CN101624414B - Nitrate medicament for inhibiting angiogenesis - Google Patents
Nitrate medicament for inhibiting angiogenesis Download PDFInfo
- Publication number
- CN101624414B CN101624414B CN 200810053763 CN200810053763A CN101624414B CN 101624414 B CN101624414 B CN 101624414B CN 200810053763 CN200810053763 CN 200810053763 CN 200810053763 A CN200810053763 A CN 200810053763A CN 101624414 B CN101624414 B CN 101624414B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- oxygen
- formula
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 C1C**CC1 Chemical compound C1C**CC1 0.000 description 2
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 angiogenesis, 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 for tumour, ocular angiogenesis new life's treatment.
Background technology:
Angiogenesis comprises two concepts: (vasculogenesis, VG) and postnatal vasculogenesis (anglogenesis, AG) occur in brephic blood vessel.VG refers to not to be had in the situation of vascular system, is divided into endotheliocyte by endothelial progenitor cell (Endothelialprogenitor cell, EPCs) or angioblast (angloblasts), and forms 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 with Germination methods.Angiogenesis among the present invention refers to postnatal vasculogenesis (anglogenesis, AG).Angiogenesis (anglogenesis) process that (such as growth, wound healing) must have during still normal physiological changes, scientists finds that also the development of the numerous diseases such as it and tumour, senile macular degeneration SMD, malignant hematologic disease has close relationship in recent years.Suppress pathologic angiogenesis, can treat or slow down the numerous diseases such as tumour, senile macular degeneration SMD, malignant hematologic disease.
The method of clinical treatment tumour is to adopt diverse ways for different tumours mostly at present, and the overwhelming majority is to treat for tumour cell.And tumor growth is the process of a complexity, and it is subject to the impact of many 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 growth of control tumour, to oncotherapy with prevent that the tumour distant metastasis is significant.Depend on the proposition of vascularization concept the beginning of the seventies along with tumor growth, the also corresponding concept 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 effectively suppress vasculogenesis.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 the multi-functional somatomedin of a class, have the effect that promotes that endothelial cell proliferation, induction of vascular form, it is generally acknowledged that suppressing vascular endothelial growth factor (VEGF) can treat or slow down pathological.
Disease such as tumour that vascular endothelial growth factor (VEGF) is relevant with new vessel, the ocular angiogenesis disease, malignant hematologic disease, the 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 such as " constitutional features and the biological function of summary VEGF " (Chinese clinic study magazine, 3 phases of 13 volumes in 2007,388), " vascular endothelial growth factor and acceptor thereof the progress in gynaecopathia " (Hebei medicine 12 phases of 28 volumes in 2006,1192-1194), " vascular endothelial growth factor and Research Progress of relation between tumor " (Guangxi Medical University's journal, 2 phases of 23 volumes in 2006,333-335), " present Research of the relevant antineoplaston of VEGF " (Jilin medical science, 5 phases of 27 volumes in 2006,454-457), " progress of target VEGF treatment malignant tumour " (modern tumour medical science, 3 phases of 14 volumes in 2006,370-372), " VEGF and PEDF are to the common regulating effect of eyeground new vessel " (foreign medical science: clinical biochemistry and ecsomatics fascicle, 11 phases of 26 volumes in 2005,819-821), " progress of eyeground new vessel control " (Recent Advances in Ophthalmology, 6 phases of 20 volumes in 2000,449-451), " vascular endothelial growth factor and acceptor thereof and disease related with intraocular neovascularization " (ophthalmology research, 1 phase of 21 volumes in 2003,103-106), " relation of VEGF and malignant hematologic disease " (foreign medical science: physiological and pathological science and clinical fascicle, 2 phases of 24 volumes in 2004,183-185), " research of level of vascular endothelial growth factor in patient with leukoaraiosis " (difficult disease magazine, 1 phase of 6 volumes in 2007,10-11), " vascular endothelial growth factor and bronchial asthma " (Chinese journals of practical medicine, the 3rd phase of the 23rd volume in 2007,433).
The known formation (vasculogenesis or new vessel form) that has multi-medicament can suppress neovascularity.For example, at the 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 to have 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 at 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: what the kapillary basilar membrane dissolved induces " (Endocrinology Vol.119:1768-1775,1986) referring to people such as lngber.
US Patent No. 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, the vasculogenesis that disclosed some steroid and heparin in the people's such as Arlstoff the patent or heparin fragment make up to suppress warm-blooded animal is disclosed in 042.The people such as L1, " angiostatic steroid that strengthens effectiveness by sulfated cyclodextrin suppresses corneal neovascularization " (Investigative ophthalmology and VisualScience, Vol 32 (11): 2898-2905, in October, 1991).The independent use of steroid can make new vessel form how much to alleviate, but only separately the use new vessel that can not effectively disappear form.
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 unusually controlling, and comprises diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
Having introduced anecortave acetate among the CN03818826 is that a kind of exploitation is used for suppressing the vasoinhibitor that the eyes neovascularity generates.This invention relates to for prevention AMD dependency visual loss, keeps AMD patient's eyesight and suppress preparation and the method that the infringement of AMD dependency develops.It is corresponding pure so that trans-scleral drug release to be provided with the anecortave acetate of 3-30mg or its that said preparation and method relate to the sclera side dressing.
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
Can be CH3 at 16, OH ,=CH2
At 17, can be OH, CH3, OCO (O) x (CH2) yCH3, or
It is the furoyl base
Wherein x is 0 or 1 integer, and y is 0 to 4 integer,
In the 16-17 position, it 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, namely 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, namely 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, namely 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, namely 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, namely 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 that 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-butynic 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-butynic 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-Isosorbide-5-Nitrae, 9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butynic 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 for the treatment of mammal neovascularization disease on above-mentioned formula (I) compound or its physiology, mammal is preferably human.
Neovascularization disease relates generally to tumour, ocular angiogenesis, malignant hematologic disease, bronchial asthma, Leukoaraiosis disease.
Tumour mainly is various noumenal tumours such as tumor stomach, lung tumors, liver's tumour, various body of gland tumour, nose tumour, ocular tumor, pharynx tumor, laryngeal neoplasm etc.; Malignant hematologic disease refers to 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 ocular angiogenesis and use:
Ocular angiogenesis generates the disease cause and relates to cornea, iris, choroid and retina etc., and the 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 the pathologic processes such as inflammation, ischemic, anoxic in most of ophthalmic; Therefore, illness in eye and ocular angiogenesis are formed with close relationship.Wherein ocular angiogenesis 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 bacterium infection, choamydiae infection, virus infection (herpes simplex virus and varicella zoster virus etc.), protozoan infection (leishmania) etc.
Iris neovascularization 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 is sick, Coat is sick, Takavas is sick 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 the treatment of disease.
The dosage of formula (I) compound in the mammiferous disease for the treatment of 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 for the treatment of 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, the pharmaceutical composition that can mix with acceptable diluent or carrier on one or more physiology in its scope.
Chinese style of the present invention (I) compound can be mixed with the preparation of any people's of being convenient to medication, and the consumption of its activeconstituents 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 excipient substance 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 the treatment ocular angiogenesis 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, concrete grammar can be according to the formulation method preparation of anecortave and ester thereof or according to pharmaceutics (the 5th edition, the method preparation of the related preparations 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, the method comprises mixes various components.
The present invention (I) compound according to a conventional method (for example) 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 the 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 the 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: suppress the medicine of tumour, the medicine that the treatment ocular angiogenesis generates the disease that causes, the medicine for the treatment of asthma.
The medicine that suppresses tumour includes, without being limited to act on the medicine (comprising alkylating agent, anthracycline and platinum compound) of DNA chemical structure; Affect the synthetic medicine (mainly being metabolic antagonist) of nucleic acid; Acting on dna profiling affects DNA and transcribes or suppress DNA dependenc RNA polysaccharase and suppress the synthetic medicine of RNA; Affect the medicine (such as homoharringtonine, Japanese yew class, vincaleucoblastine and Podophyllum emodi var chinense bases etc.) of protein synthesis; Paclitaxel analog compound; The medicine of other types (such as hormone, Asparaginase, R8923 etc.).
The preferred cis-platinum of medicine that suppresses tumour.
The medicine that the treatment ocular angiogenesis generates the disease that causes includes, without being limited to Endostatin (Endostatln), Angiostatin, anecortave etc.
The medicine for the treatment of asthma comprises and is not limited only to glucocorticosteroid, leukotriene inhibitors, broxaterol, xanthine drug, anticholinergic drug, anti-allergy agent.
A kind of above-mentioned formula (I) compound method for preparing, 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 methylene dichloride.
A kind of above-mentioned formula (I) compound method, wherein B and TH of preparing
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 the first 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 the step in the 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
Wherein acylating agent dicarboxylic anhydride (2) and (2 ') of 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 methylene dichloride.
The salt of formula (I) compound refers to R
3Be attached thereto the pharmaceutical salts that connects formation during=CO-CH2OH, the salt of pharmaceutical salts preferably phosphoric acid, succsinic acid, toxilic acid, sulfuric acid more preferably refers to sodium, potassium, magnesium, the calcium salt of phosphoric acid, succsinic acid, toxilic acid, sulfuric acid.
The corresponding TH that the present invention mentions
T1, namely 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 carboxylate that formula (I) compound is corresponding can conventional method synthesize, such as report (synthesizing of prednicarbate according to people such as Yang Jian, 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 by the method for Chinese patent application CN200510122249.0 " preparation method of mometasone furoate intermediate 21-hydroxyl ": pregnant steroid-4,9 (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 excipient substance on one or more physiology.Said composition also comprises the medicine of another kind for the treatment of 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 refers to 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 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 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.
The concrete technology flow process is as follows:
The solvent A that can be selected 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 the contracting of (5) and the solvent that can select of reaction be 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 the reactant, is 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 is selected from one or more in NaOH, KOH, yellow soda ash, the salt of wormwood, preferred yellow soda ash, used alkaline solution be 0.5～2: 1 with mol ratios compound (7) (take used alkali), react dilute with water, solvent extraction after 1～6 hour.Dry afterwards usefulness 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, 0～40 ℃ of lower reaction 2～10 hours, filter, filtrate is concentrated.Column chromatography [(ethyl acetate: sherwood oil (60～90 ℃)=1: 2 (V/V)] namely gets target product compound (9)
Acceptable salt or solvate and at least a pharmaceutically acceptable auxiliary material are made the various medicines that are applicable to oral, local (such as collunarium, eye drip, suction, cavity) and various injection liquid forms on the 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,, the 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 the organism that will need to separate is 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, connect the solution that obtains through column chromatography with several 10ml test tubes under the chromatography column, coutroi 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: the organism that will need to separate is analyzed with HPLC, and except 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/ divides
DCC is dicyclohexylcarbodiimide
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, adding is made into to get the 200ml aqueous solution, stirring at room 3h, backflow 1h by Mono Chloro Acetic Acid 22.78g (0.24mol) and yellow soda ash 12.7g (0.12mol).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, a large amount of reddish-brown γ-ray emissions are arranged, 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 acetic acid second junket.After the filtration that 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 that 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.
Formula (I) compound synthetic among the embodiment is as follows:
4-(pregnant steroid-4,9 (11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butynic 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-butynic acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester
2-(pregnant steroid-Isosorbide-5-Nitrae, 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-Isosorbide-5-Nitrae, 9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butynic 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-butynic 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-butynic 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-butynic acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester (9.1) synthetic
With step 1) the compound 8mmol that obtains is dissolved in the 300ml anhydrous methylene chloride, adds compound (8.1) 11mmol, DCC 10mmol, DMAP0.3g reacts 15h under the room temperature, and the cotton-shaped product of adularescent generates to the reaction solution, filters, and is concentrated.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-butynic 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-butynic 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; drip lower saturated yellow soda ash (0.0045mol) aqueous solution of 0 degree in 0 degree under the nitrogen protection; stir after 10 hours; with hydrochloric acid conditioned reaction system PH be neutral after pressurization concentrated; 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, is 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, gets 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 with hydrochloric acid, the static white solid of separating out, 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
With step 1) the compound 10mmol that obtains is dissolved in the 300ml anhydrous methylene chloride, adds compound (8.1) 11mmol, DCC 10mmol, DMAP0.3g reacts 15h under the room temperature, and the cotton-shaped product of adularescent generates to the reaction solution, filters, and is concentrated.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-Isosorbide-5-Nitrae, 9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-4-oxo-butynic acid [2-(3-benzenesulfonyl-1,2,5-oxadiazoles-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
Think pregnant steroid-Isosorbide-5-Nitrae, 9 (11)-triolefins-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-hydroxyl is 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
With
Pregnant steroid-4,9 (11)-diene-3,20-diketone-17,21-is two, and hydroxyl-6-α methyl is 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-butynic 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-butynic acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester mixes well as liquid (1) stand-by with a small amount of water for injection first; niacinamide is dissolved in an amount of water for injection again; add gac 0.1g; the rear placement 15mln that stirs, the coarse filtration decarburization injects water to about 900ml; be heated to 80～90 ℃ in the water-bath; slowly add liquid (1), insulation 20～30mln is cooled to room temperature after the dissolving fully.Add phenylcarbinol, regulate pH to 6.5～6.0, adjust volume to 1000ml, then placing 8h below 10 ℃, be filtered to clear and bright, embedding, 100 ℃ of circulation vapor sterilization 15min get final product.
Embodiment 7: the inhalation powder spray 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-butynic acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester dilution is mixed into 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-butynic acid-2-[2-(3-benzenesulfonyl-1; 2; 5-oxadiazoles-2-oxide compound-4-oxygen) oxyethyl group] ethyl ester dilution is mixed into the pharmaceutical composition of 200mg, in No. 4 hard capsule of packing into.
Pharmacology embodiment 1: experiment in vitro
Adopt chick chorioallantoic membrane (CAM) blood vessel hyperplasia model observation type (I) compound of growth factor-induced on the impact of 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 first 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 large culture dish of 150mm (large culture dish adds little water), cover the ware lid, place 37 ℃, 5%CO
2Cell culture incubator in cultivate.
2. on the impact of CAM blood vessel hyperplasia
With tapping and plugging machine glass fiber filter paper is made the sequin of diameter 3mm, moist heat sterilization drips each 10 μ l of reagent on glass fiber filter paper, makes the medicine film, dries up for subsequent use.Behind the chicken embryo culture 3d, be divided at random 7 groups, every group 10, the compound of embodiment 1-5 gained is made as 5 administration groups (1g/L), give simultaneously somatomedin (2 μ g/L), 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 the outer less position of 2/3 place's blood vessel of yolk cyst membrane (yolk sacmembrane, YSM).Behind the dosing 48h, microscopically is observed, large, medium and small blood vessel number in the 5mm around the counting medicine film.
Table 1 affects table (x ± s, n=10) to the CAM blood vessel hyperplasia
| 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 represent with x ± s.Relatively use the t check between group
3. result
The CAM that 1 formula (I) compound is induced VEGF
It is good that the impact of blood vessel hyperplasia the results are shown in Table 1, PBS group angiogenic growth.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 substantially gets back to normal level.
CAM is classical vasculogenesis evaluation model, has easy, the easy observation of method, the advantage such as inexpensive.It is present the most frequently used in vivo model.VEGF is important angiogenic factors, and 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 the CAM blood vessel hyperplasia that VEGF induces, and shows that formula (I) compound has the angiogenesispromoting effect 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, and is male, and 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 ", 6 phases of 8 volumes in 1996, the dosage of 0.5mg/kg is adopted in the introduction in 362-365) to mouse.
Medication 10d, 60min after the last gavage 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 the 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 capillary vessel and the tiny blood vessels of tumour intrinsic color, namely under low-power field, sweep whole tumor tissue section, select the most intensive capillary blood vessel mark zone, allly present the tawny mark single endotheliocyte or endotheliocyte string 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 clearly.Method of counting: under low power lens (10 * 10) visual field, sweep first whole tissue slice, select the most intensive visual field, 3 capillary blood vessel mark zones in tumor-infiltrated district, i.e. so-called " new vessel hot zone ", then under identical back end, 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 the microvessel count of all dyeing for standard, get its mean value as the measured value of this sample.
3.4VEGF immunohistochemical methods: VEGF immunologic combined detection reagent kit (instant), the optical microphotograph Microscopic observation: 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.Then every stained is carried out absorbancy (area density) and intensity (gray scale) mensuration by MP1AS-1000 high-definition color pathological image analytical system.
3.5 statistical method: use the 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 is to the restraining effect (x ± s, %) of S180 transplanted tumor
4.2 formula (I) compound is on the impact of S180 knurl body microvessel density (MVD)
Each is organized the cancer pathology sample and dyes through CD31, the matter blood vessel all has painted between tumor tissues, be dyed to the positive expression of tawny with endotheliocyte, microvascular size, morphological differences are larger, 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 Objects 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 impact of vegf expression on mouse S 180 sarcoma
Showed by immune group result, optical microphotograph Microscopic observation 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 is organized 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 major cause that malignant tumor patient causes death, there is conclusive evidence to show, malignant tumor patient more than 90% is finally died from metastases and recurrence, and shifting common Development, 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, the conventional treatment means such as present operation, radiotherapy, chemotherapy often suffer failure, 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 oncocyte division increment (generally is no more than 1～2mm during to certain volume
2), if still without the grow into nutritive substance and the oxygen that provide necessary and breed the needed various factor of blood vessel, the cell count that it is dead and the cell count of hyperplasia 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 restraining effect in the CAM blood vessel hyperplasia that formula (1) compound is induced VEGF, 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 the growth of tumour, 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 Combined with Cisplatin for The 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 treat or prevent relevant therewith disease can suppress growth and the propagation of tumour.
Claims (18)
1. a compound (I) or its ester or salt, described formula I compound is:
4-(pregnant steroid-4,9(11)-diene-3,20-diketone-21-hydroxyl-21-acetic ester-17-oxygen)-4-oxo-butynic acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-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-butynic acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-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-oxadiazole-2-oxide compound-4-oxygen-) oxyethyl group] ethyl ester
Pregnant steroid-the Isosorbide-5-Nitrae of 4-(, 9(11)-triolefin-3,20-diketone-16,17-22R-cyclohexylmethylene dioxy-21-oxygen)-the 4-oxo-butynic acid [2-(3-benzenesulfonyl-1,2,5-oxadiazole-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-oxadiazole-2-oxide compound-4-oxygen-) ethylamino-]-ethyl ester.
2. the application of acceptable salt in preparation inhibition mammal vascular endothelial growth factor medicine on formula I compound claimed in claim 1 or its physiology.
3. application as claimed in claim 2 is characterized in that Mammals is human.
4. the application of acceptable salt in the preparation angiogenesis inhibitor on formula I compound claimed in claim 1 or its physiology.
5. such as the arbitrary described application of claim 4, it is characterized in that Mammals is human.
6. the described formula I compound of claim 1 is in the application of preparation treatment tumour class disease medicament.
7. the application of the described formula I compound of claim 1 in the medicine of preparation treatment ophthalmology ocular angiogenesis disease.
8. the application of the described formula I compound of claim 1 in the medicine of preparation treatment malignant hematologic disease.
9. the application of the described formula I compound of claim 1 in the medicine of preparation treatment bronchial asthma.
10. the application of the described formula I compound of claim 1 in the medicine of preparation treatment Leukoaraiosis disease.
11. a medicinal compositions, said composition comprise acceptable salt on the described formula I compound of claim 1 or its physiology.
12. medicinal compositions as claimed in claim 11 is characterized in that being mixed with acceptable excipient substance on one or more physiology by acceptable salt on as claimed in claim 1 formula I compound or its physiology.
13. medicinal compositions as claimed in claim 11 is characterized in that being mixed with liquid preparation, sterilization preparation and sterile preparation, solid preparation, semi-solid preparation, aerosol.
14. an ophthalmic preparation, said preparation contain acceptable salt on formula I compound claimed in claim 1 or its physiology, and as the pharmaceutical excipient of carrier.
15. an oral preparations, said preparation contain acceptable salt on formula I compound claimed in claim 1 or its physiology, and as the pharmaceutical excipient of carrier.
16. medicinal compositions as claimed in claim 11 is characterized in that said composition also comprises the medicine of another kind for the treatment of tumour.
17. medicinal compositions as claimed in claim 11 is characterized in that said composition also comprises the medicine of another kind for the treatment of ocular angiogenesis disease.
18. medicinal compositions as claimed in claim 11 is characterized in that said composition also comprises the medicine of another kind for the treatment of bronchial asthma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810053763 CN101624414B (en) | 2008-07-07 | 2008-07-07 | Nitrate medicament for inhibiting angiogenesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810053763 CN101624414B (en) | 2008-07-07 | 2008-07-07 | Nitrate medicament for inhibiting angiogenesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101624414A CN101624414A (en) | 2010-01-13 |
| CN101624414B true CN101624414B (en) | 2013-02-13 |
Family
ID=41520423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200810053763 Active CN101624414B (en) | 2008-07-07 | 2008-07-07 | Nitrate medicament for inhibiting angiogenesis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101624414B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE027715T2 (en) | 2008-05-28 | 2016-10-28 | Reveragen Biopharma Inc | Non-hormonal steroid modulators of nf-kb for treatment of disease |
| EP2556083A4 (en) | 2010-04-05 | 2013-12-04 | Validus Biopharma Inc | Non-hormonal steroid modulators of nf- kappa b for treatment of disease |
| US20150291654A1 (en) | 2011-10-14 | 2015-10-15 | Sage Therapeutics, Inc. | 3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof |
| PL2986624T3 (en) | 2013-04-17 | 2020-11-16 | Sage Therapeutics, Inc. | 19-nor neuroactive steroids for methods of treatment |
| PT3498725T (en) | 2013-04-17 | 2021-09-09 | Sage Therapeutics Inc | 19-nor c3,3-disubstituted c21-n-pyrazolyl steroid for use in therapy |
| WO2014169831A1 (en) | 2013-04-17 | 2014-10-23 | Sage Therapeutics, Inc. | 19-nor c3,3-disubstituted c21-c-bound heteroaryl steroids and methods of use thereof |
| WO2014169836A1 (en) | 2013-04-17 | 2014-10-23 | Sage Therapeutics, Inc. | 19-nor neuroactive steroids and methods of use thereof |
| CN105555277B (en) | 2013-07-19 | 2022-01-11 | 萨奇治疗股份有限公司 | Neuroactive steroid compounds, compositions and uses thereof |
| US20160229887A1 (en) | 2013-08-23 | 2016-08-11 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
| WO2015195962A1 (en) | 2014-06-18 | 2015-12-23 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
| PL3206493T3 (en) | 2014-10-16 | 2021-01-25 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
| NZ731034A (en) | 2014-10-16 | 2024-02-23 | Sage Therapeutics Inc | Compositions and methods for treating cns disorders |
| ES2793237T3 (en) | 2014-11-27 | 2020-11-13 | Sage Therapeutics Inc | Compositions and methods for treating CNS disorders |
| RS61530B1 (en) | 2015-01-26 | 2021-04-29 | Sage Therapeutics Inc | Compositions and methods for treating cns disorders |
| DK3258939T3 (en) | 2015-02-20 | 2022-12-12 | Sage Therapeutics Inc | NEUROACTIVE STEROIDS, COMPOSITIONS AND USES THEREOF |
| WO2017004205A1 (en) | 2015-06-29 | 2017-01-05 | Reveragen Biopharma, Inc. | NON-HORMONAL STEROID MODULATORS OF NF-κB FOR TREATMENT OF DISEASE |
| IL264129B1 (en) | 2016-07-11 | 2024-01-01 | Sage Therapeutics Inc | C17, c20, and c21 substituted neuroactive steroids and their methods of use |
| US11382922B2 (en) | 2019-03-07 | 2022-07-12 | Reveragen Biopharma, Inc. | Aqueous oral pharmaceutical suspension compositions |
| MA56046A (en) | 2019-05-31 | 2022-04-06 | Sage Therapeutics Inc | NEUROACTIVE STEROIDS AND ASSOCIATED COMPOSITIONS |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221543A1 (en) * | 2002-01-29 | 2009-09-03 | Nicox S A. | New corticosteroids |
-
2008
- 2008-07-07 CN CN 200810053763 patent/CN101624414B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221543A1 (en) * | 2002-01-29 | 2009-09-03 | Nicox S A. | New corticosteroids |
Non-Patent Citations (1)
| Title |
|---|
| 陈秋虹等.新型血管生成抑制剂阿奈可他临床评估.《世界临床药物》.2006,第27卷(第7期),406-408. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101624414A (en) | 2010-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101624414B (en) | Nitrate medicament for inhibiting angiogenesis | |
| CN101412742B (en) | Nitric acid ester medicament for inhibiting angiogenesis | |
| CN102432663B (en) | Celastrol derivative and preparation method thereof and application of celastrol derivative to preparation of antitumor medicine | |
| CN101091705B (en) | Application of compounds in isorhodanic ester classes for treating diseases of prostate and skin cancer | |
| CA2304770C (en) | A use of steroidal saponins for the prophylaxis or treatment of dementia, and novel steroidal saponin compounds | |
| US6569845B1 (en) | Neovascularization inhibitor containing dienogest as the active ingredient | |
| CN102675401B (en) | Preparation of anti-tumor medicine LQC-Y and application thereof | |
| CN103980337B (en) | Bufalin derivant, its pharmaceutical composition and purposes | |
| TW200932245A (en) | Methods and compositions for inhibiting angiogenesis | |
| WO2018196581A1 (en) | Dihydroartemisinin-steroid conjugate and preparation method and use thereof | |
| TWI422377B (en) | Methods and compositions for promoting activity of anti-cancer therapies | |
| CN107530309A (en) | Eutectic composition and its medicinal usage | |
| CN103221373A (en) | Methods and compositions for treating lung cancer | |
| CN102824400B (en) | Composition containing eucommia ulmoides and teasel roots and application of composition for treating osteoporosis | |
| CN101434631B (en) | Estra nitrate ester medicament for inhibiting angiogenesis | |
| CN103739647A (en) | Non-hormonal steroid modulators of nf-kb for treatment of disease | |
| CN105283551B (en) | The TGF-β oligonucleotides of the modification of method for preventing and/or treating ophthalmology disease | |
| CN104017045B (en) | The newtype drug precursor of steroidal CYP17 inhibitor and application thereof, preparation method | |
| WO2015172712A1 (en) | Pharmaceutical composition for injection with synergistic effect of vitamin c and antitumour drugs | |
| CN101353368A (en) | Pregna medicament for treating tumor | |
| CN102781442A (en) | Method of treating scars and beta-catenin-mediated disorders using nefopam compounds | |
| EP2980096A1 (en) | 2 ,3 ,5 -trihydroxy-androst-6-one and preparation methods and use thereof | |
| CN101353366A (en) | Steroidal estrogen medicament for treating tumor | |
| JPH02174793A (en) | Beta, 17beta-hydroxy-substituted steroid and related steroid compounds | |
| WO2004035089A1 (en) | Remedy for hormone-dependent cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |