CN102952168A - Estrogen derivative used as vasoinhibitor, as well as preparation method and medical application thereof - Google Patents
Estrogen derivative used as vasoinhibitor, as well as preparation method and medical application thereof Download PDFInfo
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- CN102952168A CN102952168A CN2012105323306A CN201210532330A CN102952168A CN 102952168 A CN102952168 A CN 102952168A CN 2012105323306 A CN2012105323306 A CN 2012105323306A CN 201210532330 A CN201210532330 A CN 201210532330A CN 102952168 A CN102952168 A CN 102952168A
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- 0 C*(*Oc1c(**)cc(C(CC2)C(CC3)C4[C@@]2(C)[C@@](*)CC4)c3c1)C(*)=O Chemical compound C*(*Oc1c(**)cc(C(CC2)C(CC3)C4[C@@]2(C)[C@@](*)CC4)c3c1)C(*)=O 0.000 description 2
- GVUMMCMXFVXIQR-QYGVFRBXSA-N C[C@](CC1)(C(CC2)C(CCc3c4)C1c3cc(OC)c4OCc1ccccc1)C2=C Chemical compound C[C@](CC1)(C(CC2)C(CCc3c4)C1c3cc(OC)c4OCc1ccccc1)C2=C GVUMMCMXFVXIQR-QYGVFRBXSA-N 0.000 description 1
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Abstract
The invention relates to the field of medicinal chemistry, in particular to an estrogen derivative with a general formula (I), pharmaceutically acceptable salt thereof, a preparation method thereof and medical application thereof. The compound and the pharmaceutically acceptable salt thereof are used for treating pathological angiogenesis related diseases such as tumours, retinal diseases, rheumatic arthritis, diabetes mellitus, lupus erythematosus, chronic inflammation reaction and the like. Details of definitions of groups in the formula seeare shown in instruction.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class as the Estrogen Derivatives of vasoinhibitor.The invention also discloses their preparation method, pharmacologically active and their medicinal use.
Background technology
Vasculogenesis refers to that on original blood vessel basis endotheliocyte is by the process of sprouting or the formation neovascularity is bred and moved to the embedding form.Vasculogenesis all can occur under physiology and pathological conditions.In the normal physiological situation, the physiological stimulation in wound healing, fetal development and the reproductive process can cause local vasculogenesis.Yet pathologic angiogenesis is relevant with numerous disease, such as tumour, retinopathy, rheumatic arthritis, diabetes, lupus erythematosus, chronic inflammatory reaction etc.
Vasculogenesis is subject to the interaction of cell-cell, cell-matrix, and comprises Angiogenesis related factor and angiostatin by multiple factor adjusting.Angiogenesis related factor comprises vascular endothelial growth factor (VEGF), Thr6 PDGF BB (PDGF), angiogenin (Ang), fibroblast growth factor (FGF), transforming growth factor (TGF), Urogastron (EGF), rhIGF-1 (IGF) and tumor necrosis factor-alpha (TNF-α) etc.Supressor comprises Endostatin (endostatin), tumor chalone (tumstatin), angiostatin (vasostatin) etc.Be subjected to just the regulation and control of vasculogenesis stimulating factor and supressor, angiogenic growth just can kept dynamic physiological equilibrium.When promoting angiogenesis factor to occupy an leading position, or when suppressing the disappearance of angiogenesis factor or inactivation, neovascularity generates and occurs.
Pathologic vessels generates can cause growth and metastasis of tumours.When tumour occured, the balance of Angiogenesis related factor and angiostatin was broken.Angiogenesis related factor a large amount of synthetic and discharge disappearance and the inactivation of (or (with) Angiostatin), activate endotheliocyte, impel to produce multiple protein enzyme body, the dissolved cell epimatrix impels endotheliocyte to see through the matrix differentiation; The endotheliocyte of hyperplasia moves to the Angiogenesis related factor direction along the long chamber that the enzyme body forms in matrix, and the enzyme body is continued to discharge and invade surrounding tissue, and the endothelial cell surface that is activated has differentiation and the maturation of integrin receptor mediation blood vessel; Newly-generated endotheliocyte forms the vascular shape and forms blood vessel, interconnects between blood vessel and the blood vessel, or circlewise or reticulate, forms the tumor vessel network.The blood vessel network that forms will provide oxygen for tumour, and nutrition and waste discharge are so that tumor growth, transfer and deterioration.
Pathologic vessels generates can cause retinopathy and deterioration.A retinopathy particularly large feature of agedness yellow spot degenerative disease is retinochoroid neovascularization, abnormal vascular betides choroid, and under retina, in the retina, grow, occupy the macula retinae place, damage visual cell, cause that subretinal hemorrhage and secretory product leakage, lipidosis, retinal pigment cell separate with choroid, fibrous scar, in addition blind.
The another kind of disease excessively relevant with vasculogenesis is rheumatic arthritis.The pathologic of rheumatic arthritis changes into the persistence synovitis and pannus forms.Pannus has the aggressiveness that is similar to tumor tissues, and erodable and destruction articular cartilage tissue finally cause irreversible joint stiffness and afunction.The synovial fluid cell of rheumatic arthritis contains the vasculogenesis stimulating factor of high expression level, and rheumatic arthritis patient's intraarticular blood vessel hyperplasia is relevant with its coincident with severity degree of condition clinically.
In addition, also there is very large relation in pathological with diseases such as diabetes, lupus erythematosus, chronic inflammatory diseasess, has the blood vessel hyperplasia situation in these diseases, and vasculogenesis can be lured these advancings of disease and deterioration into.
Therefore, suppress angiogenesis, can treat tumour, retinopathy, rheumatic arthritis, diabetes, lupus erythematosus, chronic inflammatory diseases.
Having the compound of steroidal structure such as dexamethasone, Triamcinolone Acetonide, anecortave, natural product 2ME2, squalamine etc. all has been proved to be the effect that suppresses blood vessel has been arranged.Their mechanism of action or suppress the propagation of endotheliocyte by selectivity, or by suppressing vasculogenesis relevant growth-stimulating factor such as VEGF, perhaps suppress to have the polymerization of the tubulin on the endotheliocyte of blood vessel blocking target spot, or pass through cell death inducing, thereby inducing endothelial cell necrosis etc. produces vasculogenesis to be suppressed, the perhaps effect of blood vessel blocking generates disease such as tumour thereby show treatment pathologic related artery in clinical or animal experiment
,Retinopathy
,Rheumatic arthritis etc.The invention provides the compound that a class has the female steroid constructional feature, produce on the pharmacology and suppress blood vessel function, generate relative disease thereby be used for the treatment of pathologic vessels, comprise tumour, retinopathy, rheumatic arthritis, diabetes, lupus erythematosus, chronic inflammatory diseases.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of compound as vasoinhibitor.
The technical scheme that solves the problems of the technologies described above is as follows:
The compound Estrogen Derivatives of general formula I or its pharmacy acceptable salt:
Wherein:
M optional 0 or 1;
N optional 1 to 6;
P optional 1 to 6;
X represents O, S, NH, CH
2Or CO;
R
1Expression C
1-C
6Alkyl;
R
2Expression OH, SH, CN, halogen or NR
5R
6
R
3Expression OH ,=O, OSO
2CH
3Perhaps CO R ', R ' represents C
1-C
6Alkyl;
R
4Expression H, R "-OH or and R
3Form nitrogenous fragrant heterocycle, R " represent C
1-C
6Alkyl;
R
5And R
6Independently represent separately H, C
1-C
6Alkyl; Perhaps R
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or the individual heteroatoms that is selected from N, O, S of 2-3; Described monocycle or dicyclo can be by C
1-C
6Alkyl.
Preferably, described compound its have the II-VIII structure:
Wherein, n optional 1 to 6; X represents O, S, NH, CH
2Or CO; Y represents O, S, NH, CH
2Or CO; R
1Expression C
1-C
6Alkyl; R
2Expression OH, NR
5R
6, R wherein
5And R
6Independently represent separately H, C
1-C
6Alkyl; Perhaps R
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or the individual heteroatoms that is selected from N, O, S of 2-3, and described monocycle or dicyclo can be by C
1-C
6Alkyl; R
7Expression C
1-C
6Alkyl; R
8Expression H or C
1-C
6Alkyl; R
9Expression=O, OH or OSO
2CH
3R
10Expression H or C
1-C
5Alkyl.
II、
The compound that the invention provides general formula III can be prepared by following methods:
III、
The compound that the invention provides general formula I V can be prepared by following methods:
IV、
The compound that the invention provides general formula V can be prepared by following methods:
V、
The compound that the invention provides general formula VI can be prepared by following methods:
VI、
The compound that the invention provides general formula VII can be prepared by following methods:
VII、
The compound that the invention provides general formula VIII can be prepared by following methods:
VIII、
Wherein n is optional from 1 to 6; X represents O, S, NH, CH
2Or CO; Y represents O, S, NH, CH
2Or CO; R
1Expression C
1-C
6Alkyl; R
2Expression OH, NR
5R
6, R wherein
5And R
6Independently represent separately H, C
1-C
6Alkyl; Perhaps R
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or the individual heteroatoms that is selected from N, O, S of 2-3, and described monocycle or dicyclo can be by C
1-C
6Alkyl; R
7Expression C
1-C
6Alkyl; R
8Expression H or C
1-C
6Alkyl; R
9Expression=O, OH or OSO
2CH
3R
10Expression H or C
1-C
5Alkyl.
The present invention also provides a kind of pharmaceutical composition that is comprised of above-claimed cpd.
A kind of pharmaceutical composition, it is comprised of the described compound of claim or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
Another technical issues that need to address of the present invention provide the application of above-claimed cpd.
Above-claimed cpd and pharmaceutically acceptable steric isomer thereof are used for the treatment of the application in the medicine of pathological relative disease as vasoinhibitor.
Preferably, described pathological relative disease is any in the following disease: (1) cancer, (2) retinopathy, (3) rheumatic arthritis, (4) diabetes, (5) lupus erythematosus, (6) chronic inflammatory diseases etc.
The invention provides the Estrogen Derivatives that a class can be used as vasoinhibitor and have above-mentioned general formula I micromolecular compound.And be used for the treatment of pathological relative disease such as tumour, retinopathy, rheumatic arthritis, chronic inflammatory diseases, lupus erythematosus etc.
Above-claimed cpd of the present invention can suppress the migration of HUVEC, suppresses HUVEC cell proliferation, suppresses chick chorioallantoic membrane neovascularity generation in the body.In addition, described compound can also be by increasing its clinical effectiveness with chemotherapeutic agent present application or that be in the development phase or angiogenesis inhibitor or radiotherapy drug combination.
Compound of the present invention can have asymmetric center, chiral axis and chirality face, and the racemic modification that exists, and raceme mixture, and single diastereomer and all possible isomers and composition thereof comprise that optically active isomer includes in the present invention.
Term of the present invention " alkyl " means to comprise saturated fatty alkyl straight chain and side chain with particular carbon atom number.For example, " C
1-C
6Alkyl " in " C
1-C
6" definition comprise with what straight or branched was arranged having 1,2,3,4, the group of 5 or 6 carbon atoms.For example, " C
1-C
6Alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl etc.
Contain 5 or 6 atoms in used among the present invention " fragrant heterocycle " representative ring and contain at least the monocycle aromatic nucleus of a N atom.Fragrant heterocycle in this range of definition includes but not limited to: pyrroles, pyrazoles, thiazole, imidazoles, pyridine, pyrimidine, oxazole, isoxzzole, pyrazine, pyridazine; Also comprise the pyrroles that alkyl replaces, the pyrazoles that alkyl replaces, the thiazole that alkyl replaces, the imidazoles that alkyl replaces, the pyridine that alkyl replaces, the pyrimidine that alkyl replaces, the oxazole that alkyl replaces, the isoxzzole that alkyl replaces, the pyrazine that alkyl replaces, the pyridazine that alkyl replaces.
Defined " R among the present invention
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or 2-3 is individual is selected from N, O, the heteroatoms of S; Described monocycle or dicyclo can be by C
1-C
6Alkyl replaces " can form so that the example of heterocycle includes but not limited to following heterocycle, this heterocycle is optional can be by C
1-C
6Alkyl replaces:
The structure of part of compounds of the present invention is as follows:
II、
III、
| Compound?no. | n | R 1 | R 2 | X |
| III-1 | 1 | CH 3 | NH 2 | O |
| III-2 | 1 | CH 3 | NHCH 3 | O |
| III-3 | 1 | CH 3 | N(CH 3) 2 | O |
IV、
V、
| Compound?no. | R 1 | X | R 7 |
| V-1 | CH 3 | O | CH 3 |
VI、
| Compound?no. | R 1 | X | Y | R 8 |
| VI-1 | CH 3 | O | NH | H |
VII、
| Compound?no. | R 1 | X | R 2 | R 9 |
[0081]?
| VII-1 | CH 3 | O | NH 2 | ＝O |
| VII-2 | CH 3 | O | NH 2 | OSO 2CH 3 |
VIII、
| Compound?no. | R 1 | X | R 9 |
| VIII-1 | CH 3 | O | ＝O |
| VIII-2 | CH 3 | O | OH |
The below is part pharmacology test and the result of part of compounds of the present invention:
1, mtt assay is measured the HUVEC cell proliferation experiment
Test method: get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion comes off attached cell, counting 2～4 * 10
4Individual/mL, make cell suspension.Obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in 200 μ L/ holes
2Cultivated 24 hours in the incubator.Change liquid, add tested medicine, cultivated 48 hours.MTT is added in 96 orifice plates, 20 μ L/ holes, reaction is 4 hours in the incubator.Suck supernatant liquor, add DMSO, 150 μ L/ holes, jolting is 10 minutes on the dull and stereotyped shaking table.Be absorbancy (A) value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, by formula calculate cell proliferation inhibition rate: inhibiting rate=(control group A value-experimental group A value)/(control group A value-blank group A value) * 100%, and calculate IC50.。
The result: the compounds of this invention is inhibited to HUVEC cell proliferation.Wherein Compound I I-6, IV-8, IV-9, IV-10, V-1 have certain inhibition activity to Human umbilical vein endothelial cells HUVEC, and IV-16, VIII-1 and IV-18 have weak activity (10 in addition
-5M control of the concentration rate is near 50%).
2, the biological activity test of the Angio CD31SP that HUVEC is relevant
Result: II-6 is better active to Angio CD31SP's.Inhibiting rate is 90% under the 2uM system, and when concentration was brought up to 10uM, inhibiting rate reached 120%.Its IC50 is 1.55uM.
3, the cell scratch test is measured the HUVEC cellular migration inhibition
Test method: the HUVEC cell of the phase growth of taking the logarithm is inoculated in 24 orifice plates with 2 * 104cell/ hole, establish 4 parallel holes for every group, being cultured to the cytogamy degree reaches more than 90% rear with 200 μ L rifle head cuts, the PBS flushing, remove dead cell, according to default medicine gradient concentration (100 μ mol/L) dosing.Respectively 0,12h, 24h take pictures, and measures the width of intermediate blank band, record.Repeated experiments three times.
The result: the result show compound of the present invention show in various degree the inhibition cell migration ability wherein the activity of Compound I I-2, II-6, VIII-2, IV-10, IV-18 all be higher than 80%, surpass the positive control 2ME2, suppressed the better active of migration.The inhibition of metastasis rate of IV-1, IV-9 and IV-8 has has also met or exceeded 70%, has medium inhibition migratory activity.
4, anti-angiogenesis activity in chick chorioallantoic membrane test (CAM) test body
Test method: get the chicken embryo of hatching the 7th day.Find the embryo head by illumination, peel off gently the eggshell that diameter is the 1cm size with hand drill, bore an aperture at the chick embryo air sac place simultaneously, vacuum suction forms an artificial air chamber so that peel off the place of eggshell; The careful shell membrane of removing exposes chorioallantoic membrane (CAM); Dosing (10 μ l/ pieces) is on the aseptic methylcellulose gum filter paper wafer carrier for preparing, control group adds physiological saline, puts on the chick embryo air sac chorioallantoic membrane, and chick embryo air sac is sealed up with aseptic scotch tape, put into thermostat container and cultivate 37 ℃ of culture condition, humidity 60%.Take out the chicken embryo behind the 3d, the local fixedly 10min of acetone and dehydrated alcohol that adopts cuts the CAM that is placed with filter paper disk, removes filter paper.Observe its new vessel distribution situation, count and take pictures.Repeated experiments 3 times.
The result: the chick chorioallantoic membrane test shows that the compounds of this invention has the effect of angiogenesis inhibitor in the body, and wherein Compound I I-2, IV-18 and IV-8 show anti-angiogenic activity in the good body, and is active suitable with 2ME2; II-6, VIII-2 also show active preferably.
This compound can be used for preventing or treats the relevant disease of pathologic vessels generation comprising tumour, retinopathy, rheumatic arthritis, chronic inflammatory diseases, lupus erythematosus etc.
The compounds of this invention can be made preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.Can use the oral dosage form administration, but such as conventional tablet and capsule, slow releasing tablet and capsule, controlled release tablet and capsule, dripping pill dispersed powders, granule etc.; Also can be prepared into injection formulations.Can contain for example activeconstituents of 0.05% to 90% weight with carrier combinations in these medicinal preparationss, the activeconstituents of weight between more common about 15% to 60%.The compounds of this invention dosage can be 0.001～100_mg/kg/ days, also can depart from this dosage range according to the difference of disease degree or the difference of formulation.
Embodiment (described embodiment just is used for illustrating the present invention, rather than is used for limiting the present invention)
The preparation example of part of compounds is as follows:
Fusing point XT4 type micro melting point apparatus; The hydrogen nuclear magnetic resonance spectrometer is Bruker AV 500 types (TMS is interior mark); Mass spectrograph is Shimadzu GCMS-QP2010 type mass spectrograph or Mariner mass spectrograph; Infrared spectrometer is Nicolet Impact 410 types (KBr compressing tablets); Elemental analyser is Elementar Vario EL III.
Embodiment 1
The preparation of 2ME2-3-fluoroacetic acid ethyl ester (2a)
2ME2 (0.3g, 1mmol) is dissolved among the THF (10mL), adds the ethanolic soln (0.75mL) of the sodium ethylate of 2mol/L, stirring at room 30 minutes adds ethyl bromoacetate (0.33mL, 3mmol), reaction solution refluxed 10 hours, and stopped reaction adds the entry dilution, then through ethyl acetate extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure is through column chromatography for separation (petrol ether/ethyl acetate, 5: 1) obtain compound 2 (0.28_g, 74%).Oily matter.
1H?NMR(300MHz，CDCl
3)，δ(ppm)：0.79(s，3H，C18-H)，1.31(t，3H，CH
3CH
2O)，3.71-3.76(t，1H，C17-H，J＝8.1Hz)，3.86(s，3H，C2-OCH
3)，4.27(m，2H，CH
3CH
2O)，4.64(s，2H，C3-OCH
2)，6.55(s，1H，C4-H)，6.83(s，1H，C1-H).EI-MS?m/z：388(M
+).
Embodiment 2
The preparation of 2ME2-3-fluoroacetic acid (II-1)
2a (0.4g, 1_mmol) being dissolved in the methyl alcohol (10mL), being cooled to 0 ℃, add entry (1mL), NaOH (0.12g, 3mmol). reaction solution rises to room temperature, stirs 2.5 hours.1N HCl transfers pH2, ethyl acetate extraction, and anhydrous sodium sulfate drying is concentrated into driedly, obtains Compound I I-1 (0.37g, 99%) through the ethyl acetate crystallization.White solid.M.p.：194-196℃.IR(KBr)νmax(cm
-1)：3467，2924，1737，1507，1210.
1H?NMR(300MHz，CDCl
3)，δ(ppm)：0.79(s，3H，CH
3)，3.71-3.76(t，1H，C17-H，J＝8.1Hz)，3.86(s，3H，-OCH
3)，4.64(s，2H，-OCH
2)，6.55(s，1H，C4-H)，6.83(s，1H，C1-H).EI-MS?m/z：360(M
+).Anal.Calcd?for?C
21H
28O
5：C，69.98；H，7.83.Found：C，69.69；H，8.01.
Embodiment 3
The preparation of 2ME2-3-acetamide oxide (II-2)
Compound I I-1 (100mg, 0.26_mmol) is dissolved among the THF (5mL), is cooled to 0 ℃, adds ammoniacal liquor (1mL),
EDC (20mg, 0.5_mmol), stirred overnight at room temperature, reaction solution is transferred pH=7-8 through 1N HCl, ethyl acetate extraction, anhydrous sodium sulfate drying is concentrated into dried, obtain Compound I I-1 (65mg, 70%) through column chromatography for separation (petrol ether/ethyl acetate, 3: 2).White solid.M.p.：162-164℃.IR(KBr)νmax(cm
-1)：3394，2927，1682，1509，1259，1210，1119，650.
1H?NMR(300MHz，CDCl
3)，δ(ppm)：0.79(s，3H，C18-H)，3.73-3.75(q，1H，C17-H，J＝6.0Hz)，3.85(s，3H，OCH
3)，4.51(s，2H，OCH
2CO)，5.63(brs，1H，CONH
2)，6.63(s，1H，C4-H)，6.86(s，1H，C1-H)，6.97(brs，1H，CONH
2)，EI-MS?m/z：359(M
+).Anal.Calcd?for?C
21H
29NO
4：C，70.17；H，8.13；N，3.90.Found：C，69.92；H，8.28；N，3.84.
Embodiment 4
The preparation of 2ME2-N-methyl-3-acetamide oxide (II-3)
Concrete operation is with example 3.Yield 82%, white solid, m.p.:94-97 ℃ of .IR (KBr) ν max (cm
-1): 3377,2925,1665,1512,1256,1213,1115,582.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 2.90 (s, 3H, NHCH
3), 3.71-3.76 (t, 1H, C17-H, J=8.4Hz), 3.86 (s, 3H, OCH
3), 4.51 (s, 2H, OCH
2CO), 6.61 (s, 1H, C4-H), 6.86 (s, 1H, C1-H), 6.98 (brs, 1H, CONH-), EI-MS m/z:373 (M
+) .Anal.Calcd for C
22H
31NO
4: C, 70.75; H, 8.37; N, 3.75.Found:C, 68.69; H, 8.82; N, 3.12.
Embodiment 5
2ME2-N, the preparation of N-dimethyl-3-acetamide oxide (II-4)
Concrete operation is with example 3.Yield 75%, white solid
,M.p.:78-80 ℃ of .IR (KBr) ν max (cm
-1): 3413,2934,1653,1510,1263,1209,1159,559.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 2.97 (s, 3H, NCH
3), 3.12 (s, 3H, NCH
3), 3.71-3.76 (t, 1H, CH, J=8.4Hz), 3.84 (s, 3H, OCH
3), 4.70 (s, 2H, OCH
2CO), 6.66 (s, 1H, C4-H), 6.84 (s, 1H, C1-H), EI-MS m/z:387 (M
+) .Anal.Calcd for C
23H
33NO
40.75CH
3OH:C, 69.31; H, 8.82; N, 3.40.Found:C, 69.37; H, 8.61; N, 2.96.
Embodiment 6
The preparation of 2-methoxyl group 3-(1-morpholinyl carbonyl methyl) estradiol (II-6)
Concrete operation is with example 3.Yield 53%, white solid, m.p.:75-76 ℃ of .IR (KBr) ν max (cm
-1): 3414,2919,1643,1509,1445,1255,1210,1118,568.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 3.64-3.70 (m, 8H, morpholine-H), 3.71-3.83 (t, 3H, C17-H, J=8.4Hz), 3.87 (s, 3H, OCH
3), 4.69 (s, 2H, OCH
2CO), 6.66 (s, 1H, C4-H), 6.83 (s, 1H, C1-H), EI-MS m/z:429 (M
+) .Anal.Calcd for C
25H
35NO
5: C, 69.90; H, 8.21; N, 3.26.Found:C, 69.53; H, 8.55; N, 3.06.
Embodiment 7
The preparation of 2ME2-3-oxygen base isopropyl acid ethyl ester (5a)
2ME2 (0.4g, 1.32mmol) be dissolved among the THF (10mL), the ethanolic soln (1mL) that adds the sodium ethylate of 2mol/L, stirring at room 30 minutes, add bromo isopropyl acid ethyl ester (0.52mL, 4mmol), reaction solution refluxed 10 hours, stopped reaction, add the entry dilution, then through ethyl acetate extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure, through column chromatography for separation _ (petrol ether/ethyl acetate, 5: 1) _ compound 5a (0.4_g, 76%), oily matter obtained.
1H?NMR(300MHz，CDCl
3)，δ(ppm)：0.79(s，3H，C18-H)，1.31(t，3H，CH
3CH
2O)，1.64(d，3H，CH
3CH，J＝6.9Hz)，3.70-3.76(t，1H，C17-H，J＝8.1Hz)，3.86(s，3H，C2-OCH
3)，4.27(m，2H，CH
3CH
2O)，4.64(s，2H，C3-OCH
2)，6.57(s，1H，C4-H)，6.83(s，1H，C1-H).EI-MS?m/z：402(M
+).
Embodiment 8
The preparation of 2ME2-3-oxygen isopropyl acid (6a)
5a (0.4g, 1_mmol) being dissolved in the methyl alcohol (10mL), being cooled to 0 ℃, add entry (1mL), NaOH (0.12g, 3mmol). reaction solution rises to room temperature, stirs 2.5 hours.1N HCl transfers pH=2, ethyl acetate extraction, and anhydrous sodium sulfate drying is concentrated into driedly, obtains compound 6a (0.37g, 99%) through the ethyl acetate crystallization.White solid.M.p.：194-196℃.
1HNMR(300MHz，CDCl
3)，δ(ppm)：0.79(s，3H，CH
3)，1.64(d，3H，CH3CH，J＝6.9Hz)，3.71-3.78(t，1H，C17-H，J＝8.1Hz)，3.86(s，3H，-OCH
3)，4.68(m，1H，CH
3CH)，6.61(s，1H，C4-H)，6.86(s，1H，C1-H).EI-MS?m/z：374(M
+).
Embodiment 9
The preparation of 2ME2-3-oxygen Isopropamide (III-1)
Compound 6a (100mg, 0.26_mmol) is dissolved among the THF (5mL), is cooled to 0 ℃, add ammoniacal liquor (1mL), EDC (20mg, 0.5mmol), stirred overnight at room temperature, reaction solution is transferred pH=7-8, ethyl acetate extraction, anhydrous sodium sulfate drying through 1N HCl, be concentrated into dried, obtain compound III-1 (65mg, 70%) through column chromatography for separation (petrol ether/ethyl acetate, 3: 2).White solid m.p.:158-160 ℃ .IR (KBr) ν max (cm
-1): 3427,2920,1683,1509,1378,1116,860.
1HNMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 1.62-1.64 (d, 3H, CH3CH, J=6.9Hz), 3.70-3.76 (t, 1H, C17-H, J=8.1Hz), 3.85 (s, 3H, OCH
3), 4.56-4.63 (q, 1H, CH), 5.35 (brs, 1H, CONH
2), 6.65 (s, 1H, C4-H), 6.85 (s, 1H, C1-H), 7.07 (brs, 1H, CONH
2), EI-MS m/z:373 (M
+) .Anal.Calcd for C
21H
31NO
40.5H2O:C, 69.08; H, 8.43; N, 3.66.Found:C, 69.41; H, 8.42; N, 3.23.
Embodiment 10
The preparation of 2ME2-N-methyl-3-oxygen Isopropamide (III-2)
Concrete operation is with example 9.Yield 70%, white solid, m.p.:218-220 ℃ of .IR (KBr) ν max (cm
-1): 3428,3266,2945,1633,1513,1261,1122.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 1.62-1.64 (d, 3H, CH
3CH, J=6.9Hz), 2.82-2.84 (s, 3H, CH
3N), 3.71-3.76 (t, 1H, C17-H, J=8.4Hz), 3.85 (s, 3H, OCH
3), 4.56-4.63 (q, 1H, CH), 6.62 (s, 1H, C4-H), 6.85 (s, 1H, C1-H), 7.14 (brs, 1H, CONH-), EI-MS m/z:387 (M
+) .Anal.Calcd for C
22H
33NO
4.0.5H2O:C, 68.98; H, 8.73; N, 3.52.
Embodiment 11
2ME2-N, the preparation of N-dimethyl-3-oxygen Isopropamide (III-3)
Concrete operation is with example 9.Yield 82%, white solid, m.p.:157-160 ℃ of .IR (KBr) ν max (cm
-1): 3366,2919,1622,1513,1210,1122,1026,861.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 1.62-1.64 (d, 3H, CH
3CH, J=6.9Hz), 2.95 (s, 3H, NCH
3), 3.14 (s, 3H, NCH
3), 3.70-3.76 (t, 1H, CH, J=8.1Hz), 3.82 (s, 3H, OCH
3), 4.92-4.99 (q, 1H, CH), 6.59 (s, 1H, C4-H), 6.83 (s, 1H, C1-H), EI-MS m/z:401 (M
+) .Anal.Calcd for C
24H
35NO
40.75H
2O:C, 70.21; H, 8.84; N, 3.41.Found:C, 69.76; H, 9.15; N, 3.39.
Embodiment 12
The preparation of 2-methoxyl group-3-O-amine ethyl estradiol (IV-1)
Compound I I-2 (0.4g, 1.1mmol) is dissolved among the anhydrous THF (20mL), is cooled to 0 ℃, adds LiAlH
4(0.39g, 10.3mmol), reaction solution is warming up to room temperature, stirring is spent the night, and stopped reaction slowly adds entry, ethyl acetate extraction, anhydrous sodium sulfate drying, be concentrated into dried, through column chromatography for separation (petrol ether/ethyl acetate, 1: 1) obtain compound IV-1 (0.09_g, 24%), faint yellow solid, m.p.:82-89 ℃.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 2.87-2.90 (m, 2H, NCH
2), 3.72-3.75 (q, 1H, C17-H, J=6.0Hz), 3.85 (s, 3H, OCH
3), 4.30-4.32 (m, 2H, OCH
2), 6.63 (s, 1H, C4-H), 6.86 (s, 1H, C1-H); EI-MS m/z:345 (M
+).
Embodiment 13
2-methoxyl group-3-O-methylamino ethyl estradiol (IV-2)
Concrete operation is with example 12.Yield 19%,
1H NMR (300MHz, CDCl
3), δ (ppm): 0.76 (s, 3H, C18-H), 2.36 (s, 3H, NCH
3), 2.87-2.90 (m, 2H, NCH
2), 3.68-3.72 (q, 1H, C17-H, J=6.0Hz), 3.81 (s, 3H, OCH
3), 4.32-4.36 (m, 2H, OCH
2), 6.63 (s, 1H, C4-H), 6.86 (s, 1H, C1-H); EI-MS m/z:359 (M
+).
Embodiment 14
The preparation of 2-methoxyl group-3-O-dimethylamino ethyl estradiol (IV-3)
Concrete operation is with example 12.Obtain IV-3, glassy yellow oily matter.It is dissolved in the 20ml methylene dichloride, passes into dry hydrogen chloride gas, reaction 10min reacts and is spin-dried for after complete, obtains faint yellow solid, yield 61.14%.Fusing point 165-168 ℃.MS(ESI)：374.1[M+H]
+，396.1[M+Na]
+.IR(KBr)：3376，2931，2853，2654，2471，1515，1466，1444，1216.
1H-NMR：δ＝0.79(3H，s，18-CH
3)，δ＝3.96(6H，m，-N(C
H 3 ) 2 )，δ＝3.46(2H，s，(CH
3)
2NCH
2 CH 2 O-)，δ＝3.82(3H，s，2-OCH
3)，δ＝4.45(2H，s，(CH3)2N
CH2CH2O-)，δ＝6.64(1H，s，1-H)，δ＝6.83(1H，s，4-H)，δ＝12.83(1H，s，HCl)，HRMS：373.2626(Calc?Mass：373.2617)。
Embodiment 15
The preparation of 2-methoxyl group-3-O-hydroxyethyl estradiol (IV-4)
Concrete operation is with example 12.Yield 70%, white solid, m.p.:174-176 ℃ of .IR (KBr) ν max (cm
-1): 3487,2925,1516,1253,1122,525.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 3.70-3.76 (t, 1H, C17-H, J=8.4Hz), 3.84 (s, 3H, OCH
3), 3.88-3.91 (t, 2H, OCH
2CH
2O, J
1=4.2Hz, J
2=4.8Hz), 4.08-4.11 (t, 2H, OCH
2CH
2O, J1=4.2Hz, J
2=4.8Hz), 6.66 (s, 1H, C4-H), 6.84 (s, 1H, C1-H), EI-MS m/z:346 (M
+) .Anal.Calcd for C
21H
30O
4: C, 72.80; H, 8.73.Found:C, 72.97; H, 8.81.
Embodiment 16
2-methoxyl group-3-ethamine oxyethyl group-female steroid-1,3, the preparation of 5-triolefin-17 β-alcohol (IV-5)
Concrete operation is with example 12.Yield 12.5%, faint yellow solid, fusing point 136-138 ℃.MS(ESI)374.3[M+H]
+.IR(KBr)：3412，2932，2916，2871，2439，1516，1466，1448，1219.
1H-NMR：δ＝0.67(3H，s，18-CH
3)，?δ＝1.82-1.87(3H，t，18-NCH
2 CH 3 )，δ＝2.72(2H，s，N
CH 2 CH
2O-)，δ＝3.04(2H，m，-N
CH 2 CH
3)，δ＝3.52(1H，s，CH
3CH
2 NH)，δ＝3.74(3H，s，2-OCH
3)，δ＝4.22(2H，m，-NCH
2 CH 2 O-)，δ＝4.50(1H，s，-17-OH)，δ＝6.71(1H，s，1-H)，δ＝6.87(1H，s，4-H)，δ＝8.81(H，s，HCl).HRMS：373.2626(CalcMass：373.2617)。
Embodiment 17
2-methoxyl group-3-benzyloxy female steroid-1,3, the preparation of 5 (10)-triolefins-17-alcohol (9a)
2ME2 (10.0g, 33.1mmol) be dissolved in ethanol (250mL), add KOH (2.5g, 44.2mmol), stirring is warming up to backflow, add tetrabutylammonium iodide (1.0g, 2.7mmol) and Benzyl Chloride (8.5mL, 73.6mmol), after the reaction solution back flow reaction 12 hours, the filter of reaction solution heat is concentrated into about 50mL, adds entry (200mL) dilution, through ethyl acetate (3 * 100mL) extractions, anhydrous sodium sulfate drying is concentrated into driedly, adds ethanol 10mL and grinds, place refrigerator overnight, suction filtration is collected solid and is obtained compound 6a (12.5g, 94%). white solid, m.p.:86-88 ℃ (lit89-90 ℃).
1H-NMR (300MHz, CDCl
3), δ (ppm): 0.78 (s, 3H, C18-H), 3.70-3.75 (t, 1H, C17-H, J=8.3Hz), 3.85 (s, 3H, C2-OCH
3), 5.09 (s, 2H, C3-OCH
2Ph), 6.62 (s, 1H, C4-H), 6.85 (s, 1H, C1-H), 7.24-7.45 (m, 5H, ArH); EI-MS m/z:392 (M
+).
Embodiment 18
2-methoxyl group-3 benzyloxy female steroid-1,3, the preparation of 5 (10)-triolefins-17-ketone (10a)
Compound 9a (2.48g, 6.33mmol) be dissolved in the acetone (15mL), being cooled to 0 ℃, beginning slowly drips freshly prepd Jones reagent (0.5mL), add rear 0 ℃ of reaction 5 minutes, reaction solution adds entry (10mL) concentration and recovery acetone, ethyl acetate extraction afterwards, anhydrous sodium sulfate drying, be concentrated into dried, the ethyl acetate crystallization obtains compound 10a (2.12g, 84%). white solid, m.p.:154-157 ℃ (lit154-156 ℃).
Embodiment 19
The preparation of 2-methoxyl group-3-benzyl-17 α-lynoral (11a)
In three-necked bottle, add dry THF (40mL), be cooled to-10 ℃, be added dropwise to BuLi (5.17mL), passed into afterwards acetylene gas 30 minutes, afterwards with compound 10a (2.12g, 5.44mmol) THF solution (40mL) slowly splash into, 0 ℃ of reaction is after 2 hours, and reaction is also through water dilution, ethyl acetate extraction (3 * 40mL), anhydrous sodium sulfate drying, be concentrated into driedly, obtain compound 11a (1.13g through column chromatography for separation (petrol ether/ethyl acetate, 4: 1), 50%), colorless oil;
1H NMR (300MHz, CDCl
3), δ (ppm): 0.78 (s, 3H, C18-H), 2.60 (s, 1H, C17-C ≡ CH), 3.86 (s, 3H, C2-OCH
3), 5.10 (s, 2H, C3-OCH
2Ph), 6.62 (s, 1H, C4-H), 6.85 (s, 1H, C1-H), 7.24-7.45 (m, 5H, Ar-H); EI-MS m/z:416 (M
+).
Embodiment 20
2-methoxyl group-3-benzyloxy-17-ethynyl female steroid--1,3,5 (10), the preparation of 16-tetraene (12a)
Compound 11a (2.48g, 6.33mmol) is dissolved in the dry toluene (40mL), and 0 ℃ of lower DBU (4mL) that adds then slowly splashes into POCl
3(1.3mL), reaction solution is warming up to 80 ℃ of reactions 2 hours, stopped reaction adds 1N HCl (25mL) and water (25mL), ethyl acetate extraction (3 * 40mL) in the reaction solution, anhydrous sodium sulfate drying, be concentrated into driedly, obtain compound 12a (0.7g through column chromatography for separation (petrol ether/ethyl acetate, 4: 1), 65%), colorless oil;
1H NMR (300MHz, CDCl
3), δ (ppm): 0.88 (s, 3H, C18-H), 3.09 (s, 1H, C17-C ≡ CH), 3.87 (s, 3H, C2-OCH
3), 5.10 (s, 2H, C3-OCH
2Ph), 6.14 (s, 1H, C16-H), 6.63 (s, 1H, C4-H), 6.84 (s, 1H, C1-H), 7.24-7.45 (m, 5H, Ar-H); EI-MS m/z:398 (M
+).
Embodiment 21
2-methoxyl group-3-benzyloxy-19-loses carbon pregnant steroid-1,3,5 (10), the preparation of 16-tetraene-20-ketone (13a)
Compound 12a (0.65g, 1.63mmol) is dissolved in the acetone (35mL), adds entry (11mL), HgO (0.38g, 1.75mmol) and dense H
2SO
4(1.1mL), reaction solution was warming up to back flow reaction 2 hours, cool overnight, and next day, suction filtration obtained crude product, obtained compound 13a (0.63g, 93%), yellow solid through column chromatography for separation (petrol ether/ethyl acetate, 4: 1); M.p.:124-126 ℃.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.88 (s, 3H, C18-H), 2.28 (s, 3H, C21-H), 3.87 (s, 3H, C2-OCH
3), 5.10 (s, 2H, C3-OCH
2Ph), 6.63 (s, 1H, C4-H), 6.73 (s, 1H, C16-H), 6.84 (s, 1H, C1-H), 7.24-7.45 (m, 5H, Ar-H); EI-MS m/z:416 (M
+).
Embodiment 22
2-methoxyl group-3-methoxyl group-19-loses carbon pregnant steroid-1,3, the preparation of 5 (10)-triolefins-20-ketone (V-1)
Compound 13a (50mg, 0.12mmol) be dissolved in methyl alcohol (5mg) and the methylene dichloride (2mL), add 5%Pd/C, evacuate air passes into hydrogen, stirring at room reaction 4 hours, filter and remove Pd/C, concentrate solvent, through column chromatography for separation (petrol ether/ethyl acetate, 3: 1) obtain compound V-1 (30mg, 77%). white solid; M.p.185-188 ℃ of .IR (KBr) ν max (cm
-1): 3426,2920,1694,1505,1278,1207.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.66 (s, 3H, C18-H), 2.16 (s, 3H, C21-H), 2.58-2.64 (t, 1H, C17-H, J=8.7Hz), 3.86 (s, 3H, C2-OCH
3), 5.42 (brs, 1H, C3-OH), 6.64 (s, 1H, C4-H), 6.78 (s, 1H, C1-H); EI-MS m/z:328 (M
+) .Anal.Calcd forC
21H
28O
30.3H
2O:C, 75.55; H, 8.63.Found:C, 75.25; H, 8.19.
Embodiment 23
2-methoxyl group-3-benzyloxy-16-hydroxy methylene female steroid-1,3, the preparation of 5 (10)-triolefins-17-ketone (15a)
Compound 10a (0.3g, 0.32mmol) is dissolved in the dry THF (5mL), adds NaH (60%, 0.3g 8.75mmol) stirring at room is 30 minutes, drips ethyl formate 2mL, afterwards 50 ℃ of reactions 1 hour, stopped reaction, reaction solution are added in the frozen water (30mL), ethyl acetate extraction EtOAc (3 * 10mL), anhydrous sodium sulfate drying, be concentrated into dried compound 15a (0.30g, 94%), the yellow oil .EI-MS m/z:418 (M of obtaining
+).
Embodiment 24
2-methoxyl group-3-benzyloxy female steroid-1,3,5 (10)-triolefins are the preparation of [17,16-c] pyrazoles (16a) also
Compound 15a (0.3g, 0.32mmol) is dissolved in 95% ethanol (20mL) and the methylene dichloride (5mL), adds 85% hydrazine hydrate (1mL), nitrogen protection, reaction solution refluxed 30 minutes, stopped reaction, be cooled to room temperature, through 5M HCl acidifying, add the entry dilution, ethyl acetate extraction (3 * 10mL), anhydrous sodium sulfate drying, obtain compound 16a (0.15g, 51%) through column chromatography for separation (petrol ether/ethyl acetate, 1: 1). yellow solid; M.p.:100-104 ℃.
1H NMR (300MHz, CDCl
3), δ (ppm): 1.05 (s, 3H, C18-H), 3.88 (s, 3H, C2-OCH
3), 5.12 (s, 2H, C3-OCH
2Ph), 6.65 (s, 1H, C4-H), 6.84 (s, 1H, C1-H), 7.20 (s, 1H, pyrazole-C5 '-H), 7.24-7.45 (m, 5H, Ar-H); EI-MS m/z:414 (M
+).
Embodiment 25
2-methoxyl group-3-hydroxy-estra-1,3,5 (10)-triolefins be the preparation of [17,16-c] pyrazoles (VI-1) also
Compound 16a (0.15g, 0.36mmol) be dissolved in the methyl alcohol (10mL), add 5%Pd/C, evacuate air passes into hydrogen, stirring at room reaction 4 hours, filter and remove Pd/C, concentrate solvent, through column chromatography for separation (petrol ether/ethyl acetate, 3: 1) obtain compound vi-1 (110mg, 94%). white solid; M.p.234-236 ℃ of .IR (KBr) ν max (cm
-1): 3408,2927,2853,1508,1276,1126,1024.
1H NMR (300MHz, CDCl
3), δ (ppm): 1.02 (s, 3H, C18-H), 3.87 (s, 3H, C2-OCH
3), 6.67 (s, 1H, C4-H), 6.82 (s, 1H, C1-H), 7.19 (s, 1H, pyrazole-C5 '-H); EI-MS m/z:324 (M
+) .Anal.Calcd for C
20H
24N
2O
2CH
3OH:C, 70.76; H, 7.92; N, 7.86.Found:C, 70.64; H, 7.64; N, 7.53.
Embodiment 26
The preparation of 2-methoxyestrone-3-oxygen yl acetamide (VII-1)
Compound I I-2 (120mg, 0.33mmol) be dissolved in acetone (10mL), be cooled to 0 ℃, slowly drip 15 Jone ' s reagent, dropwise, 0 ℃ was stirred 5 minutes, in reaction solution impouring frozen water, stir, suction filtration obtains white solid (90mg, 76%) .m.p.:222-223 ℃ .IR (KBr) ν max (cm
-1): 3441,2927,1731,1648,11518,1256,1205,1055.
1H NMR (300MHz, DMSO-d
6), δ (ppm): 0.79 (s, 3H, C18-H), 3.75 (s, 3H, OCH
3), 4.35 (s, 2H, OCH
2CO), 6.64 (s, 1H, C4-H), 6.87 (s, 1H, C1-H), 7.28 (s, 1H, CONH
2), 7.38 (s, 1H, CONH
2), EI-MS m/z:357 (M
+) .Anal.Calcd for C
21H
27NO
4: C, 70.56; H, 7.61; N, 3.92.Found:C, 70.27; H, 7.63; N, 3.81.
Embodiment 27
The preparation of 2-methoxyl group-3-(2-amino-2-carbonyl oxyethyl group oxygen base) estradiol-17-methanesulfonates (VII-2)
Compound I I-2 (100mg, 0.28mmol) is dissolved in anhydrous pyridine (5mL), and ice bath drips methylsulfonyl chloride (0.03mL, 0.34mmol).Dropwise, rose to stirring at room 1 hour, in reaction solution impouring frozen water, separate out solid, suction filtration gets white solid (115mg, 95%) .m.p.:94-97 ℃ .IR (KBr) ν max (cm
-1): 3463,2930,1690,1509,1351,1173,962,878,530.
1H NMR (300MHz, CDCl
3), δ (ppm): 0.79 (s, 3H, C18-H), 3.02 (s, 3H, SO
2CH
3), 3.83 (s, 3H, OCH
3), 4.51 (s, 2H, OCH
2CO), 4.54-4.61 (t, 1H, C17-H, J=8.4Hz), 5.64 (s, 1H, CONH
2), 6.63 (s, 1H, C4-H), 6.84 (s, 1H, C1-H), 6.98 (s, 1H, CONH
2), EI-MS m/z:437 (M
+) .Anal.Calcd for C
22H
31NO
6S0.5H
2O:C, 59.17; H, 7.22; N, 3.14.Found:C, 59.56; H, 7.33; N, 3.04.
Embodiment 28
2-methoxyl group-16-methylol-1,3, the preparation of 5 (10)-triolefins-3-hydroxyl-17-ketone (VIII-1)
Concrete operation is with example 25.Yield 60%, white solid.m.p.191-194℃.IR(KBr)νmax(cm
-1)：3427，2930，2871，1717，1508，1276，1205，1033.
1H?NMR(300MHz，CDCl
3)，δ(ppm)：0.86(s，3H，C18-H)，3.70-3.82(m，1H，C16-CH
2OH)，3.86(s，3H，C2-OCH
3)，3.86-3.95(m，1H，C16-CH
2OH)，5.44(s，1H，C3-OH)，6.66(s，1H，C4-H)，6.78(s，1H，C1-H)；EI-MS?m/z：330(M
+).Anal.Calcd?for?C
20H
26O
4：C，72.70；H，7.93.Found：C，72.24；H，7.81。
Claims (8)
1. the compound of following general formula I or its pharmaceutically-acceptable salts:
Wherein:
M optional 0 or 1;
N optional 1 to 6;
P optional 0 to 1;
X represents O, S, NH, CH
2Or CO;
R
1Expression C
1-C
6Alkyl;
R
2Expression OH, SH, CN, halogen, NR
5R
6
R
3Expression OH ,=O, CO R ', R ' represents C
1-C
6Alkyl;
R
4Expression H, R "-OH or and R
3Form nitrogenous fragrant heterocycle, R " represent C
1-C
6Alkyl;
R
5And R
6Represent independently of one another H, C
1-C
6Alkyl; Perhaps R
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or the individual heteroatoms that is selected from N, O, S of 2-3; Described monocycle or dicyclo can be by C
1-C
6Alkyl.
2. compound according to claim 1, perhaps its pharmacy acceptable salt, it has the II-VIII structure:
Wherein, n is optional from 1 to 6; X represents O, S, NH, CH
2Or CO; Y represents O, S, NH, CH
2Or CO; R
1Expression C
1-C
6Alkyl; R
2Expression OH, NR
5R
6, R wherein
5And R
6Independently represent separately H, C
1-C
6Alkyl; Perhaps R
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or the individual heteroatoms that is selected from N, O, S of 2-3, and described monocycle or dicyclo can be by C
1-C
6Alkyl replaces; R
7Expression C
1-C
6Alkyl; R
8Expression H or C
1-C
6Alkyl; R
9Expression=O, OH or OSO
2CH
3R
10Expression H or C
1-C
5Alkyl.
3. compound according to claim 2 or its pharmacy acceptable salt, wherein X represents O, Y represents NH.
4. compound according to claim 2 or its pharmacy acceptable salt, wherein R
1Expression C
1-C
4Alkyl; R
2Expression OH, NR
5R
6, R wherein
5And R
6Represent independently of one another H, C
1-C
4Alkyl, perhaps R
5And R
6Form the monocycle of a 5-7 unit by the atom that connects them, and optionally in the formed ring contain 1 or 2-3 heteroatoms that is selected from N, O, described monocycle can be by C
1-C
4Alkyl replaces; R
7Expression C
1-C
6Alkyl; R
8Expression H or C
1-C
6Alkyl; R
9Expression=O, OH or OSO
2CH
3R
10Expression H or C
1-C
5Alkyl.
5. the preparation method of the compound of claim 2-4:
II、
The compound that the invention provides general formula III can be prepared by following methods:
III、
The compound that the invention provides general formula I V can be prepared by following methods:
IV、
The compound that the invention provides general formula V can be prepared by following methods:
V、
The compound that the invention provides general formula VI can be prepared by following methods:
VI、
The compound that the invention provides general formula VII can be prepared by following methods:
VII、
The compound that the invention provides general formula VIII can be prepared by following methods:
VIII、
Wherein n is optional from 1 to 6; X represents O, S, NH, CH
2Or CO; Y represents O, S, NH, CH
2Or CO; R
1Expression C
1-C
6Alkyl; R
2Expression OH, NR
5R
6, R wherein
5And R
6Independently represent separately H, C
1-C
6Alkyl; Perhaps R
5And R
6The monocycle or each ring that form a 5-7 unit by the atom that connects them be the dicyclo of 5-7 unit, and choose wantonly in the formed ring and contain 1 or the individual heteroatoms that is selected from N, O, S of 2-3, and described monocycle or dicyclo can be by C
1-C
6Alkyl; R
7Expression C
1-C
6Alkyl; R
8Expression H or C
1-C
6Alkyl; R
9Expression=O, OH or OSO
2CH
3R
10Expression H or C
1-C
5Alkyl.
6. pharmaceutical composition, the compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier that wherein contain in the claim 1 to 4 each form.
7. arbitrary compound and pharmacy acceptable salt thereof are used for the treatment of the application of pathological relative disease medicine in the claim 1 to 4 as vasoinhibitor.
8. application claimed in claim 7 is characterized in that in the following pathological relative disease any: (1) cancer, (2) retinopathy, (3) diabetes, (4) rheumatic arthritis, (5) lupus erythematosus, (6) chronic inflammatory diseases etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN115260276B (en) * | 2022-08-09 | 2024-06-07 | 湖南科益新生物医药有限公司 | Process for preparing steroid 16, 17-epoxy compound |
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| CN115260276A (en) * | 2022-08-09 | 2022-11-01 | 湖南科益新生物医药有限公司 | Process for the preparation of steroids 16,17-epoxides |
| CN115260276B (en) * | 2022-08-09 | 2024-06-07 | 湖南科益新生物医药有限公司 | Process for preparing steroid 16, 17-epoxy compound |
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