy group) methyl) phenyl) methoxyl group) phenyl) iminomethyl)-ethyl ester [CAS]); SB-201993 (benzoic acid; 3-((((((1E)-2-carboxy vinyl)-5-((8-(4-methoxyphenyl) octyl group) oxygen base)-2-pyridine radicals) methyl) sulfo-) methyl)-[CAS]); LY-203647 (ethyl ketone; 1-[2-hydroxyl-3-propyl group-4-(4-(2-[4-(1H-tetrazolium-5-yl) butyl]-2H-tetrazolium-5-yl) butoxy) phenyl]-[CAS]); LY-210073; LY-223982 (benzenpropanoic acid; 5-(3-carboxylbenzoyl)-2-((6-(4-methoxyphenyl)-5-hexenyl) oxygen base)-; (E)-[CAS]); LY-293111 (benzoic acid; 2-(3-(3-((5-ethyl-4 '-fluoro-2-hydroxyl [1; 1 '-diphenyl]-the 4-yl) the oxygen base) propoxyl group)-2-propyl group phenoxy group)-[CAS]); SM-9064 (pyrrolidine; 1-(4; 11-dihydroxy-13-(4-methoxyphenyl)-1-oxo-5,7,9-tridecatriene base]-; (E; E, E)-[CAS]), T-0757 (2; 6-octadiene amide; N-(4-hydroxyl-3,5-3,5-dimethylphenyl)-3, the 7-dimethyl-; (2E)-[CAS])), or its analog or derivant.
21.MCP-1 antagonist
In another embodiment, described pharmaceutically active compound be the MCP-1 antagonist (for example, nitronaproxen (2-naphthalene alkene acetic acid, 6-methoxyl group-Alpha-Methyl 4-(nitrooxy) butyl ester (α S)-[CAS]), bindarit (2-(1-benzyl indazole-3-ylmethoxy)-2 Methylpropionic acid), or its analog or derivant 1-α-25 dihydroxy vitamin d3).
22.MMP inhibitor
In another embodiment, described pharmaceutically active compound is MMP inhibitor (for example, D-9120; doxycycline (2-aphthacene carboxylic acid amides, 4-(dimethylamino)-1,4; 4a; 5,5a, 6; 11; 12a-octahydro-3,5,10; 12; 12a-penta hydroxy group-6-methyl isophthalic acid, 11-dioxo-(4S-(4 α, 4a α; 5 α; 5a α, 6 α, 12a α))-[CAS]); BB-2827; BB-1101 (2S-pi-allyl-N1-hydroxyl-3R-isobutyl group-N4-(1S-methylamino formoxyl-2-phenylethyl)-succinamide), BB-2983, solimastat (N '-(2; 2-dimethyl-1 (S)-(2-(2-pyridine radicals) carbamoyl) propyl group)-N4-hydroxyl-2 (R)-isobutyl group-3 (S)-methoxyl group succinamide); batimastat (succinamide, N4-hydroxy-n 1-(2-(methylamino)-2-oxo-1-(phenyl methyl) ethyl)-2-(2-methyl-propyl)-3-[(2-thiophene thio) methyl]-, (2R-(1 (S *), 2R *, 3S *))-[CAS]; British Biotech; UK); CH-138; CH-5902; D-1927; D-5410; EF-13 (gamma-Linolenic acid lithium salts); CMT-3 (2-aphthacene carboxylic acid amides; 1; 4; 4a; 5,5a, 6; 11; 12a-octahydro-3,10,12; 12a-tetrahydroxy-1; the 11-dioxo-, (4aS, 5aR; 12aS)-[CAS]); Marimastat (N-(2,2-dimethyl-1 (S)-(N-methylamino formoxyl) propyl group)-N, 3 (S)-dihydroxy-2 (R)-isobutyl group succinamides; British Biotech; UK), TIMP ' S, ONO-4817; rebimastat (L-valine amide; N-((2S)-2-sulfydryl-1-oxo-4-(3,4,4-trimethyl-2; 5-oxo-1-imidazolidinyl) butyl)-L-leucyl-N; 3-dimethyl-[CAS]), PS-508, CH-715; nimesulide (first sulfonamides; N-(4-nitro-2-Phenoxyphenyl)-[CAS]), six hydrogen-2-(2 (R)-(1 (RS)-(hydroxyl amino formoxyl)-4-phenyl butyl) pelargonyl group)-N-(2,2; 6; 6-tetramethyl-4-piperidyl-3 (S)-pyridazine carboxylic acid amides, Rs-113-080, Ro-1130830; cipemastat (1-piperidines butyramide; 3-(cyclopentyl-methyl)-N-hydroxyl-γ-oxo-α-[(3,4,4-trimethyl-2; 5-dioxo-1-imidazolidinyl) methyl]-; (α R, β R)-[CAS]), 5-(4 '-diphenyl)-5-(4-(4-Nitrobenzol) piperazinyl barbituric acid; 6-methoxyl group-1; 2,3,4-tetrahydrochysene-norharman-1-carboxylic acid; Ro-31-4724 (L-alanine; N-(2-(2-(hydroxyl amino)-2-oxoethyl)-4-methyl isophthalic acid-oxo amyl group)-L-leucyl-, ethyl ester [CAS]), prinomastat's (3-thiomorpholine carboxylic acid amides; N-hydroxyl-2; 2-dimethyl-4-((4-(4-piperidyl oxygen base) phenyl) sulfonyl)-(3R)-[CAS]), AG-3433 (1H-pyrroles-3-propanoic acid), 1-(4 '-cyano group (1; 1 '-diphenyl)-and the 4-yl) b-((((3S)-tetrahydrochysene-4; 4-dimethyl-2-oxo-3-furyl) carbonyl amino))-, the phenyl methyl ester, (bS)-[CAS]) PNU-142769 (2H-iso-indoles-2-butyramide; 1; 3-dihydro-N-hydroxyl-α-((3S)-3-(2-methyl-propyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl)-1, the 3-dioxo-, (α R)-[CAS]); (S)-1-[2-((((4; 5-dihydro-5-sulfo--1,3,4-thiadiazoles-2-yl) amino)-carbonyl) amino)-1-oxo-3-(pentafluorophenyl group) propyl group]-4-(2-pyrimidine radicals) piperazine; SU-5402 (1H-pyrroles-3-propanoic acid; 2-((1,2-dihydro-2-oxo--3H-indole-3-thiazolinyl) methyl)-4-methyl-[CAS]), SC-77964; PNU-171829; CGS-27023A, N-hydroxyl-2 (R)-((methoxybenzene-sulfonyl) (4-picolyl) amino]-2-(2-tetrahydrofuran base)-acetamide, L-758354 ((1; 1 ' diphenyl)-the 4-caproic acid; α-butyl-γ-(((2,2-dimethyl-1-((methylamino) carbonyl) propyl group) amino) carbonyl)-4 '-fluoro-, (α S-(α R *, γ S *(R *)))-[CAS]), GI-155704A, CPA-926, or its analog or derivant.Other representative example is included in U.S. Patent number 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,7955,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 6,6274115,514 716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,691,381; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427; 5,830,869; With 6,087, in 359.
23.NF kappa B inhibitor
In another embodiment, described pharmaceutically active compound be NF kappa B inhibitor (for example, Celgene (SP100030, SP100207, SP100393), AVE-0545, Oxi-104 (Benzoylamide, 4-amino-3-chloro-N-2-(diethylamino) ethyl)-[CAS]), dexlipotam, INDRA, R-flurbiprofen (1,1 '-diphenyl)-4-acetic acid, 2-fluoro-Alpha-Methyl), SP100030 (2-chloro-N-(3,5-two (trifluoromethyl) phenyl)-4-(trifluoromethyl) pyrimidine-5-carboxylic acid amides), AVE-0545, Viatris, AVE-0547, Bay11-7082, Bay11-7085,15 deoxidations-prostaylandin J2, bortezomib (Boronic acid, ((1R)-3-methyl isophthalic acid-(((2S)-1-oxo-3-phenyl-2-((pyrazinyl carbonyl) amino] propyl group] amino] butyl]-[CAS]), or its analog or derivant.
24.NO agonist
In another embodiment, described pharmaceutically active compound is NO antagonist (for example, NCX-4016 (benzoic acid, 2-(acetyl group oxygen base)-3-((nitrooxy methyl) phenylester [CAS]), NCX-2216, a L-arginine, or its analog or derivant.
25.P38MAP inhibitors of kinases
In another embodiment, described pharmaceutically active compound P38MAP inhibitors of kinases (for example, VX-745 (Vertex Pharmaceuticals; Inc., Cambridge, MA); GW-2286, SK86002, CGP-52411; BIRB-798, SB220025, RO-320-1195; RWJ-67657, RWJ-68354, SCIO-469; SCIO-323, AMG-548, CMC-146; SD-31145; CC-8866, Ro-320-1195, Roche (3853; 4507; 6145,8464,0945; 6257; 3391,3470,1151634; 5274; 5161,4194,1195); BIX983 (Boehringer Ingelheim); PD-98059 (4H-1-.alpha.-5:6-benzopyran-4-ketone, 2-(2-amino-3-methoxyphenyl)-[CAS]), CGH-2466; doramapimod; SB-203580 (pyridine, 4-[5-(4-fluorophenyl)-2-[4-(methyl sulfinyl) phenyl]-the 1H-imidazol-4 yl]-[CAS]), SB-220025 ((5-(2-amino-4-pyrimidine radicals)-4-(4-fluorophenyl)-1-(4-piperidyl) imidazoles)); SB-281832; PD169316, SB202190, or its analog or derivant.Other representative example is included in U.S. Patent number 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874; With 6,630,485, US publication 2001/0044538A1; 2002/0013354A1; 2002/0049220A1; 2002/0103245A1; 2002/0151491A1; 2002/0156114A1; 2003/0018051A1; 2003/0073832A1; 2003/0130257A1; 2003/0130273A1; 2003/0130319A1; 2003/0139388A1; 2003/0139462A1; 2003/0149031A1; 2003/0166647A1 and 2003/0181411A1; With PCT publication number WO 00/63204A2, WO01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO02/101015A2, WO 02/103000A2, WO 03/008413A1, WO 03/016248A2, WO03/020715A1, WO 03/024899A2, WO 03/031431A1, WO 03/040103A1, WO03/053940A1, WO 03/053941A2, WO 03/063799A2, WO 03/079986A2, WO03/080024A2, WO 03/082287A1, WO 97/44467A1 is among WO 99/01449A1 and the WO99/58523A1.
26. phosphodiesterase inhibitor
In another embodiment; described pharmaceutically active compound be phosphodiesterase inhibitor (for example; CDP-840 (pyridine; 4 ((2R)-2[3-(cyclopentyloxy)-4-methoxyphenyl]-the 2-phenylethyl)-[CAS]), CH-3697, CT-2820; D-22888 (imidazoles [1; 5-a] pyrido [3,2-e] pyrazines-6 (5H)-ketone, 9-ethyl-2-methoxyl group-7-methyl-5-propyl group-[CAS]); ((N-(2 for 8-methoxy quinoline-5-for D-4418; 5-dichloropyridine-3-yl)) 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-two chloro-4-pyridine radicals) ethyl ketone oxime carboxylic acid amides); D-4396; ONO-6126, CDC-998, CDC-801; V-11294A (3-(3-(cyclopentyloxy)-4-methoxy-benzyl)-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride); S, S '-methylene-two (2-(8-cyclopropyl-3-propyl group-6-(4-pyridylmethyl amino)-2-sulfo--3H-purine)) four hydrochloric acid, rolipram (2-Pyrrolidone; 4-(3-(cyclopentyloxy)-4-methoxyphenyl)-[CAS]); CP-293121, CP-353164 (5-(3-cyclopentyloxy-4-methoxyphenyl) pyridine-2-carboxylic acid amides), oxagrelate (6-2; 3-benzodiazine carboxylic acid; 3,4-dihydro-1-(methylol)-5,7-dimethyl-4-oxo-; ethyl ester [CAS]); PD-168787, ibudilast (1-acetone, 2-methyl isophthalic acid-(2-(1-Methylethyl) pyrazolo (1; 5-a) pyridin-3-yl)-[CAS]); oxagrelate (6-2,3-benzodiazine carboxylic acid, 3; 4-dihydro-1-(hydroxymethyl)-5; 7-dimethyl-4-oxo-, ethyl ester [CAS]), grey chain bacterium acid (α-L-talo-suffering-4-alkene furanose aldehydic acid; 1-(6-amino-9H-purine-9-yl)-3; 6-dehydration-6-C-carboxyl-1,5-dideoxy-[CAS]), KW-4490; KS-506; T-440, roflumilast (Benzoylamide, 3-(cyclo propyl methoxy)-N-(3; 5-two chloro-4-pyridine radicals)-4-(difluoro-methoxy)-[CAS]); rolipram, Mi Nong, triflusinal (benzoic acid; 2-(acetyl group oxygen base)-4-(trifluoromethyl)-[CAS]); Anagrelide Hydrochloride (imidazoles (2,1-b) quinazoline-2 (3H)-ketone, 6; 7-two chloro-1; the 5-dihydro-, monohydrochloride [CAS]), cilostazol (2 (1H)-quinolinones; 6-(4-(1-cyclohexyl-1H-tetrazolium-5-yl) butoxy)-3; 4-dihydro-[CAS]), propentofylline (1H-purine-2,6-diketone; 3; 7-dihydro-3-methyl isophthalic acid-(5-oxo-hexyl)-7-propyl group-[CAS]), and sildenafil citrate (piperazine, ((3-(4 for 1-; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo (4; 3-d) pyrimidine-5-yl)-and the 4-ethoxyl phenenyl) sulfonyl)-the 4-methyl, 2-hydroxyl-1,2; 3-tricarballylic acid salt (ester)-(1: 1) [CAS]); (also (1 ', 2 ': 1,6) pyrido (3 for pyrazine for tadalafil; 4-b) indole 1; the 4-diketone, 6-(1,3-benzo dioxole-5-yl)-2; 3; 6,7,12; 12a-six hydrogen-2-methyl-; (6R-is trans) [CAS]), and Vardenafil (piperazine, (3-(1 for 1-; 4-dihydro-5-methyl (4-oxo-7-propyl imidazole (5; 1-f) (1,2,4)-triazine-2-yl)-and the 4-ethoxyl phenenyl) sulfonyl)-4-ethyl-[CAS]); milrinone ([3; 4 '-two pyridines]-the 5-nitrile, 1,6-dihydro-2-methyl-6-oxo-[CAS]); enoximone (2H-imidazoles-2-ketone; 1,3-dihydro-4-methyl-5-[4-(methyl mercapto) benzoyl]-[CAS]), theophylline (1H-purine-2; the 6-diketone; 3,7-dihydro-1,3-dimethyl-[CAS]); ibudilast (1-acetone; 2-methyl isophthalic acid-(2-(1-Methylethyl) pyrazolo (1,5-a) pyridin-3-yl)-[CAS], aminophylline (1H-purine-2; the 6-diketone; 3,7-dihydro-1, the 3-dimethyl-; have 1; the chemical compound of 2-ethylenediamine (2: 1)-[CAS]), acebrophylline (7H-purine-7-acetic acid, 1; 2; 3,6-tetrahydrochysene-1,3-dimethyl-2; the 6-dioxo; chemical compound with trans-4-(((2-amino-3,5-dibromo phenyl) methyl) amino) Hexalin (1: 1) [CAS]), sprinkle appropriate bright (propionic acid amide.; 2-(4-chlorophenoxy)-2-methyl-N-(((4-morpholinyl) methyl) amino) carbonyl)-[CAS]); hydrochloric acid is coughed up Pu Linong (3-pyridine nitrile, 1,2-dihydro-5-imidazoles (1; 2-a) pyridine-6-base-6-methyl-2-oxo-; monohydrochloride-[CAS]), fosfosal (benzoic acid, 2-(phosphonato)-[CAS]); amrinone ((3; 4 ' two pyridines]-6 (1H)-ketone, 5-amino-[CAS]), or its analog or derivant.
27.TGF beta inhibitor
In another embodiment, pharmaceutically active compound be the TGF beta inhibitor (for example, Man-6-P, LF-984, tamoxifen (acetamide, (4-(1 for 2-, 2-diphenyl-1-butylene base) phenoxy group]-N, the N-dimethyl-, (Z)-[CAS]), tranilast, or its analog or derivant.
28. TXA2. antagonist
In another embodiment; pharmaceutically active compound be the TXA2. antagonist (for example; CGS-22652 (3-pyridine enanthic acid; γ-4 ((((4-chlorphenyl) sulfonyl) amino) butyl)-; (.+-.)-[CAS]; ozagrel (2-acrylic acid; 3-(4-(1H-imidazoles-1-ylmethyl) phenyl)-; (E)-[CAS], argatroban (2 piperidine carboxylic acid, 1-(5-((amino imino methyl) amino)-1-oxo-2-(((1; 2; 3,4-tetrahydrochysene-3-methyl-quinolyl) sulfonyl) amino) amyl group)-4-methyl-[CAS]), Leimaquban (9H-carbazole-9-propanoic acid; 3-(((4-fluorophenyl) sulfonyl) amino)-1; 2,3, the 4-tetrahydrochysene-; (R)-[CAS]); torasemide (3-pyridine sulfonamides, N-(((1-Methylethyl) amino) carbonyl)-4-((3-aminomethyl phenyl) amino]-[CAS]), gamma linoleic acid ((Z; Z; Z)-6,9,12-jeceric acid [CAS]); seratrodast (benzene enanthic acid); zeta-(2,4,5-) trimethyl-3; 6-dioxo-1; 4-cyclohexadiene-1-yl)-, (+/-)-[CAS]), or its analog or derivant.
29.TNFa antagonist/tace inhibitor
In another embodiment; pharmaceutically active compound be TNFa antagonist/tace inhibitor (for example; Celgene (CC10037; CC-11049; CC-10004; CC10083); E-5531 (2-deoxidation-6-O-(2-deoxidation-3-O-(3 (R)-(5 (Z)-laurylene acyloxy) decyl-)-6-O-methyl-2-(3-oxo myristoyl amido)-4-O-phosphono-β-D-glucopyranosyl)-3-O-(3 (R)-hydroxyl decyl)-2-(3-oxo myristoyl amido)-α-D-Glucopyranose .-1-O-phosphate (ester)); AZD-4717; glycophosphopeptical; UR-12715 (benzoic acid; 2-hydroxyl-5-((4-(3-(4-(2-methyl isophthalic acid H-imidazoles (4; 5-c) pyridine-1-yl) methyl)-piperidino)-3-oxo-1-phenyl-1-acrylic) phenyl) azo) (Z) [CAS]); PMS-601; AM-87; wood adenosine (xyloadenosine) (9H-purine-6-amine; 9-β-D-wood furyl glycosyl-[CAS]); RDP-58; RDP-59; BB2275; benzydamine; E-3330 (hendecanoic acid; 2-((4; 5-dimethoxy-2-methyl-3; 6-dioxo-1; 4-cyclohexadiene-1-yl) methylene)-; (E)-[CAS]); N-(D; L-2-(hydroxyl amino carbonyl) methyl-4-methylpent acyl group)-L-3-(2 '-naphthyl) alanyl-L-alanine; 2-amino-ethyl amide; CP-564959; MLN-608; SPC-839; ENMD-0997; ((2-(10 for Sch-23863; 11-dihydro-5-ethyoxyl-5H-dibenzo (a; d) cycloheptene-S-yl)-N; N-dimethyl-ethamine); SH-636; PKF-241-466; PKF-242-484; TNF-484A; cilomilast (cis-4-cyano group-4-(3-(cyclopentyloxy)-4-methoxyphenyl) cyclohexane extraction-1-carboxylic acid); GW-3333; GW-4459, BMS-561392, AM-87; cloricromen (acetic acid; ((8-chloro-3-[2-(diethylamino) ethyl]-4-methyl-2-oxo-2H-1-.alpha.-5:6-benzopyran-7-yl] the oxygen base]-, ethyl ester [CAS]), Thalidomide (1H-iso-indoles-1; 3 (2H)-diketone; 2-(2,6-dioxo-3-piperidyl)-[CAS]), vesnarinone (piperazine; 1-(3; 4-dimethoxy benzoyl)-4-(1,2,3; 4-tetrahydrochysene-2-oxo-6-quinolyl)-[CAS]); infliximab, lentinan, Embrel (1-235-Tumor Necrosis Factor Receptors (people) fusion rotein [CAS]) with 236-467-immunoglobulin G 1 (people γ 1-chain Fc fragment); diacerein (2-anthracene carboxylic acid; 4,5-two (acetoxyl group)-9,10-dihydro-9; or its analog or derivant 10-dioxo-[CAS]).
30. tyrosine kinase inhibitor
In another embodiment, pharmaceutically active compound be tyrosine kinase inhibitor (for example, SKI-606, ER-068224, SD-208, N-(6-benzothiazolyl)-4-(2-(1-piperazinyl) pyridine-5-yl)-2-pyrimidinamine, celastrol (24,25,26-Trinoroleana-1 (10), 3,5,7-tetraene-29-acid, 3-hydroxyl-9,13-dimethyl-2-oxo-, (9. β., 13 α, 14 β, 20 α)-[CAS]), CP-127374 (geldanamycin, 17-de-methoxy-17-(2-acrylic amino)-[CAS]), CP-564959, PD-171026, CGP-52411 (1H-iso-indoles-1,3 (2H)-diketone, 4,5-two (phenyl amino)-[CAS]), CGP-53716 (Benzoylamide, N-(4-methyl-3-((4-(3-pyridine radicals)-2-pyrimidine radicals) amino) phenyl)-[CAS]), imatinib (4-((methyl isophthalic acid-piperazinyl) methyl)-N-(4-methyl-3-((4-(3-pyridine radicals)-2-pyrimidine radicals) amino)-phenyl) Benzoylamide mesylate (ester)), NVP-AAK980-NX, KF-250706 (13-chlorine, 5 (R), 6 (S)-epoxy-14s, 16-dihydroxy-11-(hydroyimino)-3 (R)-methyl-3,4,5,6,11,12-six hydrogen-1H-2-benzene oxa-ring 14 alkynes-1-ketone), 5-(3-(3-methoxyl group-4-(2-((E)-2-phenyl vinyl)-4-oxazolyl methoxyl group) phenyl) propyl group)-3-(2-((E)-2-phenyl vinyl]-4-oxazolyl methyl]-2, the 4-oxazolidinedione, genistein, or its analog or derivant.
31. vitronectin inhibitor
In another embodiment; described pharmaceutically active compound be vitronectin inhibitor (for example; O-(9,10-dimethoxy-1,2; 3; 4,5,6-six hydrogen-4-((1; 4; 5,6-tetrahydrochysene-2-pyrimidine radicals) hydrazono-)-8-phenyl (e) Flos Chrysanthemi cyclic group)-N-((phenyl methoxyl group) carbonyl)-DL-homoserine 2,3-dihydroxypropyl ester; (2S)-(((4S)-(3-(4 for 2-for benzoyl carbonylamino-3-; 5-dihydro-1H-imidazoles-2-base is amino)-propyl group)-2,5-dioxo-imidazolidine-1-yl)-acetyl-amino)-propionate (ester), Sch-221153; S-836; SC-68448 (β-((2-2-(((3-[(amino imino methyl) amino]-phenyl] carbonyl] amino] acetyl group] amino]-3,5-dichloro-benzenes propanoic acid), SD-7784; S-247, or its analog or derivant.
32. fibroblast growth factor inhibitor
In another embodiment, described pharmaceutically active compound be fibroblast growth factor inhibitor (for example, CT-052923 ([(2H-benzo [d] 1, the 3-dioxalan-5-methyl) amino] [4-(6,7-dimethoxyquinazoline-4-yl) piperazinyl] methane-1-thioketone), or its analog or derivant.
33. kinases inhibitor
In another embodiment, described pharmaceutically active compound is kinases inhibitor (for example, KP-0201448; NPC15437 (caproamide, 2, the 6-diamino-N-((1-(oxo tridecyl)-2-piperidyl] methyl]-[CAS]); fasudil (1H-1,4-diazepine, six hydrogen-1-(5-isoquinolinesulfonylcompounds)-[CAS]); midostaurin (Benzoylamide, N-(2,3; 10,11,12; 13-six hydrogen-10-methoxyl group-9-methyl isophthalic acid-oxo-9,13-epoxy-1H, 9H-two indole [1; 2,3-gh: 3 ', 2 '; 1 '-Im] pyrrolo-[3,4-j] [1,7] benzodiazonin-11-yl)-the N-methyl-; (9 α; 10 β, 11 β, 13 α)-[CAS]); fasudil (1H-1; the 4-diazepine, six hydrogen-1-(5-isoquinolyl sulfonyl)-[CAS]), or its analog or derivant.
34.PDGF receptor kinase inhibitor
In another embodiment, described pharmaceutically active compound is pdgf receptor kinase inhibitor (for example, RPR-127963E, or its analog or derivant.
35. endothelial growth factor receptor kinase inhibitor
In another embodiment, described pharmaceutically active compound be endothelial growth factor receptor kinase inhibitor (for example, CEP-7055, SU-0879 ((E)-3-(3,5-two-tert-butyl-4-hydroxy phenyl)-2-(amino thiocarbonyl) acrylonitrile), BIBF-1000, or its analog or derivant.
36. RAR antagonists
In another embodiment, described pharmaceutically active compound is RAR antagonists (for example, etarotene (Ro-15-1570) (naphthalene; 6-(2-(4-(ethylsulfonyl) phenyl)-1-methyl ethylene)-1,2,3; 4-tetrahydrochysene-1,1,4; the 4-tetramethyl-, (E)-[CAS]), (2E; 4E)-3-methyl-5-(2-((E)-2-(2,6,6-trimethyl-1-cyclohexene-1-yl) vinyl)-1-cyclohexene-1-yl)-2; the 4-pentadienoic acid; tocoretinate (tretinoin, 3,4-dihydro-2; 5; 7,8-tetramethyl-2-(4,8; 12-trimethyl alkyl)-and 2H-1-.alpha.-5:6-benzopyran-6-base ester, (2R *(4R *, 8R *)]-(±)-[CAS]), aliretinoin (tretinoin, cis-9, anti-form-1 3-[CAS]), bexarotene (benzoic acid, 4-(1-(5,6,7,8-tetrahydrochysene-3,5,5,8,8-pentamethyl-2-naphthyl) vinyl)-[CAS]), or its analog or derivant.
37. platelet-derived growth factor receptor kinase inhibitor
In another embodiment, pharmaceutically active compound be platelet-derived growth factor receptor kinase inhibitor (for example, leflunomide (4-isoxazole carboxylic acid amides, 5-methyl-N-(4-(trifluoromethyl) phenyl]-[CAS]), or its analog or derivant.
38.Fibronogin antagonist
In another embodiment, described pharmaceutically active compound is Fibronogin antagonist (for example, a G-137 (1,3-benzene dicarboxamide, 4-methoxyl group-N, N '-two (3-pyridylmethyl)-[CAS]), or its analog or derivant.
39. antifungal
In another embodiment, described pharmaceutically active compound be antifungal (for example, miconazole, sulconizole, parthenolide, rosconitine, nystatin, isoconazole, fluconazol, ketoconazole (ketoconasole), imidazoles, itraconazole, terpinafine, elonazole, bifonazole, clotrimazole, conazole, terconazole (triaconazole) (piperazine, (((2-(2 for 4-for 1-, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolanes-4-yl) phenyl methoxyl group))-4-(1-Methylethyl)-, cis-[CAS]), isoconazole (1-(2-(2-6-dichloro-benzyloxy)-2-(2-, the 4-Dichlorobenzene base) griseofulvin (spiral shell (benzofuran-2 (3H), 1 '-(2) cyclohexane extraction)-3 ethyl)),, 4 '-diketone, 7-chloro-2 ', 4,6-trimethoxy-6 ' methyl, (1 ' S-is trans)-[CAS]), biphenyl card azoles (1H-imidazoles, 1-((1,1 '-diphenyl)-4-base phenyl methyl)-[CAS]), econazole nitrate (1-(2-((4-chlorphenyl) methoxyl group)-2-(2, the 4-Dichlorobenzene base) ethyl)-and 1H-nitric acid imidazoles), croconazole (1H-imidazoles, 1-(1-(2-((3-chlorphenyl) methoxyl group) phenyl) vinyl-[CAS]), Sertaconazole (1H-imidazoles, 1-(2-((the 7-chlorobenzene is (b) thiene-3-yl-also) methoxyl group)-2-(2, the 4-Dichlorobenzene base) ethyl)-[CAS]), omoconazole (1H-imidazoles, 1-(2-(2-(4-chlorophenoxy) ethyoxyl)-2-(2, the 4-Dichlorobenzene base)-the 1-methyl ethylene)-, (Z)-[CAS]), flutrimazole (1H-imidazoles, 1-((2-fluorophenyl) (4-fluorophenyl) phenyl methyl)-[CAS]), fluconazol (1H-1,2,4-triazole-1-ethanol, α-(2, the 4-difluorophenyl)-α-(1H-1,2,4-triazol-1-yl methyl)-[CAS]), neticonazole (1H-imidazoles, 1-(2-(methyl mercapto)-1-(2-(amoxy) phenyl) vinyl)-, monohydrochloride, (E)-[CAS]), butoconazole (1H-imidazoles, 1-(4-(4-chlorphenyl)-2-((2, the 6-Dichlorobenzene base) sulfo-) butyl)-, (+/-)-[CAS]), clotrimazole (1-((2-chlorphenyl) diphenyl methyl]-the 1H-imidazoles), or its analog or derivant.
40. diphosphate
In another embodiment, described pharmaceutically active compound be diphosphate (for example, clodronate, fosamax (alendronate), pamldronate (pamidronate), zoledronic acid salt (zoledronate), etidronate (etidronate)), or its analog or derivant.
41. E.C. 3.1.1.32 inhibitor
In another embodiment, described pharmaceutically active compound be phospholipase A l inhibitor (for example, loteprednol etabonate (Androsta-1,4-diene-17-carboxylic acid, 17-((ethoxy carbonyl) oxygen base]-11-hydroxyl-3-oxo-, chloromethyl ester, (11 β, or its analog or derivant 17 α)-[CAS].
42. histamine H 1/H2/H3 receptor antagonist
In another embodiment; described pharmaceutically active compound be histamine H 1/H2/H3 receptor antagonist (for example; ranitidine (1; the 1-ethylenediamine; N-(2-(((5-((dimethylamino) methyl)-2-furyl) methyl) sulfo-) ethyl)-N '-methyl-2-nitro-[CAS]); niperotidine (N-(2-((5-((dimethylamino) methyl) furfuryl group) sulfo-) ethyl)-2-nitro-N '-piperonyl-1; the 1-ethylenediamine); famotidine (Propanimidamide; 3-(((2-[((amino imino methyl) amino)-4-thiazolyl] methyl) sulfo-)-N-(amino-sulfonyl)-[CAS]); roxitadine acetate HCl (acetamide; 2-(acetoxyl group)-N-(3-(3-(piperidino methyl) phenoxy group) propyl group)-; monohydrochloride [CAS]); lafutidine (acetamide; 2-((2-furyl methyl) sulfinyl)-N-(4-((4-(piperidino methyl)-2-pyridine radicals) oxygen base)-crotyl)-; (Z)-[CAS]); nizatidine (1; the 1-ethylenediamine; N-(2-(((2-((dimethylamino) methyl)-4-thiazolyl) methyl) sulfo-) ethyl)-N '-methyl-2-nitro-[CAS]); ebrotidine (benzsulfamide; N-(((2-(((2-((amino imino methyl) amino)-4-thiazolyl) methyl) sulfo-) ethyl) amino) methylene)-4-bromo-[CAS]); rupatadine (5H-benzo (5; 6) ring heptan also (1; 2-b) pyridine; 8-chloro-6; 11-dihydro-11-(1-((5-methyl-3-pyridine radicals) methyl)-4-piperidines thiazolinyl)-; three hydrochloric acid-[CAS]); fexofenadine HCl (phenylacetic acid; 4-(1-hydroxyl-4-(4 (hydroxyl diphenyl methyl)-piperidino] butyl]-α; alpha-alpha-dimethyl-; or its analog or derivant hydrochloric acid [CAS]).
43. macrolide antibiotic
In another embodiment; described pharmaceutically active compound be macrolide antibiotic (for example; dirithromycin (erythromycin; 9-deoxidation-11-deoxidation-9; 11-(imino group (2-(2-methoxy ethoxy) vinyl) oxygen base)-; (9S (R)))-[CAS]); flurithromycin ethyl succinate (erythromycin; 8-fluoro-list (ethyl succinic acid ester) (ester)-[CAS]); erythromycin stinoprate (erythromycin; 2 '-propionic ester; chemical compound with N-acetyl group-L-cysteine (1: 1) [CAS]); clarithromycin (erythromycin; 6-O-methyl-[CAS]); azithromycin (9-deoxidation-9a-azepine-9a-methyl-9a-homotype Erythromycin A); (3-goes ((2 to Ketek; 6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribose-own pyrans glycosyl (hexopyranosyl)) oxygen base)-11; 12-dideoxy-6-O-methyl-3-oxo-12; 11-(oxo carbonyl ((4-(4-(3-pyridine radicals)-1H-imidazoles-1-yl) butyl) imino group))-[CAS]); Roxithromycin (erythromycin; 9-(O-((2-methoxy ethoxy) methyl] oxime] [CAS]); rokitamycin (albomycin V, 4B-butyrate (ester) 3B-propionic ester [CAS]), RV-11 (erythromycin one propanoic acid mercapto succinic acid ester); midecamycin acetate (albomycin V; 3B, 9-diacetin (ester) 3,4B-dipropionate [CAS]); midecamycin (albomycin V; 3,4B-dipropionate [CAS]), josamycin (albomycin V; or its analog or derivant 3-acetate (ester) 4B-(3 Methylbutanoic acid salt (ester)) [CAS]).
44.GP IIb IIIa receptor antagonist
In another embodiment; described pharmaceutically active compound be GP IIb IIIa receptor antagonist (for example; tirofiban hydrochloride (L-tyrosine; N-(butyl sulfonyl)-O-(4-(4-piperidyl) butyl]-; one hydrochloric acid-[CAS]); eptifibatide (L-cysteinyl amine; N6-(amino imino methyl)-N2-(3-sulfydryl-1-oxopropyl)-L-lysyl glycyl-L-α-aspartoyl-L-tryptophanyl-L-prolyl-; (1-＞the 6)-disulphide [CAS1] of ring, or its analog or derivant.
45. endothelin-receptor antagonists
In another embodiment, described pharmaceutically active compound be endothelin-receptor antagonists (for example, bosentan (benzsulfamide, 4-(1, the 1-dimethyl ethyl)-N-(5-(2-hydroxyl-oxethyl)-5-(2-methoxyl group phenoxy group) (2,2 '-two pyrimidines]-the 4-yl]-[CAS]), or its analog or derivant.
46. peroxisome Proliferators activated receptor agonist
In another embodiment; described pharmaceutically active compound be peroxisome Proliferators activated receptor agonist (for example; gemfibrozil (valeric acid; 5-(2; the 5-dimethyl phenoxy)-2; 2-dimethyl-[CAS]); fenofibrate (propanoic acid; 2-(4-(4-chlorobenzene formacyl) phenoxy group)-2-methyl-; 1-Methylethyl ester [CAS]); ciprofibrate (propanoic acid; (4-(2 for 2-; 2-dichloro cyclopropyl) phenoxy group)-2-methyl-[CAS]); rosiglitazone maleate (2; the 4-thiazolidinedione; 5-((4-(2-(methyl-2-pyridinylamino) ethyoxyl) phenyl) methyl)-; (Z)-2-butylene two acid esters (1: 1) [CAS]); pioglitazone hydrochloride (2; the 4-thiazolidinedione; 5-((4-(2-(5-ethyl-2-pyridine radicals) ethyoxyl) phenyl) methyl)-; monohydrochloride (+/-)-[CAS]); etofylline clofibrate (propanoic acid; 2-(4-chlorophenoxy)-2-methyl-, 2-(1,2; 3; 6-tetrahydrochysene-1,3-dimethyl-2,6-dioxo-7H-purine-7-yl) ethyl ester [CAS]); etofibrate (3-picolinic acid; 2-(2-(4-chlorophenoxy)-2-methyl isophthalic acid-oxopropoxy) ethyl ester [CAS]), clinofibrate (butanoic acid, 2; 2 '-(cyclohexylidene two (4; the inferior phenoxy group of 1-)) bezafibrate (propanoic acid, 2-(4-(2-((4-chlorobenzene formacyl) amino) ethyl) phenoxy group)-2-methyl-[CAS]) two (2-methyl-) [CAS]); binifibrate (3-picolinic acid; 2-(2-(4-chlorophenoxy)-2-methyl isophthalic acid-oxopropoxy]-1,3-propanediyl[CAS]), or its analog or derivant.
47. estrogen receptor reagent
In another embodiment, described pharmaceutically active compound is estrogen receptor reagent (for example, estradiol, 17-), or its analog or derivant.
48. somatostatin analogs
In another embodiment, described pharmaceutically active compound is somatostatin or somatostatin analogs (for example, angiopeptin (angiopeptin), lanretide, octreotide), or its analog or derivant.
(49.JNK Jun kinases) inhibitor
In another embodiment, described pharmaceutically active compound is JNK inhibitors of kinases (for example, Celgene (SP600125, SPC105, SPC23105), AS-602801 (Serono)), or its analog or derivant.
50. melanocortin analog
In another embodiment, described pharmaceutically active compound be the melanocortin analog (for example, HP228), or its analog or derivant.
51.RAF inhibitors of kinases
Still in another embodiment; described pharmaceutically active compound be the raf inhibitors of kinases (for example; BAY-43-9006 (N-(4-chloro-3-(trifluoromethyl) phenyl N '-(4-(2-(N-methylamino formoxyl)-4-pyridyloxy) phenyl) urea), or its analog or derivant.
52. lysyl hydroxylase inhibitor
In another embodiment, pharmaceutically active compound is lysyl hydroxylase inhibitor (for example, minoxidil), or its analog or derivant.
53.IKK 1/2 inhibitor
In another embodiment, pharmaceutically active compound be IKK 1/2 inhibitor (for example, BMS-345541, SPC839) or its analog or derivant.
Except participating in fibroid degeneration-inhibitor in the preparation or on the preparation, can also participate in another kind of bioactivator in the preparation or on the preparation, for example antiinflammatory (for example, dexamethazone or asprin), antithrombotic agents (for example, heparin, heparin complex, hydrophobicity heparin derivatives, aspirin, and/or antibiotic (for example, amoxicillin or dipyridamole),, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin with clavulanic acid salt (ester) are (clavulanate)), cefprozil, cefuroxime, cefpodoxime, or cefdinir).
Optional compositions characteristic and packing
On the one hand, the present composition comprises one or more antiseptic or bacterial inhibitor, and its effective dose with the bacterial growth in described compositions of preservation and/or the composite inhibiting exists, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, oxybenzene Ethyl formate, propylparaben, erythromycin, chlorocresol, benzalkonium chloride etc.The example of antiseptic comprises oxybenzoic acid ester, chlorobutanol, benzylalcohol, phenethanol, dehydroactic acid, sorbic acid etc.On the one hand, the present composition comprises one or more sterilizations (being also referred to as bacteria remover) agent.
On the one hand, the present composition comprises the antioxidant that one or more exist with effective dose.The example of antioxidant comprises sulphite, alpha-tocopherol, and ascorbic acid.
On the one hand, the present composition comprises one or more coloring agent, is also referred to as dyestuff, and it is to give described compositions, and for example, the observable painted effective dose of gel exists.The example of coloring agent comprises that the dyestuff that is suitable for food is such as being called F.D.﹠amp; C. those of dyestuff and natural colorant be such as the Pericarpium Vitis viniferae extractum, the beet red powder, and bata-carotene, Arnotto, fuchsin, Rhizoma Curcumae Longae, Fructus Capsici powder, etc.
On the one hand, chemical compound of the present invention and compositions are aseptic.Many medicines are made into aseptic and this standard is by USP XXII＜1211〉defined.Term " USP " refer to American Pharmacopeia (see www.usp.org, Rockville, MD).By multiple that in industry, accepted and list in USP XXII＜1211〉in method can realize sterilization in the present embodiment comprising gaseous sterilization, ionizing radiation, perhaps when suitable, filter.Can be by also being in USPXXII＜1211〉in the operation handled of the defined asceptic of being called keep sterilization.The acceptable gas that is used for gaseous sterilization comprises oxirane.The acceptable ray type that is used for the ionizing radiation method for example comprises the γ from cobalt 60 sources and electron beam.Gamma-ray typical doses is 2.5MRad.Utilize the appropriate bore size, the suitable material of 0.22 μ m for example, for example the filter of politef (for example, from E.I.DuPont De Nemours and Company, Wilmington, the TEFLON of DE) is realized filtering.
On the other hand, compositions of the present invention is included in the packing material, and this allows them to be used as the purpose of expectation, that is, and and as a kind of pharmaceutical composition.Important packing material characteristic is to allow to add the composition medium, such as water or for example brinish spatial content of other aqueous medium, acceptable light transmission, thereby prevent that luminous energy from damaging compositions in the described packing material (referring to USPXXII＜661 〉), the acceptable restriction (referring to USPXXII) of extractable in the container material is for humidity (referring to USPXXII＜671 〉) or the acceptable barrier ability of oxygen.For oxygen infiltration, can be by in container, including a kind of noble gas of malleation, such as highly purified nitrogen, or noble gas, control as argon.
The typical material that is used for production drug packaging thing comprises that USPI is to III type and NP type glass (referring to USP XXII＜661 〉), polyethylene, polytetrafluoroethylene, siloxanes and grey fourth glue.For parenteral, preferred USPI is to the glass and the polyethylene of III type.
Bioactivator is mixed in the compositions
Bioactivator directly can be mixed in the compositions, perhaps they can be mixed in a kind of secondary carrier.For directly mixing bioactivator, described preparation can maybe cannot comprise nucleophilic group or can with the group of the activatory functional group reactions of the synthetic polymer of described compositions.Bioactivator can be mixed with activatory polymer as solid, mix the acidic buffer solution that is used for dissolving activated polymer, mix in the alkaline solution, thus described alkaline solution and then increase the response time with activatory polymer mixed.In another embodiment, the combination of these methods also can be used for bioactivator is mixed described compositions.In another embodiment, described bioactivator can be before the functional group of administration of activated, simultaneously or use afterwards.On the described bioactivator suitably the existence of nucleophilic group will allow described bioactivator will be mixed in the final composition by chemical bond.Using any aforesaid possibility method the single creature activating agent directly can be mixed in the described compositions or with the combination of bioactivator mixes in the described compositions.
For by utilizing secondary carrier that bioactivator is mixed compositions, can by covalently bound on secondary carrier, physical package carries, precipitation or these interactional combinations in the adsorption, electrostatic interaction, hydrophobic interaction, partition effect, secondary carrier mixed described bioactivator in the secondary carrier.Then this bioactivator/secondary carrier compositions is directly mixed in the compositions.The secondary carrier that can be used for incorporating into these bioactivators comprises granule, microgranule, nano-particle, nanocrystal, microsphere, nanometer spheroid, liposome, micelle, Emulsion, microemulsion, dispersion, comprises coordination compound, nonionic surfactant vesicle (NISV), vesicle (niosomes), proniosomes, spirillum, immunostimulating complex (ISCOMs) and related complex.In one embodiment, can utilize and comprise: D-lactide, L-lactide, D from following monomer, L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone, trimethylene carboxylate, 1,4-diox-2-ketone or 1, the polymer or the copolymer of one or more residue units of 5-Dioxepane-2-ketone prepare microgranule, nano-particle or microsphere.In another embodiment, can utilize A-B, the block copolymer of A-B-A or B-A-B form prepares microgranule, nano-particle, or microsphere, wherein A be poly-(alkylene oxide) (for example, poly-(ethylene glycol), poly-(propylene glycol), the copolymer of oxirane and expoxy propane, or its monoalky lether), and B is a kind of degradable polyester, the D-lactide that for example comprises one or more residue units, the L-lactide, D, the L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone, the trimethylene carboxylate, 1,4-diox-2-ketone or 1, the polymer and the copolymer of 5-Dioxepane-2-ketone.Micellar preparation (for example can utilize the micromolecule surfactant, SDS) or polymeric compositions (for example, PLURONICS F127, PLURONICS F68, A-B, the block copolymer of A-B-A or B-A-B form, wherein A be poly-(alkylene oxide) (for example, poly-(ethylene glycol), poly-(propylene glycol), the copolymer of oxirane and expoxy propane, or its monoalky lether), and B is a kind of degradable polyester, for example comprises one or more monomers D-lactide, the L-lactide, D, the L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone, the trimethylene carboxylate, 1,4-diox-2-ketone or 1, the polymer and the copolymer of the residue unit of 5-Dioxepane-2-ketone.Can also utilize albumin, alginate, gelatin, starch, collagen protein, chitosan, poly-(acid anhydride), poly-(ortho esters), poly-(phosphazine) to prepare these secondary carrier.Liposome composition can comprise phosphatidylcholine, cholesterol, PHOSPHATIDYL ETHANOLAMINE and any commercially available lipid (for example, the lipid that can obtain from Avanti Polar Lipids).Can also be with non-polymeric chemical compound such as sucrose derivative (for example, sucrose acetate isobutyrate, sucrose oleate); Sterol such as cholesterol, stigmasterol, cupreol and estradiol; Cholesterol ester is such as cholesteryl stearate; C 12-C 24Fatty acid such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, mountain Yu acid and tetracosa carbon acid; C 18-C 36Single-, two-and the triacylglycerol ester such as glycerin mono-fatty acid ester, glyceryl list linoleate, the glyceryl monolaurate, glyceryl list behenic acid ester, glyceryl list myristinate, glyceryl monodicenoate, glyceryl two palmitates, glyceryl two behenates, glyceryl two myristinates, glyceryl two decylenic acid esters, glyceryl three behenates, glyceryl three myristinates, glyceryl three decenoates, glyceryl tristearate and composition thereof; Sucrose fatty acid ester such as sucrose distearate and sucrose palmitate; Sorbitan fatty acid esters such as sorbitan monostearate, sorbitan list palmitate and sorbitan tristearate; C 16-C 18Aliphatic alcohol such as hexadecanol, myristyl alcohol, stearyl alcohol and cetostearyl alcohol; The ester of aliphatic alcohol and fatty acid such as cetyl palmitate and 16-octadecyl (cetearyl) palmitate; Fatty acid anhydride such as stearic anhydride; Phospholipid comprises phosphatidylcholine (lecithin), Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols and cracking derivant thereof; Sphingol and derivant thereof; Sphingomyelins (spingomyelins) such as stearoyl, palmityl and two tridecanoyls (tricosanyl) sphingomyelins; Ceramide such as stearoyl and palmityl ceramide; Glycosphingolipid; Lanoline and lanolin alcohol, calcium phosphate also can be used as the part of secondary carrier compositions.
Bioactivator/secondary carrier can be mixed with activatory polymer as solid, mix the acidic buffer solution that is used for dissolving activated polymer, mix in the alkaline solution, thus described alkaline solution and then increase the response time with activatory polymer mixed.The combination of these methods can also be used for incorporate bioactivator/secondary carrier into described compositions.
Described bioactivator/secondary carrier compositions can comprise the group that can or can not react with the activated group of starting ingredient.In one embodiment, secondary carrier do not comprise can with the nucleophilic group of starting polymer component reaction, in this case, described secondary carrier/bioactivator by physical package carry, the combination of hydrophobic interaction, hydrogen bond, Van der Waals interaction, electrostatic interaction or these interaction forces remaines in the final compositions.
In another embodiment, described bioactivator/secondary carrier compositions can comprise the functional group that can react with arbitrary nucleophilic group of starting ingredient.In these cases, by covalent bond described bioactivator/secondary carrier compositions is remained in the final composition.Other interaction such as physical package is carried, the combination of hydrophobic interaction, hydrogen bond, Van der Waals interaction, electrostatic interaction or these interaction forces also has and helps described bioactivator/secondary carrier and remain in the final composition.
Can one or more following functional group :-NH will be comprised 2,-SH ,-OH ,-PH 2,-CO-NH-NH 2,-CO 2N (COCH 2) ,-CO 2H ,-CHO ,-CHOCH 2,-N=C=O ,-SO 2CH=CH 2,-N (COCH) ,-S-S-(C 5H 4N) etc. chemical compound mixes in the described secondary carrier, and the secondary carrier with the functional group that can react with the starting ingredient of cross-linked composition is provided thus.
The example that can mix in the described secondary carrier with useful amino-compound that the functional group on the secondary carrier is provided comprises PHOSPHATIDYL ETHANOLAMINE fat (for example, Avanti Polar Lipids, Inc.Catalogue#850757,850756,850759,850801,850758,850802,850804,850806,850697,850699,850700,850702,850745,850705,850402,850706,830756C, 830756P, 850715,850725,85T725,850755,850795,850800,850797,870125,870122,870140,870142,856705,856715,846725), alkylamine, arylamine and Cycloalkyl amine.
The example that can mix in the described secondary carrier with useful mercaptan compound that the functional group on the secondary carrier is provided comprises 1,2-two palmityls-sn-glyceryl-3-dioxy phosphorus sulfo-ethanol (sodium salt) (AvantiPolar Lipids, catalog number (Cat.No.) 870160), alkyl hydrosulfide and aryl mercaptan.
Described compositions is used to reduce the surgical operation adhesion
The formation of adhesion, a kind of under normal circumstances disjunct tissue growth complex process together, the result who is most commonly in as the surgical operation wound takes place.Can stick together behind ear surgical operation or the throat surgical operation in abdominal surgery, pelvic surgical procedure, cardiac operation, spinal surgery, tendon surgical operation, cranium surgical operation, peripheral nervous surgical operation, chirurgia nasalis operation.This surgical operation posterior synechiae occurs among the patient of the big operating 60%-90% of gynacologic of experience and represents intestinal obstruction in the industrialization world and one of sterile modal reason.The intercurrent disease of other adhesion-processing comprises chronic pelvic pain, urethral obstruction and voiding malfunction.At present, with prophylactic treatment,, be used to suppress the formation of adhesion such as placing surgical sites by inactive surgical operation barrier layer that hyaluronic acid or cellulose are made when the surgical operation.Approved in-situ cross-linked polymer formulations has been used for heart (from Cohesion Technologies, Palo Alto, the ADHIBIT of CA) surgical operation and abdominal surgery and pelvic surgical procedure (from ConfluentSurgical, Inc., Boston, the SPRAYGEL of MA).Investigated the various patterns of Film with Preventing Adhesion, comprised the sedimentary prevention of (1) fibrin, the minimizing of (2) local organization inflammation, the sedimentary removal of (3) fibrin.By the deposition of using the physical barriers layer to prevent fibrin, described physical barriers layer be machinery or comprise stickiness solution.Though many researcheres use adhesion prevention barrier layer, have a lot of technical barriers.Reduce inflammation by drug administration such as corticosteroid and NSAID (non-steroidal anti-inflammatory drug).But because the degree and the dose limitation of the inflammatory reaction that systemic side effects is brought, it is not inspirer using the result of these medicines in animal model.At last, after deliberation use proteolytic enzyme and plasmin remove the fibrin deposition.The potential complication of the clinical use of these enzymes be possible cause excessive hemorrhage.
Therefore, in the present invention on the other hand, provide the method that treats and/or prevents adhesion by polymer composition to patient's administration of activated.Said composition can also comprise bioactivator.The preferred bioactivator that is used for this application has been described above.Similarly, described above and incorporated these bioactivators in the described compositions the whole bag of tricks.
Thereby can utilize extensive various animal model to estimate specific therapeutic combination or therapeutic scheme.In brief, as the result who is seriously damaged, peritoneal adhesion takes place in animal, it often comprises the surface of two vicinities.Because ischemia, or the intervention of allogenic material, damage can be mechanical.Mechanical injuries comprise the crushing (Choate etc., Arch.Surg.88:249-254,1964) and the outer field removal of intestinal wall of intestinal or wipe (Gustavsson etc., ActaChir.Scand.109:327-333,1955).Main blood vessel with cause ischemia (James etc., J.Path.Bact 90:279-287,1965) separating of intestinal ring.The allogenic material that can get involved in described zone comprises Talcum (Green etc., Proc.Soc.Exp.Biol.Med.133:544-550,1970), mesh sponge (Lehman and Boys, Ann.Surg 111:427-435,1940), cytotoxic chemical goods (Chancy, Arch.Surg.60:1151-1153,1950), antibacterial (Moin etc., Am.J.Med.Sci.250:675-679,1965) and feces (Jackson, Surgery 44:507-518,1958).
At present, typical adhesion prophylaxis model comprises the rabbit uterus angle model, and it comprises the wearing and tearing (Linsky etc., J.Reprod.Med 32 (1): 17-20,1987) of rabbit uterus, rabbit uterus angle; Go vascularization (devascularization) to transform model, it comprises the wearing and tearing in uterus and goes vascularization (Wiseman etc., J.Invest Surg.7:527-532,1994); Sidewall model (Wiseman and Johns, Fertil. Steril.Suppl:25S, 1993) with the rabbit caecum that comprises the wearing and tearing of the speckle that excises parietal peritoneum and caecum.
Utilize reagent provided herein, extensively various surgical operation adhesion and complication can be treated or prevent to compositions and method.The formation of adhesion or the accumulation of unwanted scar tissue and/or encapsulation make many surgical procedure become complicated.As described above, the surgical operation adhesion in fact make any opening of abdominal part and pelvic cavity or interior to surgical procedure become complicated.The encapsulation of surgical implants also makes the breasst reconstruction surgical operation, joint replacement surgery, and hernia is repaired surgical operation, and operation of artificial blood vessel's spare-part surgery and neurosurgery become complicated.In each case, described implant is surrounded by the fibrous connective tissue tunicle, and described fibrous connective tissue by membrane damage or trauma surgery implant (for example, breast implant, artificial joint, surgical operation netting twine, blood vessel graft, dural speckle) function.Thereby other zone (for example, foreign body of chronic sinusitis or removal chronic inflammatory disease also takes place to correct in chronic inflammatory disease and cicatrization in surgical operation; Infection such as fungus and mycobacterium).
Can use the present composition with any way that obtains the meaningful result on the statistics.Preferable methods comprises and using in tubule week (peritubular) (directly use during operation or with endoscopic, hyperacoustic, CT, the guiding of MRI or fluoroscopy); " coating " described surgery implant; With the polymeric implant of medicine-elution is placed surgical site.
Apply tissue with the conventional method that after operation, prevents adhesion and form in, activatory polymer dissolution is lower than 6.8 biology in pH can be accepted in the buffer.When second kind of pH is higher than 7.5 biology and can accepts buffer and exist, the solution that obtains is applied to the tissue surface that needs then.Can brush by extruding, spraying or any other mode are easily used this reactant mixture to this tissue site.
In one embodiment, polyfunctional N-Hydroxysuccinimide base PEG derivant (for example, poly-(ethylene glycol) succinimido glutarate of four senses) can be applied in tissue surface.For example, in one embodiment, described multifunctional N-Hydroxysuccinimide base PEG derivant can exist with the solution form with alkaline pH (for example, be higher than 8 pH).In one embodiment, multifunctional N-Hydroxysuccinimide base PEG derivant do not mix with any other tissue reactive compounds and/or will with any component of this derivatives reaction.
After described compositions is administered to surgical site,, can remove any excessive solution from surgical site if think needs.At this time point, use usual manner (sutures, fiber (staples), biological adhesive etc.) to close described surgical site.
Can also be with the alternate ways applying said compositions.In one embodiment, activatory polymer can be administered to surgical site with solid state.After described polymer hydration, it can react with the tissue surface that it is applied to subsequently.Expection may be relatively slow with the reaction of lower surface.Can be before using the solid activated polymer and/or afterwards pH is higher than 7.5 biology and can accepts buffer and be administered to described tissue.
The synthetic polymer coating implants of administration of activated
Another application of the activatory polymer composition of the present invention is the coating material as synthetic property implant.In the conventional method that applies synthetic property implant surface, activatory synthetic polymer is administered to the surface of described implant.In a preferred application, the surface of implant has the existence of functional group, described functional group can with the activation functional group reactions of the polymer of using.Described surface functional group can be inherent in the compositions of the material that is used for preparing implant.By at first handling the surface of implant, surface functional group can be introduced described implant.Operable surface treatment comprises, but be not limited to, with the polymer-coated surface of carrying suitable functional group, the described surface of oxidation (for example, acid/potassium permanganate is handled), the polymer that will comprise suitable functional group is transplanted on the implant surface, the plasma treatment of implant surface or corona are handled (corona treatment), or the radiation of implant surface (for example, γ, UV, e-ray etc.).Can also use the combination of these surface treatment methods that suitable functional group is introduced implant surface.Can brush by extruding, dip-coating, spraying (as mentioned above), or by any mode easily, reactant mixture is applied on the implant surface.After being administered to described reactant mixture on the implant surface, allow to proceed to obtain enough reactions up to the reaction of surface functional group.Can further remove any solvent then.
Though this method can be used for the coating of the synthetic property implant surface of any kind, it is useful especially in reducing the implant that thrombosis (thrombogenicity) is important consideration, described implant such as artificial blood vessel and cardiac valve, blood vessel graft, this smooth fixed die of blood vessel, the combination of conduit and Si Tan fixed die/graft.Described method can also be used to apply transplantable surgical membrane (for example, monofilament polypropylene) or netting twine (for example being used in hernia repairs).Use said method, the cryptomere contracture is minimized thereby can also apply breast transplant.The present composition can also be used to apply lenticule (lenticule), and it is made by naturally occurring polymer or synthetic polymer.
The tumor resection position
In the present invention is aspect another, the method for handling the tumor resection position is provided, described method comprises to the patient uses the activatory polymer composition that comprises anti--microtubule agent, thus the part that suppresses cancer takes place again.
It is a great clinical problem that tumor by local behind the initial surgical resection lump (mass) takes place again always.In the patient with breast cancer of the lumpectomy (Lumpectomy) of a series of experience primary breast cancers, almost the patient of 2/3 palindromia suffers from local disease's (that is, in identical supramammary tumor), and only has 1/3 patient to have metastatic disease.Other pathological research has confirmed that most of local tumors occur in the 2cm edge of initial excision edge.Therefore, it is very essential conceiving the processing method that addresses this problem.In the surgical treatment of brain tumor, local recurrence also is a major issue.For example, in one embodiment of the invention, after the tumor that denervates, can with resist-the microtubule compositions is administered to the position of neural tumor, thereby suppress the recurrence of brain tumor (benign or virulent).In brief, brain is that the height functionalization is localized; That is, thus each particular anatomical region is the specific function of carrying out of specialization.The pathology location of brain tumor is often more important than type.Less relatively focus in crucial areal area has more destructiveness more than the much bigger focus on more unessential areal area.Similarly, can easily pass through surgical resection, then cannot (will excise it and need could arrive it) through too many important structure for the identical tumor that is positioned at the brain depths in the focus of brain surface.And owing to some following reasons, even benign tumor can be dangerous: they may be grown in crucial areal area and cause great damage; Even they can be cured by surgical resection, perhaps this be not possible; And last, if be not examined, they can cause the increase of intracranial pressure.Skull is an inextensible enclosed space.Therefore, if something is grown a position, anything else must be compressed in other position-and the result is an increase pressure or increase intracranial pressure in skull.If do not handle such situation, important structure will be compressed, thereby causes death.The sickness rate of CNS (central nervous system) malignant tumor is 8-16/100,000.Prediction to the primary malignant tumor of brain is not make us optimistic, even behind surgical resection, half survival time also is less than 1 year.These tumors, particularly glioma (gliomas) are main local diseases, by its recurrence in 2 centimetres of the initial focus of disease behind the surgical resection.
Can use the representative example of the cerebroma that compositions described herein and method treat to comprise that glioma (Glial Tumors) is (such as glioblastoma multiforme, the glioblastoma of multiform, fibrous astrocytoma, Oligodendroglioma, ependymoma, the myxopapillary ependymoma, subependymoma, papilloma of choroid plexus); Neuron tumor (for example, neuroblastoma, ganglioneuroblastoma, ganglioneuroma and medulloblastoma); Pineal gland tumor (for example, pinealoblastoma and pinealoma); Meningeal tumor (for example, meningioma, meningeal hemangiopericytoma, meningeal sarcoma); The tumor of neurilemma cell (for example, schwannoma (schwannoma) and neurofibroma); Lymphoma (for example Hodgkin lymphoma and non-Hodgkin lymphoma (comprise many hypotypes, former with secondary); Deformity (Malformative) tumor (for example craniopharyngioma, epidermoid cyst, the cyst of skin sample and gelationus cyst); With the tumor (it in fact can be derived from any tumor, and modal is lung tumors, breast tumor, melanoma, tumor of kidney, and gastroenteric tumor) that shifts.
As above annotate, gone through the representative drugs (for example, anti--the microtubule agent) of treatment adhesion above, and described medicine comprises taxanes, Colchicine and CI980 (Allen etc., Am.J.Physio.261 (4Pt.1): L315-L321,1991; Ding etc., J.Exp.Med.171 (3): 715-727,1990; Gonzalez etc., Exp.Cell.Res.192 (1): 10-15,1991; Stargell etc., Mol.Cell.Biol.12 (4): 1443-1450,1992; Garcia etc., Antican.Drugs6 (4): 533-544,1995), vinca alkaloids (for example, vinblastine and vincristine), discodermolide (ter Haar etc., Biochemistry 35:243-250,1996), and the analog of any of these and derivant.
In one embodiment of the invention, described chemical compound or compositions are directly used (for example, by brush, brush, spraying or otherwise use anti-microtubule compositions to apply the tumor resection edge) to the tumor resection position.In particularly preferred embodiment of the present invention, at the hepatotomy of malignant tumor, colon tumor excision surgical operation behind the breast tumor lumpectomy and behind neurosurgery tumor resection surgical operation, is used described anti-microtubule compositions.
For paclitaxel, the embodiment of many processing local tumor recurrences is described.In a preferred embodiment, the paclitaxel of 1-25mg is filled on the microsphere carrier, thereby participate in the activatory polymer composition and in a time cycle, to discharge solution, powder, " paste " that medicine reduces the tumor recurrence sickness rate, " film ", or " gel " form is used to removal surface.In the method for the utmost point (endoscope), the microsphere-activatory polymer formulations that will comprise the paclitaxel of 1-25mg is used to the excision position by the delivery port in endoscope (delivery ports) as " spray medicine (spray) " interior.In another embodiment, the peritoneum surgical operation flush fluid that will comprise the 10-250mg paclitaxel or is used behind surgical operation when surgical operation immediately.
For docetaxel, the embodiment of many processing local tumor recurrences is described.In a preferred embodiment, the docetaxel of 0.5-15mg is filled on the microsphere carrier, thereby participate in the activatory polymer composition and in a time cycle, to discharge solution, powder, " paste " that medicine reduces the tumor recurrence sickness rate, " film ", or " gel " form is used to removal surface.In the method for the utmost point (endoscope), the microsphere-hyaluronic acid preparation that will comprise the docetaxel of 0.5-15mg is used to the excision position by the delivery port in endoscope (delivery ports) as " spray medicine (spray) " interior.In another embodiment, the peritoneum surgical operation flush fluid that will comprise the 10-100mg docetaxel or is used behind surgical operation when surgical operation immediately.
Other application of activation synthetic polymer
The activatory polymer composition of the present invention can also be coated on the inner surface in physiology chamber, on blood vessel or fallopian tube, come the narrow and restenosis in prevention chamber behind therapeutic treatment thus as sealant, described therapeutic treatment such as, for example, remove the sedimentary ductus bursae of tremulous pulse plaque from vascular inner surface and insert art, or remove scar tissue or endometrial tissue from the fallopian tube inner surface.Preferably the thin layer of reactant mixture is administered to the inner surface (for example, passing through conduit) of blood vessel.Because the present composition is not easy degraded in vivo, the probability of restenosis is owing to the degraded of coating is minimized.Application with crosslinking polymer composition of clean neutral charge also further minimizes the probability of restenosis.
The activatory polymer composition of the present invention can also be applied to the surface to reduce " mist formation " of its application surface (mirror for example, skiing protective eye lens, glasses).
Thereby activated polymerization compositions of the present invention can also be applied to the lubricity that the surface increases described surface.This, for example, be effective in the application of conduit or contact lens.In the conventional method on the surface that applies medical apparatus, activatory synthetic polymer is administered to the surface of described device.In preferably using, the surface of described device have can with the functional group of the activation functional group reactions of the polymer of using.Surface functional group can be that to be used for preparing the compositions of material of implant inherent.Can surface functional group be introduced implant by at first handling implant surface.Operable surface treatment includes, but not limited to use (for example carries suitable functional group, chitosan, polymine) the described surface of polymer-coated, the described surface of oxidation (for example, acid/potassium permanganate is handled), the polymer that carries suitable functional group is transplanted on the graft surface, the plasma treatment of graft surface or corona are handled, or the radiation of graft surface (for example, γ, UV, or the e-ray etc.).Can also use these surface-treateds to make up suitable functional group is introduced implant surface.Reactant mixture can be brushed by extruding to using of described implant surface, dip-coating, spraying (as described above), or by any other easily mode carry out.After this reactant mixture is administered to described implant surface, allow to proceed to obtain sufficient reaction up to the reaction of surface functional group.Remove the further step of any solvent then.
Embodiment
Thereby the embodiment that proposes subsequently provides open fully and to how formulating described conjugate to those of ordinary skills, the description of the preferred embodiment of compositions and device and be not inclined to the scope of invention that the restriction inventor thinks.Though the numeral of having made great efforts to guarantee to use (for example, quantity, temperature, molecular weight, etc.) degree of accuracy, should consider some experimental erroies and deviation.Unless otherwise noted, part is a weight portion, and molecular weight is a weight average molecular weight, and temperature is with a degree centigrade expression, and pressure is atmospheric or near atmospheric pressure.
Embodiment 1
Secondary carrier comprises reactive compounds
In one aspect of the invention, bioactive compound (medicine) can be participated in the secondary carrier, and this drug/vehicle is made up combination to carry the synthetic polymer of a plurality of activated groups.At medicine is hydrophobic, and described carrier promotes that this is useful especially in the water-soluble or those situations of dispersibility of described medicine.And, be to be dissolved in water and/or dispersible at those described synthetic polymers (bonded) with described medicine, and with described surface (tissue or apparatus surface) when contacting, will situation as waterborne compositions in, this is useful especially.In these situations, it may be ideal making secondary carrier and the synthetic polymer reaction of carrying a plurality of activated groups.For this reaction is taken place, this secondary carrier must have reactive functional groups.Synthetic schemes subsequently provides and can be comprised into secondary carrier, nanometer spheroid for example, micelle, or the chemical compound in the analog.Wherein these chemical compounds have reactive functional groups.
A.R=C 17(thiol functionality hydrocarbon)
Figure A20038011006801261
Stearyl chloride (10mmol) slowly is added in outfit with magnetic stirrer, in the refrigerative cystamine (5mmol) in the dry 50mL round-bottomed flask of rubber septum and nitrogen ball and the 25mL dichloromethane solution of triethylamine (15mmol).Described mixture is warmed to room temperature and stirred its 4 hours.After the front three ammonium salt filtered, wash described organic solution with water and at Mg 2SO 4On carry out drying.Thereby solvent evaporation is produced the N that passes through the silica gel chromatography purification, N '-two-stearoyl-cystamine.Under room temperature blanket of nitrogen condition, use 10mM triphenyl phasphine in the dichloromethane of ten times of molar excess to reduce disulfide bond after yesterday.
B. R=PEG (thiol official energy PEG)
In room temperature, under the condition of pH4, when having 11mmol 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), make 10mmol PEG-carboxylate and 5mmol cystamine in 2 hours, carry out coupling.Described solution carries out dialyzed overnight and by the lyophilization separated product through distilled water on the film that dams of 1kDa molecular weight.10mM dithiothreitol, DTT by ten times of molar excess is at pH8.5, reduces disulfide bond under the condition of nitrogen gas.
C.R=C 19(thiol functionality hydrocarbon)
Under anhydrous condition, exist 11mmol dicyclohexyl-carbodiimide (DCC) when existing, 10mmol arachic acid and 5mmol cystamine are in room temperature coupling more than 4 hours in dichloromethane.Described solution is filtered, and the vaporising under vacuum solvent.Carry out purification by precipitation in methanol.The 10mM triphenyl phasphine in dichloromethane by ten times of molar excess reduces disulfide bond under condition of nitrogen gas.
D.R=C 11(thiol functionality hydrocarbon)
Figure A20038011006801271
Lauryl acrylate (10mmol) and methoxyphenol (2mg) are dissolved in the 10mL chloroform, with nitrogen purge and ice bath cooling.Cystamine (5mmol) is added, and described reactant mixture is spent the night in the stirring of room temperature lucifuge.This product is precipitated in methanol.After removing solvent, use the ambient temperature overnight under condition of nitrogen gas of the 10mM triphenyl phasphine in dichloromethane of ten times of molar excess to reduce disulfide bond.
E.R=PEG (thiol functionality PEG)
PEG-acrylate (10mmol) and methoxyphenol (2mg) are dissolved in the 10mL distilled water, cool off with nitrogen purge and with ice bath.Add cystamine (5mmol), and with the reactant mixture lucifuge in stirred overnight at room temperature.Described solution carries out dialyzed overnight and by the lyophilization separated product through distilled water on the film that dams of 1kDa molecular weight.10mM dithiothreitol, DTT by ten times of molar excess is at pH8.5, reduces disulfide bond under the condition of nitrogen gas.
F.R=C 18(thiol functionality hydrocarbon)
Figure A20038011006801282
Or
With N, N '-two (acryloyl) cystamine (5mmol) and methoxyphenol (2mg) are dissolved in the 10mL chloroform, cool off with nitrogen purge and with ice bath.Add 18-amine. and n-octadecyl mercaptan (10mmol), and this reactant mixture is spent the night in the stirring of room temperature lucifuge.This product is precipitated in methanol.Behind the evaporating solvent, the 10mM triphenyl phasphine in dichloromethane that uses ten times of molar excess reduces disulfide bond in ambient temperature overnight under condition of nitrogen gas.
G.R=PEG (thiol functionality PEG)
With N, N '-two (acryloyl) cystamine (5mmol) and methoxyphenol (2mg) are dissolved in the 10mL distilled water, cool off with nitrogen purge and with ice bath.Add amino or sulfydryl (sulfhydril) PEG (10mmol), and this reactant mixture is spent the night in the stirring of room temperature lucifuge.Described solution carries out dialyzed overnight and by the lyophilization separated product through distilled water on the film that dams of 1kDa molecular weight.10mM dithiothreitol, DTT by ten times of molar excess is at pH8.5, reduces disulfide bond under the condition of nitrogen gas.
H.R=PEG (thiol functionality PEG)
The succinimido acetyl group thiacetate (SATA) of amino-PEG and five times of molar excess is in room temperature reaction 1 hour in sodium bicarbonate-sodium phosphate buffer of 9 at pH.SATA was dissolved in the dimethyl formamide (10mg/mg) before using immediately in advance, and in the vigorous stirring process, slowly adds PEG solution.Separate functionalized PEG product by the gel filtration chromatography on Sephadex G10 post.After lyophilization, use the 50mM azanol to go down except that sulfo-perester radical group in condition of neutral pH.
I.R＝C 18
Under anhydrous condition, in dimethyl formamide, the reaction of the succinimido acetyl group thio-acid ester bond (SATA) of 18-amine. and two times of molar excess is spent the night in room temperature.SATA is dissolved in the dimethyl formamide (10mg/ml) before use immediately in advance and slowly adds hydrocarbon solution in the vigorous stirring process.Separate this functionalized product by in methanol, precipitating.Use the 50mM azanol to go down except that sulfo-perester radical group in condition of neutral pH.
J.R=PEG (thiol functionality PEG)
With similarly top, the thiol functional molecules that can use R-SH to produce to have the thioester joint.For example, succinimido 3-(2-pyridylthio) propionic ester (SPDP) that makes amino-PEG and five times of molar excess in pH is sodium bicarbonate-sodium phosphate buffer of 9 was in room temperature reaction 1 hour.SPDP is dissolved in (10mg/mL) in the dimethyl formamide before use immediately in advance, and in the vigorous stirring process, slowly adds PEG solution.Separate functionalized PEG product by the gel filtration chromatography on Sephadex G10 post.After the lyophilization, the 10mM dithiothreitol, DTT by ten times of molar excess is at pH8.5, reduces disulfide bond under the condition of nitrogen gas.
K.R＝C 18
Under anhydrous condition, 18-amine. and equimolar succinimido 3-(2-pyridylthio) propionic ester (SPDP) are spent the night in dimethyl formamide in room temperature reaction.SPDP is dissolved in (10mg/mL) in the dimethyl formamide before use immediately in advance, and in the vigorous stirring process, slowly adds hydrocarbon solution.Separate this functionalized product by in methanol, precipitating.The 10mM dithiothreitol, DTT that uses ten times of molar excess reduces disulfide bond in chloroform under condition of nitrogen gas.
L.R=C 11(the PEG-hydrocarbon sealing of amino-functional)
Figure A20038011006801301
With similarly top, the thiol functional molecules that can use R-SH to produce to have the thioester joint.For example, when having 11mmol dicyclohexyl-carbodiimide (DCC), make the coupling more than 4 hours in toluene of the amino-PEG-carboxylate of 5mmol protection and 5mmol lauryl alcohol.Filtering solution and vaporising under vacuum solvent.Purification can carry out on silicagel column.The BOC blocking group can be removed by the 50%TFA in dichloromethane.
M. R=PLGA (the PEG-PLGA sealing of amino-functional)
Under the condition of pH4, exist 1-ethyl-3-of 5.5mmol (3-dimethylaminopropyl) carbodiimide (EDC) when existing, make the amino-PEG-carboxylate of 5mmol protection and 5mmol PLGA in room temperature reaction 2 hours.Described solution carries out dialyzed overnight and by the lyophilization separated product through distilled water on the film that dams of 1kDa molecular weight.The FMOC blocking group is removed by 20% piperidines among the DMF.
N.R=polymer (the PEG-polymer blocks of amino-functional)
Can with top embodiment 1M in the chemical compound of each this structure of similar fashion system of describing.
O.R=lipid (the PEG-lipid sealing of amino-functional)
Can with top embodiment 1M in the similar fashion described prepare the chemical compound of this structure.
P.O=CH 3 , initiating groupOH .
Figure A20038011006801311
For D, the ring-opening polymerisation of L-lactide takes by weighing the 40g lactide and adds and 60g methoxyl group poly-(ethylene glycol) to be housed (MePEG is in 250mL round-bottomed flask MW=2000).This reagent vacuum drying is spent the night; When stirring, with described flask with nitrogen wash and place 130 ℃ of oil baths.After the reagent fusing, add the stannous 2-ethylhexanoate of 300mg with starting polymerization.After 5 hours, described polymer poured in the metal dish solidify.
Q.Q=COOH , initial groupNH 2
For D, the ring-opening polymerisation of L-lactide mixes the 25g lactide of dried overnight under the vacuum in the 250mL round-bottomed flask with the amino hendecanoic acid of 250mg 12-.Described flask with nitrogen wash and when stirring, is placed in 130 ℃ of oil baths.After the reagent fusing, add the stannous 2-ethylhexanoate of 100mg with starting polymerization.After 2 hours, viscid polymer poured in the metal dish solidify.In a similar fashion, thus Q can be protected amine or mercaptan produces functional block thing.
R. Above-mentioned any of R=
Figure A20038011006801312
Glass apparatus flame is dry and use anhydrous condition in esterification reaction process.Taking by weighing exsiccant PLGA (1 normal OH) adds in the reaction flask of the triethylamine that contains anhydrous methylene chloride (0.6ml/mmol) and 1 molar equivalent.This mixture is cooled off with nitrogen purge and in ice bath.Acid chloride (1.3 is normal) is added by the syringe increment.After the adding, described mixture was stirred two hours and add in the long-pending distilled water of triploid.With the washed with dichloromethane aqueous layer and use NaHCO 3The organic layer that washing merges.Use Mg 2SO 4After drying and the filtration, add the hydroquinone of 2mg, remove solvent by vacuum.Similarly, the reaction of describing can be passed through with acrylate by the methacryl functional group that obtains.
Embodiment 2
PH of buffer is to reducing the influence of adhesion
Sample preparation and using
Take by weighing four functional poly-(ethylene glycol) succinimido glutarate (4-arm-NHS-PEG, Cat#P4SG-10, Sunbio Inc., Anyang City, Korea) add in the syringe (each 100mg) of 1mL plastics, its inclosure is comprised in the paper tinsel bag of desiccant, and use γ-radiation that it is sterilized.Sodium dihydrogen phosphate (monobasic sodium phosphate) by not commensurability 0.3M sodium carbonate of combination and 0.3M thus prepare 8,8.5 and 9 buffer.These buffer of prepared fresh and the syringe filter by 0.22 micron carry out filtration sterilization before the experiment.(every 400-500g n=4) is used in the evaluation (seeing general procedure A) of carrying out each pH in the rat Ceco-wall wearing and tearing surgical operation adhesion model with the Sprague-Dawley rat.
When using sterilizing installation to use under sterilising conditions, (syringe PQ) thoroughly is dissolved in 4-arm-NHS-PEG in the 0.5mL aquesterilisa for BBraun Medical Inc., Kirkland with the fluid dispensing connector by connecting.To comprise the syringe of 4-arm-NHS-PEG solution and comprise another syringe that 0.5mL has the buffer of suitable pH and be connected in Fibrijet surgical sealing agent applicator (Micromedics Inc. with sealer applicator spraying tip, Eagan, and this preparation is sprayed at the areal area of damage MN).To spray as the mode of using composition layer thoroughly to cover sidewall and caecum.After one minute, with undergo surgery closure and allow its recovery of animal.
The result
Adhesion percentage ratio and the scoring of adhesion toughness are summarized in the table 1.
Table 1
Sample sets Adhesion percentage ratio Adhesion toughness
Contrast
100±0 2.18±0.07
PH 8-4-arm succinimido PEG 58.7±28.69 1.09±0.52
PH 8.5-4-arm succinimido PEG 70.75±14.22 1.24±0.46
PH 9-4-arm succinimido PEG 56.75±40.85 1.21±0.91
These presentation of results said compositions have the ability that reduces the adhesion percentage ratio and the adhesion order of severity on any one of these three different pH (8,8.5,9).
Embodiment 3
Polymer composition is to reducing the influence of adhesion
Sample preparation and using
Take by weighing four functional poly-(ethylene glycol) succinimido glutarate (4-arm-NHS-PEG, Cat#P4SG-10, Sunbio Inc., Anyang City Korea) is added in air pressure capsule (atmosbag) (Aldrich, the Milwaukee of silica dehydrator, WI) syringe of Nei 1mL plastics (is placed 200mg in each syringe, 300mg or 400mg) in, its inclosure is comprised in the paper tinsel bag of desiccant, and use γ-radiation that it is sterilized.Prepared fresh buffer (sodium dihydrogen phosphate that mixes 0.3M sodium carbonate and 0.3M is to pH9.2) and its syringe filter by 0.22 micron carried out filtration sterilization.(every 400-500g n=4) is used in the evaluation of carrying out each polymer concentration in general procedure A in the rat Ceco-wall wearing and tearing surgical operation adhesion model of describing with the Sprague-Dawley rat.
When using sterilizing installation to use under sterilising conditions, (syringe PQ) thoroughly is dissolved in 4-arm-NHS-PEG in the 0.5mL aquesterilisa for BBraun Medical Inc., Kirkland with the fluid dispensing connector by connecting.Another syringe that will comprise the syringe of 4-arm-NHS-PEG solution and comprise the 0.5mL buffer is connected in air and helps the spray applicator (Micromedics Inc., Eagan MN), and are sprayed at this preparation the areal area of damage.To spray as the mode of using composition layer thoroughly to cover sidewall and caecum.After one minute, with undergo surgery closure and allow its recovery of animal.
The result
Adhesion percentage ratio and the scoring of adhesion toughness are summarized in the table 2.
Table 2
Sample sets Adhesion percentage ratio Adhesion toughness
Contrast
100±0 2.12±0.06
200mg 4-arm succinimido PEG 61.25±27.2 1.19±0.06
300mg 4-arm succinimido PEG 43.5±43.2 0.78±0.9
400mg 4-arm succinimido PEG 52.5±41.1 0.925±0.8
These presentation of results said compositions have at these three different polymer concentrations (200mg in the 1.0mL solution, 300mg or 400mg (1: 1 water: the ability that reduces the adhesion percentage ratio and the adhesion order of severity on buffer) any one.
Embodiment 4
Preparation contains or does not contain the microsphere of paclitaxel
A) PVA formulations prepared from solutions
1. 1000ml distilled water and 100g PVA (Aldrich 13-23K, 98% hydrolysis) are weighed and put into the 1000ml beaker.2-inch splash bar is placed this beaker.In whipping process, suspension is heated to 75-80 ℃.PVA is thoroughly dissolved (should form clear solution).
2. filter with 10%PVA solution (w/v) cool to room temperature and by syringe line filter.Be stored in 2-8 ℃ standby.
B) preparation contains or does not contain the PLGA solution of paclitaxel
1. take by weighing the paclitaxel and the PLGA (gross weight 1.0g) of appropriate amount, and transfer in the 20ml scintillation vial.
2. the dichloromethane (DCM) that adds the 10mLHPLC level in phial contains or does not contain the PLGA of paclitaxel with dissolving.
3. by this phial being placed the polymer dissolution that will contain or not contain paclitaxel on the orbital shaker in DCM.Orbital shaker is arranged at 4.
Diameter is less than the preparation of the microsphere of 25mm
1. the 10%PVA solution of 100ml is transferred in the beaker of a 400ml.Beaker is fixed on the fume hood with two-sided tape.The device (peddler) that disseminates that will have 3 blades places 0.5cm on the beaker bottom.The beginning motor reaches 2.5 (Dyna-Mix is from Fisher Scientific).In whipping process, 10ml PLGA/ paclitaxel solution is poured in the PVA solution.To be transferred to 5.0 on the stir speed (S.S.) gradually.Keep stirring 2.5 to 3.0 hours.
2. the microsphere that the obtains diagrid by one group of 53mm (top) and 25mm (bottom) is filled in the beaker of a 100ml.When filtering, use the distilled water wash microsphere.The microsphere of centrifugal filtration (1000rpm, 10min.) and with the 100ml distilled water resuspended/washing three times is with cleaning PVA.
3. the microsphere after will washing with a spot of distilled water (20-30ml) is transferred in the freeze dried beaker.With the rear enclosed beaker and place-20 ℃ of refrigerator overnight.
4. utilize freeze dryer subsequently with about 3 days of refrigerated microsphere lyophilizing.Transfer to exsiccant microsphere in the 20ml scintillation vial and be stored in-20 ℃.
In a kind of mode similar, aforesaid other bioactivator can be participated in a kind of microspheres preparation to the above.
Embodiment 5
The official can be united to be incorporated into microsphere
Use one of synthetic reagent among PLGA polymer and the top embodiment 1, can carry out the preparation of microspheres preparation as mentioned above.
Embodiment 6
Apparatus surface coating-chitosan bottom
Use 0.2% (v/v) acetic acid preparation, 1% (w/v) chitosan soln.One section conduit is immersed in the chitosan soln, and incubation 10 minutes.Remove described conduit, allow it air-dry then.Then the conduit that chitosan is applied is immersed in poly-(ethylene glycol) succinimido glutarate (4-arm-NHS-PEG of 10% 4 sense of prepared fresh, Cat#P4SG-10, Sunbio Inc., AnyangCity, Korea) solution reaches 5 minutes in (pH is about 8).Remove described one section conduit, allow it air-dry then.Follow the one section conduit that applies with rinsed with deionized water and make it air-dry.Described then sample further carries out drying under vacuum.
Embodiment 7
Apparatus surface coating-PEI bottom
Use deionized water, preparation 5% (w/v) polymine (PEI) solution.One section conduit is immersed in the described PEI solution, and with its incubation 10 minutes.Remove described one section conduit, then that it is air-dry.Then the conduit that PEI-is applied be immersed in prepared fresh poly-(ethylene glycol) succinimido glutarate of 10% 4 sense (4-arm-NHS-PEG, Cat#P4SG-10, Sunbio Inc., AnyangCity, Korea) solution reaches 5 minutes in (pH is about 8).Remove described one section conduit, allow it air-dry then.Follow the one section conduit that applies with rinsed with deionized water and make it air-dry.Described then sample further carries out drying under vacuum.
Embodiment 8
The assessment mitoxantrone is for the filler test of the influence of cell proliferation
The fibroblast that 70-90% is converged carries out trypsinization, is re-seeded in the culture medium of 96 orifice plates with 600 cells/well and allows it adhere to spend the night.In DMSO, prepare 10 -2M mitoxantrone and dilute 10 times and preserve range of concentrations (10 to provide one -8M to 10 -2M).The drug dilution thing is diluted 1/1000 and add in the cell to provide the cumulative volume in 200 μ L/ holes in culture medium.Every kind of drug level is all tested in three holes.The flat board that will contain fibroblast and mitoxantrone is at 72 hours (In vitro toxicol. (1990) 3:219 of 37 ℃ of incubations; Biotech.Histochem. (1993) 68:29; Anal.Biochem. (1993) 213:426).
Remove culture medium to stop test by sucking-off gently.With CYQUANT 400 * GR dye indicator (Molecular Probes; Eugene, 1/1400 diluent OR) adds in 1 * cell lysis buffer solution, and the mixture of 200 μ L is added in the dull and stereotyped hole.In the room temperature incubation, lucifuge continues 3-5 minute with flat board.In the fluorescence microplate, read fluorescence in about 480nm excitation wavelength and the maximum district of about 520nm emission.Meansigma methods by getting three holes and average relative fluorescence unit and DMSO compared measured 50% inhibition concentration (IC 50).The meansigma methods of n=4 repeated experiments is used to measure IC 50Value.The results are shown among Figure 17 of test (for the propagation of human fibroblasts, IC 50=20nM).
Embodiment 9
The assessment mitoxantrone produces the filler test of the influence of nitrogen oxide for macrophage
Mouse macrophage cell line RAW 264.7 is carried out trypsinization to remove cell from flask and to place the single hole of 6 orifice plates.With about 2 * 10 6Cell places the culture medium that contains 5% heat-inactivated fetal bovine serum (FBS) in 2mL.It was adhered on the plastics in 1.5 hours in 37 ℃ of incubations in RAW 264.7 cells.In DMSO, prepare 10 -210 times of M mitoxantrone and serial dilutions are preserved range of concentrations (10 to provide one -8M to 10 -2M).Remove culture medium subsequently and the reorganization Mus IFN γ of the 1ng/mL of cell in containing the fresh culture of 5%FBS and 5ng/mL had or do not have among the LPS of mitoxantrone and carry out incubation.By directly adding the mitoxantrone DMSO stock solution of previous preparation to every porocyte adding mitoxantrone with 1/1000 diluent.To contain IFN γ, LPS and add deduct the flat board of mitoxantrone at 24 hours (Chem.Ber. (1879) 12:426 of 37 ℃ of incubations; J.AOAC (1977) 60-594; Ann.Rev.Biochem. (1994) 63:175).
Last 24 hour period, the generation of from cell, collecting supernatant and test nitrite.By in 96 orifice plates, dividing sample 50 μ L supernatant and adding 50 μ L Greiss reagent A (0.5g sulfanilamide, 1.5mLH 3PO4,48.5mLddH 2O) and 50 μ L Greiss try neat B (0.05g N-(1-naphthyl)-ethylenediamine, 1.5mLH 3PO4,48.5mLddH 2O) come each sample test three times.On the microplate spectrophotometer, read optical density (OD) immediately in the 562nm absorbance.Behind the subtracting background absorbance on three holes is being averaged and obtaining concentration value by nitroso-group salt standard curve (1 μ M is to 2mM).By average nitroso-group salinity is recently determined 50% inhibition concentration (IC mutually with positive control (with IFN γ and LPS stimulated cells) 50).The meansigma methods of n=4 repeated experiments is used to measure mitoxantrone IC 50Value.Test the results are shown among Figure 18 (the mitoxantrone IC of Greiss test in RAW 264.7 cells 50=927nM).
Embodiment 10
Assessment BAY 11-7082 produces the filler test of the influence of TNF-α for macrophage
With human macrophage system, THP-1 places 12 orifice plates, makes every hole comprise 1 * 10 in containing the 2mL culture medium of 10%FCS 6Cell.By at 2mL ddH 2Resuspended 20mg zymosan A and homogenize prepare the opsonized yeast polysaccharide up to the suspension that obtains homogeneous among the O.In the 250g precipitation and be resuspended in the human serum of 4mL, ultimate density is 5mg/mL, and incubation carried out opsonic action in 20 minutes in 37 ℃ of water-baths with the zymosan of homogenize.In DMSO, prepare 10 -210 times of M Bay11-7082 and serial dilutions are preserved range of concentrations (10 to provide one -8M to 10 -2M) (J.Immunol. (2000) 165:411-418; J.Immunol. (2000) 164:4804-4811; J.ImmunolMeth. (2000) 235 (1-2): 33-40).
Stimulate the THP-1 cell to produce TNF α by adding 1mg/mL opsonized yeast polysaccharide.By will directly adding in every hole Bay11-7082 is added in the THP-1 cell with the DMSO stock solution of the 1/1000 previous preparation of diluting.Every kind of drug level is all tested in three holes.With flat board 37 ℃ of incubations 24 hours.
After 24 hours stimulation, collect supernatant to quantize the generation of TNF α.Utilize the reorganization human TNF alpha to obtain a kind of standard curve and measure TNF α concentration in the supernatant by ELISA.Being diluted in Anti-Human TNF α capture antibody in coating buffer (0.1M sodium carbonate pH 9.5) with 100 μ L is coated with 96 hole MaxiSorb culture plates and spends the night in 4 ℃.The diluent of used capture antibody is batch specific and determines with experience.(PBS, 0.05%Tween-20) the washing culture plate is 3 times with the capture antibody sucking-off and with lavation buffer solution subsequently.Test diluent (PBS, 10%FCS pH7.0) with 200 μ L/ holes sealed culture plate 1 hour in room temperature.After the sealing, wash culture plate 3 times with lavation buffer solution.Be prepared as follows standard and sample diluting liquid: (a) with sample supernatant dilution 1/8 and 1/16; (b) the reorganization human TNF alpha of preparation 500pg/mL and serial dilution are to produce the standard curve of 7.8pg/mL to 500pg/mL.To sample supernatant and titer carry out triple tests and on adding with the culture plate of capture antibody coating after in room temperature incubation 2 hours.(biotin labeled anti-human TNF alpha detects antibody+avidin-HRP) in room temperature incubation 1 hour with culture plate washing 5 times and with 100 μ L operation detection agent.After this incubation, add 100 μ L substrate solution (N-tetramethyl benzidine, H with culture plate washing 7 times and to culture plate 2O 2) and in room temperature incubation 30 minutes.In the hole, add stop bath (2N H subsequently 2SO 4) and proofread and correct with the λ at 570nm place and to read yellow reaction at the 450nm place.Determine mean light absorbency and deduct average background by triple data values of reading.Obtain TNF α concentration value by standard curve.By average T NF α concentration is recently determined 50% inhibition concentration (IC mutually with positive control (with the THP-1 cell of the zymosan stimulation of nursing one's health) 50).The IC that the meansigma methods of n=4 repeated experiments is used to measure BAY 11-7082 50Value.Test the results are shown in (Bay11-7082IC among Figure 19 50=810nM THP-1 cell produces TNF α).
Embodiment 11
The rabbit surgical operation adhesion model of assessment fibroid degeneration inhibitor
Utilize the rabbit uterus angle model to assess the preparation ability of anti-fibroid degeneration in vivo.White (NZW) doe of ripe New Zealand is placed under the general anesthesia.Utilize aseptic preventive measure, it is two-layer to expose the uterus to open membranous part in center line.Two cornua uteris are all proposed the abdominal cavity and its size of assessment on the French of conduit Scale.Think and be suitable for this model between the angle between #8 and the #14 on the French Scale (2.5-4.5mm diameter).With the #10 scalpel blade with 45 at 2.5cm on the long and wide zone of 0.4cm two cornua uteris of scraping and relative peritoneal wall until observing a little break hemorrhage.The filling scratch-off surface is until stopped bleeding.Subsequently single cornua uteri also being used facing to peritoneal wall places two outer sutures of scraping edges of regions 2mm to sew up.Use three layers of described preparation and sealing abdominal paries.After 14 days, adhesion degree and the seriousness of animal are done assessment after death, carry out quantitatively and marking qualitatively.
Embodiment 12
The rat surgical operation adhesion model of assessment fibroid degeneration inhibitor
Prepare the Sprague Dawley rat that surgical operation is used by in airtight chamber, carrying out induction of anesthesia with 5% halothane.In whole process, keep anesthesia and intramuscular injection Buprenorphen 0.035mg/kg with halothane by nose-cone.Abdominal part is shaved hair, sterilization, wraps up and entered by the median line incision.Caecum is taken out and is positioned over on the wetted sterile gauze of normal saline from abdominal part.Utilize a kind of 10# scalpel blade with the 45 back side of 1.5cm scraping caecum and the outside of belly 45 times altogether endways.Control blade angle and pressure to be to produce disconnected hemorrhage of point, avoids serious tissue injury simultaneously or tears.
With the left side in abdominal cavity retraction and turn up with the part of the peritoneal wall that exposes the most approaching natural static caecum position.Cut 1.0 * 1.5cm 2The muscle shallow-layer (transverse abdominal muscle) of the exposure of area.Excision comprises the part below the internal oblique, stays some complete and some fibers of tearing by the second layer.The less local hemorrhage of tamponade is up to being controlled.
A kind of test preparation is loose on injured area, on the abrasive sidewall, between caecum and the sidewall.Utilize syringe spraying system or air auxiliary injection device system that described preparation is scattered.Subsequently abrasive caecum is positioned on 4 on the sidewall wound and above the edge of wound dorsal horn is tight and sews up.Large intestine is put back to the natural place that links to each other with caecum.Abdominal incision is sewed up two-layer with the 4-0 silk suture.
Follow the tracks of one week of rat, by the lethal injection its painless property is caused death after death to check marking subsequently.The toughness and the degree of the edge's adhesion by assessing caecum sidewall scratch site, scratch site independently, and be attached to the degree that exposes caecum by the assessment intestinal and come seriousness marking to tissue adhesion.Along with seriousness and flexible raising, adhesion marking is the 0-4 branch.The degree of adhesion the percentage ratio of being given a mark for the injured area that comprises adhesion.
Embodiment 13
The inhibition of the surgical operation adhesion in the rabbit uterus angle model
Use halothane female New Zealand white rabbits to be anaesthetized and prepared as the sterilization abdominal surgery.It is carried out laparotomy and two cornua uteris are taken out by abdominal part.With swipe each angle 40 times and with gauze friction 2.5 minutes of surgical blade.In six animals, 4-arm-PEG preparation is evenly sprayed on the injured angle.Six other animals are unprocessed.This angle is put back in the abdominal cavity, abdominal wound is closed in each layer.Described animal recovers and was raised 14 days.At that time, the IV with Euthanyl injects sacrifice of animal.The abdominal cavity opened and expose cornua uteri.Length along the adhesion of cornua uteri record.In the matched group average length of adhesion be 85+/-19cm.In processed group, the length of adhesion obviously reduce to 34+/-46cm (p＜.05).
With more than all in United States Patent (USP) mentioned in this article and/or that in the application information table, list, the U.S. Patent application publication, U.S. Patent application, foreign patent, foreign patent application and non-patent application full content are incorporated this paper into as a reference.
Although illustrate for example that from aforementioned should be appreciated that this paper has described specific embodiments of the present invention, can make various modifications under the prerequisite that does not depart from the scope of the invention and spirit.Therefore, unrestricted except additional claim the present invention.

Claims (240)

1. compositions, it comprises synthetic polymer and medicine, and described polymer comprises a plurality of activatory groups.
2. the compositions of claim 1, wherein said synthetic polymer has ringlike core.
3. the compositions of claim 2, wherein said ringlike core comprises the carbon ring group of 6-atom.
4. the compositions of claim 2, wherein ringlike core comprises the inositol residue.
5. the compositions of claim 2, wherein ringlike core comprises the lactose residue.
6. the compositions of claim 2, wherein ringlike core comprises the Sorbitol residue.
7. the compositions of claim 1, wherein said synthetic polymer has the side chain core.
8. the compositions of claim 7, wherein said side chain core is the polyol residue.
9. the compositions of claim 8, wherein said side chain core is a glycerol residue.
10. the compositions of claim 8, wherein said side chain core is the tetramethylolmethane residue.
11. the compositions of claim 8, wherein said side chain core is the diglycerol residue.
12. the compositions of claim 7, wherein said side chain core are poly-(carboxylic acid) chemical compound residues.
13. the compositions of claim 7, wherein said side chain core is the polyamine compounds residue.
14. the compositions of claim 7, wherein said side chain core comprises polyamino acid.
15. the compositions of claim 1, wherein said synthetic polymer comprises polyalkylene oxide.
16. the compositions of claim 15, wherein said polyalkylene oxide comprises ethylene oxide residue.
17. the compositions of claim 15, wherein said polyalkylene oxide comprises propylene oxide residue.
18. the compositions of claim 15, wherein said polyalkylene oxide have about 100 to about 100,000 molecular weight.
19. the compositions of claim 15, wherein said polyalkylene oxide have about 1,000 to about 20,000 molecular weight.
20. the compositions of claim 15, wherein said polyalkylene oxide have about 1,000 to about 15,000 molecular weight.
21. the compositions of claim 15, wherein said polyalkylene oxide have about 1,000 to about 10,000 molecular weight.
22. the compositions of claim 15, wherein said polyalkylene oxide have about 1,000 to about 5,000 molecular weight.
23. the compositions of claim 15, wherein said polyalkylene oxide have about 7,500 to about 20,000 molecular weight.
24. the compositions of claim 15, wherein said polyalkylene oxide have about 7,500 to about 15,000 molecular weight.
25. the compositions of claim 17, wherein said polyalkylene oxide have about 7,500 to about 20,000 molecular weight.
26. the compositions of claim 1, wherein said polymer have 2-12 activatory group.
27. the compositions of claim 26, wherein said polymer have 2 activatory groups.
28. the compositions of claim 26, wherein said polymer have 3 activatory groups.
29. the compositions of claim 26, wherein said polymer have 4 activatory groups.
30. the compositions of claim 26, wherein said polymer have 6 activatory groups.
31. the compositions of claim 26, wherein said polymer have 9 activatory groups.
32. the compositions of claim 26, wherein said polymer have 12 activatory groups.
33. the compositions of claim 1, wherein said activatory group are protein-reactive.
34. the compositions of claim 33, wherein said activatory group reacts with oh group.
35. the compositions of claim 33, wherein said activatory group and thiol radical reaction.
36. the compositions of claim 33, wherein said activatory group reacts with amino group.
37. the compositions of claim 1, wherein said activatory group comprises the electrophilic site.
38. the compositions of claim 37, wherein the electrophilic site is a carbonyl group.
39. the compositions of claim 1, wherein said activatory group comprises a leaving group.
40. the compositions of claim 39, wherein said leaving group are N-oxygen base butanimide groups.
41. the compositions of claim 39, wherein said leaving group are N-oxygen base maleimide base groups.
42. the compositions of claim 1, wherein said activatory group comprises the electrophilic site of a contiguous leaving group.
43. the compositions of claim 42, wherein the electrophilic site is a carbonyl group.
44. the compositions of claim 42, wherein said leaving group are selected from N-oxygen base butanimide and N-oxygen base maleimide.
45. the compositions of claim 42, wherein electrophilic group is that carbonyl and leaving group are selected from N-oxygen base butanimide and N-oxygen base maleimide.
46. the compositions of claim 1, wherein synthetic polymer comprises formula (main polymer chain)-(Q-Y) n, wherein Q is a linking group, Y is activatory functional group, and n be one greater than 1 integer.
47. the compositions of claim 46, wherein said main polymer chain comprises polyalkylene oxide.
48. the compositions of claim 46, wherein Q is selected from by in the following group of forming :-G-(CH 2) n-, wherein G is selected from O, S, NH ,-O-CO-and-O-CO-NH-(CH 2) nO 2C-CR 1H-is R wherein 1Be selected from hydrogen and alkyl; And O-R 2-CO-NH, wherein R 2Be selected from CH 2And CO-NH-CH 2CH 2
49. the compositions of claim 46, wherein n is 2-12.
50. the compositions of claim 46, wherein Y comprises the electrophilic site of contiguous leaving group.
51. the compositions of claim 50, wherein said electrophilic site is a carbonyl group.
52. the compositions of claim 50, wherein said leaving group comprises (N-CO-CH 2) 2
53. the compositions of claim 46, wherein said synthetic polymer have formula (main polymer chain)-(Q-Y) n
54. the compositions of claim 46, wherein cahin extension agent is positioned between (main polymer chain) and the Q or between Q and the Y.
55. the compositions of claim 1, wherein said synthetic polymer comprise formula (main polymer chain)-(D-Q-Y) n, wherein D is biodegradable group, and Q is a linking group, and Y is that activatory functional group and n are the integers greater than 1.
56. the compositions of claim 55, wherein said main polymer chain comprises polyalkylene oxide.
57. the compositions of claim 55, wherein D comprises and is selected from lactide, Acetic acid, hydroxy-, bimol. cyclic ester, the chemical group of 6-caprolactone and poly-('alpha '-hydroxy acids).
58. the compositions of claim 55, wherein D comprises and is selected from poly-(aminoacid), poly-(acid anhydride), the chemical group of poly-(ortho esters).
59. the compositions of claim 55, wherein Q is selected from by in the following group of forming :-G-(CH 2) n-, wherein G is selected from O, S, NH ,-O-CO-and-O-CO-NH-(CH 2) nO 2C-CR 1H-is R wherein 1Be selected from hydrogen and alkyl; And O-R 2-CO-NH, wherein R 2Be selected from CH 2And CO-NH-CH 2CH 2
60. the compositions of claim 55, wherein Y comprises the electrophilic site of contiguous leaving group.
61. the compositions of claim 60, wherein the electrophilic site is a carbonyl group.
62. the compositions of claim 60, wherein said leaving group comprises (N-CO-CH 2) 2
63. the compositions of claim 60, wherein synthetic polymer has formula (main polymer chain)-(D-Q-Y) n
64. the compositions of claim 55, wherein cahin extension agent is positioned between (main polymer chain) and the Q or between Q and the Y.
65. the compositions of claim 1, it comprises first and second polymer that carry a plurality of activated groups, and wherein first and second polymer are inequality.
66. the compositions of claim 65, wherein first and second polymer comprise different activatory groups.
67. the compositions of claim 65, wherein first and second polymer have different number-average molecular weights.
68. the compositions of claim 65, wherein first and second polymer have the activated group of different numbers.
69. the compositions of claim 1, wherein said polymer is soluble in 25 ℃ in water under the concentration of at least 1 gram polymer/99 gram water.
70. the compositions of claim 69, wherein said polymer is soluble in 25 ℃ in water under the concentration of at least 2 gram polymer/99 gram water.
71. the compositions of claim 69, wherein said polymer is soluble in 25 ℃ in water under the concentration of at least 3 gram polymer/99 gram water.
72. the compositions of claim 69, wherein said polymer is soluble in 25 ℃ in water under the concentration of at least 4 gram polymer/99 gram water.
73. the compositions of claim 69, wherein said polymer is soluble in 25 ℃ in water under the concentration of at least 5 gram polymer/99 gram water.
74. the compositions of claim 1, wherein said medicine is that effectively described cytoactive is selected from by in the following group of forming on the cytoactive of one of inhibition or combination: cell division, emiocytosis, cell migration, cell adhesion, the generation of inflammatory activator and/or release, blood vessel generation and free radical form and/or discharge.
75. the compositions of claim 1, wherein said medicine is an angiogenesis inhibitor.
76. the compositions of claim 1, wherein said medicine are 5-lipoxygenase inhibitor or antagonist.
77. the compositions of claim 1, wherein said medicine is a chemokine receptor anagonists.
78. the compositions of claim 1, wherein said medicine is a cell cycle inhibitor, or its analog or derivant.
79. the compositions of claim 78, wherein said cell cycle inhibitor is a microtubule stabilizer.
80. the compositions of claim 79, wherein said microtubule stabilizer is a paclitaxel, docetaxel or Peloruside A.
81. the compositions of claim 78, wherein said cell cycle inhibitor is a taxane.
82. the compositions of claim 81, wherein said taxane is a paclitaxel, or its analog or derivant.
83. the compositions of claim 78, wherein said cell cycle inhibitor is an antimetabolite, alkylating agent or vinca alkaloids.
84. the compositions of claim 83, wherein said vinca alkaloids is a vinblastine, vincristine, vincristine sulfate, vindesine and vinorelbine, or its analog or derivant.
85. the compositions of claim 78, wherein said cell cycle inhibitor is a camptothecine, or its analog or derivant.
86. the compositions of claim 78, wherein said cell cycle inhibitor is selected from by mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, ametycin, the group that CDK-2 inhibitor and its analog or derivant are formed.
87. the compositions of claim 1, wherein said medicine are the kinases inhibitors of cyclin dependant, or its analog or derivant.
88. the compositions of claim 1, wherein said medicine are EGF (epidermal growth factor) inhibitors of kinases, or its analog or derivant.
89. the compositions of claim 1, wherein said medicine is an elastase inhibitor, or its analog or derivant.
90. the compositions of claim 1, wherein said medicine are the Xa factor inhibitor, or its analog or derivant.
91. the compositions of claim 1, wherein said medicine is a farnesyl transferase inhibitor, or its analog or derivant.
92. the compositions of claim 1, wherein said medicine are the fibrinogen antagonisies, or its analog or derivant.
93. the compositions of claim 1, wherein said medicine are the guanylate cyclase stimulants, or its analog or derivant.
94. the compositions of claim 1, wherein said medicine are the heat shock protein 90 antagonisies, or its analog or derivant.
95. the compositions of claim 1, wherein said medicine are the HMGCoA reductase inhibitors, or its analog or derivant.
96. the compositions of claim 1, wherein said medicine are the hydroorotic acid dehydrogenase inhibitors, or its analog or derivant.
97. the compositions of claim 1, wherein said medicine are the IKK2 inhibitor, or its analog or derivant.
98. the compositions of claim 1, wherein said medicine is IL-1, ICE or IRAK antagonist, or its analog or derivant.
99. the compositions of claim 1, wherein said medicine are the IL-4 agonist, or its analog or derivant.
100. the compositions of claim 1, wherein said medicine are immunomodulating reagent.
101. the compositions of claim 1, wherein said medicine is an inosine monophosphate dehydrogenase inhibitor, or its analog or derivant.
102. the compositions of claim 1, wherein said medicine are the leukotreine inhibitor, or its analog or derivant.
103. the compositions of claim 1, wherein said medicine are the MCP-1 antagonisies, or its analog or derivant.
104. the compositions of claim 1, wherein said medicine are the MMP inhibitor, or its analog or derivant.
105. the compositions of claim 1, wherein said medicine are NF kappa B inhibitor, or its analog or derivant.
106. the compositions of claim 1, wherein said medicine are the NO antagonisies, or its analog or derivant.
107. the compositions of claim 1, wherein said medicine are the P38MAP inhibitors of kinases, or its analog or derivant.
108. the compositions of claim 1, wherein said medicine is a phosphodiesterase inhibitor, or its analog or derivant.
109. the compositions of claim 1, wherein said medicine are the TGF beta inhibitors, or its analog or derivant.
110. the compositions of claim 1, wherein said medicine are the TXA2. antagonisies, or its analog or derivant.
111. the compositions of claim 1, wherein said medicine are the TNFa antagonisies, TACE, or its analog or derivant.
112. the compositions of claim 1, wherein said medicine is a tyrosine kinase inhibitor, or its analog or derivant.
113. the compositions of claim 1, wherein said medicine is a vitronectin inhibitor, or its analog or derivant.
114. the compositions of claim 1, wherein said medicine is a fibroblast growth factor inhibitor, or its analog or derivant.
115. the compositions of claim 1, wherein said medicine is a kinases inhibitor, or its analog or derivant.
116. the compositions of claim 1, wherein said medicine is a pdgf receptor kinase inhibitor, or its analog or derivant.
117. the compositions of claim 1, wherein said medicine is an endothelial growth factor receptor kinase inhibitor, or its analog or derivant.
118. the compositions of claim 1, wherein said medicine is a RAR antagonists, or its analog or derivant.
119. the compositions of claim 1, wherein said medicine are platelet-derived growth factor receptor kinase inhibitors, or its analog or derivant.
120. the compositions of claim 1, wherein said medicine are the fibrinogin antagonisies, or its analog or derivant.
121. the compositions of claim 1, wherein said medicine is an antifungal, or its analog or derivant.
122. the compositions of claim 1, wherein said medicine is a diphosphate, or its analog or derivant.
123. the compositions of claim 1, wherein said medicine are the E.C. 3.1.1.32 inhibitor, or its analog or derivant.
124. the compositions of claim 1, wherein said medicine are histamine H 1/H2/H3 receptor antagonists, or its analog or derivant.
125. the compositions of claim 1, wherein said medicine is a macrolide antibiotic, or its analog or derivant.
126. the compositions of claim 1, wherein said medicine are GP IIb IIIa receptor antagonists, or its analog or derivant.
127. the compositions of claim 1, wherein said medicine is an endothelin-receptor antagonists, or its analog or derivant.
128. the compositions of claim 1, wherein said medicine are peroxisome Proliferators activated receptors agonist, or its analog or derivant.
129. the compositions of claim 1, wherein said medicine is an estrogen receptor agent, or its analog or derivant.
130. the compositions of claim 1, wherein said medicine is a somatostatin, or its analog or derivant.
131. the compositions of claim 1, wherein said medicine are the JNK inhibitors of kinases, or its analog or derivant.
132. the compositions of claim 1, wherein said medicine is a melanocortin, or its analog or derivant.
133. the compositions of claim 1, wherein said medicine are the raf inhibitors of kinases, or its analog or derivant.
134. the compositions of claim 1, wherein said medicine are the lysyl hydroxylase inhibitor, or its analog or derivant.
135. the compositions of claim 1, wherein said medicine are IKK 1/2 inhibitor, or its analog or derivant.
136. the compositions of claim 74, wherein said medicine is a cytokine modulators.
137. the compositions of claim 74, wherein said medicine is a cytokine antagonist.
The compositions of 138 claim 1, wherein said medicine are water-insoluble.
139. the compositions of claim 1, it exists with anhydrous form.
140. the compositions of claim 1, it exists with sterile form.
141. the compositions of claim 1, wherein said polymer account for about percent 0.5-40 of described composition weight.
142. the compositions of claim 1, it also comprises solvent.
143. the compositions of claim 142, wherein said solvent comprises water.
144. the compositions of claim 1, it also comprises buffer.
145. the compositions of claim 144, wherein said buffer maintains the pH of described compositions in the scope of 4-10.
146. the compositions of claim 144, wherein said buffer maintains the pH of described compositions in the scope of 5-9.
147. the compositions of claim 144, wherein said buffer maintains the pH of described compositions in the scope of 6-8.
148. the compositions of claim 144, wherein said buffer comprises phosphate.
149. the compositions of claim 1, it also comprises protein.
150. the compositions of claim 149, wherein protein is collagen protein.
151. the compositions of claim 149, wherein said protein comprises the primary amino radical group.
152. the compositions of claim 1, it also comprises polysaccharide.
153. the compositions of claim 152, wherein polysaccharide is glysoaminoglycan.
154. a method that influences biological process in the body, it comprises
A) the interior biological organization of body of the X of functional group is carried in selection;
B) provide the compositions that comprises synthetic polymer and medicine, described polymer carries a plurality of activated group Y, wherein Y and X reaction;
C) at i) X and Y reaction and ii) the biological process of contiguous described tissue by under the condition of described drug influence the tissue of step a) is contacted with the compositions of step b).
155. the method for claim 154, wherein said biological organization with experienced the surgical operation damage before the compositions of step b) contacts, make tissue have the risk that forms adhesion thus.
156. the method for claim 155, wherein the formation of adhesion is undesirable by-product in the abdominal surgery.
157. the method for claim 155, wherein the formation of adhesion is undesirable by-product in the cardiac operation.
158. the method for claim 155, wherein the formation of adhesion is undesirable by-product in the spinal surgery.
159. the method for claim 155, wherein the formation of adhesion is undesirable by-product in the nose surgical operation.
160. the method for claim 155, wherein the formation of adhesion is undesirable by-product in the throat surgical operation.
161. the method for claim 155, wherein the formation of adhesion is undesirable by-product in the breast surgical operation.
162. the method for claim 155, wherein said biological organization with experienced the surgical operation damage, described surgery operating removing tumor before the compositions of step b) contacts.
163. the method for claim 162, wherein said surgical operation are the breast surgical operations.
164. the method for claim 162, wherein said surgical operation are the mammary neoplasms lumpectomies.
165. the method for claim 162, wherein said surgical operation are the brain surgical operations.
166. the method for claim 162, wherein said surgical operation is a hepatectomy.
167. the method for claim 162, wherein surgical operation is the colon tumor excision.
168. the method for claim 162, wherein surgical operation is the neurosurgery tumorectomy.
169. the method for claim 154, wherein said tissue are the inner surfacies in physiology chamber.
170. the method for claim 169, wherein said tissue is a blood vessel.
171. the method for claim 169, wherein said tissue is a fallopian tube.
172. the method for claim 169, wherein said organizing experienced balloon catheter insertion art.
173. a method, it comprises:
A) make to organize in vivo and contact with the synthetic polymer that carries a plurality of activatory groups, wherein said activatory group is a tissue-reactive;
B) thus make described synthetic polymer and tissue reaction make the synthetic polymer covalency adhere to tissue.
174. the method for claim 173, wherein tissue is a blood vessel.
175. the method for claim 173, wherein tissue tends to restenosis.
176. the method for claim 173, wherein after described synthetic polymer and described tissue reaction, the adhesion of described tissue and secondary tissue is alleviated.
177. the method for claim 173, wherein said not organizing reacted with any other synthetic polymer.
178. the method for claim 173, wherein said synthetic polymer not with any other polymer mixed, the reaction of described polymer and described synthetic polymer.
179. the method for claim 173, wherein said synthetic polymer not with any other polymer mixed, described polymer and described tissue reaction.
180. the method for claim 173, wherein said synthetic polymer comprises alkylene oxide residue.
181. the method for claim 173, wherein said synthetic polymer are 4-arm PEG.
182. the method for claim 173, wherein said synthetic polymer comprises a plurality of thiol-reactive groups.
183. the method for claim 173, wherein said synthetic polymer comprises a plurality of hydroxyl-reactive groups.
184. the method for claim 173, wherein said synthetic polymer comprises a plurality of amine-reactive groups.
185. a method, it comprises:
A) lifeless surface is contacted with the synthetic polymer that carries a plurality of activated groups, wherein said activatory group is a tissue-reactive.
B) thus make described synthetic polymer and described surface reaction that described synthetic polymer is covalently adhered on the described surface.
186. the method for claim 185, wherein said surface are the surfaces of conduit.
187. the method for claim 185, wherein said surface are the surfaces of contact lens.
188. the method for claim 185, wherein after making described synthetic polymer and described surface reaction, described surface and living tissue adhesion are alleviated.
189. the method for claim 185, wherein said surface are not reacted with any other synthetic polymer.
190. the method for claim 185, wherein said synthetic polymer not with any other polymer mixed, described polymer reacts with described synthetic polymer.
191. the method for claim 185, wherein said synthetic polymer not with any other polymer mixed, described polymer and described surface reaction.
192. the method for claim 185, wherein said synthetic polymer comprises alkylene oxide residue.
193. the method for claim 185, wherein said synthetic polymer are 4-arm PEG.
194. the method for claim 185, wherein said synthetic polymer comprises a plurality of thiol-reactive groups.
195. the method for claim 185, wherein said synthetic polymer comprises a plurality of hydroxyl-reactive groups.
196. the method for claim 185, wherein said synthetic polymer comprises a plurality of amine-reactive groups.
197. a preparation feedback method for compositions, described method comprises:
A) provide the synthetic polymer that carries a plurality of activated groups;
B) thus make described synthetic polymer and have pH and be lower than 6 buffer and combine and form uniform solution; With
C) pH of uniform solution is elevated to greater than about 7.8, it is reactive making synthetic polymer thus.
198. the method for claim 197, wherein said synthetic polymer comprises alkylene oxide residue.
199. the method for claim 197, wherein said synthetic polymer comprises thiol-reactive group.
200. the method for claim 198, wherein said synthetic polymer are carried N-oxygen base succinimido group.
201. the method for claim 198, wherein said synthetic polymer combines with medicine.
202. the method for claim 201, wherein said medicine is hydrophobic.
203. the method for claim 202, wherein said medicine are to link to each other with secondary carrier, and described secondary carrier is disperseed in aqueous medium.
204. a method that makes synthetic polymer adhere to in-vivo tissue, described method comprises:
A) provide the synthetic polymer that carries a plurality of activatory groups;
B) thus making synthetic polymer and pH be lower than 6 buffer combines the solution that forms homogeneous;
C) pH of uniform solution is elevated to be higher than about 7.8, it is reactive making described synthetic polymer thus; With
D) make the reaction of described reactive synthetic polymer and in-vivo tissue.
205. the method for claim 204, wherein said synthetic polymer comprises alkylene oxide residue.
206. the method for claim 204, wherein said synthetic polymer comprises thiol-reactive group.
207. the method for claim 204, wherein said synthetic polymer comprise N-oxygen base succinimido group.
208. the method for claim 204 wherein is raised at the pH with uniform solution and described synthetic polymer is contacted before being higher than about 7.8 with described tissue.
209. the method for claim 204 wherein is elevated at the pH with described uniform solution and is higher than after about 7.8, and described synthetic polymer is contacted with described tissue.
210. the method for claim 204, wherein said synthetic polymer combines with medicine.
211. the method for claim 210, wherein said medicine is hydrophobic.
212. the method for claim 211, wherein said medicine links to each other with described secondary carrier, and described secondary carrier is scattered in the aqueous medium.
213. a compositions, it comprises:
A) carry the synthetic polymer of a plurality of activatory groups; With
B) aqueous buffer solution;
Wherein said compositions is that pH is lower than 6 uniform solution.
214. a compositions, it comprises:
A) carry the synthetic polymer of a plurality of activated groups;
With
B) aqueous buffer solution;
Wherein said compositions is that pH is higher than about 7.8 uniform solution.
215. the compositions of claim 213 or 214, wherein said compositions do not comprise any polymer with described synthetic polymer reaction.
216. the compositions of claim 213 or 214, wherein said compositions also comprises medicine.
217. the compositions of claim 213 or 214, wherein said compositions also comprises hydrophobic drug.
218. the compositions of claim 213 or 214, wherein said compositions also comprises the hydrophobic drug that links to each other with secondary carrier.
219. the compositions of claim 213 or 214, wherein said secondary carrier exists with micelle or nanometer spherical form.
220. the compositions of claim 213 or 214, wherein said synthetic polymer comprises alkylene oxide residue.
221. the compositions of claim 213 or 214, wherein said synthetic polymer comprises thiol-reactive group.
222. the compositions of claim 213 or 214, wherein said synthetic polymer comprise N-oxygen base succinimido group.
223. the compositions of claim 213 or 214, wherein said synthetic polymer are 4-arm PEG.
224. the compositions of claim 213 or 214, it exists with sterile form.
225. the method for a coating unit, described method comprises:
(a) to the polyfunctional N-Hydroxysuccinimide base of the surface applied PEG derivant of installing; With
(b) make functional group reactions on described derivant and the apparatus surface.
226. the method for claim 225 is wherein used surface treatment method, and the functional surface group on the device is incorporated into described device.
227. the method for claim 226, wherein said surface treatment method are the plasma treatment methods.
228. the method for claim 226, wherein said surface treatment method comprise use polymer-coated apparatus surface, wherein said polymer comprise can with the functional group of multifunctional N-Hydroxysuccinimide base PEG derivatives reaction.
229. the method for claim 228, wherein said polymer comprises amino group.
230. the method for claim 229, wherein said polymer is a chitosan.
231. the method for claim 229, wherein said polymer is a polymine.
232. being four senses, the method for claim 225, wherein multifunctional N-Hydroxysuccinimide base PEG derivant gather (ethylene glycol) succinimido glutarate.
233. a method that reduces the surgical operation adhesion, it comprises uses multifunctional N-Hydroxysuccinimide base PEG derivant to tissue surface.
234. the method for claim 233, wherein said multifunctional N-Hydroxysuccinimide base PEG derivant exists with the solution form, and wherein said solution has alkaline pH.
235. the method for claim 234, wherein said pH is greater than 8.
236. being four senses, the method for claim 235, wherein multifunctional N-Hydroxysuccinimide base PEG derivant gather (ethylene glycol) succinimido glutarate.
237. the method for claim 233, wherein said multifunctional N-Hydroxysuccinimide base PEG derivant is not mixed with any other tissue reactive compounds.
238. the method for claim 233, wherein multifunctional N-Hydroxysuccinimide base PEG derivant is not mixed described component and described derivatives reaction with any component.
239. a method that reduces the surgical operation adhesion, it comprises uses the tissue reactive compositions of being made up of multifunctional N-Hydroxysuccinimide base PEG derivant basically to tissue surface.
240. a method that reduces the surgical operation adhesion, it comprises uses the tissue reactive compositions of being made up of sense N-Hydroxysuccinimide base PEG derivant to tissue surface.
CNA2003801100685A 2002-12-30 2003-12-30 Tissue reactive compounds and compositions and uses thereof Pending CN1756571A (en)

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CN102137926A (en) * 2006-12-13 2011-07-27 Tgr生物科学私人有限公司 Promoting ECM production by fibroblast cells and/or promoting migration of fibroblast cells in a biological system
CN101861174B (en) * 2007-11-19 2013-08-28 伊西康公司 Derivatized tertiary amines and uses thereof
CN104371098A (en) * 2013-08-14 2015-02-25 北京键凯科技有限公司 Multi-branched hydrophilic polymer-isocyanate derivative
CN104755128A (en) * 2012-11-02 2015-07-01 考司美德制药株式会社 Retinoic acid microneedle
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CN102137926A (en) * 2006-12-13 2011-07-27 Tgr生物科学私人有限公司 Promoting ECM production by fibroblast cells and/or promoting migration of fibroblast cells in a biological system
CN101861174B (en) * 2007-11-19 2013-08-28 伊西康公司 Derivatized tertiary amines and uses thereof
TWI511753B (en) * 2010-04-07 2015-12-11 Baxter Int Hemostatic sponge
CN104755128A (en) * 2012-11-02 2015-07-01 考司美德制药株式会社 Retinoic acid microneedle
CN104371098A (en) * 2013-08-14 2015-02-25 北京键凯科技有限公司 Multi-branched hydrophilic polymer-isocyanate derivative
US11808833B2 (en) 2016-10-28 2023-11-07 Ppg Industries Ohio, Inc. Coatings for increasing near-infrared detection distances
US11712421B2 (en) 2017-05-17 2023-08-01 Massachusetts Institute Of Technology Self-actuating articles
CN110996878B (en) * 2017-05-17 2022-11-15 麻省理工学院 Self-righting system, method and related assembly
CN110996878A (en) * 2017-05-17 2020-04-10 麻省理工学院 Self-righting system, method and related assembly
US11809933B2 (en) 2018-11-13 2023-11-07 Ppg Industries Ohio, Inc. Method of detecting a concealed pattern
CN111607101A (en) * 2020-06-29 2020-09-01 南京大学 Dendritic macromolecule with active oxygen responsiveness and preparation method and application thereof
CN114702419A (en) * 2022-03-08 2022-07-05 重庆交通大学 Preparation method of aliphatic monomer containing disulfide bond
CN114702419B (en) * 2022-03-08 2024-03-01 重庆交通大学 Preparation method of aliphatic monomer containing disulfide bond

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