CN102875466A - Isoquinolinone derivatives, and preparation method and medical purpose thereof - Google Patents
Isoquinolinone derivatives, and preparation method and medical purpose thereof Download PDFInfo
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Abstract
The invention relates to the fields of pharmaceutical chemistry and organic chemistry, in particular to isoquinolinone derivatives. The compounds can be used for treating various medical indications associated with postmenopausal symptoms, uterine fiber lesions and arterial smooth muscle cell proliferation, particularly ER-(+) breast cancer by inhibiting alpha-estrogen receptor subtype (ER alpha) and through vascular endothelial growth factor receptor (VEGFR-2) bi-target. Meanwhile, the compounds have an obvious inhibiting effect on tumor metastasis, and have a general formula I.
Description
Technical field
The present invention relates to pharmaceutical chemistry and organic chemistry filed, be specifically related to the Isoquinolinium ketone derivatives.These compounds can be treated the multiple medical indications relevant with post-menopause syndrome with the two target spots of vascular endothelial growth factor receptor (VEGFR-2) by suppressing estrogen receptor alpha hypotype (ER α), and uterus fiber pathology and arterial smooth muscle cell hyperplasia, particularly be applicable to treat ER-(+) type mammary cancer.Simultaneously, this compounds also has obvious restraining effect to metastases.
Background technology
When " post-menopause syndrome " refers to that the women is in or finished physiological metamorphosis and is menopause, the multiple pathologic condition that descends and cause because of the estrogen secretion amount.It is mainly manifested in: osteoporosis, estrogen dependent cancer disease (mammary cancer, carcinoma of endometrium and ovarian cancer), cardiovascular disorder and senile dementia etc.
For the decline of postmenopausal estrogen level, the controversies in hormone replacement in the elderly of taking in the past (estrogen replacement therapy, ERT) has developed the sexual hormoue alternative medicine female, that progestogen is united use afterwards.If life-time service still may increase the incidence of mammary cancer and carcinoma of endometrium, these untoward reactions have limited ERT and HRT prolonged application clinically.Therefore, people try hard to seek and a kind of bone and cardiovascular systems are had estrogen-like effects, and uterus and mammary gland are shown the medicine of oestrogenic hormon antagonistic action.
Mammary cancer is another common disease of middle aged and aged women, main chemotherapy is to use selective estrogen receptor modulators Selective Estrogen Receptor Modulators at present, (SERMs), selective estrogen receptor modulators is in order to seek safer and more effective medicine, the new pharmaceutical field that researchdevelopment is got up the nineties in last century on Hormone Replacement Therapy (Hormone Replacement Therapy, HRT) basis.Wherein tamoxifen (Tamoxifen) in the highest flight.But tamoxifen also has very large shortcoming, and it shows the character of estrogen agonist in the uterus, and the cancer cells in uterus is had hormesis.
ER mechanism of action according to classics, SERMs is combined with ER and is formed dimer, in nucleus with target gene on estrogen response element (ERE) combination, and raise the co-activation factor or the co-suppression factor, and then start target gene and transcribe, in different tissues, show as ER agonist or antagonist.But studies confirm that in recent years, except nuclear receptor the function of classics pattern, SERMs can also with cytolemma on ER or G albumen coupling estrogen receptor (GPER/GPR30) combination, split the signal transduction mechanism of source activated protein kinase (MAPK), phosphatidylinositol3 3 kinase (PI3K), Tyrosylprotein kinase by starting silk, or bring into play fast physiological effect by regulating the film ionic channel.Recent experimental research achievements finds that ERK2 not only has signal transduction functionality, can also participate in ER directly to the transcriptional control of target gene.
MAPKs mainly comprises three inferior approach of classics: ERK, p38 and c-Jun.The ERK path is that various kinds of cell somatomedin (Growth factors) is such as the main kinases chain in Tyrosylprotein kinase (RTKs) the superfamily member downstreams such as vascular endothelial growth factor receptor (VEGFR), IGF-1 (IGFR), EGF-R ELISA (EGFR), platelet-derived growth factor acceptor (PDGFR)
Vascular endothelial growth factor (VEGF) is combined with VEGFR as stimulating factor can activate the ERK path, promotes endothelial cell division propagation, the induced tumor vasculogenesis.The VEGFR inhibitor is exactly the medicine that a class can suppress by suppressing the MAPK signal transduction pathway tumor-blood-vessel growth and apoptosis of tumor cells.
There are in the recent period bibliographical information Tamoxifen and VEGFR-2 kinase inhibitor Brivanib drug combination to treat the effective of ER-(+) mammary cancer than using separately separately, can reduce the endometrial hyperplasia side effect, reduce resistance.
Compound with the two target spot effects of ER α and VEGFR-2, active and the inhibition tumor angiogenesis by regulation and control ER alpha transcriptional, energy anti-ER-(+) Cells Proliferation of Human Breast Cancer, avoid the endometrial hyperplasia side effect or suppress ER-(+) carcinoma of endometrium, also might treat post-menopause syndrome, metastases is also had obvious restraining effect.
Summary of the invention
The invention discloses compound isoquinolinone derivatives and the pharmacy acceptable salt thereof of a class general formula I:
General formula I
R wherein
1, R
2Represent independently of one another H, OH, C
1-C
4Alkoxyl group, C
1-C
6Carbalkoxy;
R
3, R
4Expression-CO (CH independently of one another
2)
2CH
3,-CO (CH
2)
3CH
3Or C
1-C
6Alkyl; Or R
3And R
4And coupled nitrogen-atoms is combined into piperidyl, pipecoline base, homopiperidinyl, morpholinyl, pyrrolidyl, 3-methylpyrrole alkyl, 3,3-alkyl dimethyl pyrrole, 3,4-dimethoxy pyrrolidyl, piperazinyl, N methyl piperazine base, NEP base, N-Phenylpiperazinyl, N-benzyl piperazine base.
X represents O, S, NH, CH
2Or-CO-;
M=0 or 1;
N=2 or 3;
R
1, R
2Preferred expression OH or methoxyl group.
R
3, R
4Preferably be connected to form pyrrolidyl, piperidyl or methylpiperazine base, methyl, ethyl, propyl group, sec.-propyl or normal-butyl with the N atom.
X preferably represents O.
Compound of Formula I of the present invention can prepare with following method:
R wherein
1, R
2, R
3, R
4, X, n, m definition the same.
The structure of part of compounds of the present invention is as follows:
| The compound code name | R 1 | R 2 | n | R 3，R 4 |
| Ia | CH 3O | CH 3O | 2 | CH 3 |
| Ib | CH 3O | CH 3O | 2 | ((CH 2) 2) 2NCH 3 |
| Ic | CH 3O | CH 3O | 2 | (CH 2) 5 |
| Id | CH 3O | CH 3O | 2 | (CH 2) 4 |
| Ie | CH 3O | CH 3O | 2 | (CH 2) 2O(CH 2) 2 |
| If | CH 3O | CH 3O | 2 | CH 2CH 3 |
| Ig | OH | OH | 2 | CH 3 |
| Ih | OH | OH | 2 | (CH 2) 5 |
| Ii | OH | OH | 2 | (CH 2) 4 |
| Ij | OH | OH | 2 | ((CH 2) 2) 2NCH 3 |
| Ik | CH 3O | CH 3O | 3 | (CH 2) 4 |
| Il | CH 3O | CH 3O | 3 | (CH 2) 5 |
| Im | OH | OH | 3 | (CH 2) 4 |
| In | OH | OH | 3 | (CH 2) 5 |
The pharmacy acceptable salt of compound of the present invention and salt formation is included in the present invention equally, compound of Formula I can with following salt formation pharmaceutical salts: hydrochloride, vitriol, phosphoric acid salt, acetate and maleate etc.
The invention further relates to the compound of general formula I and the medicinal compositions that pharmaceutically acceptable carrier forms.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 tablet, capsule 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 0.001-100mg/kg/ days, can depart from this dosage range according to the difference of disease degree or the difference of formulation.
Pharmacological testing shows that the compounds of this invention can be used for alleviating the symptom of post-menopause syndrome, ER-(+) type mammary cancer particularly, cardiovascular relevant pathological state and osteoporosis.Simultaneously, the compounds of this invention also can obviously suppress metastases.
Compound of the present invention is equally applicable to suppress women's uterus fiber pathology and people's arterial smooth muscle hyperplasia, particularly restenosis.
The below is part pharmacology test and the result of part of compounds of the present invention:
The experiment of 1ER (α) avidity
1.1 experiment material
Estrogen Reeptor-alpha(ERα)Human Recombinant
The fluorescence aglucon
ES2 Screening Buffer(Invitrogen，USA)
384 hole black microwell plates (Corning, USA)
Rifle head (Axygen, USA)
1.2 experimental procedure
1)Prepare Reagents
Every kind of accurate weighing of testing compound adds the DMSO solvent and becomes mother liquor, then uses ES2 Screening Buffer preparation testing compound solution to desired concn
2) Prepare the 2X fluorescence aglucon/ER α Complex
Use ES2 Screening Buffer preparation 2X fluorescence aglucon and ER α mixed solution to make final fluorescence aglucon concentration be 9nM, ER α concentration is 30nM.
3)Perform the Competition Assay
First every hole adds the 50ul compound, and every hole adds 50ul 2X fluorescence aglucon and ER α mixing solutions again.Add simultaneously 50ul estradiol solution (1nM), in conjunction with contrast, adding 50ul Buffer, 50ul 2X fluorescence aglucon and ER α mixing solutions are competed in conjunction with contrast as 0% and are added 100ulBuffer as blank as 100% competition for 50ul 2X fluorescence aglucon and ER α mixing solutions.The lucifuge operation.Room temperature (20-25 ℃) is hatched 90min.
1.3 data processing
Calculate each testing compound to the inhibiting rate (Inh%) of estrogen receptor according to formula
1.4 active result (0.1mg/ml)
| The compound code name | Inh％ | The compound code name | Inh％ |
| Tamoxifen | 100 | Ih | 87.14 |
| Ia | 63.12 | Ii | 95.93 |
| Ib | 62.09 | Ij | 87.94 |
| Ic | 72.83 | Ik | 57.57 |
| Id | 63.60 | Il | 59.65 |
| Ie | 64.84 | Im | 95.70 |
| If | 69.10 | In | 99.89 |
| Ig | 88.57 | - | - |
With the positive contrast of tamoxifen, synthetic part isoquinolines-compounds has been carried out the experiment of ER α avidity, experimental result shows, 3,7 be respectively the para hydroxybenzene based structures compound activity will significantly better than 3,7 be respectively the compound of p-methoxyphenyl structure, supposition is because the bonding force of hydroxyl and related amino acid residue is better than the bonding force of methoxyl group and amino-acid residue.Wherein Compound I i, Im, In carry out multiple sieve, and IC50 is respectively 3.1 μ M, 2.3 μ M, 1.3 μ M, and the IC50 of positive drug tamoxifen is 1.9 μ M.
The experiment of 2KDR kinase inhibiting activity
2.1 materials and methods:
2.1.1 material:
KDR kinases (Invitrogen, USA)
HTRF KinEASE-TK(Cisbio，USA)
ATP, MgCl2, MnCl2, DTT (domestic)
384 low volume blanks (Corning, USA)
Import rifle head (Axygen, USA)
2.1.2 method:
1) every hole adds KDR kinase solution 2 μ l, substrate solution 2 μ l, damping fluid or compound to be sieved 4 μ l, ATP2 μ l in reaction vessel.Reacted 1 hour.
2) every hole adds TK-Ab 5 μ l, SA-XL665 5 μ l, incubated at room 1 hour.
3) utilize Beckman Coulter detection platform HTRF module to detect.
2.2 testing sample and positive compound detect:
The mother liquor of testing sample for putting and provide to magnificent teach problem assembly.
The KDR positive drug is selected inhibitor Sunitinib.
| The compound code name | Inh％ | The compound code name | Inh％ |
| Sutent | 100 | Ih | 84.83 |
| Ia | 66.07 | Ii | 49.87 |
| Ib | 79.43 | Ij | 103.34 |
| Ic | 65.30 | Ik | 98.46 |
| Id | 83.80 | Il | 72.75 |
| Ie | 51.19 | Im | 48.33 |
| If | 92.54 | In | 100.26 |
| Ig | 79.43 |
With the positive contrast of Sunitinib, synthetic part compound of isobioquin group has been carried out the experiment of KDR kinase inhibiting activity, result of study shows, majority of compounds all shows certain inhibition activity to the KDR kinases, wherein Compound I j and In's is active best, carries out multiple sieve, surveys its IC
50For being respectively 1.9 μ M and 1.4 μ M, and the IC of Sunitinib
50Be 1.03 μ M.
The experiment of 3MCF-7 Cells Proliferation of Human Breast Cancer
The method of reference Journal of Medicinal Chemistry.1997.40.1407-1416 is changed slightly.
3.1 experiment material
3.1.1 clone
Human breast cancer cell MCF-7 is available from Nanjing Kai Ji biotech company
3.1.2 reagent
RPMI1640 substratum, two anti-, the calf serums of blue or green chain are available from GIBCO company;
3-(4,5)-2-thiazole-(2,5)-dimethyl bromination tetrahydrochysene azoles blue (MTT) is available from Nanjing Sheng Xing biotech firm;
Other reagent are domestic analytical pure.
3.1.3 main laboratory apparatus
U.S. Revco CO
2Incubator; The full-automatic microplate reader of Labsystems Multiskan Ascent; Germany Carl Ziess Axiovert 40 CFL type fluorescence inverted microscopes.
3.2 experimental technique
3.2.1 cell cultures
The MCF-7 cell with RPMI1640 substratum (containing 10% calf serum, the Streptomycin sulphate of the penicillin of 100U/ml and 100 μ g/ml) in 5%CO
2, cultivate in 37 ℃ of incubators, changed a subculture in about two days, passed once generation in 3-4 days; During passage cell, outwell old substratum, D-hanks washes twice and (washes phenol red in the substratum off, because the phenol red digestion effect that can affect pancreatin), add a small amount of 0.25% trypsin 25mg trypsinase, 100mlD-hanks), at the bottom of paving bottle, cell rounding is observed in about 2 minutes of 37 ℃ of lower digestion under the inverted microscope, outwell pancreatin, D-hanks washes once, adds fresh culture, the piping and druming mixing, divide and implant in the new culturing bottle, continue to cultivate.Cell counting, the cell suspension that takes a morsel mixes with 0.4% trypan blue solution equal-volume, blow and beat mixing with suction pipe, getting a little (15 μ l-20 μ l) mixture splashes in the space, top of tally and cover glass, mainly do not produce bubble, under 200 times of low-power microscope, observe, dead cell can be by Trypan Blue, and viable cell can not, mobile tally is to seeing the counting grid, and number goes out the cell count of being unstained of each four large lattice in diagonal angle, and record comprises the cell of pressing right line and reaching the standard grade, roll off the production line and disregard the large gitter cell number of cell count/ml=25% lattice * 10 with left line
4
3.2.2MTT detection method
Measuring method is as follows: be 1 * 10 with concentration
5The MCF-7 cell of individual/ml is seeded to respectively in 96 orifice plates, and cultivated 24 hours in 100 μ l/ holes; Add the pastille substratum in 100 μ l/ holes, the medicine final concentration is respectively 1 * 10
-4Mol/L, 1 * 10
-5Mol/L 1 * 10
-6Mol/L 1 * 10
-7Mol/L, 4 multiple holes of each concentration replace cancer therapy drug to organize in contrast with the substratum with volume, and blank group is 200 μ l substratum.Add 5mg/mlMTT20 μ l/ hole after cultivating 48hr, continue to cultivate 4hr, liquid in the careful sucking-off hole adds DMSO150 μ l/ hole, surveys each hole absorbancy OD value under the 570nm wavelength, calculates cell inhibitory rate and IC
50
| The compound code name | IC 50(μM) | The compound code name | IC 50(μM) |
| Tamoxifen | 1.89E-6 | Ih | 3.63E-6 |
| Ia | 2.38E-3 | Ii | 1.18E-5 |
| Ib | 4.29E-4 | Ij | 9.45E-6 |
| Ic | 3.22E-4 | Ik | 4.79E-4 |
| Id | 8.63E-4 | Il | 5.29E-3 |
| Ie | Invalid | Im | 1.27E-5 |
| If | 3.83E-4 | In | 2.73E-6 |
| Ig | 1.89E-5 |
With the positive contrast of tamoxifen, synthetic part compound of isobioquin group has been carried out the MCF-7 cell experiment, result of study shows that part of compounds shows the MCF-7 cell and suppresses preferably active, wherein Compound I n's is active best, its IC
50Be 2.73 μ M.Can observe simultaneously 3,7 be respectively the para hydroxybenzene based structures compound activity will significantly better than 3,7 be respectively the compound of p-methoxyphenyl structure, supposition is because the bonding force of hydroxyl and related amino acid residue is better than the bonding force of methoxyl group and amino-acid residue.This is with ER α avidity experimental result and KDR kinase inhibiting activity experimental result are consistent before.
4MTT method test HUVEC cell proliferation test
Testing method: HUVEC cultivates with the RPMI-1640 that contains 10% foetal calf serum, and the vegetative period cell of taking the logarithm is used for experiment.Adjusting cell density is 2 * 104/mL, be inoculated in 96 orifice plates, cultivate after 24 hours, the pastille substratum that adds 100 μ l/ holes, 4 multiple holes of each concentration are organized in contrast with the substratum replacement testing drug of equal volume, and blank group is 200 μ l substratum, continue behind the mixing to cultivate after 48 hours, add 20 μ l/ hole MTT (concentration is 5mg/ml).After continuing to cultivate 4h, abandon supernatant liquor, every hole adds DMSO 150 μ l/ holes, enzyme mark detector is measured every hole absorbancy (A) value in 570nm wavelength place, 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 compound code name | IC 50(μM) | The compound code name | IC 50(μM) |
| Tamoxifen | 5.3 | Ih | 8.52 |
| Ia | 3.14 | Ii | 4.18 |
| Ib | 2.56 | Ij | 2.71 |
| Ic | 2.47 | Ik | 6.38 |
| Id | 2.60 | Il | 3.53 |
| Ie | 7.8 | Im | 6.34 |
| If | 1.15 | In | 2.79 |
| Ig | 2.20 |
The result: it is active that compound exhibits of the present invention goes out good inhibition HUVEC, in conjunction with the anti-migratory activity experiment, illustrates that compound can suppress migration and the increment of cell simultaneously.
Blood vessel formation against function in the body of 5 chick chorioallantoic membranes test detection of drugs
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); Divide (3 μ M/ pieces of four concentration gradients, 10 μ M/ pieces, 30 μ M/ pieces) dosing is on the aseptic methylcellulose gum filter paper wafer carrier for preparing, control group adds physiological saline, put on the chick embryo air sac chorioallantoic membrane, 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.
Description of drawings:
Fig. 1 is the vascular development situation map that DMSO control group chick chorioallantoic membrane was cultivated 72 hours
Fig. 2 is the vascular development situation map that Sunitinib/3 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 3 is the vascular development situation map that Sunitinib/10 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 4 is the vascular development situation map that Sunitinib/30 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 5 is the vascular development situation map that Ij/3 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 6 is the vascular development situation map that Ij/10 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 7 is the vascular development situation map that Ij/30 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 8 is the vascular development situation map that Ij/3 μ M chick chorioallantoic membrane was cultivated 72 hours
Fig. 9 is the vascular development situation map that Ij/10 μ M chick chorioallantoic membrane was cultivated 72 hours
Figure 10 is the vascular development situation map that Ij/30 μ M chick chorioallantoic membrane was cultivated 72 hours
The result: the chick chorioallantoic membrane test shows that Compound I j and In have the effect of angiogenesis inhibitor in the good body.
Carried out in addition the external scratch experiment of Human umbilical vein endothelial cells (HUVEC), experimental result shows: most compounds can suppress the migration of cell, and the prompting compound has certain restraining effect to the transfer of tumour.
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 AV500 type (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 7-methoxyl group-3-(4-the p-methoxy-phenyl)-heterochromatic alkene of 1H--1-ketone (IVa)
Meta-methoxy homophthalic acid (0.18g, 0.86mmol), anisoyl chloride (0.09g, 3.44mmol), 200 ℃ were stirred 6 hours, added the 50ml methylene dichloride, the saturated sodium carbonate washing, organic phase is spin-dried for, and column chromatography gets white solid (0.092g, 35%).m.p.144-146℃
Embodiment 2
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-hydroxy phenyl) isoquinoline 99.9-1 (2H)-ketone (Va)
7-methoxyl group-3-(4-the p-methoxy-phenyl)-heterochromatic alkene of 1H--1-ketone (1g, 3.54mmol), para hydroxybenzene amine (1.93g, 17.7mmol), acetic acid 2ml, return stirring 4 hours is spin-dried for, the methylene dichloride dissolving, the 1NHCl washing, organic phase is spin-dried for, column chromatography, get white solid powder 0.67g, yield 51.1%.m.p.236-240℃。
1H-NMR(CDCl
3)δ：3.76(s，3H，OCH3)，3.94(s，2H，OCH3)，6.67～7.75(m，12H，Ar-H&C4-H)，9.58(s，1H，OH)。EI-MS m/z：374[M]
+。
Embodiment 3
The preparation of N-(2-chloroethyl) piperidine hydrochlorate (VIa)
With 1.70g, be equivalent to the piperidines of 2ommol, 0.67ml, the ethylene chlorhydrin and the 2ml toluene that are equivalent to 10mmol adds in the reaction flask successively, be warming up to back flow reaction 3h, be cooled to room temperature, separate out solid, suction filtration, filter cake 1ml toluene wash, filtrate temperature control drip the 2ml thionyl chloride in about 75 ℃, drip and finish back flow reaction 2h.Be cooled to room temperature, be evaporated to driedly, resistates dehydrated alcohol recrystallization obtains white solid 2.17g, yield 59.2%.m.p.229-233℃。
Embodiment 4
The preparation of N-(3-chloropropyl) piperidine hydrochlorate (VIb)
With 1.72g, be equivalent to the piperidines of 20.3mmol, 2ml, the 3-propylene chlorohydrin that is equivalent to 24.3mmol and 10ml toluene add in the reaction flask successively, are warming up to back flow reaction 4h, add 5%NaOH4ml, back flow reaction 1h is cooled to room temperature, uses the 5%NaOH solution washing, organic layer saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate drips 3ml, is equivalent to the thionyl chloride of 40.6mmol under ice bath, drip and finish, the stirred overnight at room temperature reaction.Reaction solution is evaporated to dried, and resistates dehydrated alcohol recrystallization obtains khaki color solid 2.4g, yield 59%.m.p.218-220℃。
Embodiment 5
The preparation of 2-dimethylamino monochloroethane hydrochloride (VIc)
With 16.1ml, the ethylene chlorhydrin that is equivalent to 0.24mol splashes into 13.4ml, be equivalent in the dimethylamine of 0.2mol, drip and finish, be warming up to back flow reaction 4h, be cooled to room temperature, add 40ml 4NNaOH solution, 30ml benzene, after the vigorous stirring, leave standstill and tell the benzene layer, water layer washs with benzene, the combined benzene layer, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, obtain 22ml oily matter, add the dissolving of 40ml tetracol phenixin, the ice-water bath cooling drips the solution that the 10ml thionyl chloride is dissolved in the 10ml tetracol phenixin, drip and finish, in room temperature reaction 4h, be evaporated to dried, the resistates re-crystallizing in ethyl acetate, dry white, needle-shaped crystals 17.5g, the yield 60.8% of getting.m.p.199-203℃。
Embodiment 6
The preparation of 3-dimethylamino chloropropane hydrochloride (VId)
With 16.1ml, the 3-propylene chlorohydrin that is equivalent to 0.24mol splashes into 13.4ml, be equivalent in the dimethylamine of 0.2mol, drip and finish, be warming up to back flow reaction 4h, be cooled to room temperature, add 40ml 4NNaOH solution, 30ml benzene, after the vigorous stirring, leave standstill and tell the benzene layer, water layer washs with benzene, the combined benzene layer, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, obtain 22ml oily matter, add the dissolving of 40ml tetracol phenixin, the ice-water bath cooling drips the solution that the 10ml thionyl chloride is dissolved in the 10ml tetracol phenixin, drip and finish, in room temperature reaction 4h, be evaporated to dried, the resistates re-crystallizing in ethyl acetate, dry white, needle-shaped crystals 17.5g, the yield 60.8% of getting.m.p.140-142℃。
Embodiment 7
The preparation of 2-diethylin monochloroethane hydrochloride (VIe)
With 16.1ml, the chloroethanol that is equivalent to 0.24mol splashes into 20.6ml, be equivalent in the diethylamine of 0.2mol, drip and finish, be warming up to back flow reaction 4h, be cooled to room temperature, add 40ml 4NNaOH solution, 30ml benzene, after the vigorous stirring, leave standstill and tell the benzene layer, water layer washs with benzene, the combined benzene layer, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, obtain 22ml oily matter, add the dissolving of 40ml tetracol phenixin, the ice-water bath cooling drips the solution that the 10ml thionyl chloride is dissolved in the 10ml tetracol phenixin, drip and finish, in room temperature reaction 4h, be evaporated to dried, the resistates re-crystallizing in ethyl acetate, dry white, needle-shaped crystals 16.1g, the yield 46.6% of getting.m.p.207-210℃。
Embodiment 8
The preparation of 3-diethylin chloropropane hydrochloride (VIf)
With 10ml toluene, 3ml, the diethylamine that is equivalent to 28.9mmol and 2.9ml, the 3-propylene chlorohydrin that is equivalent to 34.6mmol add in the reaction flask successively, be warming up to back flow reaction 6h, be cooled to room temperature, use successively 5%NaOH solution, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate drips 4.2ml under condition of ice bath, the thionyl chloride that is equivalent to 57.7mmol, drip and finish in stirred overnight at room temperature, reaction solution is evaporated to dried, the resistates re-crystallizing in ethyl acetate, obtain white solid 2.1g, yield 40%.m.p.80-82℃。
Embodiment 9
The preparation of N-(2-chloroethyl)-4-methylpiperazine dihydrochloride (VIg)
With 10ml, 25%NaOH, add successively in the reaction flask with 1ml, the 4-methylpiperazine that is equivalent to 9mmol, be warming up to 50 ℃, drip 1.8ml, be equivalent to the 1-bromo-2-monochloroethane of 18mmol, drip and finish in 50 ℃ of reaction 6h, be cooled to room temperature, the reaction solution ethyl acetate extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dried, drip a small amount of ethanol/hydrogen chloride solution, jolt, place refrigerator and leave standstill, be evaporated to dried, obtain white solid 0.43g, yield 23%.m.p.227-230℃。
Embodiment 10
The preparation of N-(3-chloropropyl)-4-methylpiperazine hydrochloride (VIh)
With 10ml25%NaOH, add successively in the reaction flask with 1ml, the 4-methylpiperazine that is equivalent to 9mmol, be warming up to 50 ℃, drip 1.8ml, be equivalent to the 1-bromo-3-chloropropane of 18mmol, drip and finish in 50 ℃ of reaction 6h, be cooled to room temperature, the reaction solution ethyl acetate extraction, use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dried, drip a small amount of ethanol/hydrogen chloride solution, jolt, place refrigerator and leave standstill, be evaporated to dried, obtain white solid 0.21g, yield 11%.m.p.255-257℃。
Embodiment 11
The preparation of N-(2-chloroethyl) Pyrrolidine hydrochloride (VIi)
With 165ml, be equivalent to the Pyrrolidine of 2mol, 67ml, the ethylene chlorhydrin that is equivalent to 1mol and 200ml toluene add in the reaction flask successively, be warming up to back flow reaction 3h, be cooled to room temperature, separate out solid, suction filtration, filter cake 20ml toluene wash, filtrate temperature control drip the 200ml thionyl chloride in about 75 ℃, drip and finish back flow reaction 2h.Be cooled to room temperature, be evaporated to driedly, resistates dehydrated alcohol recrystallization obtains white solid 105g, yield 62.3%.m.p.198-203℃。
Embodiment 12
The preparation of N-(2-chloroethyl) Pyrrolidine hydrochloride (VIj)
With 165ml, be equivalent to the Pyrrolidine of 2mol, 67ml, the 3-propylene chlorohydrin that is equivalent to 1mol and 200ml toluene add in the reaction flask successively, be warming up to back flow reaction 3h, be cooled to room temperature, separate out solid, suction filtration, filter cake 20ml toluene wash, filtrate temperature control drip the 200ml thionyl chloride in about 75 ℃, drip and finish back flow reaction 2h.Be cooled to room temperature, be evaporated to driedly, resistates dehydrated alcohol recrystallization obtains white solid 105g, yield 62.3%.m.p.169-173℃。
Embodiment 13
The preparation of 2-diisopropylaminoethyl monochloroethane hydrochloride (VIk)
Add 5ml, be equivalent to the Diisopropylamine of 35.7mmol, drip 3.6ml, be equivalent to the ethylene chlorhydrin of 53.6mmol, drip and finish, be warming up to back flow reaction 5h, be cooled to room temperature, add 8%KOH, 10ml benzene stirs, and tells the benzene layer, use the saturated common salt water washing, anhydrous sodium sulfate drying filters, drip 5.2ml, be equivalent to the thionyl chloride of 71.3mmol, drip and finish, in room temperature reaction 12h, be evaporated to driedly, obtain white solid 2.73g, yield 38%.m.p.129-131℃。
Embodiment 14
The preparation of N-(2-chloroethyl) morpholine hydrochloride (VIl)
5g, the morpholine that is equivalent to 57mmol are dissolved in 15ml toluene, drip 4.6ml, be equivalent to the ethylene chlorhydrin of 69mmol, drip and finish, be warming up to backflow 5h, cooling adds the 20ml5%NaOH washing, organic layer saturated common salt water washing, anhydrous sodium sulfate drying filters, filtrate is cooled off under ice bath, drips 8.3ml, is equivalent to the thionyl chloride of 114mmol, drips to finish under room temperature and reacts 12h, be evaporated to dried, the resistates re-crystallizing in ethyl acetate obtains white solid 5.9g, yield 55%.m.p.182-184℃。
Embodiment 15
The preparation of N-(3-chloropropyl) morpholine hydrochloride (VIm)
With the 5ml acetonitrile, 2.3ml, be equivalent to 1-bromo-3-chloropropane and the 1ml of 23mmol, the morpholine that is equivalent to 11.5mmol adds in the reaction flask successively, stirs 1h, adds 0.5ml5%NaOH solution, in stirring at room reaction 12h, add the 3ml concentrated hydrochloric acid, 10ml water, lower floor discards, alkalize with 5%NaOH in the upper strata, the saturated common salt water washing of ethyl acetate extraction, organic layer, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dried, drips a small amount of ethanol/hydrogen chloride solution, jolts, the placement refrigerator leaves standstill, be evaporated to driedly, obtain white solid 1.4g, yield 60%.m.p.168-170℃。
Embodiment 24
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(2-dimethylamino ethoxy) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ia)
With 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-hydroxy phenyl) isoquinoline 99.9-1 (2H)-ketone (0.3g, 0.80mmol), 2-dimethylamino monochloroethane hydrochloride (0.22g, 1.55mmol), salt of wormwood (0.49g, 3.54mmol) and the catalytic amount potassiumiodide join in the acetone (30ml), stir and be heated to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 6a (0.12g, 30%).m.p.148-149℃。
1H-NMR(CDCl
3)δ：2.35(s，6H，NCH
3)，2.73(t，2H，NCH
2，J
1＝5.55，J
2＝5.25)，3.76(s，3H，OCH
3)，3.93(s，3H，OCH
3)，4.03(t，2H，OCH2，J
1＝5.46，J
2＝5.43)，6.53(s，1H，C4-H)，6.69～7.60(m，11H，Ar-H，)。EI-MS m/z：445[M]
+。
Embodiment 25
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(2-(4-methylpiperazine) oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ib)
With 0.27g, be equivalent to the compound V of 0.72mmol, 0.2g, be equivalent to the salt of wormwood of 1.44mmol, 0.14g, the compound vi g that is equivalent to 1.44mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.1g, yield 28%.m.p.124-126℃。
1H-NMR(CDCl
3)δ：2.38～2.67(m，11H，NCH
2NCH
3)，2.80(d，2H，NCH
2，J＝4.95)，3.73(s，3H，OCH
3)，3.90(s，3H，OCH
3)，4.03(d，2H，OCH2，J＝5.25)，6.52(s，1H，C4-H)，6.68～7.84(m，11H，Ar-H)。EI-MS m/z：500[M]
+。
Embodiment 26
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(2-piperidines oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ic)
With 0.27g, be equivalent to the compound V of 0.72mmol, 0.2g, be equivalent to the salt of wormwood of 1.44mmol, 0.29g, the compound vi b that is equivalent to 1.44mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.11g, yield 31%.m.p.114-116℃。
1H-NMR(CDCl
3)δ：1.17～1.78(m，6H，3，4-tetrahydropyridinyl-H)，2.97(s，2H，NCH2)，3.45(d，4H，2-tetrahydropyridinyl-H，J＝9.66)，3.69(s，3H，OCH
3)，3.87(s，3H，OCH
3)，4.33(s，2H，OCH2)，6.63(s， 1H，C4-H)，6.74～7.61(m，11H，Ar-H)。EI-MS m/z：485[M]
+。
Embodiment 27
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(2-tetramethyleneimine oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (Id)
With 0.27g, be equivalent to the compound V of 0.72mmol, 0.2g, be equivalent to the salt of wormwood of 1.44mmol, 0.25g, the compound vi i that is equivalent to 1.44mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.94g, yield 28%.m.p.118-120℃。
1H-NMR(CDCl
3)δ：1.88～2.01(m，4H，2-pyrrolidinyl-H)，3.09(s，2H，NCH2)，3.54(s，4H，3-pyrrolidinyl-H)，3.69(s，3H，OCH3)，3.88(s，3H，OCH3)，4.29(s，2H，OCH2)，6.63(s，1H，C4-H)，6.75～7.67(m，11H，Ar-H，)。EI-MS m/z：471[M]
+。
Embodiment 28
7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(preparation of 4-(2-morpholinyl phenyl) isoquinoline 99.9-1 (2H)-ketone (Ie)
With 0.27g, be equivalent to the compound V of 0.72mmol, 0.2g, be equivalent to the salt of wormwood of 1.44mmol, 0.26g, the compound vi l that is equivalent to 1.44mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.1g, yield 30%.m.p.80-82℃。
1H-NMR(CDCl
3)δ：3.19(s，2H，NCH
2)，3.46(s，4H，2-morpholinyl-H)，3.09(s，2H， NCH
2)，3.69(s，3H，OCH
3)，3.81(s，4H，3-morpholinyl-H)，3.87(s，3H，OCH
3)，4.37(s，2H，OCH2)，6.63(s，1H，C4-H)，6.69～7.70(m，11H，Ar-H，)。EI-MS m/z：487[M]
+。
Embodiment 29
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(2-diethylamino ethoxy) phenyl) isoquinoline 99.9-1 (2H)-ketone (If)
With 0.27g, be equivalent to the compound V of 0.72mmol, 0.2g, be equivalent to the salt of wormwood of 1.44mmol, 0.27g, the compound vi f that is equivalent to 1.44mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.85g, yield 25%.m.p.183-185℃。
1H-NMR(CDCl
3)δ：1.29(t，6H，CH
3，J
1＝J
2＝7.05)，3.26(s，4H，NCH
2)3.52(s，2H，NCH
2)，3.93(s，3H，OCH
3)，3.88(s，3H，OCH
3)，4.36(s，2H，OCH2)，6.69(s，1H，C4-H)，6.81～7.77(m，11H，Ar-H，)。EI-MSm/z：473[M]
+。
Embodiment 30
The preparation of 7-hydroxyl-3-(4-hydroxy phenyl)-2-(4-(2-dimethylamino ethoxy) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ig)
With 0.5g, be equivalent to the Compound I a of 1.12mmol, acetic acid 3ml, 40%HBr1.5ml, return stirring 24h is spin-dried for column chromatography and gets faint yellow solid 0.38g, yield 81%.m.p.188-190℃。
1H-NMR(CDCl
3)δ：2.76(s，6H，NCH
3)，2.79(s，2H，NCH
2)，4.24(s，2H，OCH
2)，6.54～7.70(m，12H，Ar-H&C4-H，)，9.55(s，1H， OH)，9.99(s，1H，OH)。EI-MS m/z：417[M]
+。
Embodiment 31
The preparation of 7-hydroxyl-3-(4-hydroxy phenyl)-2-(4-(2-piperidines oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ih)
With 0.54g, be equivalent to the Compound I c of 1.12mmol, acetic acid 3ml, 40%HBr1.5ml, return stirring 24h is spin-dried for column chromatography and gets faint yellow solid 0.383g, yield 75%.m.p.190-192℃。
1H-NMR(CDCl
3)δ：1.42～1.76(m，6H，CH
2&CH
3)，3.01～3.24(m，4H，NCH
2)，3.41(s，2H，N)，4.31(s，2H，OCH
2)，6.60～7.65(m，12H，Ar-H&C4-H)，9.60(s，1H，OH)，10.04(s，1H，OH)。EI-MS m/z：457[M]
+。
Embodiment 32
The preparation of 7-hydroxyl-3-(4-hydroxy phenyl)-2-(4-(2-tetramethyleneimine oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ii)
With 0.53g, be equivalent to the Compound I d of 1.12mmol, acetic acid 3ml, 40%HBr1.5ml, return stirring 24h is spin-dried for column chromatography and gets faint yellow solid 0.39g, yield 78%.m.p.180-182℃。
1H-NMR(CDCl
3)δ：1.88～2.01(m，4H，3，4-pyrrolidinyl-H)，3.10(s，2H，NCH
2)，3.56(s，4H，2-pyrrolidinyl-H1)，4.28(s，2H，OCH
2)，6.54～7.69(m，12H，Ar-H&C4-H)，9.58(s，1H，OH)，10.00(s，1H，OH)。EI-MS m/z：443[M]
+。
Embodiment 33
The preparation of 7-hydroxyl-3-(4-hydroxy phenyl)-2-(4-(2-(4-methylpiperazine) oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ij)
With 0.56g, be equivalent to the compounds ib of 1.12mmol, acetic acid 3ml, 40%HBr1.5ml, return stirring 24h is spin-dried for column chromatography and gets faint yellow solid 0.45g, yield 85%.m.p.178-180℃。
1H-NMR(CDCl
3)δ：2.26(s，3H，NCH
3)，2.35(s，8H，NCH
2)，2.79(s，2H，NCH
2)，4.24(s，2H，OCH
2)，6.54～7.70(m，12H，Ar-H&C4-H，)，9.55(s，1H，OH)，9.99(s，1H，OH)。EI-MS m/z：472[M]
+。
Embodiment 34
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(3-pyrrolidyl propoxy-) phenyl) isoquinoline 99.9-1 (2H)-ketone (Ik)
With 0.22g, be equivalent to the compound V of 0.59mmol, 0.33g, be equivalent to the salt of wormwood of 2.36mmol, 0.15g, the compound vi j that is equivalent to 0.88mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.1g, yield 35%.m.p.140-142℃。
1H-NMR(CDCl
3)δ：1.89～2.28(m，6H，2-pyrrolidinyl-H&3-pyrrolidinyl-H)，2.89(s，2H，2-pyrrolidinyl-H)，2.98(s，2H，NCH
2)，3.69(s，3H，OCH
3)，3.87(s，3H，OCH
3)，4.01(s，2H，OCH2)，6.62(s，1H，C4-H)，6.74～7.95(m，11H，Ar-H)。EI-MSm/z：485[M]
+。
Embodiment 35
The preparation of 7-methoxyl group-3-(4-p-methoxy-phenyl)-2-(4-(3-piperidyl propoxy-) phenyl) isoquinoline 99.9-1 (2H)-ketone (Il)
With 0.22g, be equivalent to the compound V of 0.59mmol, 0.33g, be equivalent to the salt of wormwood of 2.36mmol, 0.15g, the compound vi b that is equivalent to 0.88mmol and 30ml acetone add in the reaction flask successively, are warming up to back flow reaction 12h, filtered while hot, filtrate decompression is concentrated into dried, with the dissolving of 20ml methylene dichloride, filters insolubles, filtrate decompression is concentrated into dried, column chromatography purification obtains faint yellow solid 0.11g, yield 39%.m.p.128-130℃。
1H-NMR(CDCl
3)δ：1.68～1.77(m，6H，3，4-tetrahydropyridinyl-H)，2.13(s，2H，2-tetrahydropyridinyl-H)，2.86(s，2H，2-tetrahydropyridinyl-H)，3.16(s，2H，NCH
2)，3.69(s，3H，OCH
3)，3.87(s，3H，OCH
3)，4.00(t，2H，OCH2，J
1＝5.46，J
2＝5.43)，6.62(s，1H，C4-H)，6.74～7.70(m，11H，Ar-H，)。EI-MS m/z：499[M]
+。
Embodiment 36
The preparation of 7-hydroxyl-3-(4-hydroxy phenyl)-2-(4-(3-tetramethyleneimine propoxy-) phenyl) isoquinoline 99.9-1 (2H)-ketone (Im)
With 0.54g, be equivalent to the Compound I k of 1.12mmol, acetic acid 3ml, 40%HBr1.5ml, return stirring 24h is spin-dried for column chromatography and gets faint yellow solid 0.408g, yield 80%.m.p.168-170℃。1H-NMR(CDCl3)δ：1.97(s，4H，3，4-pyrrolidinyl-H)，2.15(s，2H，2-pyrrolidinyl-H)，3.41(s，2H，2-pyrrolidinyl-H)，2.79(s，2H，NCH2)，4.17(s，2H，OCH2)，6.60～7.75(m，11H，Ar-H)，9.62(s，1H，OH)，10.07(s，1H，OH)。EI-MS m/z：457[M]+。
Embodiment 37
The preparation of 7-hydroxyl-3-(4-hydroxy phenyl)-2-(4-(2-piperidines oxyethyl group) phenyl) isoquinoline 99.9-1 (2H)-ketone (In)
With 0.56g, be equivalent to the Compound I l of 1.12mmol, acetic acid 3ml, 40%HBr1.5ml, return stirring 24h is spin-dried for, column chromatography gets faint yellow solid 0.39g, yield 75%.m.p.166-172℃。1H-NMR(CDCl3)δ：2.36(s，4H，3-morpholinyl-H)，2.79(s，2H，NCH2)，3.65(s，4H，2-morpholinyl-H)，4.01(s，2H，OCH2)，6.57～7.62(m，11H，Ar-H)，9.58(s，1H，OH)，10.01(s，1H，OH)。EI-MS m/z：471[M]+。
Embodiment 38
Get gained compound 0.5g among the embodiment 29, starch 2g, dextrin 1g mixes, and makes wetting agent with an amount of 30% ethanol, granulates compressing tablet.
Embodiment 39
Get gained compound 0.2g among the embodiment 30, be dissolved in the 20ml methylene dichloride, stir and pass into HCl gas under 25 ℃, behind the 10min solvent is spin-dried for, the gained faint yellow solid is the hydrochloride of Compound I g.
Claims (9)
1. the compound of general formula I or its pharmacy acceptable salt:
General formula I
R wherein
1, R
2Represent independently of one another H, OH, C
1-C
4Alkoxyl group, C
1-C
6Carbalkoxy;
R
3, R
4Expression-CO (CH independently of one another
2)
2CH
3,-CO (CH
2)
3CH
3Or C
1-C
6Alkyl; Or R
3And R
4And coupled nitrogen-atoms is combined into piperidyl, pipecoline base, homopiperidinyl, morpholinyl, pyrrolidyl, 3-methylpyrrole alkyl, 3,3-alkyl dimethyl pyrrole, 3,4-dimethoxy pyrrolidyl, piperazinyl, N methyl piperazine base, NEP base, N-Phenylpiperazinyl, N-benzyl piperazine base.
X represents O, S, NH, CH
2Or-CO-;
M=0 or 1;
N=2 or 3;
2. the compound of claim 1 or its pharmacy acceptable salt, wherein X represents O or S.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein R
1, R
2Represent independently of one another OH or methoxyl group.
4. the compound of claim 1 or its pharmacy acceptable salt, wherein R3, R4 and N atom are connected to form pyrrolidyl, piperidyl, methylpiperazine base, methyl, propyl group, sec.-propyl or normal-butyl.
5. the preparation method of the compound of claim 1 comprises:
R wherein
1, R
2, R
3, R
4, X, Y, Z, m, n definition with claim 1.
6. the isoquinolines compound of claim 1 and its pharmacy acceptable salt, wherein pharmacy acceptable salt is hydrochloride, vitriol, phosphoric acid salt, acetate and maleate etc.
One kind treat post-menopause syndrome, to the inhibited pharmaceutical composition of metastases, wherein contain compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
8. the compound of Formula I of claim 1 or its pharmacy acceptable salt have the purposes of obvious restraining effect medicine for the preparation of the treatment post-menopause syndrome, to metastases.
9. the purposes of claim 10, wherein post-menopause syndrome is osteoporosis, hysteromyoma, estrogen-dependent mammary cancer, Proliferation of Aortic Smooth Muscle or restenosis.
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Application publication date: 20130116 |