CN101624414A - Nitrate medicament for inhibiting angiogenesis - Google Patents
Nitrate medicament for inhibiting angiogenesis Download PDFInfo
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- CN101624414A CN101624414A CN 200810053763 CN200810053763A CN101624414A CN 101624414 A CN101624414 A CN 101624414A CN 200810053763 CN200810053763 CN 200810053763 CN 200810053763 A CN200810053763 A CN 200810053763A CN 101624414 A CN101624414 A CN 101624414A
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Abstract
The invention provides a nitrate medicament for inhibiting angiogenesis. The general formula (I) of the medicament is T-(B-M)t1, wherein t1 is 1 or 2, T-Ht1 is a steroidal compound, and T-H means that oxygen atoms of the T are connected with the H to form the hydroxyl connection, namely the O-H typed connection. The compound of the formula(I) can be synthesized by taking the steroidal compound T-Ht1 as a raw material, and can be used for preparing the medicaments of treating angiogenesis diseases of human or mammals, particularly the medicaments of treating the diseases such as tumors, ocular neovascularization, malignant blood diseases, bronchial asthma, leukoaraiosis and the like.
Description
Technical field:
The invention belongs to field of medicaments, particularly formula (I) compound and synthetic method thereof.The present invention also relates to purposes and the medicinal preparations of this compound on medicine, particularly at tumour, ocular angiogenesis new life's treatment.
Background technology:
Angiogenesis comprises two notions: brephic blood vessel take place (vasculogenesis, VG) and postnatal vasculogenesis (anglogenesis, AG).VG refers to not to be had under the situation of vascular system, by endothelial progenitor cell (Endothelialprogenitor cell, EPCs) or angioblast (angloblasts) be divided into endotheliocyte, and form vasoganglion.AG refers at the adult blood vessel, breaks through the migration of tube wall matrix by the mature endothelial cell that has existed, and propagation and reconstruct make the blood vessel branch continue to prolong in the germination mode.Angiogenesis among the present invention be meant postnatal vasculogenesis (anglogenesis, AG).Angiogenesis (anglogenesis) process that (as growth, wound healing) institute must have during still normal physiological changes, scientists finds that also the development of numerous diseases such as it and tumour, senile macular degeneration SMD, malignant hematologic disease has confidential relation in recent years.Suppress pathologic angiogenesis, can treat or slow down numerous diseases such as tumour, senile macular degeneration SMD, malignant hematologic disease.
The method of clinical treatment tumour is to adopt diverse ways at different tumours mostly at present, and the overwhelming majority is to treat at tumour cell.And tumor growth is the process of a complexity, and it is subjected to influence of various factors, comprising the foundation of tumor vessel net.Many researchs have proved that tumor growth must rely on vasculogenesis, by suppressing some link or the whole process of vasculogenesis, and then the control growth of tumor, to oncotherapy with prevent that the tumour distant metastasis is significant.Depend on the proposition of vascularization notion the beginning of the seventies along with tumor growth, the also corresponding notion that has proposed anti-angiogenic formation treatment, i.e. generation and/or the expansion of new vessel net and/or generation or the foundation that the destruction new vessel stops little solid tumor by stoping new vessel is to stop tumor growth, development and transfer.The more heparin of external report adds the hydrogenation cortisone. and be acknowledged as and can suppress vasculogenesis effectively.Experiment confirm, its two combined utilization can suppress the generation of blood vessel on the chick chorioallantoic membrane, and well can make tumor regression and stop and shift, and also can suppress the rabbit corneal angiogenesis that tumour causes.
And vascular endothelial growth factor (VEGF) is a class multifunctional growth factor, has the effect that promotes that endothelial cell proliferation, induction of vascular form, and it is generally acknowledged that suppressing vascular endothelial growth factor (VEGF) can treat or slow down pathological.
Vascular endothelial growth factor (VEGF) and new vessel diseases associated such as tumour, the eye neovascular disease, malignant hematologic disease, diseases such as bronchial asthma have substantial connection, by suppressing vascular endothelial growth factor (VEGF), can treat or slow down these diseases, lot of documents all has the report of this respect as " constitutional features and the biological function of summary VEGF " (Chinese clinic study magazine, 2007 13 3 phases of volume, 388), " vascular endothelial growth factor and acceptor thereof the progress in gynaecopathia " (2006 28 12 phases of volume of Hebei medicine, 1192-1194), " vascular endothelial growth factor and tumour concern progress " (Guangxi Medical University's journal, 2006 23 2 phases of volume, 333-335), " present Research of the relevant antineoplaston of VEGF " (Jilin medical science, 2006 27 5 phases of volume, 454-457), " progress of target VEGF treatment malignant tumour " (modern tumour medical science, 2006 14 3 phases of volume, 370-372), " VEGF and PEDF are to the common regulating effect of eyeground new vessel " (foreign medical science: clinical biochemistry and ecsomatics fascicle, 2005 26 11 phases of volume, 819-821), " progress of eyeground new vessel control " (ophthalmology new development, 2000 20 6 phases of volume, 449-451), " vascular endothelial growth factor and acceptor thereof and intraocular neovascularization disease " (ophthalmology research, 2003 21 1 phases of volume, 103-106), " relation of VEGF and malignant hematologic disease " (foreign medical science: physiological and pathological science and clinical fascicle, 2004 24 2 phases of volume, 183-185), " research of the loose patients serum VEGF level of alba " (difficult disease magazine, 2007 61 phases of volume, 10-11), " vascular endothelial growth factor and bronchial asthma " (practical medical journal, 2007 the 23rd the 3rd phases of volume, 433).
The known formation (vasculogenesis or new vessel form) that has multiple medicine can suppress neovascularity.For example, at people such as Crum " steroid that a class is new suppresses vasculogenesis in the presence of heparin or heparin fragment " (Science, Vol.230:1375-1378, on December 20th, 1985) in the literary composition, the steroid that can suppress vasculogenesis in the presence of heparin or specific heparin fragment is disclosed.The author is called described steroid " blood vessel suppresses (anglostatic) " steroid.This type of is found has dihydro and tetrahydro metabolites that cortisone and deoxidation cortisone are arranged included in the inhibiting steroid of blood vessel.Prove in the follow-up study of test about the hypothesis of described mechanism: heparin/angiostatic steroid composition causes the membrane holder dissolving, is connected with the anchorage dependence endothelium on described support, thereby causes kapillary atrophy (involution); Wherein said mechanism is that steroid suppresses the mechanism of vasculogenesis by it; " the possible mechanism that suppresses vasculogenesis by angiostatic steroid: kapillary basilar membrane dissolved is induced " (Endocrinology Vol.119:1768-1775,1986) referring to people such as lngber.
U.S. Pat 4 people such as Aristoff, one group of tetrahydro steroids that can be used for suppressing vasculogenesis is disclosed in 975,537. the described compound of this patent disclosure can be used for treating head trauma, spinal trauma, septic shock or traumatic shock, apoplexy and hemorrhagic shock.In addition, this patent has also been discussed these compounds in embryo's implantation and the effect in treatment cancer, sacroiliitis and arteriosclerosis.At United States Patent (USP) us4771, disclose in people's such as Arlstoff the patent disclosed some steroid and heparin or heparin fragment in 042 and made up the vasculogenesis that suppresses warm-blooded animal.People such as L1, " angiostatic steroid that strengthens effectiveness by sulfated cyclodextrin suppresses cornea rebirth blood vessel formation " (Investigative ophthalmology and VisualScience, Vol 32 (11): 2898-2905, in October, 1991).The independent use of steroid can make new vessel formation how much alleviate, and new vessel forms but only independent use can not effectively be disappeared.
Urocortisone is as angiostatic steroid, " angiostatic steroid " (Anglostaticsteroids people such as Folkman, Ann.Surg, Vol.206 (3), 1987) open in the literary composition, wherein the document proposes angiostatic steroid and may can be used for treating by new vessel and form the disease of being controlled unusually, comprises diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
Having introduced anecortave acetate among the CN03818826 is that a kind of exploitation is used to suppress the vasoinhibitor that the eyes neovascularity generates.Preparation and method that this invention relates to and is used to prevent AMD dependency visual loss, keeps AMD patient's eyesight and suppresses AMD dependency infringement development.Said preparation and method relate to the sclera side dressing with the anecortave acetate of 3-30mg or its corresponding alcohol so that trans-scleral drug release to be provided.
Summary of the invention:
A kind of compound of following general formula (I) or its ester or salt:
T-(B-M)
T1, t1 is 1 or 2, T-H
T1Be steroidal compounds, T is to link to each other with H with the Sauerstoffatom on the T with H, and the formation hydroxyl is that the form of O-H links to each other.
Wherein, 9,11 among the T must be two keys
Wherein, the substituting group of the H in the CH base described in the replacement general formula or two hydrogen H2 among the CH2 can be as follows:
At 1,2, can be two keys
At 2, can be F, Cl, Br, OCH3
At 3, can be=O (ketone group) ,-O-CH2-CH2-Cl, OH
In the 4-5 position, can be two keys;
In the 5-6 position, can be two keys;
At 6, can be Cl, F, CH3 ,-CHO;
At 7, can be Cl, Br, 9-(4,4,5,5,5-five fluorine penta sulfinyl) nonyl
At 16 can be CH3, OH ,=CH2
At 17, can be OH, CH3, OCO (O) x (CH2) yCH3, or
Wherein x is 0 or 1 integer, and y is 0 to 4 integer,
In the 16-17 position, can be following radicals;
Wherein, R ' and R " can be identical or different, and can be the saturated or unsaturated alkyl of hydrogen or 1 to 8 carbon, can be the straight chain side chain, or ring.
R1, R2 can be identical or differ from one another, and can or have the straight or branched alkyl of 1 to 4 carbon atom for hydrogen
R3 can be-CO-L-Q,
L is-(CR4R5)
B1(O)
B2(CR4R5)
B2(CO)
B3(O)
B4(CO)
B5(CR4R5)
B6-
Q is H, OH, CH3, Cl, OCH2CN, SCH2CN, SH, SCH2F, the hydrocarbon polymer of 1 to 16 carbon
B1, b2, b3, b4, b5, b6 can be identical or different, and be 0 to 6 integer, R4, R5 is identical or different, and is selected from H, the hydrocarbon polymer of 1 to 6 carbon, R4, the definition of R5 in different groups can be different.
B is-CO (O)
a(CR4R5)
B 'D (CR4R5)
B "CO-R7-
A=0 or 1, b '; b " can be identical or different, and be 0 to 6 integer, R4, R5 is identical or different, and is selected from H, the hydrocarbon polymer of 1 to 6 carbon, D can not exist also can be for containing the hydrocarbon polymer of 0 to two heteroatomic 1 to 8 carbon, heteroatoms is N, O, one or both among the S, B links to each other with the ester bond form with t1 hydroxyl on the T, be t1 on the T substituent-O among OH respectively with t1 B on-the C=O-formation-O-CO-that links to each other, when t1 is 2, with two B groups that t1 hydroxyl on the T links to each other with the ester bond form can be identical or different.
R7
Be selected from a kind of in the following groups:
-O (R8) O-(linking to each other with M), R8 is the alkylidene group of C1～C4
-O (CH2) 2O (CH2) 2 O-(linking to each other) with M ,-NHCH2CH2O-(linking to each other) with M, perhaps
-OCH2C (Ph) O-(linking to each other) with M ,-O (CH2) 2C (Ph) O-(linking to each other) with M, Ph represents phenyl.
M discharges nitric oxide production functional group, is selected from
R6 is the saturated or undersaturated alkyl of H or C1～C8
Wherein B links to each other in such a way with M, and the oxygen that B links to each other with M is above-mentioned R7 group
Arbitrary R4 described in R3 and the B, R5 substituting group can be identical or different in the scope of its definition.
Arbitrary R4 substituting group described in R3 and the B can be identical or different in the scope of its definition.
Arbitrary R5 substituting group described in R3 and the B can be identical or different in the scope of its definition.
Preferably: R1, R2 is methyl.
Preferably: t1 is 1 o'clock, and B links to each other with the ester bond form with hydroxyl on 17 or the R3, promptly on 17 or the R3-on O among the OH and the B-the C=O-formation-OCO-that links to each other.
Preferably: t1 is 1 o'clock, and 17 is OH, and B links to each other with the ester bond form with 17, promptly on the O in 17 and the B-the C=O-formation-OCO-that links to each other
Preferably: t1 is 1 o'clock, and R3 is-CO-CH2OH, and B links to each other with the ester bond form with hydroxyl on the R3, i.e. TH
T1R3 on-on O among the OH and the B-the C=O-formation-OCO-that links to each other
Preferably: t1 is 2 o'clock, 2 B respectively with 17 with R3 on hydroxyl link to each other with the ester bond form, promptly 17 with R3 on-O among the OH respectively with B on-the C=O-formation-OCO-that links to each other.
Preferably: t1 is 2 o'clock, and 17 is OH, and R3 is-CO-CH2OH, two B respectively with 17, R3 on hydroxyl link to each other with the ester bond form, promptly 17 with R3 on-O among the OH respectively with two B on-the C=O-formation-OCO-that links to each other.
Preferably: R3 is-CO-CH2OH or 17 are OH
Preferably: R3 can be-CO-L-Q, and Q was not OCH2CN when L did not exist, SCH2CN, SH, SCH2F, 17 is OH, B links to each other with the ester bond form with 17, promptly on the O in 17 and the B-the C=O-formation-OCO-that links to each other.
Preferably: R3 can be-CO-L-Q, and L is CH2, CH2O, and CH2OC=O, CH2OCOO, during CH2OCOOC=O,
Q is H, OH, CH3, Cl, the hydrocarbon polymer of 1 to 16 carbon.
Preferably: R3 can be CO-CH3, CO-CH2OH, and CO-CH2OCOCH3, CO-CH2OCOCH2CH3, CO-CH2Cl, CO-CH2OCOOCH3, CO-CH2OCOOCH2CH3, CO-OCH2CN, CO-SCH2CN,
CO-SH，CO-SCH2F，CO-CH2OCO(CH2)3CH3，，CO-CH2OCO(CH2)14CH3
Preferably: TH
T1Be anecortave and ester or salt
Preferably: B is-CO (O)
a(CR4R5)
B 'D (CR4R5)
B "-R7-
A is 0 o'clock, R4, and R5 is identical or different, and is selected from H, and the straight or branched hydro carbons of 1 to 6 carbon, D can not exist also can be for containing the hydrocarbon of 0 to 2 heteroatomic 1 to 8 carbon.
Preferably: B is-CO (O)
a(CR4R5)
B 'D (CR4R5)
B "-R7-
A is 1 o'clock, R4, and R5 is identical or different, and is selected from H, and the hydrocarbon polymer of 1 to 6 carbon, D can not exist also can be for containing five yuan or six-ring hydrocarbon polymer of 0 to 2 heteroatomic 1 to 8 carbon.
Preferably: B is-CO (O)
a(CR4R5)
B 'D (CR4R5)
B "-R7-
A is 0 or 1 o'clock, b ', b " be 0, D is five yuan or the hexa-atomic cyclic hydrocarbon that contains 0 to two heteroatomic 1 to 8 carbon, heteroatoms is on ring.
Preferably: B is-CO (O)
a(CR4R5)
B 'D (CR4R5)
B "-R7-
A is 0 o'clock, and D can not exist also can be for containing five yuan or hexa-atomic cyclic hydrocarbon of 1 to two heteroatomic 1 to 8 carbon, and heteroatoms is on ring.
Preferably: TH
T1H, H2, R1, R2, R3 have the defined structure of following listed compound; Hydrocortisone, Modrasone, beclometasone, Betamethasone Valerate, Chloroprednisonum, clobetasol, clobetasone, Syntestan, cortisone, cortisone dragon, dexamethasone, diflorasone, diflucortolone, fluorine compound, fluprednisolone, halometasone, Topicon, loteprednol, Zpoflogin, meprednisone, methylprednisolone, Mo Mitasong, paramethasone, prednisolone, prednisolone phosphate disodium, prednisone, W-4869, rimexolone, triamcinolone, fluticasone, budesonide, ciclesonide, Triamcinolone Acetonide, triamcinolone, fluocinolone acetonide.
Preferred formula (I) compound is:
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
2-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-21-oxygen-)-2-oxo-acetic acids-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
4-(pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butyric acid [2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
6-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-6-α methyl-21-oxygen)-6-oxo-caproic acid-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) ethylamino-]-ethyl ester
Acceptable salt or the solvate application in the medicine that suppresses the mammal vascular endothelial growth factor on above-mentioned formula (I) compound or its physiology, mammal is preferably human.
Acceptable salt or the solvate application in the medicine of treatment mammal neovascularization disease on above-mentioned formula (I) compound or its physiology, mammal is preferably human.
Neovascularization disease relates generally to tumour, eye new vessel, malignant hematologic disease, bronchial asthma, the loose disease of alba.
Tumour mainly is various noumenal tumours such as tumor stomach, lung tumors, liver's tumour, various body of gland tumour, nose tumour, ocular tumor, pharyngeal tumour, laryngeal neoplasm etc.; Malignant hematologic disease is meant the malignant tumour of blood system, mainly comprises leukemia, lymphoma, multiple myeloma and malignant histocytosis etc.
This compound also can generate in the disease that causes at the eye new vessel and use:
The eye new vessel generates the disease cause and relates to cornea, iris, choroid and retina etc., and pathological changes such as it causes oozes out, hemorrhage and hyperplasia are the major reasons that causes visual disorder to the infringement of eye structure and function.All there are pathologic processes such as inflammation, ischemic, anoxic in most of ophthalmic; Therefore, illness in eye and eye new vessel are formed with confidential relation.Wherein the eye new vessel generates the disease cause and comprises:
Cornea rebirth blood vessel illness in eye: in the eye disease relevant with cornea rebirth blood vessel, modal is cornea rebirth blood vessel disease due to the wearing of contact lens, other cause that the eye disease of cornea rebirth blood vessel has the cornea wound, alkali and other chemical substances burn, operation on cornea, various infection comprise infectation of bacteria, choamydiae infection, virus infection (herpes simplex virus and varicella zoster virus etc.), protozoan infection (leishmania) etc.
Iris neovascular illness in eye: common have neovascular glaucoma, and retinal detachment, wound, diabetic retinopathy, tumour (retinoblastoma), central vein of retina embolism etc. are its common inducements.
Retinal neovascularization illness in eye: diabetes, tumour, retinal detachment, central retinal vein occlusion, periphlebitis of retina, systemic lupus erythematosus, Eales disease, Coat disease, Takavas disease etc. all can cause.
Choroidal neovascularization illness in eye: senile macular degeneration SMD, high myopia, the exudative retinochoroiditis of centrality, wound, tumour, ocular histoplasmosis's syndrome, serpiginous choroidopathy etc. all can cause this kind illness in eye.
Those skilled in the art can think, related " treatment " of this paper can extend to the prevention of disease and to determine treatment of diseases.
The dosage of formula (I) compound in the mammiferous disease of treatment is with TH
T1Count 0.001mg-5mg/kg/ days, preferred 0.005mg-2mg/kg/ days.Formula (I) compound suppresses the drug dose of mammal vascular endothelial growth factor with TH in treatment
T1Count 0.001mg-5mg/kg/ days, preferred 0.005mg-2mg/kg/ days.Formula (I) compound at the dosage of treatment mammal neovascularization disease medicine with TH
T1Count 0.001mg-5mg/kg/ days, preferred 0.005mg-2mg/kg/ days.During as treatment people's disease, people's body weight is generally calculated according to 50Kg, so the dosage of human described in the present invention can calculate according to people's ABW, also can calculate according to above-mentioned dosage * 50.
Chinese style of the present invention (I) compound can be mixed with any preparation of being convenient to medication, so the present invention also comprises The compounds of this invention in its scope, can with acceptable diluent on one or more physiology or carrier blended pharmaceutical composition.
Chinese style of the present invention (I) compound can be mixed with the preparation of any people's of being convenient to medication, and its absorption of active ingredient is with TH in the said preparation treatment disease
T1Count 0.001mg-5mg/kg/ days, preferred 0.005mg-2mg/kg/ days.During as treatment people's disease, people's body weight is generally calculated according to 50Kg, so the consumption of people described in the present invention can calculate according to people's ABW, also can calculate according to above-mentioned consumption * 50.
A kind of medicinal compositions, said composition comprise acceptable salt or solvate on formula (I) compound of each definition or its physiology.Above-mentioned medicinal compositions comprises on formula (I) compound or its physiology acceptable salt or solvate mixes with acceptable drug auxiliary material on one or more physiology.Above-mentioned medicinal compositions can be mixed with liquid preparation, sterilization preparation and sterile preparation, solid preparation, semi-solid preparation, aerosol, above-mentioned preparation type can be according to pharmaceutics (the 5th edition, People's Health Publisher, Cui Fude chief editor) related definition in is understood.
Acceptable salt or solvate can be used as the medicine that treatment eye new vessel generates the disease that causes on formula (I) compound or its physiology.
A kind of ophthalmic preparation, said preparation contain acceptable salt or solvate on formula (I) compound or its physiology, and as the pharmaceutical excipient of carrier.This ophthalmic preparation can be made eye drops, injection, implants, and concrete grammar can be prepared according to the formulation method preparation of anecortave and ester thereof or according to the method for the related preparations in the pharmaceutics (the 5th edition, People's Health Publisher, Cui Fude chief editor).A kind of eye is identical with the position of anecortave and ester effect thereof with the position of injection injection.
A kind of injection formulations contains acceptable salt or solvate on formula (I) compound of each definition or its physiology in the said preparation, and as the pharmaceutical excipient of carrier.
Non-active ingredient in the injection formulations contains water for injection or oil for injection.
A kind of oral preparations, said preparation contain acceptable salt or solvate on formula (I) compound or its physiology, and as the pharmaceutical excipient of carrier.This oral preparations can be according to the method preparation of the related preparations in the pharmaceutics (the 5th edition, People's Health Publisher, Cui Fude chief editor).
The present invention further provides the method for the such pharmaceutical composition of preparation, this method comprises mixes various components.
The present invention (I) compound (for example) according to a conventional method is mixed with the preparation of oral, oral cavity, hypogloeeis, non-enteron aisle, injection, heeling-in, local application or rectal administration, the preparation of especially oral or injection.Wherein oral preparations comprises and is not limited only to the liquid that oral solid such as tablet, capsule, powder, granule and oral liquid etc. can be oral; Injection comprises and is not limited only to the solid that injectable liquid such as injection, suspensoid, infusion solution or powder injection etc. can be used for injecting.
Non-active ingredient in the oral preparations contains one or more in starch, lactose, the water.
Compound of the present invention and pharmaceutical preparation can be selected from following other treatment agent with one or more and unite use or comprise one or more such therapeutical agents: the medicine, the treatment eye new vessel that suppress tumour generate the medicine of the disease that causes, the medicine of treatment asthma.
The medicine that suppresses tumour includes, without being limited to act on the medicine (comprising alkylating agent, anthracene nucleus class and platinum compound) of DNA chemical structure; Influence nucleic acid synthetic medicine (mainly being metabolic antagonist); Acting on dna profiling influences DNA and transcribes or suppress DNA dependenc RNA polysaccharase and suppress RNA synthetic medicine; Influence the medicine (as homoharringtonine, Japanese yew class, vincaleucoblastine and Podophyllum emodi var chinense bases etc.) of protein synthesis; Paclitaxel analog compound; The medicine of other types (as hormone, Asparaginase, R8923 etc.).
The preferred cis-platinum of medicine that suppresses tumour.
The medicine that treatment eye new vessel generates the disease that causes includes, without being limited to Endostatin (Endostatln), Angiostatin, anecortave etc.
The medicine of treatment asthma comprises and is not limited only to glucocorticosteroid, leukotriene inhibitors, broxaterol, xanthine drug, anticholinergic drug, anti-allergy agent.
The above-mentioned formula of a kind of preparation (I) compound method, when t1=1, it comprises:
1) will be that T-H obtains intermediate (3) with acylating agent dicarboxylic anhydride (2) reaction as the cortin of cortin residue T representative in alkali organic solvent, catalyzer can exist or not exist,
2) intermediate (3) generates the corresponding nitric oxide-releasing glucocorticosteroid formula of target product (I) compound with NO donor (8) through esterification again
Alkaline organic solvent in above-mentioned (1) the step reaction is trialkylamine or pyridine etc., and catalyzer is DMAP, and the needs in the reaction of (2) step add DCC and DMAP, and organic solvent is a methylene dichloride.
The above-mentioned formula of a kind of preparation (I) compound method, wherein B and TH
T1Formula (I) the compound method that links to each other of 21 hydroxyl, when t1=1, it comprises:
1) will be that T-H obtains intermediate (3) with acylating agent dicarboxylic anhydride (2) reaction as the cortin of cortin residue T representative in alkali organic solvent, catalyzer can exist or not exist,
2) intermediate (3) generates the corresponding nitric oxide-releasing glucocorticosteroid formula of target product (I) compound with NO donor (8) through esterification again
T1 is 2 formula (I) compound in a kind of preparation formula (I) compound, identical or different B respectively with TH
T1R3 link to each other with 17 hydroxyl, it comprises:
(1) with TH
T1In the presence of alkaline organic solvent, obtain intermediate (3) with first kind of acylating agent dicarboxylic anhydride (2) reaction; Catalyzer can exist or not exist, then
(2) with above-mentioned intermediate (3) in the presence of alkaline organic solvent with in the step reaction of identical or different acylating agent dicarboxylic anhydride (2 ') obtain intermediate (3 '); Catalyzer can exist or not exist, then
(3) intermediate (3 ') that obtains in the above-mentioned reaction is generated target product corresponding nitric oxide-releasing glucocorticosteroid formula (I) compound through esterification with NO donor (8) again in organic solvent
Acylating agent dicarboxylic anhydride (2) and (2 ') of wherein above-mentioned (1) to (3) in the step, intermediate (3) and each substituting group in (3 ') can be identical or different in its range of definition.
Alkaline organic solvent in above-mentioned (1) (2) the step reaction is trialkylamine or pyridine etc., and catalyzer is DMAP, and the needs in the reaction of (3) step add DCC and DMAP, and organic solvent is a methylene dichloride.
The salt of formula (I) compound is meant R
3Be attached thereto the pharmaceutical salts that connects formation during=CO-CH2OH, pharmaceutical salts preferably phosphoric acid, succsinic acid, toxilic acid, vitriolic salt more preferably refer to phosphoric acid, succsinic acid, toxilic acid, vitriolic sodium, potassium, magnesium, calcium salt.
The corresponding TH that the present invention mentions
T1, promptly Δ 9 (11) steroid compounds can prepare by the method that CN200510014479.5 " preparation methods of Δ 9 (11) steroid compounds " patent application is mentioned.17 or 21 bit esterified things of the corresponding carboxylate of formula (I) compound can conventional method synthesize, for example according to people such as Yang Jian report (synthesizing of prednicarbate, Chinese Journal of Pharmaceuticals, 1999,30 (11), 490) synthetic method obtain, also can be by buying to enterprise such as Tianjin Tianyao Pharmaceutical Co., Ltd..
The pregnant steroid-4 that obtains according to embodiment 7 in Chinese patent application CN200510014479.5 " preparation methods of Δ 9 (11) steroid compounds " patent application, 9 (11)-dienes-3, the pregnant steroid-4 that 20-diketone-17 Alpha-hydroxy-6 Alpha-Methyl, embodiment 9 obtain, 9 (11)-dienes-3, the pregnant steroid-1 that 20-diketone-17 Alpha-hydroxy, embodiment 10 obtain, 4,9 (11)-triolefins-3, the pregnant steroid-1 that 20-diketone-17 Alpha-hydroxy, embodiment 4 obtain, 4,9 (11)-triolefins-3,20-diketone-17 Alpha-hydroxy-6 Alpha-Methyl.
Above-claimed cpd can conventional method synthesize, the 21-hydroxylic species that for example prepares above compound: pregnant steroid-4 by the method for Chinese patent application CN200510122249.0 " preparation method of furancarboxylic acid Mo Meitasong intermediate 21-hydroxyl ", 9 (11)-dienes-3,20-diketone-17 α, two hydroxyl-6 Alpha-Methyls of 21-, pregnant steroid-4,9 (11)-dienes-3,20-diketone-17 α, the two hydroxyls of 21-, pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-17 α, the two hydroxyls of 21-, pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-17 α, two hydroxyl-6 Alpha-Methyls of 21-.
2-methoxylation compound TH
T1Method for making can be referring to the method among the Chinese patent application 200710058414.X " a kind of pregna medicament for the treatment of tumour ".
A kind of medicinal compositions, said composition comprise acceptable salt or solvate on described arbitrary formula (I) compound of the invention described above or its physiology, and mix with acceptable drug auxiliary material on one or more physiology.Said composition also comprises the medicine of another kind of treatment inflammatory, allergy or anaphylactic disease.The medicine of another kind of inflammatory, allergy or anaphylactic disease can be beta 2 adrenoreceptor agonists.Said composition can also comprise the medicine of inhibition or kill microorganisms, and the medicine of inhibition or kill microorganisms is meant antibiotic.
Above-mentioned medicinal compositions can be mixed with liquid preparation, sterilization preparation and sterile preparation, solid preparation, semi-solid preparation, aerosol, sprays and powder inhalation.The definition of above-mentioned preparation type is by the relevant formulation definition in the pharmaceutics (the 5th edition, Cui Fude chief editor, People's Health Publisher's publication).
A kind of medicinal dust cloud agent formulation, said preparation contain acceptable salt or solvate on formula (I) compound of above-mentioned each definition or its physiology, and as the lactose or the amino acid of carrier.
Compound of the present invention can be prepared by following method: will be T-H (1) as the cortin of cortin residue T representative; H links to each other with the corresponding O of T; obtain intermediate (3) with corresponding acylating agent dicarboxylic anhydride (2) reaction, (3) generate the corresponding nitric oxide-releasing glucocorticosteroid of target product (9) with NO donor (8) through esterification again.
NO donor (8) is with R
6-SH (4) is a starting raw material, with the Mono Chloro Acetic Acid condensation, through hydrogen peroxide oxidation, again with the nitric acid effect, again and H-R
7-H reaction obtains.
Concrete technical process is as follows:
The solvent A that can be selected for use by the reaction of (1) to (3) is selected from one or more in the amine, ketone, ethers of pyridine, DMF, DMSO, tetrahydrofuran (THF), C1～C6.Preferred pyridine, triethylamine.
By (4) to (5) contract and react that the solvent that can select for use is selected from, in the ketone of pyridine, DMF, DMSO, tetrahydrofuran (THF), C1～C4, chlorinated hydrocarbon, ethers one or more, preferred C1～C4's, the aqueous solution that adds an amount of alkali during reaction, described alkali is NaOH, KOH, yellow soda ash, salt of wormwood, preferred NaOH and salt of wormwood.The alkali that adds and the mol ratio of compound (2) are 1.5～3: 1.Temperature of reaction is 0～50 ℃.
, in the reaction of (7) compound (5) is dissolved in 2～10 times of (weightmeasurement ratio) solvents by (5), described solvent is selected from one or more in tetrahydrofuran (THF), C1～C4 ketone, ester class, chlorinated hydrocarbon, ether, the carboxylic-acid.The H that adds 1.5～5 times (mol ratios)
2O
2, stirring reaction 1～10h without separation, adds the nitrosonitric acid of 5～15 times (mol ratios) in reactant, be warming up to 50～110 ℃ of reaction 1～6h, and cold filtration obtains compound (7).
The preparation of compound (8): with mol ratio 2～6: 1 H-R
7-H and compound (7) are dissolved in an amount of solvent, used solvent is selected from the alcohols of water, pyridine, DMF, DMSO, tetrahydrofuran (THF), C1～C4, in ketone, ester class, chlorinated hydrocarbon, the ethers one or more, one or more in the hydrochloric ether of preferred THF, pyridine, DMF, DMSO, C1～C4.The alkaline solution of adding 10～50%, described alkali be selected from NaOH, KOH, yellow soda ash, the salt of wormwood one or more, preferred yellow soda ash, used alkaline solution and mol ratios compound (7) (in used alkali) are 0.5～2: 1, react dilute with water, solvent extraction after 1～6 hour.Dry back column chromatography [(ethyl acetate: sherwood oil (60～90 ℃)=1: 2 (V/V)] separate.
The preparation of compound (9), mol ratio is (0.5～1.5): (0.5～1.5): 1: DCC, compound (3) and (8) be dissolved in an amount of solvent, add DMAP an amount of (with compound (8) mol ratio be 0.01～0.1) used solvent is selected from one or more in the ketone, ester class, chlorinated hydrocarbon, ethers of pyridine, DMF, DMSO, tetrahydrofuran (THF), C1～C4, preferred hydrochloric ether, reacted 2～10 hours down at 0～40 ℃, filter, filtrate concentrates.Column chromatography [(ethyl acetate: sherwood oil (60～90 ℃)=1: 2 (V/V)] promptly gets target product compound (9)
Acceptable salt or solvate and at least a acceptable accessories are made the various medicines that are applicable to oral, local (as collunarium, eye drip, suction, cavity) and various injection liquid forms on prepared compound of the present invention and the physiology thereof.Can make tablet, capsule, ointment, ointment, liniment, film, suppository, inhalation, injection liquid, lipidosome injection, liquid preparation, sterilization preparation and sterile preparation,, medicament such as solid preparation, semi-solid preparation, aerosol, sprays and powder inhalation.The carrier of powder inhalation is for being preferably lactose or amino acid.
Embodiment:
Column chromatography method among the present invention:
The minimum 70cm of the length of chromatography column, inner filling 254-silica gel, and will need isolating organism to be dissolved in minimum chloroform entirely: methyl alcohol=in 1: 1, this solution absorption is placed on the top of silica gel in the chromatography column with minimum 254-silica gel, use the moving phase wash-out, chromatography column connects the solution that obtains through column chromatography with several 10ml test tubes down, the control flow velocity is 10ml/3min, the solution of each test tube is analyzed with HPLC, the test tube solution that retention time is identical merges, the compound of getting principal point carries out recrystallization, obtains corresponding product.
Determine the method for principal point: will need isolating organism to analyze with HPLC, except that the point of the peak area maximum of raw material point is defined as principal point, its retention time is the retention time of principal point.
HPLC can be according to T-(COCH3)
T1The correlation method of (mode that T links to each other with COCH3 is identical with the mode that T links to each other with B) is measured, and also can measure by following condition, and the method minimum with principal point content is as the criterion:
Equipment: HP 1084B liquid chromatograph, HP 79850 BLC terminals and UV detector
Column material: Hypersll C18,5um, 125 * 4.6mm
Detect wavelength: 242nm
Moving phase: methyl alcohol: water=5.3: 4.7
Column temperature: 40 ℃
Flow velocity: about 1.1ml/ branch
DCC is a dicyclohexyl carbon imide
DMAP is 4-N, the N dimethyl aminopyridine,
Synthesizing of NO donor
1) benzene Thiovanic acid (5.1) is synthetic
With thiophenol (4.1) 24.2g (0.22mol), sodium hydroxide 8.8g (0.22mol) is dissolved in the 150ml ethanol, add by Mono Chloro Acetic Acid 22.78g (0.24mol) and yellow soda ash 12.7g (0.12mol) be made into the 200ml aqueous solution, stirring at room 3h, backflow 1h.Adding 6mol/L hydrochloric acid transfers pH to equal 2 after being cooled to room temperature, pressure reducing and steaming ethanol, and the adularescent precipitation generates, and filters, and gets white rhabdolith 33.3g, yield 90%, m.p.62-63 ℃.
2) 3,4-two benzenesulfonyls-1,2,5-oxadiazoles-2-oxide compound (7.1) synthetic
(5.1) 20.16g (0.12mol) is dissolved in the 90ml Glacial acetic acid, drips 24.3ml 30%H
2O
2, stirring at room 3h gets (6.1).Product is without separation.Directly slowly drip nitrosonitric acid 48ml in reaction solution, interior temperature is no more than 40 ℃, drips off in the 1h.Be warming up to 100 ℃ of reactions, have a large amount of reddish-brown gases to produce, solution gradually becomes yellow, reddish-brown from colourless.4h afterreaction liquid is cooled to room temperature, and the adularescent needle-like crystal is separated out, and filters, dry 16.8g, yield 76%, m.p.153-155 ℃ of getting
3.1) 2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethanol (8.1) synthetic
Glycol ether 1.06g (10mmol) and (7.1) 1g (2.7mmol) are dissolved among the 10mlTHF, splash into 25% aqueous sodium hydroxide solution (0.5ml, 3mol), after 2 hours, reaction solution from faint yellow become orange-yellow.In reaction solution impouring 20ml water, (3 * 20ml) extractions add the saturated common salt washing once after organic layer merges, use anhydrous sodium sulfate drying with acetate second junket.After the filtration filtrate is concentrated.Column chromatography [ethyl acetate: sherwood oil (60-90 ℃)=1: 2 (V: V)] oily matter 0.32g, yield 30%.ESLMS:[M ten H1 '=331.
3.2) 2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) ethylamino-] ethanol (8.2) synthetic
Thanomin 0.6g (10mmol) and (7.1) 1g (2.7mmol) are dissolved among the 10mlTHF, splash into 25% aqueous sodium hydroxide solution (0.5ml, 3mmol), after 2 hours, reaction solution from faint yellow become orange-yellow.In reaction solution impouring 20ml water, (3 * 20ml) extractions add the saturated common salt washing once after organic layer merges, use anhydrous sodium sulfate drying with ethyl acetate.After the filtration filtrate is concentrated.Column chromatography [ethyl acetate: sherwood oil (60-90 ℃)=1: 2 (V: V)] faint yellow oily thing 0.26g, yield 35%.ESLMS:[M ten H] '=331.
Synthetic formula (I) compound is as follows among the embodiment:
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
2-(pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-17-hydroxyl-21-oxygen-)-2-oxo-acetic acids-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
4-(pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butyric acid [2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
6-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-6-α methyl-21-oxygen)-6-oxo-caproic acid-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) ethylamino-]-ethyl ester
Embodiment 1 4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
1) 4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid (3.1) is synthetic
With 15mmol pregnant steroid-4,9 (11)-dienes-3,20-diketone-17, the two hydroxyls of 21--21-acetic ester is dissolved in the 80ml pyridine, 0.30mmolDMAP, add the 30mmol Succinic anhydried, reflux is stopped reaction after 5 hours, pours into after the cooling in the saturated icy salt solution of 200ml, transfer pH=5 with hydrochloric acid, the static white solid of separating out filters, washes, and obtains product 8.1mmol.
2) 4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester (9.1) synthetic
The compound 8mmol that step 1) is obtained is dissolved in the 300ml anhydrous methylene chloride, adds compound (8.1) 11mmol, DCC 10mmol, and DMAP0.3g reacts 15h under the room temperature, and the cotton-shaped product of adularescent generates to the reaction solution, filters, and concentrates.The column chromatography ethyl acetate: sherwood oil (60～90 ℃)=1: 2 (V: V)], obtain target compound 4.1mmol.
Ultimate analysis calculated value (%): C, 58.64; H, 5.80; N, 3.51; O, 28.04; S, 4.01
Determination of elemental analysis value (%): C39H46N2O14S C, 58.59; H, 5.83; N, 3.49; O, 28.13; S, 4.05
13C-NMR (CDCl
3): 1 numerical value to 39 carbon:
| The position of C | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 |
| ?? 13C-NMR | ??34.5 | ??34.3 | ??198.3 | ??123.5 | ??170.6 | ??33.0 | ??31.7 | ??38.1 |
| The position of C | ??9 | ??10 | ??11 | ??12 | ??13 | ??14 | ??15 | ??16 |
| ?? 13C-NMR | ??145.6 | ??40.8 | ??116.5 | ??35.8 | ??55.4 | ??48.5 | ??26.8 | ??23.2 |
| The position of C | ??17 | ??18 | ??19 | ??20 | ??21 | ??22 | ??23 | ??24 |
| ?? 13C-NMR | ??102.4 | ??17.1 | ??25.8 | ??213.1 | ??68.2 | ??174.0 | ??30.4 | ??30.8 |
| The position of C | ??25 | ??26 | ??27 | ??28 | ??29 | ??30 | ??31 | ??32 |
| ?? 13C-NMR | ??173.9 | ??67.0 | ??71.1 | ??71.0 | ??69.9 | ??150.5 | ??137.6 | ??136.5 |
| The position of C | ??33 | ??34 | ??35 | ??36 | ??37 | ??38 | ??39 | |
| ?? 13C-NMR | ??128.9 | ??130.9 | ??133.9 | ??131.6 | ??129.0 | ??171.2 | ??20.9 |
Embodiment 2 4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
With 4mmol 4-(pregnant steroid-4; 9 (11)-dienes-3; 20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester is dissolved among methyl alcohol and chloroform (1: the 1) 10ml; under the nitrogen protection in 0 degree drip 0 degree saturated down yellow soda ash (0.0045mol) aqueous solution; stir after 10 hours; with hydrochloric acid conditioned reaction system PH is that the pressurization of neutral back concentrates; remove chloroform; this solution dilution in the 40ml frozen water, is filtered the dry title compound crude product that gets.Crude product is carried out column chromatography, be the moving phase wash-out with methyl alcohol and chloroform (1: 4), gets wherein that the principal point compound carries out concentrating under reduced pressure, pours methyl alcohol and carries out recrystallization, must target compound 0.0021mol.
Ultimate analysis calculated value (%): C, 58.72; H, 5.86; N, 3.70; O, 27.48; S, 4.24
Determination of elemental analysis value (%): C37H44N2O13S C, 58.88; H, 5.89; N, 3.67; O, 27.39; S, 4.17
13C-NMR (CDCl
3): 1 numerical value to 37 carbon:
| The position of C | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 |
| ?? 13C-NMR | ??34.5 | ??34.3 | ??198.3 | ??123.5 | ??170.6 | ??33.0 | ??31.7 | ??38.1 |
| The position of C | ??9 | ??10 | ??11 | ??12 | ??13 | ??14 | ??15 | ??16 |
| ?? 13C-NMR | ??145.6 | ??40.8 | ??116.5 | ??35.8 | ??55.4 | ??48.5 | ??26.8 | ??23.2 |
| The position of C | ??17 | ??18 | ??19 | ??20 | ??21 | ??22 | ??23 | ??24 |
| ?? 13C-NMR | ??102.4 | ??17.0 | ??25.8 | ??212.7 | ??67.1 | ??174.1 | ??30.4 | ??30.8 |
| The position of C | ??25 | ??26 | ??27 | ??28 | ??29 | ??30 | ??31 | ??32 |
| ?? 13C-NMR | ??173.9 | ??67.0 | ??71.1 | ??71.0 | ??69.9 | ??150.5 | ??137.6 | ??136.5 |
| The position of C | ??33 | ??34 | ??35 | ??36 | ??37 | |||
| ?? 13C-NMR | ??128.9 | ??130.9 | ??133.9 | ??131.6 | ??128.9 |
Embodiment 3 2-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-21-oxygen-)-2-oxo-acetic acids-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
1) 2-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-21-oxygen-)-2-oxo-acetic acids (3.3) is synthetic
With 15mmol pregnant steroid-4,9 (11)-dienes-3,20-diketone-17, the two hydroxyls of 21-are dissolved in the 80ml pyridine, add 30mmol oxalic acid acid anhydride, reflux is stopped reaction after 5 hours, pour into after the cooling in the saturated icy salt solution of 200ml, transfer pH=5, the static white solid of separating out with hydrochloric acid, filter, wash, obtain product 10.3mmol.
2) 2-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-21-oxygen-)-2-oxo-acetic acids-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester (9.3) synthetic
The compound 10mmol that step 1) is obtained is dissolved in the 300ml anhydrous methylene chloride, adds compound (8.1) 11mmol, DCC 10mmol, and DMAP0.3g reacts 15h under the room temperature, and the cotton-shaped product of adularescent generates to the reaction solution, filters, and concentrates.The column chromatography ethyl acetate: sherwood oil (60～90 ℃)=1: 2 (V: V)], obtain target compound 4.8mmol.
Ultimate analysis calculated value (%): C, 57.68; H, 5.53; N, 3.84; O, 28.54; S, 4.40
Determination of elemental analysis value (%): C35H40N2O13S C, 57.60; H, 5.52; N, 3.86; O, 28.61; S, 4.41
13C-NMR (CDCl3): 1 numerical value to 35 carbon:
| The position of C | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 |
| ?? 13C-NMR | ??34.4 | ??34.1 | ??196.0 | ??123.0 | ??171.1 | ??32.7 | ??31.9 | ??38.1 |
| The position of C | ??9 | ??10 | ??11 | ??12 | ??13 | ??14 | ??15 | ??16 |
| ?? 13C-NMR | ??146.0 | ??41.8 | ??116.4 | ??34.9 | ??57.0 | ??47.7 | ??26.3 | ??32.7 |
| The position of C | ??17 | ??18 | ??19 | ??20 | ??21 | ??22 | ??23 | ??24 |
| ?? 13C-NMR | ??89.0 | ??16.2 | ??26.2 | ??206.6 | ??64.7 | ??158.0 | ??158.1 | ??64.4 |
| The position of C | ??25 | ??26 | ??27 | ??28 | ??29 | ??30 | ??31 | ??32 |
| ?? 13C-NMR | ??69.6 | ??70.1 | ??69.7 | ??151.0 | ??138.1 | ??136.1 | ??129.4 | ??132.2 |
| The position of C | ??33 | ??34 | ??35 | |||||
| ?? 13C-NMR | ??134.1 | ??132.2 | ??129.4 |
Embodiment 4 4-(pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butyric acid [2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
Think pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-hydroxyl is a raw material, obtains target compound according to the method for embodiment 3 and Succinic anhydried, compound (8.1) reaction.
Ultimate analysis calculated value (%): C, 61.10; H, 6.06; N, 3.24; O, 25.90; S, 3.71
Determination of elemental analysis value (%): C44H52N2O14S C, 60.99; H, 6.02; N, 3.30; O, 25.97; S, 3.72
13C-NMR (CDCl
3): 1 numerical value to 44 carbon:
| The position of C | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 |
| ?? 13C-NMR | ??155.0 | ??127.4 | ??186.0 | ??123.7 | ??167.0 | ??33.0 | ??31.9 | ??36.7 |
| The position of C | ??9 | ??10 | ??11 | ??12 | ??13 | ??14 | ??15 | ??16 |
| ?? 13C-NMR | ??142.8 | ??45.9 | ??120.1 | ??35.7 | ??50.1 | ??42.0 | ??25.9 | ??84.9 |
| The position of C | ??17 | ??18 | ??19 | ??20 | ??21 | ??22 | ??23 | ??24 |
| ?? 13C-NMR | ??100.1 | ??17.0 | ??26.8 | ??204.6 | ??68.1 | ??101.9 | ??174.1 | ??29.4 |
| The position of C | ??25 | ??26 | ??27 | ??28 | ??29 | ??30 | ??31 | ??32 |
| ?? 13C-NMR | ??29.8 | ??174.1 | ??67.3 | ??69.0 | ??69.8 | ??69.9 | ??151.3 | ??138.5 |
| The position of C | ??33 | ??34 | ??35 | ??36 | ??37 | ??38 | ??39 | ??40 |
| ?? 13C-NMR | ??136.5 | ??129.2 | ??132.0 | ??134.3 | ??132.0 | ??129.2 | ??36.3 | ??24.2 |
| The position of C | ??41 | ??42 | ??43 | ??44 | ||||
| ?? 13C-NMR | ??26.2 | ??26.0 | ??26.2 | ??24.2 |
Embodiment 5 6-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-6-α methyl-21-oxygen)-6-oxo-caproic acid-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) ethylamino-]-ethyl ester
Pregnant steroid-4,9 (11)-diene-3,20-diketone-17,21-is two, and hydroxyl-6-α methyl is a raw material, reacts according to method and adipic anhydride, the compound (8.2) of embodiment 3 to obtain target compound.
Ultimate analysis calculated value (%): C, 60.21; H, 6.44; N, 5.27; O, 24.06; S, 4.02
Determination of elemental analysis value (%): C40H51N3O12S C, 60.29; H, 6.48; N, 5.24; O, 23.99; S, 4.00
13C-NMR (CDCl
3): 1 numerical value to 40 carbon:
| The position of C | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 |
| ?? 13C-NMR | ??34.5 | ??34.3 | ??199.4 | ??121.1 | ??167.3 | ??33.4 | ??38.6 | ??33.9 |
| The position of C | ??9 | ??10 | ??11 | ??12 | ??13 | ??14 | ??15 | ??16 |
| ?? 13C-NMR | ??146.8 | ??48.9 | ??116.0 | ??34.8 | ??57.1 | ??48.1 | ??26.5 | ??33.1 |
| The position of C | ??17 | ??18 | ??19 | ??20 | ??21 | ??22 | ??23 | ??24 |
| ?? 13C-NMR | ??90.0 | ??16.8 | ??22.9 | ??207.2 | ??68.2 | ??174.0 | ??33.9 | ??24.9 |
| The position of C | ??25 | ??26 | ??27 | ??28 | ??29 | ??30 | ??31 | ??32 |
| ?? 13C-NMR | ??24.9 | ??34.0 | ??174.2 | ??64.5 | ??49.1 | ??49.4 | ??69.2 | ??151.2 |
| The position of C | ??33 | ??34 | ??35 | ??36 | ??37 | ??38 | ??39 | ??40 |
| ?? 13C-NMR | ??138.7 | ??136.4 | ??128.5 | ??130.1 | ??134.2 | ??130.1 | ??128.5 | ??20.1 |
Embodiment 6: injection
Main ingredient:
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester 5g
Auxiliary material:
Niacinamide 70g
Phenylcarbinol 7.5ml
Water for injection adds to 1000ml
[preparation] is with 4-(pregnant steroid-4; 9 (11)-dienes-3; 20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester earlier mixes well as soup (1) stand-by with a small amount of water for injection; niacinamide is dissolved in an amount of water for injection again; add gac 0.1g; place 15mln after stirring, the coarse filtration decarburization adds the injection water to about 900ml; be heated to 80～90 ℃ in the water-bath; slowly add soup (1), insulation 20～30mln dissolves postcooling fully to room temperature.Add phenylcarbinol, regulate pH to 6.5～6.0, adjust volume to 1000ml, placing 8h below 10 ℃ then, be filtered to clear and bright, embedding, 100 ℃ of circulation vapor sterilization 15min get final product.
Embodiment 7: suck the powder inhalation capsule
With lactose in small, broken bits with 20mg4-(pregnant steroid-4; 9 (11)-dienes-3; 20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] the ethyl ester diluted mixture becomes the pharmaceutical composition of 200mg, in No. 4 hard capsule of packing into.
Embodiment 8: oral capsule
With starch in small, broken bits with 20mg 4-(pregnant steroid-4; 9 (11)-dienes-3; 20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] the ethyl ester diluted mixture becomes the pharmaceutical composition of 200mg, in No. 4 hard capsule of packing into.
Pharmacology embodiment 1: experiment in vitro
Adopt the influence of chick chorioallantoic membrane (CAM) blood vessel hyperplasia model observation type (I) compound of growth factor-induced to blood vessel hyperplasia, understanding formula (I) compound is to the effect of vasculogenesis.
Experiment material:
The instar chicken embryo on the 3rd of being fertilized
Glass fiber filter paper
Vascular endothelial growth factor (VEGF) Chemlcon company product
The compound that embodiment 1-10 is made with the DMSO dissolving, is diluted to needed concentration (DMSO concentration＜0.1%) with PBS earlier again
Experimental technique
1.CAM the foundation of model:
75% ethanol cleans chicken ovigerm shell and dries up in super clean bench, behind the horizontal positioned 5min, carefully chorion is broken into pieces at 100mm culture dish edge, and the ovum content places culture dish (culture dish is added with 10ml DMEM substratum in advance).This culture dish is put into the big culture dish of 150mm (big culture dish adds little water), cover the ware lid, place 37 ℃, 5%CO
2Cell culture incubator in cultivate.
2. to the influence of CAM blood vessel hyperplasia
With tapping and plugging machine glass fiber filter paper is made the sequin of diameter 3mm, moist heat sterilization, each 10 μ l drips on glass fiber filter paper with reagent, makes the medicine film, dries up standby.Behind the chicken embryo culture 3d, be divided into 7 groups at random, every group 10, the compound of embodiment 1-5 gained is made as 5 administration groups (1g/L), give somatomedin (2 μ g/L) simultaneously, and the independent stimulating group (positive controls) of somatomedin (VEGF) and PBS (phosphate buffered saline buffer, PH7.4) stimulating group (negative control group).The medicine film is affixed on CAM and yolk cyst membrane (yolk sacmembrane, YSM) the outer less position of 2/3 place's blood vessel.Behind the dosing 48h, microscopically is observed, large, medium and small blood vessel number in the 5mm around the counting medicine film.
Table 1 pair CAM blood vessel hyperplasia influence table (x ± s, n=10)
| Group name | Little blood vessel | P (each group is to the VEGF group in the little blood vessel) |
| ??PBS | ??8.75±0.43 | ?＜0.01 |
| ??VEGF | ??16.50±0.78 | |
| Embodiment 1 | ??6.50±2.38 | ?＜0.01 |
| Embodiment 2 | ??6.50±2.52 | ?＜0.01 |
| Embodiment 3 | ??6.70±2.19 | ?＜0.01 |
| Embodiment 4 | ??6.75±2.78 | ?＜0.01 |
| Embodiment 5 | ??6.25±2.42 | ?＜0.01 |
Annotate: the statistical method data are represented with x ± s.Relatively use the t check between group
3. result
1 formula (I) compound is to VEGF inductive CAM
The influence of blood vessel hyperplasia the results are shown in Table 1, and PBS group angiogenic growth is good.It is obvious that VEGF organizes little blood vessel hyperplasia, and the blood vessel hyperplasia of respectively organizing of formula (I) compound obviously is suppressed.Little blood vessel significantly reduces, and gets back to normal level substantially.
CAM is classical vasculogenesis evaluation model, has easy, the easy observation of method, advantage such as inexpensive.Be at present the most frequently used in the phantom type.VEGF is important short angiogenesis factor, and the hyperplasia and the migration of energy stimulating endothelial cell promote vasculogenesis, and find overexpression in the kinds of tumors tissue.Originally studies show that: formula (I) compound suppresses VEGF inductive CAM blood vessel hyperplasia, shows that formula (I) compound has the short angiogenic action that suppresses VEGF.
Formula (I) compound has restraining effect to vasculogenesis, has further confirmed to have the potentiality that suppress tumor-blood-vessel growth.
Pharmacology embodiment 2: experiment in the body
1. laboratory animal and knurl strain
Kunming mouse is selected in experiment for use, and male, body weight (20 ± 2) g, divides 14 groups, 10 every group by 140.
Murine sarcoma knurl strain S180
2. medicine
Cis-platinum (DDP) injection liquid: 20ml:20mg/ props up.
3. method
3.1 the foundation of knurl mouse model: the strain of murine sarcoma S180 knurl, the abdominal cavity inoculation of going down to posterity.When treating the ascites well-grown, extract ascites out, cell counting, adjusting cell concn is 2 * 107 cell/ml, at mouse oxter subcutaneous injection S180 sarcoma cell, every inoculation 0.25ml observed the local tumor growing state in the 11st day.
3.2 treatment and grouping: 140 mouse were divided into 14 groups in inoculation the same day at random.Pressing the tabulation lattice gives and medicine
Test grouping information slip
| Group number | Activeconstituents | Administering mode | Dosage |
| Control group | Physiological saline | Every day is once oral | ??0.4ml |
| The DDP group | Cis-platinum | The next day abdominal injection once | ??0.5mg/kg |
| ??1 | Embodiment 1 | Every day is once oral | ??1mg/kg |
| ??2 | Embodiment 2 | Every day is once oral | ??1mg/kg |
| ??3 | Embodiment 3 | Every day is once oral | ??1mg/kg |
| ??4 | Embodiment 4 | Every day is once oral | ??1mg/kg |
| ??5 | Embodiment 5 | Every day is once oral | ??1mg/kg |
| ??6 | Embodiment 1 | Every day is once oral | ??0.01mg/kg |
| ??7 | Embodiment 1 | Every day is once oral | ??0.1mg/kg |
| ??8 | Embodiment 1 | Every day is once oral | ??10mg/kg |
| ??9 | Embodiment 1 | Every day is once oral | ??20mg/kg |
| DDP unites group | Embodiment 1 and DDP | Embodiment is once oral 1 every day, and abdominal injection once next day of DDP | Embodiment 1,1mg/kg DDP, 0.5mg/kg |
Annotate: dosage is by activeconstituents in the embodiment test group.
According to document " cis-platinum is to the genotoxic research of mouse bone marrow cells " (" canceration. distortion. sudden change ", 1996 86 phases of volume, the dosage of 0.5mg/kg is adopted in the 362-365) introduction in to mouse.
Medication 10d, 60min behind the last filling stomach puts to death and respectively organizes mouse, strips the knurl piece, weighs, and the knurl piece is made the pathology tissue slice.
By formula calculate tumour inhibiting rate: tumour inhibiting rate=(the average knurl of the average knurl weight-experimental group of control group is heavy)/average knurl of control group heavy * 100%.
3.3 capillary blood vessel dyeing: immunohistochemical methods SABC method dyeing blood vessel, instant capillary blood vessel staining kit (CD31) is Wuhan doctor's moral biotech firm product.After each is organized the knurl body and peels off, cut sample, fixing, embedding, section.Section after dyed, endotheliocyte is brown to be dyed, and blood vessel is tawny, is easy to identification.
The mensuration of MVD (microvessel density, microvessel density): MVD is according to people such as Weldner (Weldner N, SempleJP, Welch WR.Et al.Tumor ang logenesis and Metastastasis correlation in invasive breastcarcinonma, N Engl J Med, 1991,324, method 1-8) and judging criterion are carried out, calculate the capillary vessel and the tiny blood vessels of tumour intrinsic color, promptly under low-power field, sweep whole tumor tissue section, select the most intensive capillary blood vessel mark zone, the all single clearly endotheliocyte of tawny mark or endotheliocyte strings of presenting have the great vessels of thicker flesh wall and tube chamber area not to count greater than the blood vessel of 8 red blood cell diameters all as an isarithmic capillary blood vessel.Method of counting: under low power lens (10 * 10) visual field, sweep whole tissue slice earlier, select the most intensive visual field, 3 capillary blood vessel mark zones in tumor-infiltrated district, promptly so-called " new vessel hot zone ", then at the bottom of the identical back of the body, under the back of the body concrete conditions in the establishment of a specific crime, with high power lens (20 * 20) visual field (0.72mm
2) count all painted microvessel count for standard, get the measured value of its mean value as this sample.
3.4VEGF immunohistochemical methods: VEGF immunologic combined detection reagent kit (instant), opticmicroscope is observed down: the VEGF positive staining the positive expression of brown yellow granule occurs with tumour cell and near vascular endothelial cell slurry or after birth thereof.Every stained is carried out absorbancy (area density) and intensity (gray scale) mensuration by MP1AS-1000 high-definition color pathological image analytical system then.
3.5 statistical method: utilization SPSS statistical software, adopt the q check.There is statistical significance P＜0.05 for difference.
4. result
4.1 respectively organizing mice-transplanted tumor, S180 heavily changes comparison
The variation that knurl is heavy: each treatment group knurl weight average significantly is lower than control group, compare with control group, difference all has statistical significance, experimental result shows that various formulas (I) compound has obvious restraining effect to the S180 transplanted tumor, share with DDP and to have synergism, and the formula of various dose (I) compound also has the positively related restraining effect of dosage to the S180 transplanted tumor, and particular case sees Table 2.
Table 2 formula (I) compound to the restraining effect of S180 transplanted tumor (x ± s, %)
4.2 formula (I) compound is to the influence of S180 knurl body microvessel density (MVD)
Each is organized the tumour Pathologic specimen and dyes through CD31, the matter blood vessel all has painted between tumor tissues, dyed the positive expression of tawny with endotheliocyte, microvascular size, morphological differences are bigger, what have only is single endotheliocyte and endotheliocyte family, the tube chamber that has is not obvious or form is irregular, and the MVD of borderline tumor tissue is higher than central authorities.See a large amount of new trichoblast blood vessels in the control group tumour, positive target be positioned at tumor tissues and between the tawny particle that distributes of matter slabbing or lumps, each medication group positive expression cell granulations reduces, and sees Table 3.
The average microvessel density of table 3 S180 knurl body (MVD) (x ± s, %)
| Group | Mouse number (only) | Average microvessel density | P value (each group and control group) |
| Control group | ??10 | ??126.9±37.8 | |
| The DDP group | ??10 | ??78.9±21.1 | ?＜0.01 |
| ??1 | ??10 | ??66.8±18.2 | ?＜0.01 |
| ??2 | ??10 | ??68.9±19.1 | ?＜0.01 |
| ??3 | ??10 | ??70.4±20.1 | ?＜0.01 |
| ??4 | ??10 | ??77.2±21.7 | ?＜0.01 |
| ??5 | ??10 | ??75.4±20.4 | ?＜0.01 |
| ??6 | ??10 | ??88.7±23.2 | ??＜0.05 |
| ??7 | ??10 | ??72.5±20.6 | ?＜0.05 |
| ??8 | ??10 | ??60.1±15.9 | ?＜0.01 |
| ??9 | ??10 | ??52.4±13.6 | ?＜0.01 |
| DDP unites group | ??10 | ??54.5±10.6 | ?＜0.01 |
4.3 formula (I) compound is organized the influence of vegf expression to mouse S180 sarcoma
Showed by immune group result, opticmicroscope observe down the control group tumor tissues and therebetween matter see a large amount of in the form of sheets or the brown yellow granule that distributes of lumps, each medication group positive expression cell obviously reduces.Vegf expression average area density and average gray be the results are shown in Table 4.
Table 4 S180 sarcoma organize the vegf expression data sheet (x ± s, %)
| Group | Mouse number (only) | Centre plane density | P (each group and control group) | Average gray | P (each group and control group) |
| Control group | ??10 | ??39.20±3.39 | ??157.3±32.84 | ||
| The DDP group | ??10 | ??18.63±3.74 | ??＜0.01 | ??81.2±23.95 | ??＜0.01 |
| ??1 | ??10 | ??6.78±2.05 | ??＜0.01 | ??73.5±24.06 | ??＜0.01 |
| ??2 | ??10 | ??7.29±2.62 | ??＜0.01 | ??76.1±24.27 | ??＜0.01 |
| ??3 | ??10 | ??7.61±2.23 | ??＜0.01 | ??77.2±21.84 | ??＜0.01 |
| ??4 | ??10 | ??8.01±2.31 | ??＜0.01 | ??79.7±23.5 | ??＜0.01 |
| ??5 | ??10 | ??8.30±2.27 | ??＜0.01 | ??80.3±24.3 | ??＜0.01 |
| ??6 | ??10 | ??10.14±2.69 | ??＜0.01 | ??96.3±23.4 | ??＜0.05 |
| ??7 | ??10 | ??9.08±3.01 | ??＜0.01 | ??76.7±27.9 | ??＜0.05 |
| ??8 | ??10 | ??6.54±2.44 | ??＜0.01 | ??74.4±23.2 | ??＜0.01 |
| ??9 | ??10 | ??6.40±2.49 | ??＜0.01 | ??55.3±15.1 | ??＜0.01 |
| DDP unites group | ??10 | ??7.05±2.69 | ??＜0.01 | ??51.2±12.84 | ??＜0.01 |
5 conclusions
Invasive growth and metastatic potential are the essential characteristics of malignant tumour, it also is the lethal major cause of malignant tumor patient, there is conclusive evidence to show, malignant tumor patient more than 90% is finally died from metastases and recurrence, and shifting usually early stage the generation, about 50% patient has produced distant metastasis when clinical diagnosis goes out primary tumor.For the metastatic tumor of fast breeding, few apoptosis, the distribution of many kitchen ranges property, heterogeneous growth, conventional treatment means such as present operation, radiotherapy, chemotherapy are often failed, final death.Shifting real is malignant tumour intractable and intractable basic reason.Studies show that: in growth, infiltration and the transfer of solid tumor, the vasculogenesis that continues is a key factor.When rising in value to certain volume, oncocyte division (generally is no more than 1～2mm
2), if still there is not the grow into nutritive substance and the oxygen that provide necessary and breed the needed various factor of blood vessel, cell count that it is dead and outgrowth cell count about equally, oncocyte group stops expansion and reaches metastable state.When tumor promotion host's vascular proliferation, some new vesseles are grown into behind the tumor tissues, and tumor cell group increases sharply, and volume increases, tissue infiltration towards periphery, and have metastasis tendency.Pharmacology embodiment 1 shows that there is this obvious suppression effect in formula (1) compound to VEGF inductive CAM blood vessel hyperplasia, has confirmed that further this compound has the potentiality that suppress tumor-blood-vessel growth.Show by experimental result in pharmacology embodiment 2 bodies, formula (1) compound can suppress growth of tumor, and, formula (1) compound is united group (tumour inhibiting rate 61.2%) with the DDP of DDP coupling and is compared with DDP group (tumour inhibiting rate 54.4%) with test group 1 (tumour inhibiting rate 51.0%), tumour inhibiting rate is significantly improved, with the DDP of same dose and (I) MVD of compound group and control group, vegf expression is compared all and is obviously reduced, and DDP unites the MVD of group, the VEGF value reduces more obvious, this shows formula (I) compound and cisplatin combined treatment tumour, has synergy, reduce angiogenesis, improved anticancer effect.
Can prove that by the data in pharmacology embodiment 1 and 2 formula (I) compound is inhibited to mammiferous angiogenesis and VEGF, can treating or prevent therewith, diseases associated can suppress growth of tumor and propagation.
Claims (10)
1. the compound of a following general formula (I) or its ester or salt:
T-(B-M)
T1, t1 is 1 or 2, T-H
T1Be steroidal compounds, T is to link to each other with H with the Sauerstoffatom on the T with H, and the formation hydroxyl is that the form of O-H links to each other.
Wherein, 9,11 among the T must be two keys
Wherein, the substituting group of the H in the CH base described in the replacement general formula or two hydrogen H2 among the CH2 can be as follows:
At 1,2, can be two keys
At 2, can be F, Cl, Br, OCH3
At 3, can be=O (ketone group) ,-O-CH2-CH2-Cl, OH
In the 4-5 position, can be two keys;
In the 5-6 position, can be two keys;
At 6, can be Cl, F, CH3 ,-CHO;
At 7, can be Cl, Br, 9-(4,4,5,5,5-five fluorine penta sulfinyl) nonyl
At 16 can be CH3, OH ,=CH2
At 17, can be OH, CH3, OCO (O) x (CH2) yCH3, or
Wherein x is 0 or 1 integer, and y is 0 to 4 integer,
In the 16-17 position, can be following radicals;
Wherein, R ' and R " can be identical or different, and can be the saturated or unsaturated alkyl of hydrogen or 1 to 8 carbon, can be straight chain, side chain, or ring;
R1, R2 can be identical or differ from one another, and can or have the straight or branched alkyl of 1 to 4 carbon atom for hydrogen
R3 can be-CO-L-Q,
L is-(CR4R5)
B1(O)
B2(CR4R5)
B2(CO)
B3(O)
B4(CO)
B5(CR4R5)
B6-
Q is H, OH, CH3, Cl, OCH2CN, SCH2CN, SH, SCH2F, the hydrocarbon polymer of 1 to 16 carbon
B1, b2, b3, b4, b5, b6 can be identical or different, and be 0 to 6 integer, R4, R5 is identical or different, and is selected from H, the hydrocarbon polymer of 1 to 6 carbon, R4, the definition of R5 in different groups can be different,
B is-CO (O)
a(CR4R5)
B 'D (CR4R5)
B "CO-R7-
A=0 or 1, b '; b " can be identical or different, and be 0 to 6 integer, R4, R5 is identical or different, and is selected from H, the hydrocarbon polymer of 1 to 6 carbon, D can not exist also can be for containing the hydrocarbon polymer of 0 to two heteroatomic 1 to 8 carbon, heteroatoms is N, O, one or both among the S, B links to each other with the ester bond form with t1 hydroxyl on the T, be t1 on the T substituent-O among OH respectively with t1 B on-the C=O-formation-O-CO-that links to each other, when t1 is 2, with two B groups that t1 hydroxyl on the T links to each other with the ester bond form can be identical or different;
R7
Be selected from a kind of in the following groups:
-O (R8) O-(linking to each other with M), R8 is the alkylidene group of C1～C4
-O (CH2) 2O (CH2) 2O-(linking to each other) with M ,-NHCH2CH2O-(linking to each other) with M, perhaps
-OCH2C (Ph) O-(linking to each other) with M ,-O (CH2) 2C (Ph) O-(linking to each other) with M, Ph represents phenyl;
M discharges nitric oxide production functional group, is selected from
R6 is the saturated or undersaturated alkyl of H or C1～C8
Wherein L links to each other in such a way with M, and the oxygen that B links to each other with M is above-mentioned R7 group
Arbitrary R4 described in R3 and the B, R5 substituting group can be identical or different in the scope of its definition
Arbitrary R4 substituting group described in R3 and the B can be identical or different in the scope of its definition
Arbitrary R5 substituting group described in R3 and the B can be identical or different in the scope of its definition.
2. formula as claimed in claim 1 (I) compound is:
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-17-oxygen)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
2-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-21-oxygen-)-2-oxo-acetic acids-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
4-(pregnant steroid-1,4,9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butyric acid [2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
6-(pregnant steroid-4,9 (11)-diene-3,20-diketone-17-hydroxyl-6-α methyl-21-oxygen)-6-oxo-caproic acid-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) ethylamino-]-ethyl ester.
As acceptable salt or solvate on formula (I) compound of each definition among the claim 1-2 or its physiology as the application in the medicine of treatment mammalian diseases.
4. acceptable salt or solvate is characterized in that as the application in the medicine of treatment mammalian diseases described medicine is for suppressing the medicine of mammal vascular endothelial growth factor on formula (I) compound as claimed in claim 3 or its physiology.
5. acceptable salt or solvate is characterized in that as the application in the medicine of treatment mammalian diseases described medicine is the medicine of angiogenesis inhibitor on formula (I) compound as claimed in claim 3 or its physiology.
6. medicinal compositions, said composition comprise acceptable salt or solvate on formula (I) compound of each definition among the claim 1-2 or its physiology.
7. medicinal compositions as claimed in claim 6 is characterized in that described medicinal compositions also contains acceptable drug auxiliary material on one or more physiology.
8. injection formulations, said preparation contain acceptable salt or solvate on formula (I) compound of each definition in claim 1 or 2 or its physiology, and as the pharmaceutical excipient of carrier.
9. oral preparations, said preparation contain acceptable salt or solvate on formula (I) compound of each definition in claim 1 or 2 or its physiology, and as the pharmaceutical excipient of carrier.
10. as formula (I) compound of each definition of claim 1 or 2, the dosage in the mammiferous disease of treatment is with TH
T1Count 0.001mg-5mg/kg/ days.
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